I3
There are different kinds of lymphocytes that may look the same. what are they?
"Resting" T cells and B cells Cytotoxic T eclls or NK cells We can identify different cell types by describing patterns of protein expression that define different cell types
What is the mechanism , metabolism, PK, Adverse Rxns, special consideration s of action for Clopidogrel and Prasurgrel?
"grel" -- irreversible: forms disulfide bond with puring receptor essential for platelet activation Clopidogrel = prodrug activated by CYP2C19, Prasugrel = prodrug activated by CYP3A, CYP2B6, more predictable clinical effects (i.e. less genetic variations for this PD -- Clopidegrel = slow activation F = 50% Prasugrel = >80% activation, fast adverse reactions: Clo. Premature discontinuation events Pra. Premautre discontinuation events, more bleeding than clopidogrel Special considerations: Clo: CYP2C19 = poor metabolizers increase risk of MI/stroke/death Prasugrel: contraindicated if history of stroke/TIA (stronger agent so more risk of bleeding)
What is the switch between pro-inflammatory eicosanoids and pro-resolution molesules called?
"lipid mediator class switching"
What do target cells look like? What is another name for them?
(codocytes) They look like bullseye -- any disease that cause too little volume or too much membrane will be associated with this thalasemia as an example.
What are the calcineurin inhibitors?
*Cyclosporin A and FK506* (drugs used to inhibit T cell activation and are commonly used in *Transplant settings*) block calcium signaling pathway/NFAT dependent gene transcription by inhibiting calcineurin activity.
What state does iron need to be to be active and travel in body?
+2
How is iron taken up by cells?
- 2Fe3+Tf binds to receptor and is endocytosed into the target cell. The endosome has a lower pH which causes the Fe3+ to be displaced from the Tf-TfR complex. the free iron is reduced from Fe3+ to Fe 2_ transported out of the endosome and into the cytosol to be used for the biosynthesis of various compounds and proteins requiring iron. The Tf-TfR complex is recycled back to the cell membrane where the Tfr is reinserted into the membrane and the Tf is released to the circulatory system to retrieve more Fe3+.
What is heparin induced thrombocytopenia (HIT)? Does it happen more with UFH or LMH? How do you treat it?
- 5x more common with UFH than LMH - Ab detected by ELISA assay to PF4 and heparin - platelets can drop to very low levels - Potentially serve thrombotic complications - Must substitute direct thrombin inhibitors (--other blood It causes an antibiotic reaction that results in reduction in platelet count -- acquired - platelets might not just go away so you can get weird clotting.
what is the mechanism of action of ACTH on cortisol-secreting cells in the adrenal cortex?
- ACTH binds to its receptor - PKA phosphorylates cholesteryl ester hydrolase (CEH), increasing its activity - more free cholesterol is formed summary: ACTH "frees up" cholestorol as a substrate for corticosteroid synthesis/
What are the risks for early death with sickle cell disease?
- Acute chest syndrome - Renal failure - Seizures - Baseline WBC > 15000 - Low Hgb F
Describe how acute porphyria occurs
- Acute intermittent prphyroa can come from up-regulated ALA synthase -XS early metabolites lead to neurological dysfunction (mania-madness) and fits of abdominal pain ALA mimics NT and stimulates pain receptors
What is Acute Chest Syndrome? How do you manage this ?
- Acute pulmonary infiltrates in Sickle cell patient - Often associated: chest pain, fever, hypoxia, acute decrease in hemoglobin and platelet count, SOB Management: Maintain oxygenation, empiric antibiotics, red cell transfusion (simple or exchange - take one, give two), role for inhaled nitric oxide unclear.
What can you used bone marrow examination in anemias?
- Amount of erythropoiesis in marrow: total cellulatiry, M:E ratio -Errythrocytic maturation sequence -Iron stores: Histiocytic, Sideroblastic -Hematopoeitic or metastatic neoplasms
What are the normocytic anemias? (he said remember the 5 normocytic ones -- even though there are defs more)
- Aplastic anemia - Anemia of chronic disease (some) -Myelophthisic anemia -Hemolytic anemias (most) - Acute blood loss
What is the mechanism of action of glucocorticoids?
- Binds cytosolic glucocorticoid receptor - Bind to a glucocorticoid response element on the regulatory region of the gene and *gene expression is altered*
What can recognize DAMPs?
- Both NOD-like receptors and TLR's can recognize DAMPs
What is blue top tube used for?
- Calcium citrate is typically used as anti-coagulant which allows the clotting reaction to be induced during laboratory testing. Samples collected in blue top tubes are used to analyze clotting factors and clotting function of blood
What is volume reduction?
- Centrifugation and removal or majority of plasma from cellular blood products Purpose: remove incompatible antibodies, prevent volume overload.
Visually how do chromosome 16 and chromosome 11 hemoglobin genes look like? Remember that they are transcribed sequentially like yo life!
- Chromosome 16 and Chromosome 11 Notice the order of the transcription on 11: G gamma, A gamma, delta, Beta 16: just alpha
What is antithrombin? What happens when there is a deficiency?
- Circulating plasma protease inhibitor = antithrombin. - neutralizes thrombin, 10a, 9a, 12a, 11a by forming irrecersible complexes - defieincy thus leads to increased amounts of activating clotting factors. rare <.2% of pop'n
What are things to consider when deciding when a child should start school?
- Consider child's unique abillities and local circumstances - Gather accurate info about the child's development - Talk with pediatrician, preschool teacher, and/or childcare provider
What is the function of Macrophages? what are they made of? How do they look different from dendritic cells?
- Constitutively in the tissues: surveillance - Monocytes also migrate from blood and differentiate into macrophages (and dendritic cells) - Have receptors that recognize pathogens and "danger" - Phagocytic cells
What are the pathophyiologic classification of anemias?
- Decreased RBC production - Increased RBC destruction (hemolytic anemias) - RBC loss (acute hemorrhage)
What are the three etiologies (causes) of iron deficiency anemia?
- Decreased iron intake: Inadequate diet or malabsorption (gastric surgery, celiac disease, increased gastric pH, tannis in tea) - Increased loss: GI/GU loss (gastritis, peptic ulcer disease, menstrual loss) - Increased requirements: pregnancy, childhood.
What are the four things that inflammation needs to be?
- Defensive (neutralizes or kills pathogens) - Immediate (within seconds) - Nonspecific (no pre-sensitization) - Localized (limits injury)
What is the primary and secondary cause of Antiphospholipid syndrome? What does diagnosis require?
- Diagnosis requires BOTH clinical and laboratory criteria to be met Causes: primary: no underlying disease, seconday: Immune disease (SLE), medications, infections, malignancy. Antiphospholipid antibody increase proafulants and vascular tone -- leads to clotting
What is Gestational Thombocytopenia?
- Dilutional issue vs mild ITP - Platelet count is 70-150 000/dl - Mothers can be delivered normally - No association with fetal thrombocytopenia - Occurs in 5-7% of all pregnancies - patients should recieve routine OB care
How do larger molecules pass through the endothelium?
- Fenestrations (holes) in the endothelial cytoplasm allow larger molecules to enter or leave the vessel lumen
What is the role of the innate immunity?
- First line of defense (rapid) - Broad specificity - Initiation of local tissue inflammation - Containment of infection: - killing pathogens, preventing spread of pathogens. - [Regulation of subsequent adaptive responses]
What are the variables that may alter hematocrit, hemoglobin, and RBC count?
- Gender: after puberty, higher in men - Age - higher values in newborn; lower in children until puberty - Living at high altitude: decreased oxygen tension induces increased epo production -Posture: prolonged bed rest decreases values (important for patients who are hospitalized for a long time) - Stress, Extreme excercise: increases values - Dehydration: increases values ("hemoconcentration") - Overhydration (e.g. IV fluids): decreases values ("hemodilution")
What are Thrombocytopenias of Pregnancy
- Gestational Thrombocytopenia - Immune Thrombocytopenic Purpura - Human Immunodeficiency Virus -Preeclampsia/ HELLP Syndrome - SLE/Various Vasculitides - TTP/HUS
What is metabolism in RBC limited to? Why? (i.e., which pathways does it depend on)
- HMP shunt - NADPH (for free radical fighting systems - Rapoport Luebering shunt - for oxygen delivery - Free radical scavenging mechanisms - Glycolysis - energy for Na/K+ pump to maintain ionic enviornment (osmolarity)
What are the 5 hallmarks of inflammation?
- Heat - Redness, - Swelling - Pain, - Loss of function
What lab tests should you absolutely order when testing for anemia?
- Hematocrit, hemoglobin, RBC count, -RBC indices (CBC) -Peripheral smear evalutation -Reitculocyte count Maybe: Iron studies, B12 and folate studies, hemoglobin degradation products, LDH -Specific tests for hemolytic anemias - Bone marrow examination
What kind of information is obtained from CBC?
- Hemoglobin (g/dl), Hematocrit (%), and RBC indicies - MCV (mean corpuscular volume (how big the RBC is) - Mean corpuscular hemoglobin (MCH) (how much hemoglobin/RBC) - Platelet number (cells/ul) - WBC number - White blood cell differential (% and cells/ul)
What are the specific symptoms of iron deficiency anemia?
- History of GI or GU bleeding - iron deficiency anemia - PICA (clay, Ice, etc.) iron deficiency anemia
What is the role of PGI2? What synthesizes it?
- It is synthesized by vascular endothelium - Inhibits platelet aggregation (counteracts TXA2) - Vasodilation - Relaxation of SM - Role in inflammation and tx of pumonary hypertension
How does the endothelial function in the oxidation of lipoproteins?
- LDLs, VLDLs, cholesterol are oxidized by free radicals that are produced by endothelial cells - Oxidized lipoproteins are phagocytized by sub-endothelial macrophages --> foam cells . This is the *first step in atheroslerotic plaque formation
What is an abscess? What kind of exudate is found there?
- Localized liquefactive necrosis of tissue within an organ or body cavity, surounded by more normal tissue - suppurative exudate (pus) is trapped within the necrotic focus
What are factors that can cause sickling of red cells?
- Low oxygen levels - Dehydration - Infection - Fever - Temperature change - Physical Activity - Stress
What does the lymphatic system consist of?
- Lymphocytes and supporting phagocytic cells - Lymph (latin-lympha = clear water) - Lymphatic vessels - Lymphoid tissues and organs
What are the cornerstone of treatment for beta thalassemias?
- Management in a comprehensive thalassemia center: endocrinology, cardiology, social services - In selected populations, heterozygote screening and antenatal diagnosis - Transfusion- maintain hemoglobin 9-10.5 g - Iron chelation-reduce liver Fe <5 mg/g -Stem cell transplantation - Hydroxyurea: increases the production of fetal hemoglobin
What is Bone Marrow Core Biopsy used for?
- Marrow cellularity - 90% in young children to 30% in elderly. - General maturation of hematopoietic lineages (aspirate is much better) - Fibrosis - biopsy only - Foreign cells - better than aspirate for most - Granulomas - Biopsy only -Microorganisms - Especiallly fungi and mycobacteria - Bone morphology
What do we get a bone marrow apirate smear to test?
- Marrow cellularity - estimate only - Myeloid: erythroid (M:E) ratio - normal is 3:1 -maturation of hematopoietic lineages - detailed cytologic evaluation possible -low frequency elements - plasma cells, lymphocytes, histiocyes, etc. -iron stores - histiocytic (long term) and sideroblastic (short term in red cells themselves) - ( iron is stored in marrow histiocytes in the form of hemosiderin) -foreign cells-metastatic neoplasm (core biopsy a bit better though) -microorganisms
What cells undergo peripheral development?
- Monocyte --> Macrophage - B cell --> Plasma cell - T cell --> Effector T cell
What is beta thalassemia?
- Mutant protein, promoters, LRCs, and splicing mutations - Hb is alpha subunit rich, or contains mutant betas - Binds oxygen tightly like myoglobin- usually lethal -alternate beta globin genes!! can replace beta and still impart parital to near total functionality in oxygen transport. -Gene switching from gamma globin fails to occur and HbF expression is partially maintained. -Adoption of a higher level of HbA2 isoform via increased delta clobin production. HbF and HbA2 are both easily capable of edelivering ocygen to tissues.
What is alpha-thalassemia? Why is it lethal?
- Mutant protein, promotors, or LRCs (locus of regional control) of alpha subunits. - Hb is all beta subunits, or non-functional alphas. - Binds oxygen tightly, like myoglobin - Letahl
What are the appx proportions of the leukocytes (Neutrophil, Eosinophil, Basophil, Monocyte, Lymphocyte)
- Neutrophil : 40-75 % - Lymphocyte : 20-50% - Monocyte : 2-10 % - Eosinophil: 1-6 % - Basophil: <1%
What makes aspirin different?
- Non-selective *irreversible* inhibitor of both COX-1 and COx-2 It acetylates the active side
What are the three important classifications of anemia?
- Normocytic nomochromic anemia - Microcytic hypochromic anemia - Macrocytic normochromic anemia-- megoblastic anemia
What is a deep venous thrombosis? What are the sympotoms?
- Obstruction of deep vessels (femoral, illiac, popliteal) symptoms: *Asymmetrical* swelling, pain, erythema (reddening of the skin, usually in patches).
What are phases in acute inflammation (generally)?
- Phase I: Vascular response - Phase II: Cellular Response
Describe the process of fibrinolysis
- Plasminogen and tissue-type plasminogen activator (tPA, released by enothelial cells) bind to lysine residues on the fibrin clot. -This complex converts the proenzyme plasminogen to plasmin - Plasmin can cleave fibrin, fibrinogen, and clotting factors. -When plasmin cleaves the polymerized fibrin standards at multiple sites, it releases degradation products including D-dimer.
What are skills that help the first year of school go smoothly?
- Play well with other children with minimal fighting or crying - Remain attentive and quiet when being read a story - Use the toilet on their own - Successfully use zippers and buttons - Say own name, address, and telephone number
What is chronic inflammation?
- Prolonged active inflammation, - concurrent healing and repair, - adaptive immune: mediated component, inlcudes lymphocytes and plasma -Macrophages are key effector cells - Lymphocyte/ macrophage infiltrate with variable number of plasma cells
What is a pulmonary emolism
- Pulmonary embolism (obstruction of pulmonary artery or one of its branches by material thatoriginated someone where else
What is the reticulocyte count?
- RBCs stained for RNA; immature RBCs have residual RNA - Quantitation of number of immature RBCs present in peripheral blood
What are the two roures that the blood in the penicillary arterioles reach the venous circulation?
- Rapid route: faster -- normal circulatory system Slow route; sinusoids with fenestrated endothelial cells --> cords of billroth The filtration will occur in the slow route.
What should you do to improve school readiness?
- Read to child in infancy - Help child acquire basic skills like recognizing and remembering letters, numbers, and colors - Expose child to enriching and learning experiences: trips to museum, community art or science programs - To promote social skills development, encourage child to play with other children of both sexes in the neighborhood and to participate in organized community-sponsored activities
What are the three main activities of the complement pathway?
- Recruitment of inflammatory cells -Oponization of pathogens, - Killing pathogens.
What are the five classic signs of acute inflammation (in english and greek)? LOL latham is really doing the most.
- Redness (Rubor) - Warmth (Calor) -b/c increase blood flow - Swelling (Tumor) - b/c increase in edema - Pain (Dolor) - b/c increase blood flow and edema - Lost funciton (functio Laesa)
How does a tube of blood look like after centrifuged? What is at the bottom, what is at the top?
- Separate cellular and acellular components of whole blood when spin in a centrifuge. - Adult blood volume: 5-6 liters At the bottom is the red blood cells. This is one way to determine the hematocrit At top is plasma: contains may ions, molecules, and multiple proteins that may serve as biomarkers of health/disease -Albumin, Globulins, Fibrinogen, Organ-associated enzymes
What do you do once there has been a transfusion reaction?
- Stop the transfusion - Keep the IV line open - Perform clerical check of products and patients - Signs and symptoms: Follow and document vital signs, supportive treatment, anti-pyretics, anti-histamines, anti-inflammatories, send pertinent labs (e.g. assess hemolysis, bacteria contamination) -note type of product - notify and send patient tube and product to blood bank
A women tried to conduct blood tests with a drop of blood and it failed. What were the 2 flaws in the business plan of this company?
- The danger of this is that you are going to get a huge number of false positive results which will cost lots of money in the healthcare system and stress to the patient. -- The test also didn't work (lol) her technology was not reliable, she misrepresented investors and regulatory bodies
Describe the endothelial ultrastructure (components that are part of the endothelial)
- Tight junctions (Zonna occludents): Selective permeability barrier - Gap junctions: Communication -Membrane bound Weibel- Palade (W) bodies in the cytoplasm which contain von Willebrand factor (a.k.a. factor VIII-related antigen) synthesized by (mostly) arterial endothelial cells -- They allow for platelet aggregation and adhesion coagulation
What are the three categories of risk factors?
- Transient (like surgery) , persistent (like having cancer or being in a wheelchair), inherited (liike Protein S or C deficiency)
What is the treatment for DIC?
- Treat underlying disease! - Supportive care (platelet or FPP or cryofibrinogen transfusion)
Who should you screen for hereditary thrombophilia
- VTE patients with fx history - Young (<50 yo), idopathic clots - Recurrent, idiopathic clots - Women who clot on OCPs - Asymptomatic first degree relatives of pts with VTE and PC, PS, AT deficiencies (risk of VTE us 1.5%/yr) - asymptomatic women prior OCP/pregnancy if very strong family history (ideally screen affected family members first)
What is the mechanism of hemostasis? what is primary hemostasis? What about secondary hemostasis?
- Vascular response, - Formation of platelet plug (primary hemostasis) - Propagation of clotting by coagulation cascade (secondary hemostasis) Then.. - Termination of clotting, - Removal of clot by fibrinolysis
What is the pathogenesis of post transfusion graft-versus-host disease (GVHD)
- Viable donor T cells in product engraft and proliferate in transfusion recipient. Usually fatal: 90-100%
What is the function of lymph nodes? What forms the framework of the node?
- filter lymphatic fluid, sites of Ag presentation and cell traffic - "reactive barrier" against infection and tumor spreading Lymph nodes have a fibrous capsult from which trabeculae extend towards the center, forming a framework for the lymphatic sinuses, blood vessels, and parenchyma (cortex, paracortex, and medulla)
What is the clinical result of the alpha chain precipitates caused by beta thalassemias?
- ineffective erythropoiesis, hemolysis, marrow expansion, extramedullary hematopoiesis
What is an ulcer? What kind of exudate is found here?
- localized necrosis of tissue at tissue surface. - Suppurative exudate accumulates within the area of focal necrosis or sloughs away to leave a hollow cavity - Extends beyond epidermis or mucosa into deeper tissue layers In this pic, you don't see pus because of the acidity of the stomach, it has dissolved all of the cells.
What is the role of the TXA2 prostanoid? What makes it?
- platelet aggregation (made from COX-1) - Cannot be resynthesized by platelets (because they have no nucleus) - Vasoconstriction/Bronchoconstriction - Contraction of respiratory smooth muscle. - Increase platelet/leukocyte interactions (inflammation)
What are the factors affecting clinical features of anemia?
- rate at which anemia develops - degree of cariac or pumonary compensation -metabolic requirements -underlying conditions
Which women are at highest risk for NAIT?
- related to other women with NAIT - Prior pregnancy complicated by NAIT - lacking HPA-1a and HPA-5b Ag Diagnosis made in a well infant with very low platelet count Subsequent pregnancies more affected than first.
How common is a febrile (non-hemolytic) transfusion reaction? What causes it? What are the signs and symptoms? What should you do if this occurs?
- relatively common - cause: cytokines from donor leukocytes - Signs and symptoms: fecer, chills within a few hours of transfusion, hypotension - Action: discontinue transfusion, support and monitor, OK to give next transfusion if no hemolysis Leukoreduction brings incidence down to 1-2%
How does primary hemostasis occur? What are the steps? What happens normally during an intact endothelium?
- remember, this is the formation of the platelet plug. 1. Platelet adhesion 2. Shape change 3. Granule release (ADP,TXA2) 4. Recruitment 5. Aggregation (hemostatic plug) Platelets are activated at the site of vascular injury to form a platelet plug that provides the initial hemostatis response to stop bleeding. Normally, the intact endothelium prevents the adherence of platelets by production of *NO and protacyclin*
What anemias under affecting stem cells primarily cause decreased RBC production?
-Aplastic anemia - Pure red cell aplasia - Myelodysplastic syndromes - Anemia of renal failure (EPO deficiency)
What are the functions of Eisosanoids?
-Eicosanoids bind to and activate specific receptors (many are G-protein coupled receptors) in the cell membrane to trigger cellular activities related to inflammation.
What are the general symptoms of anemia?
-Fatigue, - Dyspnea on exertion, - Faintness, - Vertigo, - Angina pectoris (pain in chest) - Claudication (pain in the lower extremities) - Palpitation (patient senses their blood pumping)
How can MetHb be used as a tx for cyanide poisoning?
-Infusion with HbM or tx with sodium nitrate will cause HbM to suck up large amounts of cyanide poisoning before it can bind to cytochrome in mitochondrial electron transport complex 4 which usually results in death.
What are the microcytic anemias?
-Iron deficiency -Thalassemia -Sideroblastic anemia -Anemia of chronic disease (some)
What do Eosinophils look like? What is their activated function?
-Killing of antibody-coated parasite -And some allergic inflammatory disorders -- circulate in blood and migrate to tissue sites during certain types of inflammatory responses (e.g.,
What does arachiconic acid lead to production of?
-Prostaglandins, Thrombozanes, Leukotrienes.
What are Loss of function in NOD-like Receptors (NLR)?
-intracellular sensors of PAMPs that enter the cell via phagocytosis or pores and DAMPs that are associated with cell stress. They are part of pattern recognition receptors and play key roles in regulation of innate immune response. NLRs can cooperate with Toll-like receptors and regulate inflammatory and apoptotic response
What is the lost of RBC circulatory population per day in percentage?
0.8% -- regulated via hematopoiesis
What are the three layers of defense in the immune system?
1) Varriers: Skin, pH, enzymes, secretions 2) Innate ummune system: Neutrophils, macrophages, dendritic cells, NK cells, others adaptive Immune system: Lymphocytes (T cells, B cells)
How are subendothelial substances released when there is damage?
1) collagen - strong platelet agonist causes dense granule release 2) Glycoprotein 2b/3a exposed on platelet surface 3) Thrombospondin 4) Fibrinonectin 5) Tissue Factor --> clotting cascade
What are the 3 mechanisms of neuroendocrine control?
1) stress responsiveness of HPA 2) feedback inhibition of cortisol of ACTH secretion 3) episodic secretion and the circadian rhythm of ACTH (lots at night)
What are general the steps in secondary hemostasis?
1- tissue factor release (from subendothelium and on damaged endothelial cells) 2- phospholipid complex expression 3- Thrombin activation 4- Fibrin polymerization
Which sub-categories fall under decreased RBC production?
1. Affecting stem cells primarily 2. Affecting differentiating cells
Describe the flow of the lymph in the lymph nodes?
1. Afferent lymphatics: carry lymph to nodes 2. Subcapsular sinus 3. Peritrabecular sinus 4. Medullary sinus 5. Efferent lymphatics: carry lymph from nodes.
What are the major metabolic pathways of the RBC?
1. Glycolysis (net = 2 ATP) = 50% of the RBCs ATP goes to the Na/K+ ATPase pump 2. Hexose Monophosphate Shunt - 2NADPH reducing equivalents are generated for fighting off free radical damage 3. Rapoport-Luebering Shunt - Generates 2,3-bisphosphoglycerate (2,3-BPG) and O2 release from hemoglobin into tissues
What are the two major functions of the spleen?
1. Hemopoietic functionL It is responsible for the destruction of old RVCs and retrieval of iron from erythrocyte hemoglobin 2. Immune function: It is a major site for mounting the immune response.
What are the 7 functions of the endothelium?
1. Maintenance of selective permeability barrier at the *capillary and venule level* 2. Maintenance of non-thrombogenic barrier 3. After injury then secretion of pro-thrombogenic substances 4. Modulation of vascular resistance (BP) - via SM contraction/relaxation 5. Modulation of immune, inflammatory response 6. Synthesis and Secretion of hormonal regulatory factors 7. Oxidation of Lipoproteins H-hormones L-Lipoprotein B- BP I- Immune T- thrombosis A- Anti-thrombosis B-barrier TABBLIH
Describe the permeability of endothelium. How do molecules get through?
1. Maintenance of selective permeability barrier at the capillary and venule level that is dependent on molecular size and charge. Aside from this image there is also pinocytosis (H2O soluble proteins, small molecules) , receptor mediated endocytosis (for LDL, cholesterol, transferrin etc) Fenestrations are also there (holes)
What are the two branches of hematopoietic differentiation? What types of cells do they produce?
1. Myeloid -- RBC, megakaryocytes, monocytes, dendritic cells, granulocytes (neutrophils, eosinophils, basophils) 2. T-lymphocytes B-lymphocytes Natural killer cells Dendritic cells** (it is ambiguous whether these are from myeloid or lymphoid)
What are the causes of Vit B12 (cobalamin) deficiency? (7)
1. Pernicious anemia -autoimmune, associated with vitilligo, hypothyroidism, failure to secrete IF (Antibody directed against IF or parietal cells) 2. Surgical - several years s/p total gastrectomy/gastic bypass or resection terminal ileum 3. Zollinger-Ellion syndrome- gastric acid inactivated pancreatic proteaases which impairs B12 binding to IF 4. Pancreatic exocrine deficiency 5. Blind loop syndrome- stasis; colonizing bacteria bing cobalamin 6. Diphyllobothrium latum infestation - bind cobalamin and prevent absorption 7. Dietary deficiencies- vegans
What are the four steps in healing and repair?
1. Removal of edema and debris 2. Regeneration of native tissues 3. Organization - proliferation of 3 major cell types (activated macrophages, endothelial cells, fibroblasts) 4. Fibrosis - scar
What occurs in phase I of the vascular response?
1. Smooth muscle relaxation in arteries and arterioles (after very brief contraction) 2. Vascular dilation (hyperemia = increased blood flow) 3. Endothelial cells (EC) contract, creating intraceullular gaps (predominate effects on post-capillary venules) 4. Increase vascular permeability as gaps widen. - first water and salts leak out, then LMW proteins, including fibrinogen and immunoglobins
Describe what components are involved in primary hemostsis? What happens when there are deficiencies in these components? Which specific diseases?
1. Tissue injured and exposes subendothelium -- including elements like collagen, tissue factor, vWF, and glycoproteins. 2. platelet binds to vWF incorporated into the subendothelial matrix through GP1b9 (really GP1b/IX). This provides the initial tethering of platelets, i.e. platelet adhesion. Forming a layer across the exposed subendothelium. 3. Platelets then undergo aggregation when linked with fibrinogen through GP2b-3a (GPIIb-IIIa). Platelet plug formed! complex, forming platelet plug. The GP2b-3a comples is only exposed on activated platelets so they don't bind normally. Deficiency of any component of the GP1b9 complex leads to congenital bleeding disorders. SPECIFCALLY *Bernard Soulier disease*. Deficiency of vWF = *vWD*
How does a trauma burn stimulate the acute immune response?
1. Trauma burns --> Mast cells, platelets --> Cell degranulation: immediate release, preformed, histamine
What are the 4 differences in artery and vein morphology?
1. Venous walls are thinner relative to their diameter than arterial walls 2. Lumes of veins are often collapsed, with irregular shapes 3. Indistinct layers in veins; adventitia is thickest layer 4. Veins may have valves
What does a folic acid deficiency look like in labs?
1. low serum folate concentration 2. Low serum RBC folate concentration 3. Elevated serum homocysteine level
What is the treatment of carbon monoxide poisoning?
100% oxygen (1atm) and hyperbaric oxygen
How long is the RBC lige span?
120 days!
How many platets shoud you count if 100x field?
15 - 40 you can multply by 10 000 to get microL so 15 = 150 000/microL
When a patient has had a PE/DVT, how long should you provide tx?
2 or more unprovoked events = indefinite 1 unprovoked life threatening event = indefinite 1 unprovoked event with APLS, AT deficiency, combined thrombophillia = indefinite 1 provoked event with persistent RF (paralysis, MPNs, metastatic cancer, etc = indefinite 1 provoked event iwth transient risk fact (central line, surgery, trauma, etc.) - 3-6 months or until RD is resolved, whichever is longer)
What is the effect of the RL shunt on the oxygen binding curve of hemoglobin?
2,3-BPG is a glycolysis byproduct in RBC. 2,3-BPG helps stabilize the deoxy-conformation by adding *6 additional salt-bridges* between the beta subunits. This helps eject oxygen from /Hb in anoxic tissues through stabilization of the deoxy Hb form. This occurs when there is acidicty, CO2, and decreased oxygen tensions, BPGMase (biphosphoglycerate mutase) becomes allosterically activated to manufacture 2,3-BPG. This agent binds to the central pore of the Hb tetramer.
What is the importance of 4-1B on CD8 T cells?
4-1BB on CD8 T cells is another co-stimulatory molecule that seems particularly important for CD8 T cell activation (in addition to CD28).
How many cells/liter are there in humans?
5 x 10^12 cells/liter in humans (males have a bit more than females b/c of menses)
How many platelets should you see in the typical high power field? How large is the central pallor?
5-10 platelets. The central pallor is 1/3 the side of the fiameter.
Which steps of heme synthesis are susceptible to lead poisoning? At which step are pre-erythrocytes/erythroblasts/early reticulocytes particularly sensitive to lead?
5-ALA synthesis and ferrochelatase - The ferrochelatase is the step that the pre-erythrocytes/erythroblasts/early reticulocytes are particularly sensitive to.
How many blood donors are CMV seropositive (giving a positive result in a test of blood serum, e.g., for the presence of a virus.)?
50% or more!! WOWZA, good thing we have ways to remove it from samples
How many types of epithelioreticular cells are there?
6; three in the cortex and three in the medulla
What is the mean corpuscular hemoglobin (MCH)?
95% of the RBC protein load (cell dry weight) = 30 picograms
What is the blood-thymus barrier? Is this unique? If so, why?
A continuous endothelium (thick) that prevents blood borne antigens from reaching the cortex; it protects the immature T cells. Unique layering! we need to protect developing T cells. Layers of the barrier: capillary endothelium --> thick bm of the capillary --> peri-vascular CT space (macrophages) --> layer of reticular cells (type 1)
What is a delayed hemolytic transfusion reaction? How did this get passed the screen?
A delayed hemolytic transfusion reaction (DHTR) s defined as fever and other symptoms/ signs of hemolysis more than 24 hours after transfusion; confirmed by one or more of the following: a fall in haemoglobin (Hb) level or failure of Hb level to rise after transfusion First time you are exposed to it (via a negative antibody screen -- whoops), you get a primary immune response, not huge. BUT then you get exposed again, and the immune system remembers so you have a larger response. i
What are eicosanoids?
A family of pro-inflammatory factors released when inflammation occurs -- (prostaglandins, leukotrienes, histamine, bradykinin
What is a hematocrit?
A hematocrit is packed cells/ total volume and is typically determined via centrifugation in normal values runs about 45%
What is factor V leiden? Which
A mutation in factor V gene translates Activated Protein C (APC) resistant factor V named as factor V Leiden i.e. usually activated protein C (enhanced by protein S) inactivates factor 5 a and factor 8a, FVL = point mutation which abolishes cleaving site of APC. FVL has 20 fold slower deraation time than normal DC, so extended thrombin generation.
What is the structure and bioavaiability of heparin
A natural polysaccharide A glycosoaminoglycan: alternating amino and acid sugars highly sulfated, exteremly acidic -- IT is charged so has to be given IV, will not cross BBB or placental barrier (can be given to preggo bitches). It has a very low Vd
What is the mutation that results in a beta globin acting like a myoglobin? What odes this mean?
A point mutation in an intron yielding alternative splice site. This adds an additional 21 nucleotides to the beginning of the exon (longer exon, shorter intron). These 21 nucleotides (or 7 AA) are in frame and alterst the beta globin protein to act as an oxygen storage molecule (hence myoglobin). This makes it a poor transporter This is one form of a beta-thalassemia
What are the acute and chronic porphyria symptomologies?
Abdominal pain, red urine, muscle weakness, skin rashes - purple splotches, sensitivity to sun-light, psychotic episodes, neurological deficit, anxiety attacks, schizophrenia
What does granulation tissue look like? What is it?
Accumulation of activated macrophages -Proliferation of fibroblasts, with a fibrin matrix, - Fine colalgen strands - New capillaries - neovasularity, angiogenesis Pic shows early wound organization
What are the other mechanisms that neutrophils use?
Acidification, toxic oxygen-derived produces, toxic nitrogen oxides, antimicrobial peptides, enzymes, competitors.
Bleeding case: 75 y/o F in ER for 1 day gross hematuria as well as bruising + nosebleeds x 1 week No personal or fam hx, hypertension, arthirits, uncomplicated dental surgery 2 months ago, cholecystecomy 40 years ago - uncomplicated meds: aspirin PEX: vitals normal; large ecchymosos on torso, upper and lower extremities, and left flank Is this acquired or congenital?
Acquired, she just had surgery and is fine, also no family hx
How do T cells provide co-timulatory signals to APC (incl. B cells)?
Activated T cells express CD40-ligand which interacts with CD40 on APC (B cells, macrophages, and DC)q
What is an example of activating receptor signaling initiating negative feedback loops that terminate signaling events?
Activation of ubiquitin ligases (e.g. cbl) that ubiquinate molecules involved in signaling will promote degradation of proteins involved in signal transduction.
What is the difference between acute and chronic inflammation?
Acute : -pulse of injury -host response is nonspecific -Onset is abrupt, well-defined - Symptoms are prominent - Prominent vascular effects and exudate - *exudate is neutrophils* -*CT proliferation occurs as inflammation subsides* Persistent injury - Host response is variably immune - Mediated onset is vague - Symptoms are often subdued - Mild tissue effects - Exudate is *lymphocytes and macrophages* - *CT proliferation is concurrent with on-going inflammation*
What is the most severe adverse effect of glucocorticoid use (in regards to withdrawal of therapy)
Acute adrenal insufficiency (this can be fatal): HPA suppression usually occurs after prolonged therapy with high doses.
What are some of the symptoms of acute porhyria?
Acute intermittent, variegate, hereditary coproporphyria, episodic -comes and goes Acute pathophysiology (all of the ones mentioned before) - abdominal pain, skin rashes: purple splotches, red urine, muscle weakess, psychotic episodes, neurological deficit, anxiety attacks, schizophrenia (king george II had it and was going cray) *remember red urine*
What population is more likely to be affected by alpha and beta thalassemia trait?
African Americans
How does Phospholipase A2 (enzyme) lead to the production of eicosanoids? what is a key step in this process? How are omega fatty acids involved?
After stimulus such as mechanical damage, phospholipase A2 becomes activated to hydrolyze omega fatty acids at the sn2 position of phospholipid molecules in the inner layer of the cell membrane yielding: mostly arachidonic acid (AA) (omega-6 (w6)) and some Eicosapentaenoic acid (omega-3). EPA and aracadonic acid are metabolized into omega-3 and omega 6 eicosanoids, respectively.
What affects the treatment of iron deficiency anemia?
After treating underlying cause -- you supplement with iron- milk, tea, cereals, impair absorption
Which area of the adrenal gland is aldosterone made in? Which zone of the adrenal gland is aldosterone made in? What is it stimulated by?
Aldosterone is made in the zona glomerulosa. Stimulated by angiotensin 2 and K+
What cells are in the myeloid linage?
All of thecells except lymphocytes! Cells of the myeloid lineage include neutrophils, eosinophils, basophils, monocytes/macrophagse, dendritic cells as well as platelets and erythrocytes. All of these cell lineages derive from a common myeloid progenitor. the development of different individuals lineages is regulated by a series of hematopoitic growth factors
What are the most common transfusion reactions?
Allergic, Febrile non-hemolytic
What is the difference between an alloantibody and an auto-antibody?
Allo-antibody -- you are making it against something foreign Auto-antibody -- you are making it against your own boy.
What is the correlation between factor 8 inhibitor and hemophillia A patients?
Alloantibiodies occur 25% of patients with severe hemophillia A after numerous exposures to foreign factor 8
what is alpha 2 antiplasmin? Where is it mae?
Alpha -2-plasmin is made by liver and is present within platelets. It inhibits plasmin
What are the hemoglobins in the alpha family?
Alpha hemoglobin and Zeta hemoglobin
What are the thrombolytics> What is their mechanism of action?
Alteplase and Streptokinase Works best on fresh clots (less fibrin cross-linking)? Works best on fresh clots (less fibrin cross-linking) High doses are required to overcome the PAI inhibiton system. Ateplase (rt-PA): Binds to fibrin so preferentially activates plasminogen to fibrin - "clot specifically", In reality circulating plasminogen is also active Streptokinase: no fibrinogen binding so no clot specificity. Greater activation of circulating plasminogen.
How does aspirin affect pro-resolution molecules?
Among NSAIDs, aspirin is unique in its ability to increase pro-resolution molecules.
What is an opsonin? What is its purpose?
An opsonin is a substance which promotes binding between a particle (e.g. microbe) and a phagocyte (e.g. macrophage, neutrophil), thus promoting phagocytosis. The purpose is that it enhances phagocytosis
Neutrophils (and other phagocytes) can phagocytose via anaerobic or aerobic. Explain both of these processes. Why is this importan?
Anaerobic: binding of matter to cell surface. Opsonin- C3B, binds C3b Fc receptor - binds antibody (ab:ag) Toll-like/LPS receptors bind pathogens -Plagocytosis engulfs matter --> phagosome -Julling in phagolysosome (lysozyme) Aerobic: (more effective) Prespiratory burst (O2 consumed Killing by O2, OH radicals Killing by mmyeloperoxidase can occur in presence of iron! It is important to be able to do this without oxygen because a tissue area may be undergoing ischemia
What are the therapeutic uses of aspirin?
Analgesic Antipyretic: at low doses (at toxic doses get pyretic effect) Antiinflammatory: irreverisbly inhibits both COx-1 and COX-2 -unique! cardiovascuar: cardioprotective at low doses (reduce platelet aggregation): TXA synthesis prevents.
What is Anemia? What will you see?
Anemia = the inability to get sufficient oxygen to tissues You will see decreased hematocrit (RBC numbers) and decreased hemoglobin concentration per RBC.
Which one of the following causes of anemia cannot be diagnosed without bone marrow examination? A. autoimmune hemolytic anemia B. Chemotherapy with a folate antagonist C. Myelophthisic anemia D. Iron deficiency anemia E. Thalassemia
Answer is C. Myelophthisic anemia -- this is caused by a space occupying disease you have to do bone marrow The other ones can be done through other tests + med. hx
What is clotting a balance between?
Anti-clotting and clotting
Case on otehr side hoe
Anti-phospholipid syndrome is lupus antigogulants!!
What is the pathology of Thrombic thrombocytopenic Purpura (TTP)?
Antibody blocks function of vWF cleaving ADAMTS-13 (can't so its job!) Increase level of high molecular weight vWF multimers Increased platelet adhesion without activating coagulation cascade Patients rapidly die without proper therapy
What is Heparin Induced thrombocytopenia (HIT)?
Antibody mediated thrombocytopenia with paradoxical thrombosis. 1) Early exposure(s): produce "foreign" antigen 2) Development of antibodies agaisnt heparin-platelet complexes 3) Later exposure(s): Antibody immune complex activate platelets = micro white clots Antibody mediated thrombocytopenia with paradoxical thrombosis
How does the Neurophil phagocytosis work?
Antibody or C3b coating on particular matter functions as a opsonin. binding to specific receptors for Fc fradment or C3b, an so enhancing phagocytosis. ALSO PAMPS, such as LPS, can bind to toll-like receptors on PMNs and Macs
What are plasma cells?
Antibody secreting cells. Plasma cells are part of the B lymphocyte lineage. Upon receiving appropriate signals from cells and molecules in the lymphoid tissue microenvironment, B cells can develop into plasma cells during an immune response.
How do Dendritic cells look like? What is their activated function?
Antigen uptake in peripheral sites - Antigen presentation - Cytokine production, regulation of inflammatory responses. Tissue resident leukocyte.
What is the role of antithrombin? How does heparin impact this?
Antithrombin is circulating plasma protease inhibitor. Neutralizeses thrombin, 10a, 9a, 12a, 11a. (basically all) Heparin binds to antithrombin and increases its activity
What is the Durg class, Pharmacodynamics, Adverse Rxn, Interactions, Special conditions, contraindication, LMWH - enoxaprin
Antithrombotic PD: Predominately Xa Adverse: Bleeding Interactions: numerous *Special considerations BBW: spinal anesthesia/puncture --> hematomas --> paralysis, reduce administration* Contrainications: HIT
How do LT act as a cell-derived mediator of acute inflammation?
Aracadonic acid metabolite (lipoxygenase) --> permeability, *chemotactic to neutrophils (LTB4)*
What is the APLS clinical diagnosis?
Arterial or venous thrombosis (i.e. stroke, DVT, PE, renal infarct, etc.) OR Pregnancy morbidity: unexplained fetal death over 10 weeks gestation OR one premature birth < 34 weeks from eclapsia, preeclampsia, or placental insufficiency OR 3 or more unexplained embryonic <10 week pregnancy losses (mischarages) BUT remember clinical diagnosis is not enough on its own, you also need
What happens to old RBCs?
As the RBC ages, it is slowly losing various enxymatic activites and/or integrity of its membrane. These old cells are trapped in the microcirculation where they are engulfed by macrophages and digested. - Hemoglobin is released and broken down into amino acids, iron and bilirubin.
Describe the proccess of erythopoiesis/ hematopoiesis?
As the proerythroblast differentiates, three normoblast forms can be identified -- early normoblast, intermediate normoblast, and the late normoblast. During this differentiation these blast cells are becoming smaller. The nucleus begins to condense and is extruded during the late normoblast stage, along with the other sub-cellular organelles. Hemoglobin synthesis bengins in the early normo-blast stage and continues through the reticulocyte stage The reticulocyte is released from the bone marrow into the blood where it matures into an erythrocyte in several days. Erythropoiesis requires about one week
What are the bone marry spicen types?
Aspirate (smear, clot) Core biopsy
What are the drugs we need to know for O'Brien's NSAID lecture? Do you know them? Think of the three categories!
Aspirin and friends: Aspirin, salicylate NSAID's: ibuprofen, naproxen, celecoxib I am not an NSAID!: Acetaminophen
How does aspirin affect platelets?
Aspirin irreversibly affects platelets, so body is affected for like span of platelets (about 8 days)
What is the function of 15-LOX in the resolution of inflammation? How does this occur?
At high concentrations, PGD2 and PGE2 stimulate up-regulation of 15-LOX to induce *"lipid mediator class switching"* in neutrophils, mucosal epithelial cells and fibroblasts to synthesize pro-resolution molecules (lipoxins, resolvins, protectins, and maresins).
What happens when you give high doses of acetaminophen? How does alcohol affect this?
At high doses, glucuronidation and sulfation become saturated -- so you go through CYP2E1 metabolism that leads to N-acetyl-p-benzoquinoneimine -- this is toxic. alcohol increases the amount of CYP2E1. Induction of CYP2E1 increases the risk of toxicity
Compare the therapeutic effects of NSAIDs at lower and higher doses?
At lower doses: analgesia (pain relief) and antipyretic (lowering fever) At higher doses: (anti-inflammatory), closeure of patent ductus arteriosus)
What are the general indications for White Clot Tx with antiplatelet (+ or - anticoagulat)?
Atherosclerosis (plaques forming on large arteries, they are pro-inflammatory, when a plaque ruptures, you can get a clot forming -- can cause heart attack if completely occludes) Foreign objects
Describe the defect in globin production for : B+ -thal, B0-thal, delta-beta0thal, hemoglobin lepore, and hereditary persistence of fetal hemoglobin (HPFH)
B+ -thal: diminished b chain B0-thal: no b chain delta-beta0-thal: no beta or delta chain hemoglobin lepore: no beta chain, delta chain replaced by delta/beta hybrid and hereditary persistence of fetal hemoglobin (HPFH): No beta or delta chain; defect fully compensated by gamma chain production
What are the B0-thal mutations and B+-thal mutations?
B0-thal mutation: totally abolish expression of affected gene by critical point mutation or deletion B+: paritally abolish gene expression, -mily, moderate, severe-depending on amount of HbA produced
How does lack of vitamin b12 effect available folate?
B12 is the only way to use N5-folate to regenerate methionine from homocysteine... remobilizing the folate pool as it were -- folate trap
What will you see in the labs for megloblastic anemia?
B12 or folate deficiency Pancytopenia (anemia,leukopenia, thrombocytopenia) may be seen with b12 deficiency
What does a hypersegmented neutrophil indicate? What about oval shaped macro-ovalocytes?
BOTH INDICATE Megaloblastic anemia -- typically B12
How is the blood component prepared from a donation?
Basically centrifuged a bunch of times, first get whole blood, then separation of plasma from whole blood, then separation of platelets from plasma.
How do basophils look like? What is their activated function?
Basophils promote allergic responses and aumentation of anti-parasitic immunity -- very rare cell. Circulates in blood and can migrate to tissue upon inflammatory stimulus
What are the types of Beta thalassemias? What are the consequences of this?
Beta Thalassemias = Impaired beta chain synthesis: heterozygote - Thal minor, Homozygote - Thal major Consequences: decreased RBC hemoglobin, increased Free alpha chains, precipitate in RBCs
What are the hemoglobins in the beta chain family?
Beta, gamma, delta, epsilon
What is the difference in color and solubility between biliverdin and bilirubin?
Biliverdin is green (note verdin-- sounds lie green) and is modestly soluble. Bilirubin undegoes a rotation around the methylene carbon which allows it to fold on over itself. This makes it sparingly soluble. It is red/orange if there is high concentrations or yellow if low.
What is the color of biliverdin? What about bilirubin?
Billiverdin = green Billirubin = yellow/red
What does binding of aspirin to the active sites of Cox-1 and Cox-2 result in biochemically? How do the two enzymes react differently to this?
Binding of aspiring to the active sites of Cox-1 and Cox-2 results in the acetylation of the enzymes -Acetylated Cox-1 is a dead enzyme -Acetylated Cox-2 can use Arachidonic acid, EPA, and DHA to produce intermediates that are the precursors for the synthesis of a series of pro-reolving molecules.
How does the binding of one oxygen affect the other subunits in the hemoglobin? What about the releasing of an oxygen?
Binding oxygen to one subunit increases affinity at all the other three subunits for oxygen and releasing an oxygen from one subunit decreases the affinity at all other subunits for oxygen -- Cooperativity!
How does aldosterone regulate extracellular volume?
Binds to mineralcorticoid receptor (MR) in renal cortical collecting duct MR goes to nucleus, binds the response elecment (GRE/MRE). Therefore functions as a *transcription factor* This increases Na/K+ ATPase on surface, drives the uptake of potassium and export of sodium Increase in H20 and extracellular volume contributes to hypertension
What is the major adverse reaction of Heparin, LMW heparin, anf Fondaparinux?
Bleeding
What are the adverse effects of Warfarin?
Bleeding, inhibition of Protein C and S occurs rapidly, can lead to initial procoagulant state Protein C and S have rapid turnover -- early on they can have enhanced clotting, this is why it is contraindicated in HIT -- so never give warfarin by itself -- start of with heparin, then introduce later.
What is the thrombolytic drug adverse reactions? What is the most serious complication?
Bleeding, stroke, the most serious complication is hemorrhagic stroke.
What is the mechanism of action for Argatroban? What is it used for?
Blocks the catalytic site of thrombin It is used for anticoagulation in HIT patients
What is the difference between a blue-top tube and a purple-top tube?
Blood anti-coagulated with na-citrate (blue-top tube) - Used to measure functionality of coagulation cascade using plasma drom blue top tube (won't work with purple top tube) - Prothrombin time (PT), Partial thromboplastin time (PTT) Purple top: blood collected with anticoagulat Na-EDTA can be a window to asses cells in the blood, RBC, platelets, WBC
What will happen if a tube has no anti-coagulant? What is left
Blood collected with no anti-cogulant (red top) will clot -- this clot is a tangle of cells or "formed elements" and insoluble protein that form during coagulation Straw colored fluid serum is left = plasma without clotting factors
When is sepsis most common? What is it in relation to transfusions?
Blood components contaminated by bacteria Most common in platelets because stored at room temperature Always let blood bank know if septic reaction is suspected so products can be cultures
What is the location, target, source of mannose-binding lectin (MBL) - (bloodstream, tissue fluids)
Bloodsteam, tissue fluids, Mannose-containing microbial carbohydrates (cell walls),
What are PAMPS?
Body must recognize presence of microorganisms. The body does this by recognizing molecules unique to groups of related microorganisms and are not associated with human cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPs.
What are the primary lymphoid tissues?
Bone marrow and thymus
Which of the following immune responses would NOT be expected within 1 day following first time pulmonary infections with Steptococcus pneumonia? A. Beta deffensin, mediated bacterial lysis B. Mannose binding protein mediated activation of the complement cascase C. Anti-streptococcal antibody mediated activation of C5-C9 D. Macrophage production of TNF-alpha E. Neutrophil phagocytosis
C! Antibodies would take several days
What are C5a, C3a (C4a)? What is their function?
C5a, C3a (C4a) are components of complement. They help in the recruitment of neutrophils (PMNs) to tissues. lowercase a = chemoATTRACT
What are the lab findings of iron deficiency? CBC? Serum tests?
CBC: - increase RDW, platelets - decrease MCV, MCH, MCHC, RBS, Hb, Hct Retic count NOT INCREASED Serum tests - decreased iron, decreased iron saturated (ratio of serum iron to TIBC (<20 %), decreased ferritin - increased total iron-biding capacity (TIBC): maximum amount of iron needed to saturate plasma or serum transferrin, transferrin receptor.
What does the CD16/CD56 nomenclature mean?
CD16/CD56 are expressed by NK cells, can be defined by being CD3-, CD16/56+ cells.
What does CD3+ mean in the CD nomenclature?
CD3: protein complex associated with T cell antigen receptor. All mature T cells express CD3 (CD3+) Cells that do not express CD3 are not mature CD3 cells
What receptor family does CD40 belong to? Why is this significant?
CD40 is a member of the TNF receptor super family. Member of the TNF receptor superfamily often act as co-stimulatory molecules and ligand mediated trimerization of the receptor results in activation of the NF-kB pathway ( among other things)
Why is CD40 signaling important for B cells? What can it be thought of as?
CD40 signaling cen be thought of as signal 2 for B cells. CD40 signaling is critical for germinal center formation, isotype switichin, and somatic hypermutation
What are two types of progenitor cells (stem cells)
CLP - common lymphoid progenitor CMP - common myeloid progenitor
What does the common lymphoid progenitor make? Do these cells undergo further activation? If so, where does this happen?
CLP makes pre-T-cell and Pre-B cells. These are commited progenitors The T-cell than become a marture T-lymphocyte in the Thymus the B-cell then becomes a B-lymphocyte in the spleen (and other peripheral tissues) -- The B-lymphocyte then becomes a plasma cell
describe the formation of neutrophils?
CMP --> myeloblast/promyelocyte (at this point you start to see granules) --> myelocyte/metamyelocyte --> band forms / neutrophils
Where is CMV found in the patients and how can we prevent it?
CMV is found in peripheral blood leukocytes, stem cells and in cells of those organs which are targets for infraction. (sometimes it can be douns in the plasma) We prevent it by leukoradiation -- removing the WBCs from the sample.
How does Cyanide hurt us?
CN binds to heme iron and in cytochrome C oxidase, blocks ETC and oxidative phosphorylation
describe the pathwway of heme destruction. What is a toxic release of this?
CO is released
How is the HPA (Hypothalmic-pituitary-adrenal) axis regulated?
CRH- released from hypothalamic neurons ACTH released from anterior pituitary ACTH stimulates cortisol synthesis and release *negative feedback regulation*
What is the half life of warfarin? What genes affect the efficacy of Warfarin? What should you do bout this?
CYP2C9 and VKORC genes affect the warfarin efficacy -- INR monitoring essential half life = 20-60h
What is calciuneurin?
Calcineurin, a phophatase, is activated when calcium concentration is increased into the cytoplasm (from release out of the ER).this dephosphorylates NFAT which translocates to the nucleus and initiates gene transcription
What do Nucleated RBCs (NRBC) look like? When does this happen?
Can be released if some defect in mechanism or body is trying to get this ish out fast.
What is a harmful product released from the breakdown of RBC?
Carbon monoxide is released when Hemin is converted to biliverdin. (this is why the E7 is important... remember?)
What is the affect of glucocorticoids on carbohydrate/protein/lipid metabolism, CV system, and calcium homeostasis?
Carbs/protein/lipid - maintain blood glucose levels during fasting (increase during stress) - at high levels: muscle wasting, redistribution of body fat (back of neck and face) CV: hypertension with prolonged high levels Calcium homeostasis: At high levels -- inhibit collagen synthesis/bone deposition, slows bone growth inchildren
How many African Americans have the sickle cell gene (carriers)? What are the types of sickle cell? Which are most severe? How common are they?
Carrier: HGB AS - 1 in 12 AA (8%) HGB SS: most common, most severe -- 1 in 650 AA HGB SC: 1 in 1120 AA - have similar symptoms to individuals with Hb SS. However, the anemia is less severe. HGB S B THAL - 1 in 3200 AA - affects beta globin gene production. The size of the red blood cell is reduced because less beta protein is made HGB SD - Rare
What is the purpose of pathogen reduction? What are the issues with it?
Causes viruses, bacteria and parasites less pathogens Conceptually: Margin of safety for emerging infectious diseases, reduces pathogen risk Uses UVE light to intercalate DNA blocks - replication, transcription, and translation. Issues: balance between pathogen inactivation and qualify/functionality of product difficult - No RBC equivalent process approved; Mi- PLATE study recruiting
What is the difference between inflammatory and homeostatic chemokines?
Chemokines that are in the same location at all times are homeostatic/ Chemokines that induce movement to another place are inflammatory.
List two stimuli that regulate the movement of dendritic cells from tissue into lymph nodes.
Chemokines, PAMPs
What is an important symptom of CN poisoning>
Cherry red skin color from inc. venous blood HbO2 concentration no where for O2 to go with block on cytochrome C oxidase (heme-CN complex)
What is the difference between acute anemia and chronic anemia?
Chronic - slow onset, acute - sudden onset
What are monocytes?
Circulate in blood and migrate to tissues during inflammatory response. Develop into macrophages (and some types of dendritic cells) when in tissue
What is the Durg class, Pharmacodynamics, Adverse Rxn, Interactions, Special conditions, contraindication, and monitoring of Heparin Sodium?
Class: Antithrombin catalyst PD: Increases AT neutralization of activated coagulation factors Thrombin (Xa): long chains Adverse Rxn: bleeding, HIT Interactions: Numerous Apecial considerations: heparin lock (fatal pediatric hemorrhage) Indications: PPx/Tx of DVT/PE, Block Thrombosis of extracorporeal devices, MI/unstable angina. Contraindications: neonates, infants, pregnancy (benzyl alcohol associated neonatal death Monitor: appt (1.5-2 times normal)
What is seen clinically in Beta-thal major? What is the treatment? What are the risks if this treatment?
Clinically: Severe Anemia, high output congestive failure, "chipmunk facies", Extramedullary hematopoiesis Tx: Transfusion -- this migh help with the anemia BUT YOUR ARE RISKING DEATH VIA HEMOCHROMATOSIS
What does chronic porphyria look like?
Congenital erythropoitic prophyria, prophyria cutanea tarda, veriegate porphyroa - long term stable presentation - chronic pathophysiology: dermatological issues - blistering, sloughing, ulcers, ligh sensitive pain - red urine WEREWOLF SYNDROME: fine ot moderate light downy hair body wider, light sensitive - pain -vampire syndrome: red gums and stained teeth, light sensitive - pain -These people can not toerate garlic as it sets off uncomfortable reactions stemming from porphyrin precursors
What happens to the blood flow as edema increases? Why is this important?
Congestion (decreased blood flow) occurs and stasis as edema increases. This results in loss of laminar flow -- traffic jam. So the selectin move from going fast in the centre of the vessel to sticking to the endothelial wall. this allows neutrophils to attach
How does NO act as a cell-derived mediator of acute inflammation?
Constitutive in endothelium, macrophage synthesis -- antimicrobial activity macrophages
What does the white pulp contain?
Contains T cells, B cells, and accessory cells - mounts an immunological response to antigens within the blood. - Is present in the form of a periarteriolar lymphoid sheath (PALS) - This sheath contains B cell follicles and T cells. T cells are around the artery mainly.
What are the two types of dendritic cells leiteinberg talked about?
Conventional dendritic cell: Tissue resident cells that produce cytokines and migrate to Lymph nodes to serve as antigen presenting cells for naive T cells Plasmacytoid dendritic cell: Produce very large amounts of Type 1 interferons early after viral infections (1000x more IFN alpha/beta than other cells)
What is the international normalized ratio (INR)? What is it intended for?
Corrects for differing tissue factor reagent sensitivities in use by labs by incorporating into INR calculation the International Sensitivity Index (ISI) of reagent. Only intended for warfarin monitoring.
What is the result of inhibition of COX 2 synthesis by glucocorticoids?
Cox 2 is the isoenzyme that is induced under inflammatory conditions Clucocorticoids inhibit the synthesis of Cox-2 such that prostaglandin metabolite is decreased.
What are the two major enzymes in the prostanoid (prostaglandin path)?
Cyclooxygenase 1 (COX1) and cyclooxygenase 2 (COX2) - AA --> PGH2
What is signal 3 for T cells?
Cytokine receptor signaling. Cytokines produced by APC or other locally present cells can influence/promote T cell activation irectly or indirectly.
What are the soluble factors that macrophages release?
Cytokines Chemokines Vasodilators
What mediates hematopoiesis?
Cytokines! They are pleiotrophic (having multiple effects on different cells), but there are some key cytokines for specific lineages
How does leukocytosis act as a systemic sign of acute inflammation?
Cytokines, predominately IL-1, increase release of neutrophils from marrow
How does C-reactive protein act as a systemic sign of acute inflammation?
Cytokines, predominately IL-6 and IL-1 Stimulate increased liver synthesis of acute-phase proteins, including CRP (binds to dead cells/pathogens and activates complement cascade)
How does the erythroccyte sedimentation rate (ESR) act as a systemic sign of acute inflammation?
Cytokines, predominately IL-6 and IL-1, increase liver synthesis of acute-phase proteins, including fibrinogen - Increased fibrinogen causes RBC aggregation --> sediment
What is Cytomegalovirus (CMV) infection?
Cytomegalovirus (CMV) is a virus found around the world. It is related to the viruses that cause chickenpox and infectious mononucleosis (mono). Between 50 percent and 80 percent of adults in the United States have had a CMV infection by age 40. Once CMV is in a person's body, it stays there for life. Cytomegalovirus (CMV) Transmission, Treatmen
Where do NLR reside? What does binding of bacterial ligans to NLR result in?
Cytoplasmic NOD proteins reside in the cytoplasm in an active form Bindibg of bacterial ligands to NOD proteins induces NF-kB
What is the D-Dimer Test?
D-Dimer is a fibrin monomer, part of the fibrin degradation product Elevated in presence of clot turnover, therefore a marker of fibrinolysis AND if you go one step futher, a marker of recent/ongonig blood coagulation
How is inflammation induced during a sterile (i.e. non-microbial) tissue injury?
DAMPS (danger/damage associated molecular patterns) -- they are associated with necrosis. - Molecules released upon tissue injury, but not by healthy cells OR during programmed cell death cause inflammation
In what bleeding disorder do you see schistocytes?
DIC (remember it is when you have prolonged PT and PTT) - low fibrinogen and high Ddimer and low platelets
What are the two major biochemical events that must occur during erythropoiesis?
DNA synthesis and protein biosynthesis, especially hemoglobin
What do teardrop cells look like? What is another name for them?
Dacryocytes -- this happens a lot of myltpthistic (or whatever) diseases -- space occypying disease in bone marrow
What is porphyria?
Defective enzymes in heme biosynthesis cause this. There are many forms depending on enxyme deficiency Symptomology occurs primarily in the liver, skin, nervous cystem or combo
What is the differential for prolonged PT and PTT?
Deficiencies of final common pathway factors (uncommon though)- 10, 5, prothrombin, fibrinogen -Severe vit k deficeincy - Severe liver disease (remember pt stops first, then PTT enlongates after) - Disseminated intracascular coagulation (DIC) - low fibrinogen and high Ddimer and low platelets
When there is acidity, carbon dioxide increase, and 2,3-BPG, how many salt bridges does the deoxy-form hb have? How many does the oxy form have? Which is more stable?
Deoxy: 8 original + 2 protonated histidines + 2 carbamoylated N-terminals + 6 from 2,3-BPG = 18 deoxy-stabilizers vs only 6 in the oxy-form.. so the deoxy is more stable!
How do you diagnose DIC?
Diagnosis: prolonged PT, PTT, thrombin - Low fibrinogen - Low platelets - increased FP and Ddimer - Microangiopathic hemolytic anemia
What is the therapeutic use of dexamethasone?
Diagnostic application: It is used to diagnose various causes of hypercorticism The dexamethasone suppression test (DST) is used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone.
What is DIC?
Diffuse activation of coagulation (uncontrolled production of thrombin) == causing arterial an venous cloting and tissue ischemia Consumptive of factors -- causing bleeding Secondary fibrinolysis (as all clots are being broken down = causing bleeding as large amount of FDP can impair normal platelet aggregation.
What are the specific tests for hemolytic anemias?
Direct antiglobin (coombs) test - Test for sickling hemoglobin -Hemoglobin electorphoresis -RBC enzymes assays for G--6-PD and other enzymes deficiences
What is transrepression?
Directly interact and alter the function of otehr transcription factors, such as NF-kB in the nucleus of cells (vs. GRE)
What is plasma used for?
Documented factor deficiency AND active bleeding OR about to have procedure Warfarin reversal or vitamin K deficiency, significant bleeding or procedure immitent.
Describe how a transfusion can cause a urticarial/allergic reaction (lower severity). What do you do after this has occured?
Donor protesin cause IgE mediated histamine release in patient Flushing, pruritis, uticaria Usually no temp increase Treat with antihistamines. *Okay to re-start transfusion at slower rate if symptoms are mild (no respiratory distress) and subside or stabilize*
What are the outcomes of acute inflammation?
Down-regulation of inflammatory mediators, upregulation of anti-inflammatory mediators such as IL-10, TGF-beta
What do sickle cells look?What's another name for them?
Drepanocytes (this image is a combination of target cells and sickle cells)
What is the Drug class, PD, PK, advese reactions, Interactions, special considerations, and contraindications of Dabigatran?
Drug class: 2a inhibitor (thrombin) PD: Competitive inhibitor 2a active site PK: metabolized in liver to active compounds. Renal excretion Adverse Rxns: bleeding Interactions: transported by P-glycoprotein, numerous other potential interactions!! Special considerations: BBW: spinal anesthesia/puncture -> hematomas --> paralysis, monitor neurologic status
What is the Durg class, Pharmacodynamics, Adverse Rxn, Interactions, Special conditions, contraindication, of Fondaparinux
Drug class: At just increases At neutralization of Factor 10 Adverse reactions: bleeding Interactions: numberous *Special considerations: BBwW: spinal anesthesia/puncture --> hematomas --> paralysis, monitor neurologic status IndicatiosnL can be used for HIT
What is the drug class, PD, PK, Adverse Rxn, and contraindication of Aspirin (Acetylsalic acid)
Drug class: NSAID PD: Non-specific irreversible COS inhibitor. Blockade of COX1; decrease Arachidonic --> thromboxane (TXA2); decrease platelet Adverse Rxns: Bleeding, dyspepsia/gastritis/ulcers Contraindication:
What is the drug class, PD, Adverse reaction, and Special consideration of RivaroXaban?
Drug class: Oral factor Xa inhibitor PD: competitive inhibitor of Xa active site Adverse Rxns: Bleeding Special considerations: *BBW: Spinal anesthesia/puncure --> hematomas --? paralysis, monitor, neurologic status
What is the drug class, PD, PK, Adverse reaction, Interaction, Special consideration, and contraindications for Clopidogrel?
Drug class: Thienopyridine Antiplatelet drug PD: irreversible disulfide bond with P2Y12 ADP receptor, decreases platelet activation/aggregation. Adverse Rxns: Bleeding, dyspepsia, increased eveents with premature discontinuation Interactions: Avoid CYP2C19 Special considerations: CYP2C19 poor metabolizers with ACS or PCI and treated with standard dose at increased risk of MI/stroke/death. Contraindications: Bleeding
What is the drug class, PD, PK, Adverse reaction, Interaction, Special consideration, and contraindications for Prasugrel?
Drug class: Thienoyridine anti-platelet agents PDL: irreversible disulfide bond with P2Y12ADP receptor. Decrease platelet activation/aggregation. Adverse Rxns: Bleeding (more than clopidogrel) Special considerations: BBW, avoid in <60kg (severe bleeding), >75 y (intracranial hemorrhage), patients likely to have urgen CABG, premature discontinuation. Contraindications: Bleeding, stoke, TIA
What is the drug class, PD, PK, adverse RXn, Interactions, Special consideration, Contraindication, and Monitoring of warfarin?
Drug class: Vitamin K antagonist PD: Blocks regeneration of vitamin K by inhibiting VKORC, PK: Liver metablism (half life= 20h -60h), CYP2C( and VKORC gene variants affect effectiveness Adverse Rxns: bleeding Interactions: numberous! Special considerations: Vit K Contraindication: Pregnancy Monitor: INR
What happens to leukocyte traffic during inflammation?
During inflammation, upregulate the ligands, so you have slower and slower movement. More interaction between LFA-beta 2 integrin and CAM Chemokines produced by tissue promote high interaction between LFA beta integrin 2, and ICaM molecules. This makes the WBC stop in its tracts and interact with more ligands. Will then crawl through the intracvascular space and go to the place where the chemokines will be produced. This is called *extravasion*
What is Neonatal Alloimmune thrombocytopenia (NAIT)? What is the most common isoantibodies?
During pregnancy, the mother's antibodies cross the placenta (afterbirth) and attach to the platelets in the baby's blood. They attack the foreign baby's platelet resulting in a low platelet count. This is called thrombocytopenia. The disease process that happens in the fetus or baby is known as Neonatal Alloimmune Thrombocytopenia. OR siegal's way of saying it Fetal inheritance of platelet isoantigens not present in the mother (inherited from the fater) Fetal thromboxytopenia --when isoantibodies cross placenta Most common Ag: HPA-1a and HPA-5b
What is dysfibrinogenemia? How can you test for it?
Dysfibrinogenemia is a coagulation disorder caused by a variety of structural abnormalities in the fibrinogen molecule that result in abnormal fibrinogen function. You have to test both Functional (clot based) and immunologic (antigenic) Both assays have to be used to rule out dysfibrinogenemia -- in dysfibrinogenemia functional assay is decreased but immunologic assay is normal
What is angiogenesis? What GF stimulates this process?
EPC (endothelial progenitors) from maro enter site of injust and differentiate Endothelial buds grow from pre-existing capillaries Neovascularization VEGF (the most importnat) Simulates EPC from marro, and proliferation of endothelial cell buds
Which cytokine mediated RBC differentiation?
EPO - erythropoietin
Where is EPO produced? What about TPO (thromboopoeitin) ? Is TPO production constant?
EPO is produced in kidney, TPO is produced in liver TPO production is constant!
What is the locus of control region (LCR)? How does it play a role in globin gene expression? What happens when the LCR region is mutated or deleted?
Each globin gene has individual promotors that play a reduced role in gene expression than doesa very significant upstream element called the locus of control -- it triggers sequential activation of the inividual promoters. If mutated, you get cirtually no expression of globin genes (even though the individual genes are okay). This has been observed in various foms of thaleassemia -- a disease with under expression (or total lack) of either lapha or beta proteins. This is invariably fatal.
The other side is gonna show angiogenesis in granulation tissue
Early wound organization
What doe ovalocytes look like? What is another name for them?
Elliptocytes
How can you waive routine testing?
Emergency release form and procedure -- no time! Universal blood components used. Important to send patient sample to lab aSAP for testing even if after transfusion Switch to type specific blood asap to conserve universal blood products.
What is the function of electron dense granules in platelets?
Energy hoe!! They have adenine nucleotides, ca++, serotonin
What is the 504 plan?
Ensure that a child who has a disability and is attending an elementary secondary educational institution receives *accommodations(that will ensure their academic success to the learning environment.
Important points about chronic porphyria
Enzyme defects later in the pathway typically demonstrate skin sensitivity to sun light. - Cutaneous lesions from free radical damage due to porphyrin precursor in the skin interacting with sunlight generating OH radicals - Overlapping symptomology with pain and neurological manidestations. - porphyrin intermediates can form crystals in liver and bile duct, also forms cytotoxic bile Porphyrin intermediates interference with normal redox rxns -hereditary coproporhyria Veriegate porphyria -erythropoietic porphyria -porphyria cutanea tarda: vampire/werewolf syndromes
What are the cells that are considered innate immune cells?
Epithelial (only one not hematopoeitcally derived) macrophages, Dendritic, Mast cells, Neutrophils, Eosinophils, Basophils, NK cells Innate-like lymphocytes
List two sources of antimicrobial peptides
Epithelial cells and neutrophils
What is the cytokine that allows for proliferation/differentiation of red blood cells?
Epo
What is an erythroid island?
Erythroblastic islands, the specialized niches in which erythroid precursors proliferate, differentiate, and enucleate
In which cells is the iron metabolism elevated in?
Erythroid blast cells, GI endothelial cells, liver hepatocytes, and muscle.
Compare the pro-, early, intermediate, and late erythroblast in appearance
Erythroii progenitors always appear with round nuclei and cytoplasm is agranular!
What is the clinical presentation of people with the sickle cell trait (Hgb AS)
Essentially assymptomatic Pts: Problems: Occasional Hematuria, Isosthenuria (can't concentrate urine -- can't conserve water well), Extreme stress
What does the common myeloid progenitor cell differentiate into? does further development of these cells occur? If so, which cell does it happen in
Everything other than the lymphocytes and dendritic cells (sometimes) Yeee monocyte/marcrophage/kupffer, langerhans , dendritic cell, osteoclats -- which develop in peripheral tissues
How does Jaundice form? Where do you see the effect ?
Excesive RBC turnover, hemolytic anemias, blockage of billiary duct, liver disease (blocked glucuronylation) can all lead to a build up of these sparingly soluble (particuraly unconjugated billirubin). They love to accumulate in fatty tissues under the skin, whites of the eye,. The primary symptom of jaundive is a yellowing of the skin and eyes. This is a yellow and not orange-red because distruption of the pathway happens after billirubin is made.
Increased RBC destruction (Hemolytic Anemias) are split into two categories, what are they?
Extracorpuscular - Immune-mediated - Non-immune mediated Intracorpuscular -Acquired -Inherited (most are): RBC membrane defects, RBC enzyme deficiencies (g6pd for examples), globin chain structural defects, globin chain synthesis defect s
T/f: inflammation is always associated with microbial infection
FALSE, not always..
What are the 5 things you will see with TTP (Thrombotic thrombocytopenic purpura)?
FAT RNs F- fever A- Anemia (microangiopathic hemolytic) T- thrombocytopenis R- Renal failure N - Neurological problems
What is factor 5 made from?
Factor 5 is released from the platelet alpha granules during platelet activation and cleaved by thrombin to form 5a, binds to 10a. The F10a:F5a complex forms an enzyme on the platelet phospholipid surface that converts one molecular prothrombin aka (FII) to one molecule of thrombin (FIIa)
How do factor 8 levels affect the person's abillity to clot? Talk about percentages?
Factor levels: 5-30% = mild; bleed after surgery or moderate trauma 1-5% = moderate; bleed after slight trauma <1% = severe; spontaneous bleeding, often in joints and muscles
Which factors will PT test?
Factors: 8, 10, 5, prothrombin, fibrinogen
What parts of the patient's history is important in diagnosing anemia?
Family history, diet, travel, medication (antacids can effect iron absorption), blood loss, other symptoms like weight loss, fever should be elicited. (you are worried that the weight loss could be cancer)
Why must we maintain we maintain hemoglobin in Fe+2 state?
Fe3+ auses free radicals which can damage membrane.
What is febrile non-hemolytic transfusion reaction?
Febrile non-hemolytic transfusion reaction is a type of transfusion reaction that is associated with fever but not directly with hemolysis. It is most commonly caused by antibodies directed against donor leukocytes and HLA antigens. Note that these risks are much higher than the infections (HIV etc.) that people are scared of.
What does mid-late wound organization look like in granulation tissue? What is composed of? What stimulates the growth of the particular cell type?
Fibroblasts: proliferating of fibroblasts Differentiation to myofibroblasts (? epithelial cells can also differentiate to myofibroblasts) - Circulating fibrocytes TGF-beta, FGF, PDGF: stimulate fibroblast proliferation/motility, collagen, and fibronectin synthesis.
What does late wound organization look like for Granulation tissue? What processes are occuring?
Fibrosis - Scar: dense collagen sclerosis, few cells, vascular regression, remodeling of scar
Describe the fourth step in the healing and repair process.
Fibrosis - scar Macrophages recognize fibrovascular granulation tissue to adapt to lines of stress -Fibroblasts /myofibroblastss contract to close the wound and synthesize collage to create strength within the scar. -Mature scar has few cells and little vascular support.
What is leukoreduction? What is the purpose?
Filtration to remove WBCs (100% prestorage) - Purpose: --- Prevent CMV transmission (CMV safe) --- Prevent formation of HLA antibodies ---- Reduce febrile non-hemolytic transfusion rxn
What is plasma?
Fluid compartment of blood. When blood is anti-coagulated, and cellular elements are separated out by centrifugation the plasma is left. Contains coagulation proteins, plus other soluble molecules present in blood.
What is serum?
Fluid component of blood that remains after coagulation occurs and cells are removed. Contains most soluble molecules present in blood with the exception of coagulation-related proteins that become insoluble as a result of clot formation.
What deficiency occurs more rapidly, folate or b12?
Folate deficiency occurs rapidly; B12 deficiency takes years to develop
How does formation of non-ABO antibodies occur?
Formation of non-ABO antibodies ONLY occurs after exposure to foreign antigens through blood transfusion or pregnancy.
Describe the evolution of globin structure?
From one primordial globin gene, arose a number of globin genes and aborted "mistakes" - pseudogenes (they don't have activity). The original gene underwent recombination to place the parental alpha and beta genes on separate chromosomes. From here more duplications and independent assortment of various mutations, deletions and amplifications lead to a series of related globin and globin like genes on two separate chromosomes
Which cytokine mediates neutrophil differentiation?
G-CSF
Why is it very important to find the underlying cause of iron deficiency anemia?
GI malignancy may present with iron deficiency anemia as the only manifestation. SO ANEMIA CAN INDICATE CANCER HOMIE
What part of the body is the most common for blood loss? What about specifically in females in reproductive age?
GI tract is commonly a source of blood loss; mentrual blood loss is a common cause in females in reproductive age
What are the adverse effects GI, Renal, and Uricosuric effects of aspirin?
GI: prevents synthesis of protective PG's for GI epithelial cells in stomach lining (increase acid secretion) Renal: analgesic nephropathy -- slowly progressive renal failture because of decreased renal perfusion. Urosuric: *AT LOW DOSES*: decrease extretion and elevation in plasma urate *HIGH DOSES*: induce uricosuria (uric acid in urine), and lower plasma urate levels - decreases urate reabsoprtion 5g/dau
What are the Common Adverse Effects for NSAIDs?
GI: the classic, pain nausea etc BUT also GI hemorrhage, perforation and inhibition of Pgs that are gastroprotective (i.e. inhibit acid secretion from parietal cells) Renal: renal insufficiency, renal failure, decrease effectiveness of antihypertensive meds, *analgesic nephrophathy:* slowly progressive renal failure, b/x of high doses of combinations of NSAIDs and frequent UTIs, Decreased PGE2 = less renal blood flow, additive toxicities of several NSAIDs taken chronically.
What is irradiation?
Gamma or x-ray irradiation of cellular blood products, we do this for all red cells - Purpose: prevent transfusion-associated graft vs host disease (GVHD) in highly immunosuppressed patients (fatal, ma dude!)
What is pernicious Anemia? How does it effect vitamin B12 absorption?
Gastric parietal cells normally make intrinsic factor (IF). But they fail to do so because of autoimmune, bariatric surgery, removal or IF producing cells - Without IF, B12 is not transported from gut lumen into enterocytes and on to the circulation leading to profound lack of b12 - This results in an increases in methylmalonate in circulation which will have effects on mental acuity and neuropsychiatric symptoms.
What are the general and specific clinical features of anemia?
General features: result from reduced oxygen carrying capacity of blood. 1. Tissue Hypoxia 2. Compensatory mechanisms to prevent tissue hypoxia Specific features: related to specific etiology of anemia
What is the treatment for hemophillia? What about for a hemophilia cpatient with acute bleed? What about prophylaxis? When do you use this?
Give factor: plasma-derived or recombinant (factor 8 concentrates) or factor 9 for hemophillia B DDAVP in mild hemophilia A (nasal spray) -- to stimulate release of factor 8 from endothelium (yo this is a nasal spray, dope!) Acute bleed: given appropriate factor to try and get 30% of normal factor levels Prophylaxis: for upcoming surgery, long acting factors 2-3 times a week to keep troughs > 3% to prevent spontaneous bleeds. Routine in children now. -- any child should be getting injectiosn to prevent devastating blee.
What are gamma-carboxyglutamate (Gla) domains?
Gla attaches Coag factors to platelets Gla domains are on coagulation facotots. They have many Gla residues, chelate calcium, enable attachment to platelet membrane, required to have functional coagulation factor occur on both Pro- and Anti-coagulant factors.
What provides the energy to the RBC?
Glycolysis provides all metabolic beeds to the RBC
What are examples of sterile inflammatory diseases?
Gout, periodic fever syndromes, atherosclerosis, traunmativ tissue injury, autoimmunity/allergy
What granules are released by platelets in primary hemostasis? What is the purpose of the release of granules from platelets in primary hemostasis? What shape do platelets undergo in primary homeostasis and what is the purpose?
Granules released: - ADP and seratonin recruit additional platelets - Thromboxane A2 (TXA2) promotes vasoocontriction (which helps with platelet aggregation). - Fibrinogen gives platelets more fibrinogen to aggregate with in addition to what is in the plasma -PDGF helps with tissue repair and "activation" of platelets. Shape change is to more elongated forms making them sticky.
Compare how Myleoblast, promyeloblast, myelocye, metamyleocyte, and band cell/ form look differently on histology.
Granulocyte progenitors develop granules as linage commitment progresses
What does it mean when cells are divided into granulocytes and mononuclear cells?
Granulocytes = Neutrophils, Eosinophils, and basophils Mononuclear = Lymphocytes and monocytes
How do macrophages promote healing?
Growth factors EGF, VGF, FGF, TGF-alpha (promotes cell growth) - Fibrinogenesis - TGF-beta (promotes fibroblasts to produce collagen) - Metalloproteinases (important in wound remodeling)
What is the difference between haptoglobin and hemopexin?
Haptoglobin binds to hemoglobin and hemopexin binds to free heme. Buth prevent damage to kidney
Describe the Developmental switching of hemoglobin
Hb (embryo) to HbF to HbA/HbA2 yolk sac: Hb embryo = Hb Gower = 2 zeta-globin and 2 epsilon-proteins (pre-alpha and pre-beta forms respectively) then @ 5 weeks preggo, liver: HbF = 2 alpha-globin proteins, 2 gamma proteins. then @ 8 months preggo, bone marrow: starts to express beta globin and there is an increase in HbA1 (aka HbA) minor isoform delta globin is being produced too
What are the ways to test for hemoglobinopathies in the lab?
Hb electrophoresis (OLD WAY) HPLC (high performance liquid chromatography) Molecular biology (gene sequencing, PCR) -Rate of globin synthesis (beta:alpha)
When does hemoglobin synthesis occur in erythropoiesis/ hematopoiesis?
Hb syn. begins in the early normoblast stage and continues on through the reticulocyte stage. Hb synthesis in the new RBCs stops shortly after the late stage normoblast extrudes all cellular formed elements: nucleus, mitochondria, etv. continuing Hb synthesis only up until all the globin mRNA has been lost in the reticulocyte maturation phase.
What are the automated counters measure?
Hb, MCV, and RBC are numbers directly; other parameters are calculated
What is the problem with methemoglobin? How does it form? What amount of Met-Hb is normal? What amount can kill you? What does the blood look like with look like with excess Met-Hb
Hb-Fe2+ can be oxidized to Methemoglobin-Fe3+ in the presence of oxygen or use of nitrates, drugs, ROS, decreased activity of NADH-cytochrome B5 reductase (a.k.a. NADH-met-hemoglobin reductase) - The superoxide radicals are detoxified by sequential user of superoxie dismutase and catalse to yield water and oxygen -MethHb-Fe3+ *does not bind to oxygen* and therefore oes not transport oxygen to tissues leading to systemic hypoxia. -1-2% MetHb-Fe3+ in circulation is clinically normal. MetHb>5% can kill you. -Xs MetHb-Fe3+ gives blood a bluish-chocolate appearance
What is Hb-S?
Hb-S causes sickle cell anemia and is a result of beta chain #6 position glutamate to valine substitution mutation (E6V). The function of the glutamate was to increase the solubility of the beta subunit due to its polar-ionic character. furthermore, it sits squarely in a hydrophobic surface domain in order to perform this function. The valune completes the hydrophobic field on the surface of the beta-subunit, and in the deoxyform of Hb-S, beta subunits will associate with each other through hydrophobic interaction at these interfaces. Under hypoxic conditions, the deoxy-Hb-S will polymerize into long twisting bundles or fibers. these fibers reduce structural interity of the RBC so that they lyse more readily in passthing through deep tissue capillary beds and the spleen, leading to lysis and anemia, vascular blockage and tissue (ischemia (extremelt painful, potentially lethal).
What is the structure HbA1? What about HbA2? What about HbF?
HbA1 (major adult hemoglobin) = 2 alpha, 2 beta HbA2 (secondary adult hemoglobin)= 2 alpha, 2 delta HbF (fetal hemoglobin) = 2 alpha, 2 gamma
What is HbA1c? How can a doc tell if a patient was cheating on their diabetic diet.
HbA1c is elevated in diabetes Elevated circulatory glucose Glucose cyclic conformation _> aldohexose linear -Aldehyde forms adducts with lysine side chains on HbA forming HbA1c (glycosylated hemoglobin) - HbA1c levels diagnostic for elevated circulatory glucose levels and degree/severity of diabetes -also reflects success of diabetic treatments with decreased HbA1c levels... and cheating with bday cake
Why is the hemoglobinF deoxy form less stable than the HbA? Why is this important?
HbF deoxy has one less histidine in each fetal Hb-gamma subunit than in the adult Hb-B This results in a less stable deoxyform in fetus than "mommy" upon binding 2,3-BPG Thereofre,t he net flow of xygen from mother to fetus across placental barrier because mom's deoxy is more stable than HbF - gamma
What are the general local effects of inflammatory cytokines?
Heat, redness, swelling, pain, vasodilation, recuiring other cells
When does hemoglobin synthesis occur? What is needed for this? What is synthesis of heme coordinated with?
Hemoglobin synthesis occurs in blast cells and reticulocytes prior to maturation into erythrocytes (RBC ). - Nuclear DNa, RNA transcrtiption and translation machinery. Synthesis of Heme is coordinated with alpha and beta synthesis. Heme synthesis and hemoglobin sythesis are precisely matched in a coordinated production scheme in the megakaryocytes and reticulocytes RBC precursor cells with both nucleus for genetic input and mitochondria for energy production.
What is the function of Hb?
Hemoglobin transports ocygen, carbon dioxide, and protons between the lungs and peripheral tissues. It delivers substrates, collects wastes and adjusts the circulatory pH... miracle of nature!
What is HELLP Syndrome? How many preclamptic patients have HELLP? what are the symptoms of HELLP? What is the treatment for HELLP?
Hemolysis (microangiopathic) Elevated Liver Enzymes Low Platelets HELLP Syndrome is a series of symptoms that make up a syndrome that can affect pregnant women. HELLP syndrome is thought to be a variant of preeclampsia, but it may be an entity all on its own. 12% of preeclamptic patients have HELLP Symptoms include naursea, malaise, abdominal pain. HELLP patients should be delivered ASAP, HELLP patients may remain with low platelets for several days after delivery, plasmapheresis for refractory patients
What is hemopexin?
Hemopexin binds free heme preventing clearance by kidney and recycles iron through the reticuloendothelial system
What is the likely cause of joint bleeding?
Hemophillia
What is hemostasis? What is it a balance of? What are the three requirements of hemostasis?
Hemostasis is a balance between clotting and bleeding. Specifically: - Protection against bleeding (pro-coagulants) vs Protection against clotting (anti-coagulants) - The three reuquirements are that it is rapid, localized, and reversible
What will happen to the thrombin bleeding time if a patient is taking heparin? What should you do about it fake dr.?
Heparin will increase the bleeding time because it blocks thrombin (factor 2) Therefore, you should use a substance derived from snake venom called reptilase (also called batroxobin) instead of thrombin Reptilase has a similar action to thrombin but unlike thrombin it is not inhibited by heparin
What do heparins do?
Heparins catalyze antithrombin (AT) -- increases it 1000-fold. Neutrolizes coagulation proteases
Girl has sprain on hand, she is wearing ring on finger. She has immediate pain. What do we do?
Her hand is swollen, after ruling out a rfracture, get her to take of the ring. Then rest, protect, ice for like two days to reduce edema
Histo slide on other side!
Here you are looking at neutrophils with swollen nuclei, thy do have multiple nuclei and generous pink cytoplasm (so you know that it is not a lymphocyte-- they have multiple lobes so not a monocyte)
What is the result of taking high concentrations of omega 3?
High concentrations of omega 3 acid in cells "soften" inflammation in three ways: 1. Competitively inhibit delta6-desaturase which is the enzyme that convertes linoleic acid (from diet) to omega 6 (arachidonic acid) 2. omega 3 fatty acids compete with arachidonic acid for COX and LOX 3. omega 3 and omega 6 eicosanoids compete for the same receptors and the activity of omega 3 eicosanoids is weaker than that of omega 6.
What are the functions of leukotrienes?
Histamine and leukotrienes induce leukocyte infiltration into the affected site
How does histamine act as a cell-derived mediator of acute inflammation? How fast does it react?
Histamine: release of performed granules --> Immediate effect (<30 min) --> early vasodilation/ permeability
What type of allergic reactiosn occur in transfusions? Why?
Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps -hypersensitivity reactions -proteins in donor plasma cause hypersensitivity reaction in recipient - Idiosyncratic
What is hemoglobin Bart's hydrops fetalis? Why does this ocur
Homozygous alpha thalassemia (--/--) -No functional alpha globin genes: Hb Barts (Y4) Eclampsia in mother - Eclampsia is a severe complication of preeclampsia. It's a rare but serious condition where high blood pressure results in seizures during pregnancy. Stillbirth - Erythroblastosis in infant - This happens in fetal life, you only have gamma chain (no alpha) -- they bind avidly to oxygen so none of it gets to the tissues -- they die in utero
What are the general indications for red clots tx with anticoagulants ?
Hypercoagulable states, Stasis Foreign objects
What is an Aspirin Allergy? How many people have this?
Hypersensitivity (0.5-2.5%) -- like asthma symptoms -- theory that this is because of diversion to Leukotriene pathways. -if you get this with one NSAID, you will get them for all there is cross sensitivity for all NSAIDs
What is hypoproliferative and hyperproliferative anemia?
Hypoproliferative anemia - the bone marrow does not have adequate compondents (iron, b12, etc) to proliferate RBC Hyperproliferative anemia- Bone marrow is proliferating rbc but the peripheral areas are destroying them
Desribe how the anaphylactic reaction occurs in a blood transfusion?
Hypotension, dyspnea, airway edema, anxiety, larger rash Requires emergent care Anti-histamines Epinephrine, corticosteroids, vasopressors, and intubation if necessary Can consider volume reducing platelets to reduce plasma exposure May have to wash platelets or RBCs (blood products) for future
What is an Individualized educational plan (IEP)?
IEP is a plan to ensure that a child who has a disability identified under the *law* and is attending an elementary or secondary educational institution receives *specialized instruction and related services*
What are the three things that Type 1 inteferons (IFN) do?
IFN-alpha, IFN-beta Induce resistance to viral replication in all cells Increase MHC class I expression and antigen presentation in all cells Activate NK cells to kill virus -infected cells
Which cytokine mediates eosinophil differentiation?
IL-5
What cytokine mediates T cell differentiation?
IL-7
How does Warfarin affect Gla formation?
IT BLOCKS IT -- therefore reducing clotting Specifically, it ihibits VKORC blocks regeneration of vitamin K (reduced) Vitamin K is needed to form Gla from glutamate.
What is Immune Thrombocytopenia?
IT IS THE SAME THING AS IDIOPATHIC - occurs in 0.1 to 1 in 1000 women -A diagnosis of exclusion - Paltelet count is 20-30 000/dl - Lower than in gestational thrombocytopenia - Diagnosis is suggested when a mother with pre-existing ITP develops profound thrombocytopenia
What is immune memory? Why is this important for vaccines?
IT is a hallmark of the adaptive immune resposne. Most lymphocytes after activation and clonal expansion will die. But some will develop into long-live "memory" cellls. When one is re-exposed to an antigen after primary exposure, it is the memory cells that expand in precursor frequency, that will respond. This is the basis for why the adaptive immune response is more efficient upon subsequent exposure to antigens and is the basis for why vaccines are effective?
Where is the iron from the diet absorbed?
IT is absorbed in the intestinal lining
What is vitamin B12 used for in the body?
IT is used for 1) Methionine synthase - methionine to homo without methionine synthase, methionine supplies would diminish and one carbon metabolism would be compromised. (This is important for methylation reactions on DNA, RNA, proteins, etc...) 2) Branched chain AA metabolism (methylmalonyl-CoA mutase) 3) Branched chain fatty acid metabolism (methylmalonyl-CoA mutase) -methylmalonyl-CoA mutase converts the break down product of branched chain amino acid degradation and odd-chained fatty acid degradation into a common TCA intermediates, succinyl-CoA, for either energy production or gluconeogenesis. Build up of methylmalonyl-CoA and its hydrolysis to methylmalonate + CoA can alter membrane dynamics and also mimic NT inhibiting normal NT function -- neurological dysfunction + mental abnormalities + dementia -- THis is seen in elderly -- poor diet (the source for b12_ 4) DNA synthesis-- THF and DHF- thymidine synthesis
Which NSAIDs generally need higher doses?
Ibuprofen and aspirin (although I'm not sure this card is important )
what is the interaction between NSAIDs and aspirin?
Ibuprofen impairs aspirin's ability to acetylate the active side of COX (more on this shortly)
What is salicylate? How is it metabolized? How is it excreted?
If aspirin is metabolized, it will can make salicylate and acetate Salicylate is a competitive, reversible inhibitor of COX Excretion: secreted by proximal tubule as well as glomerular filtration. soo.. kidney
What is the dexamthasone suppression test?
If high cortisol is coming from HPA, dexamethasone will suppress it but if it is a tumor it will not be suppressed by dexamethasone
What does the reticulocyte count help with determining if an anemia is hypo-proliferative or hyper-proliferative?
If retic. is low, then it tells us that the patient doesn't have the element in the BM to make new RBC If retic. is high, then it tells us that the patient doesn't have the elements in the BM to make new rbc.
What is the treatment of APLS?
If thrombosis: anticoagulation for at least 6 months if not indefinite. 20-45% recurrence risk after stopping AC If pregnancy morbitidy: LMWH and aspirin 81 mg during pregnancy and postpartum
Describe the non-linear relationship between coagulation factors and PT/INR? What is the normal INR of plasma?
If your INR is above 2, even a small change in a factor level you get a huge change in INR if you change your % of coagulation a bit. Less than 1.7, INR doesn't change that much. Normal INR of plasma = 1 But boy is higher than one, you lose some factors in sotrage.
What is the most common site of bone marrow biopsies and aspirates?
Illiac crest -- this is in the pelvis (most common generally vertebral and pelvis)
What is the main physiological action of glucocorticoids?
Immune system: Immunosuppressive, anti-inflammatory
What anemias under affecting differentiating cells cause decreased RBC production?
Impaired DNA synthesis - B12 or folate deficiency - Impaired B12 or folate metabolism Impaired Hemoglobin synthesis - Iron deficiency - Thalassemia (decreased globin chain synthesis) - Sideroblastic anemia (defective heme synthesis) Multiple mechanisms - Anemia of chronic disease -Myelophthisic anemia
What is the NALP/inflammasome complex good for? What does it secrete? What are the regulatory points in the pathway?
Important for secretion of IL-1b (b as in beta) -- this is an endogenous pyrogen) When this inflammasome assembles, when exposed to DAMPS, it can make caspases, which can cleave proteins to make pro il- IL There are two regulatory points, one is activating the caspases, the other one is pattern recognition receptors
How is MetHb-Fe3+ converted back to Hb-Fe2+? What about clinically? What is the problem with having Xs MetHb-Fe3+?
In RBc this is done by the actions of NADH, cytB5 reductase and methemoglobin reductase. -Methylene blue is used clinically to reoxidize mettHb-Fe3+ to Hb-Fe2+ however, this is inefficient. -Vitamin B12 is also used as a treatment to absorb CN into a non-toxic form. -MetHb-Fe3+ may not bind to oxygen, but it has a very high affinity for cyanide (CN-)\
How does Urine seidment hemosiderin reflect hemolytic anemia?
In cases of severe intravascular hemolysis, the binding capacity of haptoglobin is exceeded rapidly, and free hemoglobin is filtered by the glomeruli. The renal tubule cells may absorb the hemoglobin and store the iron as hemosiderin
What are the chemical treatments for Cyanide poisoning in Europe? What about US?
In eurpoe: massive injections of vitB12 to form the less toxic cyanocobalamin. USA: methylene blue! -- oxidize Hb+2 to Hb+3 which allow the absorption of a good deal of cyanide poison before it can get to complex 4 ETC.
In general how do therapeutic actions and toxicities of NSAIDs compare? What about the reversibility?
In general, most NSAIDs: similar therapeutic actions and toxicities Most are reversible competitive inhibitors of COX1 and 2. Aspirin is an irreversible inhibitor tho!
What is the difference between transudate and exudate?
In step 4 of phase 1, you have fluid moving to the extravascular space causing edema. At first the fluid is low in protein = transudate (gaps between the endothelial are small) Then high in protein = an exudate (inflammatory edema = exudate)
What happens downstream in the intestine once the conjugated billrubin is taken there?
In the intestine, glucoronic acid is removed by bacteria. The resultin billirubin is coverted to urobillinogen. Some of the urobillinogen is reabsorbed from the gut and enters the portal blood A proteion of this urobillinogen particpates in the enterohepatic urobillinogen cycle. The remained of the urobillinogen is transported by the blood to the kidney, where it is converted to yellow urobillin and excreted, giving urine the characteristic color. Urobillinogen is oxidized by intestinal bacteria to the brown stercobillin.
How many levels of protein binding affect the action of glucocorticoids?
In the plasma, they need to be boun dto a protein. When hormones are given as therapy there should be a protein binding. Levels of protein binding might change and affect delivery.
Describe the steps in the intrinsic pathway?
In the presence of a negatively charged surface from damage, the plasama proteisn are activated including kininogen, kallikrein, and factor 12. then the path goes down in to the final common pathway.
Where does most of the RBC turnover happen?
In the spleen, and they are devoured by endocytic macrophages.
What kind of cells are found in the thymic cortex? How do they look like? What are the called? What is the appearance of
In the thymic cortex there is an abundance of developing T-cells or *thymocytes*. Their scant (lack of) cytoplasm allows for close packing of these cells at this stage of their development --> *"small dark blue cells"* the much larger, *epithelial-derived, thymic reticular* cells are characterized by much more *abundant cytoplasm*; stellate shaped and interspersed among the thymocytes; an appearance described as *starry sky.*
What is the two signal model of lymphocyte activation?
In this model, a lymphocyte requires two distinct signals in order for full activation to occur. The first signal is provided by the interaction of the T cell receptor (TCR) on the lymphocyte with major histocompatibility class (MHC) antigens on the antigen-presenting cell (APC). *Signal 1 = AgR signaling* The second, costimulatory, signal is required to avoid an apoptotic or anergic response by the lymphocyte. The interaction of CD28 on the lymphocyte with B7 proteins on the APC provides this necessary costimulatory second signal. If the lymphocyte only receives signal 1 (i.e. TCR engagement) from the APC, the lymphocyte becomes apoptotic or anergic, thus unable to respond to antigen. *signal 2 =CD28 interaction with B7-1/2 (CD80/CD81) molecules on antigen presenting cell is required for efficient T cell activation*
What do you think the consequences of defects in antimicrobial production might be?
Increased susceptibility to infection or increased inflammation iat the barrier tissue sites.
Is MCHC increased or decreased in hemolytic anemias?
Increased!
What are the indications for Whole Blood? what are the advantages and disadvantages?
Indications: Provide oxygen carrying capacity (RBCs), platelets, and coagulation factors all in one product (typically, used for massively bleeding pt. in situations where blood components are not available --> military, pre-hospital civilian trauma) Advantages: all in one product, fewer donor exposures Disadvantages: Volume overload, ABO group specific or low-titer group O required.
What are the indirect and direct anticoagulant target clotting factors?
Indirect (i.e. don't specifically act on coagulation enzymes): Antithrombin catalysts: Heparin, Enoxaprin, Fondaparinux Block clotting factor synthesis (post-translational modification): warfarin --- Direct: (direct 10a inhibitors): RivaroXaban, ApiXaban Direct thrombin (2a) inhibitors: DabigaTran, Argatroban, Desirudin, Dibalirudin
What is an antibody screen? What are the two types?
Indirect coombs test and Direct Coombs test
What are the two categories that innate immune cell receptor signal cells to do?
Induce killing: by binding of bacteria to phagocytic repcetpros on macrophages. Promote secretion of soluble factors (cytokines, other bioactive molecules): by binding bacterial components to signal receptors on macrophages.
What is the function of PGI2
Induces vasodilation and inhibits platelet aggregation.
What are the sources of carbon monoxide?
Inefficient combustion (industrial, gas engines, BBQs) - Heme metabolism
What causes adverse outcomes associated with transfusion?
Infections disease, wrong blood in tube, transfusion reactions
What is the first line of protective response and what is the reason for it?
Inflammation is the first line of protective response designed to eliminate cause of injury, remove necrotic debris, repair damag.
what is the classiication of chemokine system? Are they constitutive or inducable?
Inflammatory: innate = constitutive or inducible Adaptive = inducible Homeostatic: constitutive
What is the timeline of the coordinated temporal events of self-limited acute inflammation
Initiation -- Edema, PMNs Resolution == lipid mediator class switching
Do innate receptors come from your parents? What about adaptive?
Innate receptors come from mama and papa, adaptive receptors are largeley developed over a time-course
When is the innate, early induced innates, an adaptive immune system initiated?
Innate: Immediate (0-4 hours) Early induced innate response (early: 4-96 hours) Adaptive immune response (late: > 96 hours)
How are dendritic cells at the interface of innate and adaptive immunity?
Innate: Maturation or differentiation in response to microbial and other stimuli. Make cytokines that regulate recruitement and activation of innate immunce cells (similar to macrophages Adaptive: efficient antigen uptake, process, and pressentation of peptide - MHC complexes to T cells
Compare The adaptive cell receptors vs the innate receptor function?
Innate: Specificity inherited in the genome, expressed by all cells of a particular type (e.g. macrophages), triggers immediate response, recognizes broad classes of pathogens (PAMP), interacts with a range of molecular structures of a given type Adaptive: encoded in multiple gene segments, requires gene rearrangement, clonal distribution, able to discriminate between even closely related molecular structures.
What does the treatment of cobalamin deficiency entail?
Intramuscular B12; usually 1000 mcg a month; may give weekly early on in severe deficincy - Can give oral B12 -- 1000 mcg/day - prophylactic therapy in patients with gastric bypass or ileal resection - Hypokalemia may occur early on in Rx in severe cases (this is because we are quickly having a lot of rbc production
Once iron makes it into the body through a highly regulated process, it is very difficult to remove it. What are ways that the iron is removed? What is teh most effective way?
Iron is lost through GI epithelial cells and skin cell turnover. BUT the single most effective way is bleeding/hemmorhage
What is thrombin-activatable fibrinolysis inhibitor - TAFI?
It circulates in the plasma. TAFI gets activated by thrombin and removes lysine residues from partially digested fibrin to impair ability for plasminogen an tPA from lysing. Thrombin protects itself by activating TAFI. The concentration of thrombin required for the activation of TAFI is substantially higher thant hat for fibrinogen clotting. Thus, TAFI activation requires amplification of thrombin through feedback activation of facttor 5, 8 and 11 by the samlle amount of intially generatd thrombin. Hemophilliacs factor 8 deifcincy and pts with factor 11 deficiency may have longer bleeding b/c of suboptimal activation of TAFI, leading to premature clot lysis.
How do human get tetrahydrofolate (THF)?
It comes from folate which comes from the diet. IT is then modified to dihydrofolate (DHF) and on to tetrahydrofolate (THF) by dihydrofolate reductase.
How does myoglobin release it's oxygen?
It doesnt! -- oxygen storage UNTIL oxygen is very very low (p50 = 1mmHg
What is the Membrane-Attack Complex (MAC)? What are the complement components that mediate the MAC complex
It generates a pore in the lipid bilayer membrane C5-9 = MAC
What is the mechanism of celecoxib?
It inhibits cox-2.. so do the other things that end in 'coxib' selective!
What are leukotrienes (LT) made from? Which enzyme makes it happen? What generally is the result of LT generation?
It is (initially made by arachidonic acid) but then made by the enzyme 15-lipoxygenases (LOX), although (5 and 12 play a role too) They increase neutrophil infiltration, bronchoconstriction and vascular permeability
What is the likely cause when someone has some bruising, more aggressive menstrual periods, and nose bleeds but is otherwise feeling well?
It is Immune/Idiopathic Thrombocytopenia
What is the role of C5a/
It is a chemotazin
What is a bone marrow aspirate?
It is a liquid sample! Used for cytogenetics (look to see if the patient has mutations) and immunophenotyping (Use antibodies to identify problem) NOTICE the stain looks different
What is Alteplase? What about streptokinase
It is a recombinant form of human tissue plasminogen activator. Used in m'erica Streptokinase is a bacteria protein with tPA activity
What is Celecoxib? Why did it not work as well? Which patients should you not use them in?
It is a selective COX 2 inhibitor. OOO selective!? sounds great right? *wrong.* It only inhibits COX2- therefore inhibiting PGI2, therefor inhibiting the breakup of platelets while allow TXA2 to be uninhibited and aggregate platelets -Avoid in patients prone to cardiovascular or cerebrovascular disease.
What is a Trephine core biopsy? What are you using it to assess?
It is a solid sample! NOtice how the stain looks different from the other type. You also end up cutting some cells from the sample in half. You get this strip looking thing You are using this to assess bone marrow cellularity
What is a black box warning?
It is a warning on a product monograph highligheted in a black box. Reasonable evidence of an association of a serious hazard.
What is the function of activated protein C? How is it activated? What about protein c?
It is activated by thrombin/thrombomodium complex on the endothelial surface. It works with cofactor protein S to inactivate factor 8a and 5a.
What is it called if hematopoiesis occurs outise of the bone marrow after birth?
It is called extramedullary hematopoiesis, this can be pathologic
what is cryoprecipitate? How do you make it?
It is composed of factor 8, 13, vWF, and fibrinogen You make it by slowly thawing FFP (plasma) in the cold. You will get white preciptates at the top. One "pool" = 6-10 donor units = one adult patient
What is warfarin Contraindicated in?
It is contraindicated as an initial treatment of HIT.
How is the importance of bacteria on our epithelial lining evident?
It is evdent by the problems associated with antibiotic therapty that alters the gut microflora:
What is hepcidin?
It is expressed with high Fe levels in the liver, binds to and helps degrade ferroportin to regulate Fe uptake
What is the Hassall's corpuscle? What does it look like? Where is it located? what is it's purpose
It is located in the thymic medulla: (dead reticular cells) - structures of unknown purpose -aggregates of degenerating thymic reticular cells (type VI) - show some concentratic arrangement (sometimes keratinization) -acidophillic and the center appear hyalinized.
Which area of the adrenal gland is cortisol made in? Which zone of the adrenal gland is cortisol made in? What is it stimulated by?
It is made in the adrenal cortex Cortisol is made in the zona fasiculata (large zone) It is stimulated by ACTH
Are B12 and folate deficiencies megaloblastic or non-megaloblastic? How can you differentiate it from hemolytic anemia in the lab
It is megaloblastic because -Ineffective erythropoiesis i.i. destruction of red cells within the marrow may be seen in B12 def; labs suggestive of hemolytic anemia BUT retic count in low.
What is the purpose of the E7 portion of the hemoglobin?
It is not covalently bound to the iron. the distal histidine promotes angular binding of the oxygen ligand to the heme iron and effectively blocks and linear ligand binding such as carbon monoxide. Molecular oxygen prefers angular binding ue to the angular orientation of it's non-bonding electron pair. The distal histidine also acts as a "sweep" to clear the heme iron of ligands (O2) in the deoxy conformation.
Whe should someone take a high amount of omega 3 fatty acids? Why?
It is recommended to individuals with chronic inflammation. Omega -3 eicosanoids are weak and omega 6 eicosanoids are strong
How is NK cell activity regulated?
It is regulated by a balance of positive and negative signals.
How is leukocyte trafficking regulated?
It is regulated by chemokines/chemoattractants and adhesion molecules.
What is the major biological effect of NSAIDs related to?
It is related to inhibition of prostaglandin synthesis.
What does deficiency in G6PDH and or pyruvate kinase (PK) Lead to? Why?
It leads to anemia -no PK = no ATP production = anemia - G6PDH prduces NADPH which provides protection against free radicals via GSH and provides energy.
Where does the conjugated bilirubin idiglucuronide go after being released by hepatocytes?
It leaves the hepatocyte and is targeted for hepatic bile which is concentrated in the gall bladder and released into the GI tract.
What does healing by first intention mean? What does healing by second intention mean?
It means that you can approximate the wound (you can bring the wound together via stitches), if you can approximate the edges, you can increase the healing speed Second intention: you can't approximate (bring together) the edges, the tissue underneath may have damaged the underneath portion -- scar is formed. these cells have contractile properties, the body will lay down the provisional scar and if it is scar tissue, it will contract. This will help reduce damage.
What is anisocytosis?
It means variation in size of RBC
What is the function of Protein kinase C? How is it activated?
It promotes NF-kB activation PKC is activated by DAG
Why is CD40 signaling important for macrophages and dendritic cells?
It promotes cytokine production (and other stuff too)
How does the endothelial function in the synthesis and secretion of hormones?
It releases growth and inhibitory factors to regulate hematopoeisis - ACE converts angiotensin I to angiotensin II (lung capillaries) - part of rennin/angiotensin system-- increases BP - Inactivators of blood borne NE, thrombin, prostaglandins etc.
How does the endothelial change after injury in regards to thrombosis?
It secrets pro-thrombogenic substances - Von Wilebrand factor and Factor VIII (platelet aggregation) - Plasminogen activator inhibitor (promotes fibrin formation) - Tissue thromboplastin (initiation of thrombin formation for coagulation cascade)
Desribe the process for heme biosynthesis
It starts with an AA and a TCA cycle intermediate (glycine and succinyl-CoA) to generate 5-aminolevulinate (5-ALA). This is the rate limiting step for heme synthesis in liver and is catalyzed by 5-ALA synthase. Two 5-ALA molecules form porphobilnogen by the action of 5-ALA dehydratase. 4 porphobilinogens form the cycliic structure uro-porphyrinogen III. The enzyme, ferrochelatase inserts an Fe2+ into this structure generating heme.
Why is hydrocortisone or dexamethasone given to preggo women who are predicted to deliver prematurely?
It stimulates the development/surfactant production which helps with delivery
What happens when there is deficiency in energy production in RBC?
It will lead to osmolysis because Na+/K+ pumps can no longer keep the osmolarity
What is the function of COX-1? How is it expressed?
It's a PGH synthase -- constitutive expression in most tissues. - Synthesizes prostanoids for "housekeeping" functions - Inhibition leads to GI-related side effects (PGs inhibit acid secretion from parietal cells) -- stomach ulcers
What are the specific symptoms of hemolytic anemia?
Jaundice, dark urine, dry atrophic skin and nail changes
How do NK cells recognize infected host cells? What is the "Missing-self" hypotehsis?
KAR: killing activating receptors KIR: killing inhibitory receptors If *normal* cells (KIR at work): MHC calss I on normal cells is recofnized by inhibitor receptors that inhibit signals from activating. NK cell does not kill the normal cell. "Missing-self" hypothesis: Altered or absent MHC calss 1 cannot stimulate a negative signal. The NK cell is triggered by signals from the KAR. It releases granule contents, inducing killing!
What are examples of ITIM containing receptors?
KIR receptors on NK cells; "negative co-stimulatory" mulecules expresssed on T cells like CTLA-4 and PD-1 or negative regulatory FcgammaRIIb on B cells
Which factors do PTT test for?
Kinninogen, kallikrien, 12, 11, 9, 10, 5, prothrombin, fibrinogen.
What condition does the loss of function mutation of NOD-like receptors associated with?
LOF of NLR is assocaited with subset of chron's disease (because they interupt the balance and increase risk of proinflammatory factors)
What is the role of LOX in asthma?
LOX increases asthma symptoms by producing leukotrines
What TLR is LPS recognized by?
LPS is recognized by TLR-4. It is important constituent on gram negative back. It is a reason peopel get sepsis
How do leukoteines play an anti-inflammatory role? How is aspirin involved?
LTA4, B4 converted into lipoxins LXA4, LXB4, respectively = anti-inflammatory and play role in resolution of inflammation, aspirin can generate epilipoxins which are similar in action to LXA4, LXB4.
What are lacteals?
Lacteals are lymphatic vessels found in the intestinesphatcLym
How are neutrophils recruited to tissues? Where are they stored beforehand.
Large reserved os neutrophils are sotred in the bone marrow and are released when needed to fight infection. Neutrophils are rapidly recruited to tissues by chemokines they then kill and due in the tissues and are engulfed by macrophages.
What is a massive transfusion?
Large volume replacement of blood components Indication: uncontrolled hemorrhage Set ratios of blood components. It has set ratios of blood components: RBC, plasma, platelets, cryoprecipitate (we don't just give whole blood because issues with storage, degradation etc.)
What are azurophillic granules?
Larger granular lumphocytes have azurophilic granules. they are usually associated with cytotoxic effector function. can be cytotoxic T lymphocytes OR NK cells
Why can megaloblastic anemia be an issues?
Larger than normal cells, sensitve to free radical damage and lysis in tight capilary beds
What does the law say regarding when a child must be enrolled in school? What is controversial about this? What is the currently accepted concept?
Law: Children must be in school at age 5 for kindergarten and by 6 for first grade. Controversial: The idea that because of their birth date some children are "ready for school" and others are not Currently accepted concept: Schools need to be ready for children
What does TLR signaling lead to? Which cytokines and factors does it increase
Leads to activation of transcription factors (e.g. NF-kB) and promotes transciptionr of many cytokine genes that are usually pro-inflammatory (TNFalpha, IL-6, IL-1, IL-2, IFNs)
What is the mechanism of action for Hirudo medicinalis?
Leeches! saliva has an anticoagulation -- faster revasulation -- has hirudin insaliva
Answer which of the following bone marrow samples is from a patient with: Recent exposure to high-level radiation? What about recent severe acute hemorrhage?
Left - acute hemorrhage, right - recent exposure too high-level radiation
Why is diapedesis important for the immune response?
Leukocyte extravasation, less commonly called diapedesis, is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response
What are the systemic signs of acute inflammation
Leukocytosis, Fever C-reactive protein (CRP) -Erhythrocyte Sedimentation rate
Which eicosanoids stimulate bronchoconstriction?
Leukotrines (LTA, LTB, LTC), PGE and PGD
Describe the JAK/STAT signaling pathway?
Ligand recognition results in JAK-mediated tyrosine phosphorylation and homodimerization of STAT proteins which act as transcription factors. Phosphorylation and dimerization of STATs results in STAT translocation to nucleus and gene transcription.
what is the likely cuase of mucosal bleeding - (nose bleeds, easy brusing etc.)
Likely platelet problems
What is linked recognition?
Linked recognition refers to the concept that T cell help to B cells is linked to recognition (of usually) different epitopes on the same antigenic complex. B cell receptor recognition of antigen causes (among other things), internalization of the BCR-antigen complex and processing and presentation of that antigen as MHC II peptide complexes. Thus B cells present an epitope from the specific antigen that was recognized by BCR. This results in activation of T cells specific for that antigen leading to antigen-specific B cell help.
Why is local inflammation good?
Local inflammation is good because it helps to contain infection .. prevents induction of systemic inflammation. That would be real bad!!
What is the location, target, source, and effect of recognition of completment?
Location: bloodstream, tissue fluids Target: Microbial cell wall components Effect: Recruit, kill, opsonize
What is the receptor location, target, and effect of toll-like receptors?
Location: cell surface, or internal compartments Target: Microbial components not found in hosts Effect: Induces innate responses
What are the potential adverse ourcomes of chronic inflammation?
Loss of organ cell function (eg. liver failure) Irreversible (?) accumulation of collagen that distorts functional architecture (eg. liver cirrhosis and portal hypertension) Persistent regeneration of surviving cells favors those adapted to abnormal microenvironments and those with mutations --> cancer (e.g. chroniic hepatitis C -> hepatocellular carincoma)
What is antiphospholipid syndome? what will help correct this?
Lupus anticoagulants (aka antiphospholipid antibodies) are antibodies directed against plasma proteins bound to phospholipids. The mixing study wont correct this BUT addition of phospholipid does correct it. The syndrome with lupus anticoagulants and increased arterial and venous clotting called antiphospholipid syndrome.
What are the secondary or peripheral lymphoid organs?
Lymph nodes, spleen, tonsils , lymphoid tissues associated with other organs (GALT, MALT, SALT)
What is the purpose of the lymphatic capillaries? Why do we even need a lymphatic system?
Lymphatic capillaries are the route of cells and *large molecules* from tissue spaces back to the blood -
Desribe the structure of lymphatic capilaries?
Lymphatic capillaries have an irregular outline -- a spaced endothelial cell lining lacking tight junctions, and no RBS in the lumen Compare the thickness of the wall of the lymphatic capillaries to that of the wall of the arterials. The lumen of the arteriols have RBC (she will not ask us to identify lympatic vessels though)
Where do lymphocytes get activated? Where do important functions happen?
Lymphocyte get activated in the lymphoid tissue and then can migrate to "peripheral" tissues/inflammatory sites Important functions happen at tissue sites (not in blood)
What are lymphoid nodules?
Lymphocytes are densely packed here. - found in the respiratory, digestive, and urinary tracts
What cells are part of the lymphoid lineage? Where do they develop
Lymphocytse (T,B and NK) arise from a common lymphoid progentiro cells B - from bone marrow T cells migrate from bone marrow into the htymous. T cell development occurs in the thymus.
Which cytokine mediates the monocyte lineage?
M-CSF
What is the difference between classically activated macrophage (M1) and alternatively activated macrophage (M2)?
M1 = Microbial actions: pahgocytosis and killing of bacteria and fungi + inflammation M2 = anti-inflammatory effects, wound repair, fibrosis
Which cells take over after the neutophils have done a bit of their thing at the acute response?
MACROPHAGES! Key effector cells in healing and repait
What MCV classifies microcytic anemia? What is the most common cause?
MCV of < 80 fl Most likely cause is iron deficiency or [anemia of chronic disease (AC)]
What are the main two things that the common myeloid progrnitor differentiate to?
MEP - megakaryocyte erythroid progenitor GMP - Granulocyte monocyte progenitor
How does the Megakaryocyte Erythroid progenitor cell (MEP) make erythrocytes?
MEP forms the pro-erythroblasts (quite big) The pro-erythroblasts then make the early, intermediate, and late erythroblast. This then forms the reiculocyte (which still has reminants of rRNA -- stains light blue!). The reticulaocyte then forms the erythrocyte
Macorphages and dendritic cells have different (but overlapping) roles. Describe this. Which are better than other cells?
Macrophages: - Engulf pathogens / kill secrete cytokines STAY ON SITE - contain infection -attract other leukocytes Beter at killing Dendritic Cells: -Engluf pathogens (not very microbial) - Secrete cytokines LEAVE -Stimulate adaptive immunity (APC) More likely to migrate and go into lymph nodes and stimulate response
What role do macrophages play in the immune response?
Macs: up-regulate inflammation and promote healing
What is the main producer, the target, and effect of Il-1, IL-6, IL-12, TNF-alpha, and CXCL8 (IL-*)
Main producer IL-6, IL-8 (CXCL8), IL-12, TNF-alpha = macrophages and dendritic cells IL-1 = macrophages and keratinocytes Target: IL-1 and IL-6 = Lympocytes and liver IL-8 (CXCL8) = Phagocytes IL-12 = Native T calls, NK cells TNF-alpha = vascular endothelium Effect: IL-1 and IL-6 = enchances responses and induces actue-phase protein secreation IL-8 = chemoattractant for neutrophils IL-12: diverys immune response to T(helper)1 TNF-alphas: induces chances in vascular endothelium, cell-adhesion molecules (selectin), changes in cell-cell junctions with increased fluid loss, local blood clotting)
What are the beneficial uses for therapeutic glucocorticoids?
Mainly anti-inflammatory and immunosuppressive actions (glucocorticoids)
What are the two main treatment goals in autoimmune thrombocytopenia (AITP)
Maintain hemostaisis Minimize toxicity
Do NK cells produce cytokines? Which one does it make a lot of? What is one cytokine it responds to?
Makes: It makes a lot of IFN-gamma tat regulate development of immune response. Responds to: IL-12 can also be made and responded by NK
How do P-gp and CYP3A4 synergize to reduce bioavailablility?
Many drugs bind both to P-gp and CYP3A4. Inducing/inhibiting P-gp/CYP3A4 can produce large changes in plasma drug levels P-gp shuffles drug back into teh GI lumen, If any gets through CYP3A4 will do a bit more metabolizing
Where is marrow collected?
Marrow is collected from flat bones, routinely from the iliac crest.
What is the MCH?
Mean corpuscular hemoglobin (MCH) - Measure of the average total hemoglobin content of individual RBCs - Parallels the MCV and MCHC
What is MCHC?
Mean corpuscular hemoglobin concentration -- measure of the average concentration of hemoglobin (per unit cytoplasmic volume) in individual RBCs - Often decreased in microcytic anemias
What is MCV?
Mean corpuscular volume: measure of the average volume (size) of individual RBCs in a population - Used for morphologic classification of anemias - Childten have it lower because they are children
What is Hb count? How is it measured? What may interfere with this?
Measured by colorimetric/photometric method; increased levels of lipid, proteins, WBCs may interfere with measurement.
What is a sign of megaloblastic in anemia (specifically in the WBCs)
Megaloblastic anemia has hypersegmented nuclei -- >5 lobes
Describe Aspirin's pharmacokinetics
Metabolism -- hydrolysis to acetate and salicylate Salicylate is a competitive, reverisble inhibitor of COX
What is the source target for CRP (C-reactive protein)?
Microbial membranes, Complement activation, opsonization.
How does microcytic hypochromic anemia occur?
Microcytic hypochromic anemia comes from iron deficiency and leads to reduce production of hemoglobin in erythroblasts. Cells appear smaller and pinkish not red. Note: iron stimulates production of heme and hemoglobin in erythrocytes.
What is Microcytic Hypochromic anemia?
Microcytic: small Hypochromic: low color - Low to normal hematocrit - RBCs are smaller than normal and appear pink to white - Less hemoglobin and/ore heme synthesis in reticulocytes
Describe the mixing study?
Mixing studies can be donw on any patient who has a prolonger PT or PTT by mixing half patient and half normal blood and measuring PTT. If studies correct, it is a sign of a factor deficiency. IF they don't, you have an inhibitor You only need 30-40% factor level required for normal aPTT
How common is vW disease? What is vWF?
Most common inherited bleeding disorder vWF is a huge molecules that bindds to platelets to exposed subendothelium, carrier for factor 8, increasing factor 8 half life like 5 fold. Defect/deficiency leads to mucocutaneous bleeding. Not only does it increase the half life of factor 8, it also helps bind platelets to exposed collagen
How is the iron in the body distributed?
Most of it is in hemoglobin Hemoglobin - 65% Myoglobin - 10% Storage (ferritin - 25% Heme-enzymes -1-5% total body iron
Where does most of the RBC turnover occur?
Most of it occurs in the spleen and they are devoured by endocytic macrophages. h
What is the proposed mechanism for TRALI? What can we do about it?
Most often due to HLA - human leukocyte antigen (the antibodies that are used to identify own cells, but if the donor has their own HLA antibodies against your own body, it can cause blood vessel lining damage) -These prime recipient neutrophils and trigger an inflammatory response -Accumulation of activated neutrophils in lungs with microvascular occulusion, endothelial damage, and capillary leak - Mitigation: plasma/platelets only collected from men, women who have never been pregnant or women who have been screen for HLA antibodies
What is a protein C or S deficiency? How common is it?
Much less common than FVL Activated protein C inactivated factor 8a and factor 5a Protein S increases rate of inactivation of APC several fold. Deficiency leads to increase in clotting risk by 8-fold
For platelet dysfunction or low platelet count what kind of bleeding will you see?
Mucosal bleeding: petechiae, easy bruising, heavy menstrual persiods, abnormal bleeding time *YOU WILL NOT SEE MUSCLE OR JOINT BLEEDING* -- this is for hemophillia patients
How do you tell the difference between myelocytes and erythroblasts
Myelocytes have more abundant, granular cytoplasm compared to intermediate erythroblasts.
What are the neuropsychiatric features of cobalamin deficincy?
Myelopathy: - posterior columns (ascending fibers) - sensory disturbances, - incoordination (legs); ataxia, - Diminished vibration, position sense -Lateral columns (descending fibers) weakness, spasticity
What are the acquired disorders of Platelet function?
Myeloproliferative disorders (in bone marrow) Myelodysplastic syndrome (in bone marrow) Dysproteinemias AML Uremia (renal dysfunction = platelet dysfunction) Acquired Von Willebrand's disease Acquired storage pool deficiency Drugs: aspirin, NSAIDs, protacyclin
What are the symptoms that can cause arterial and venous clotting?
Myeloproliferative neoplasms -- DIC -APLS
Compare the structure of myoglobin, alpha and beta globin proteins. What is the globin fold?
Myoglobin, alpha and beta proteins are structurally identical. Globin proteins = I The globin fold is a highly conserved structure with 8 alpha helical domains and a hydrophobic heme binding pocket.
So what actually happens in the bohr effec ?
N terminal NH3+ (postive) is reversibly converted to a COO- (negative). This forms 4 additional salt links, one on each alpha and beta.. the deoxy form is further stabilized allowing the delivery of more O2 to metabolizing tissues. The carbamoylation is reversible in the lunds allowing Hb to give off CO2, hence Hb can be considered to be a CO2 transporter as well.
What is the anictode for aspirin? How does this work?
N-acetylcysteine (Mucomyst) is the antitode. It couples with reactive metabolite to be excreted (because it didn't take te normal glucoronidate path)
Are plasma anti ABO antibodies naturally occurRing or aquired?
NATURALLY OCCURRING! Antibodies made in first 6 months of life. Only blood group system where antithetical antibodies predictably present (i.e. you don't need to be exposed to foreign blood to develop antibodies)
Does evidence support low-dose aspirin in healthy individuals without CV risk factors?
NO - brain/GI bleeding risk main concern
Do the same prostanoids dominate all cells?
NO! Enzymes are expressed in a cell-specific manner: certain prostanoids dominate in different cells.
Should you give someone with the alpha thal-trait iron?
NO! It will look like an iron deficiency but it is not
Is the lamina of the lymphatic capillary continuous?
NO, it is a discontinuous basal lamina -- no zona occludens
Is endothelium just a physical barrier? What is the vascular response to vessel injury? How does this happen?
NO, it is also responsible for release of many proteins. At site of vesssel injury, there is a release of locally active vasoactive agents such as endothelin that result in vasoconstriction at the site of injury therefore leads to reduced blood flow? -- First thing is vasoconstriction--
Is iron deficiency anemia a diagnosis in itself?
NO, it is caused by an underyling problem. We don't just lose iron, we conserve it (normally), expcet from the shedding of epithelium/GI/etc.
Can Fondaparinux cause Heparin induced thrombocytopenia (HIT)?
NO, it is so small that it cannot cause HIT, it can be used to treat this (the other heparins cannot be used)
Does anticoagulation dissolve a blood clot?
NO, it thins the rest of the blood to stop the clot from expanding, prevents PE and reduces the risk of recurrent thrombosis. The clot is dissolved by body's natural systems
Do steroids treat the underlysing disease?
NO, steroids do not prevent or suppress the underlying disease process that results in inflammation... but they can suppress the inflammation associated with multiple inciting events.
Do NK cells usually eliminate the virus?
NO, they can control viral replication but do not usually eliminate the virus. T cells help out a lot
Do you need to screen every woman prior to pregnancy or OCP use.
NO? Only if strong family history
What is the receptor location, target (source), and effect of NOD family receptors?
NOD+ family receptors (intracellular) Target: Bacterial cell wall components Effect of recognition: induces innate responses
Was INR designed to be predictive of bleeding?
NOPE, but sometimes clinicians do it anyway (*what's new*)
When is a CBC indicated?
NOT indicated as a screening test in health or mildy ill patients during routine exam or during routine pre=operative testing - DO NOT do repeat testing in stable hospitalized patients - May be indicated in patients with history and physical indicating suspicion of anemia (low RBC) or thromboxytopenia (low platelets) or leukopenia (low WBC) - May be indicated in patients if suspect serious infection (but not very sensitive or specific for infection), or other systemic inflammatory disease
Should you take NSAIDs to prevent gastric cancers?
NSAIDs do help prevent incidence (because reduce inflammation) but the side effect of long term NSAIDs are not worth it.
What are the innate-like lymphocytes? Why are they called as such?
Natural Killer Cells! They act quickly and use broad patterns, they also don't have memory, their response wont change in subsequent infections -- all sounds like innate! -- makes sense why they are called natural killers! BUT they are in the lymphocyte lineage so we call them innate like
What are the three categories of porphyria that we were taught?
Neuro-psych, cutaneous, mixed
What are the specific symptoms of B12 deficiency causing anemia?
Neurologic complaints, Red swollwn tongue, certain neurologic signs
Will neurological changes in b12 deficiency always be accompanied by anemia?
Neurological changes in B12 deficiency may occur without anemia; reversal of changes with Rx is variable.
What happens when the neutrophil catches the microbe?
Neutrophils (like macrophages have broadly specific receptors for microbial molceular patterns (Pattern recognition receptors))
What are the white blood cells present in the blood?
Neutrophils, monocytes, lymphocytes These may also be present in the tissues though
Do platelets have DNA? What about a nucleus? What about proteins?
No DNA, No Nucleus BUT Yes to Proteins!: structural, granule (stored), Glyoproteins, Enzymes
What is the red top tube for?
No anticoagulant, and is used to analyse serum components (e.g. electrolyte levels, proteins/enzymes, lipids)
What is the mitigation strategy for TRALI (how do we prevent it)?
No plasma platelets from females who have been pregnant (unless HLA antibody screen is negative) maternal directed donations may cause hemolysis or TRALI due to maternal antibodies.
What is unique about acetaminophen?
No strong anti-inflammatory activity!... but can result in liver failure
Can you just give people with a factor 8 inhibitor factor 8? What should you use?
No you can't because they have an antibody -- you can try to give a steroid to suppress the antibody if they don't have hemophillia Use bypassing agents: FEIBA , NovoSeven
What is unique about Naproxen?
Non selective NSAID with 14hour half life!
Does all hematopoetic development happen in the same place in a lifetime?
Nooo! Initially it occurs in the yolk sac and then the liver and spleen, then the bone marrow at later stages of fetal development
Is routine monitoring required for Oral Direct Acting Inhibitors (Rivaroxaban, Dabigatran)? What is an adverse effect?
Nope! Routine monitoring not required, they have a predictable response. An adverse effect is bleeding
What are the categories when evaluating bleeding disorders using PT and PTT?
Normal PT and PTT, isolated prolonged PT, isolated prolonged PTT, Prolonged PT and PTT.
What is the normal platelet count? What will you see in terms of bleeding in different counts of platelets?
Normal platlet count is 150 000-400 000/microL Prolonged bleeding can be seen when levels are less than 100 000 If platelets are less than 50 000 concern of bleeding with surgery If platelets are <10 00 then you will have a concern for spontaneous bleeding
What is normocytic normochromic anemia?
Normocytic: right size, Nomochromic: right color Amemia -- just not enough - Low hematocrit -- not so many RBCs (<40%) - RBCs of normal size and hemoglobin content - Can arise from hemolytic anemia - can arise from excessive bleeding/ blood loss (even from heavy menses)
Is there inhibitor of aldosterone of ACTH secretion?
Not really, unlike cortisol, aldosterone levels are really low.
What is the reuslt in prothrombin gene mutation?
Not what you would think! IT increases prothrombin levels by 30%
Unfortunately you cannot put pics on this side but know what these labels mean
Notice hassell's corpuscle is the distinctive feature (i.e. how you can tell that this is not the spleen)
What does the globin chain switching look like from fetus to adult?
Notice that gamma and beta are somewhat reciprocal. You are also making small amounts of delta hemoglobin
The other side of the card shows a gross speicimen of appendicitis
Notice that green shit on the surface -- this is the fibrinous exudate!, It is on the surface because htere is so much fibrin build up!
What is more potent? Omega 6 or Omega 3 eicosanoids?
Omega-6 is more potent in terms of inflammatory activities.
What is the laboratory criteria for APLS?
One or more of the following present on two occasions, at least 12 weeks apart: lupus anticogulant, beta 2 glycoprotein, anticaridolipin
What is the alpha thal trait?
One or two genes nonfunctional (remember there are 4 in general) -equivalent in symptomolgy as beta minor -without symptoms or mild symptoms
32 year old woman with signs and symptoms of anemia. What is the first thing you need to know?
Order a CBC, she is low 10 g/dL and reference 12-16 Why does she have anemia. Wither you bone marrow isn't making enough rbc or they're getting destroyed after being made
Desribe the third step in heealing and repair.
Organization - proliferation of 3 major cell types: forms provisional "granulation tissue" (temporary) Activated macrophages --> growth factors induce prolideration of endothelial cells and fibroblasts Endothelial cells - proliferate in response to VEGf, FGF, TGFb --> to develop new arterioles, angiogenesis (neovasculatization Fibroblasts - proliferate in repsonse toin respose to FGF, TGFb
How do NK kill?
Originally identified as cells that spontaneously kill certain tumor targets without prior immunization. Killing is mediated by release of lytic granules Kill host cells infected with intracytoplasmic pathogens (esp. viruses) Produce cytokines that regulate immune response.
What is the process of transporting oxygen and CO2 through RBC?
Oxygen binds to heme iron (Fe 2+) - Carbon dioxide forms carbamino-hemoglobin by binding to the N-terminal amine groups of all 4 globin subunits (2 alpha, 2 beta) - Hemoglobin also acts as a pH buffer by transporting H+ (Histidine) - Hb adopts two stable conformations: oxy-Hb (lungs) and deoxy-Hb (deep tissues)
What is found in platelet Plasma membrane?
PF-3 (receptors for clotting factors and aggregating agents)
What is the function of COx-2? How is it expressed? How is it related to cancer?
PGH synthase - expression is induced by "stress", growth factors, cytokines, and inflammatory mediators - Major source of prostanoids at sites of inflammation (cancer). -- you see chronic inflammation here -- so they are thinking it can be drug target
What are Granular leukocytes?
PMNs (poluymorphonuclear) - Neutrophils, eosinophils, basophil
A patient is not on any medication. They have a prolonged PTT that did not correct? What is the most likely cause?
PTT did not correct so either antibody (8,9,11), heparin, or lupus anticoagulant. They are not taking any medication so not heparin or lupus. Factor 8 antibody is the most common! so it is this one :)
What are the general signs of anemia>
Pallor (pale) - Hypotension - Tachycardia - Systolic murmur
What are prostagladins?
Part of eicosanoid family. They induce dialation as well as increased permeability of blood vessels at the affecte sites (resulting in local accumulation of blood, plasma proteins and fluid --> redness, heat, and swelling.
what is thrombosis?
Pathological blood clotting ("hemostasis in the wrong place)"
what is the intervention from birth to 6 years for a patient with SCD?
Penicillin prophylaxis, conjugate pneumococcal vaccine -aggressive evaluation of fever: ED evaluation/treatment, liberal hospitalization for IV antibiotics.
List three examples of pathogen associated molecular patterns
Peptinoglycans, since stantard or double stranded ma, mannose (sugars), lipopolysaccaride, flagelin
What is the WBC differential?
Percent and concentration of individual white blood cell subset
What are the proteins in granules released by NK cells and what are their actions on target cells? How does this compare to the molecules used by cytotoxic T cells to kill target cells?
Perforin = polymerizes to form a pore in target membrane Granzymes: serine proteases- activate apoptosis once in the cytoplasm of the target cell Same molecules are used by cytotoxic T cells to kill target ells.
How do you assess bleeding clinically?
Personal bleeding history, medication use, family hx bleeding
What are macrophages?
Phagocytic cells with anti-microbial function. Also important for producing cytokines that regulate immune and inflammatory responses. Also pay an important function during tissue repair and wound healing.
How does the macrophage look like? What does it do?
Phagocytosis and activation of bacterial mechanisms - Antigen presentation - Cytokine production, regulation of inflammatory responses (including healing)
How does a neutrophil (PMN, polymorphonuclear) look? What is their activated function?
Phagocytosis and activation of bacterial mechanisms Circulate in blood and migrate to tissue sites
What are the 4 steps in phase II of acute inflammation? What are the major effector cells of acute inflammation?
Phase II - cellular response Neutrophils are major effector cells of acute inflamamtion. 1. Marginate and roll 2. Adhere to EC 3. Transmigrate through EC gaps 4. Move to site of injury along chemoattractant gradient
How does calcium get released into the cytoplasm?
Phospholipase c-gamma1 cleaves phsophatidyl inositol (PIP2) into inositol tris phosphate (IP3) and diacyl glycerol (DAG) IP3 induces a calcium release from endoplasmic reticulum which promotes opening of extracellular calcium channels
what are the inherited disorders of platelet function?
Plasma membrane defects: Glanzmann's thrombasthenia, Bernard Soulier Syndrome Storage pool disease: decrease or absence of dense granules diminished or absent second wave aggregation to most agonists. alpha granule deficiency (grey platelet deficinecy) diminished response to epi, ADP , collagen Von willebrand's disease
How does an incorrect plasma to anticoagulant rate (in the tube) cause incorrect results?
Plasma to anticoagulant ratio should be (9:1) altered with very high or very low hematocrits (greater than 55% or less than 25%) -- need to be in this range
What is the natural selection for sickle cell trait? Name of organism?
Plasmodium falciparum --> the protozoan parasite causing malaria! This organism needs to develop isnide human RBCs/ Humans with sickle cell trait, one good WT gene and one mutated beta-globin gene (E6V = glu-beta #6 val), can still form polymeric hemoglobin under extreme anaerobic conditions but polymerization of deoxyHbA/S is somewhat limited and asymptomatic... it forms clumps of HbS rather than long fibers. BUT.. it does shorted life span which reduces p.falciparum viability
How does primary hemostasis (platelet defects) look differently from secondary hemostasis (coagulation disorders)? compare general bleeding patterns, excessive bleeding after minor cuts, petechiae, ecchymoses (bruising), Hemarthroses (joint) and muscle bleeds, Bleeding with invasive procedure
Platelet defects (primary hemostasis): General- Primary: mucocutaneous bleeding: overal cavity, nasal, GI, GU Secondary: deep tissue bleeding: joints and muscles Excessive bleeding after minor cuts: Primary: yeee seconday: nah (you can form the initial clot!) Petechiae: Primary: common, seconday: nope! Ecchymoses (bruising): primary: small and superficial Secondary: large and subcutaneous and soft tissue hematomas Joint (hemarthroses) and muscle bleed: Primary = uncommon, seconday: common in sever deficiency or with injury in mild/moderate factor Bleeding with invassive procedures/ surgeries: Primary: immediate Secondary may be immediate or delayed.
What is Polychromasia?
Polychromasia (also known as polychromatophilia) is a disorder where there is an abnormally high number of immature red blood cells found in the bloodstream as a result of being prematurely released from the bone marrow during blood formation
What are the pathological problems with Hb-S?
Polymerized Hb-S drives structural change in RBC membrane structure; very fragile... tends to block vessels (pain and localized ischemia). Sickle cells tend to rupture in capillary beds due to stress on membrane cytoskeletal system, causing anemia. Released hemoglobin protein and heme prophyrin ring structures cause blocked/ reuced kidney function and toxicity in both kidney and liver.
What are the sites for bone marrow biopsy? Are they population and specimen specific? If so, how?
Posterior, superior illiac spine -Sternum (aspirate only!) - Anterior tibia (young children)
What does pre-hepatic jaundice indicate? What about hepatic jaundice? What about post-hepatic jaundice?
Pre-hepatic jaundice indicates events in the blood stream; the major cause would be various forms of hemolytic anemia Hepatic jaundice signifies events in the liver, such as the various types of hepatitis or other forms of liver disease (e.g., cancer). Post hepatic jaundice refers to events in the biliary tree, for which the major causes are obstruction of the common bile duct by a gallstone (biliary calculus) or by cancer of the head of the pancreas.
What do the lymphocytes look like? What are they used for?
Predominately associated with lymphoid tissue, but some in tissue and some will also migrate to inflammatory sites upon activation. Critical for "adaptive" immune response.
What is preeclampsia? How many does it affect? What is the treatment? What can it result in?
Preeclampsia is a condition during pregnancy where there is a sudden rise in blood pressure and swelling, mostly in the face, hands, and feet Happens to 5-15% of all pregnancies It can result in Thrombocytopenia in 15-50% of patients. the treatment is immediate delivery
What are the sites of developmental hematopoiesis?
Prenatal: AGM + Yolk Sac --> Liver + spleen BIRTH! --> Bone marrow
What are basophils?
Present in lower amount in WBC differential (around 1% of WBC). Associated with allergic inflammatory responses. Intracellular granules contain histamine and cells function similarly to mast cells when migrate to tissues.
What does the card on the other side show?
Primary hemostasis
What conditions do you think of when you have a normal PT and PTT?
Primary hemostasis problem: - Thrombocytopenia (most common bleeding disorder) - Qualitative platelet defect (normal # but something wrong with them) - Von Willebrand disease (most common inherited bleeding disorder) secondary hemostasis: Factor 8 deficiency, rare vascaulr problem: vascular purpas
What are the primary organs of the lymphatic system? Why are they primary?
Primary lymphoid organs: Bone marrow and thymus. They are primary because these are the organs producing and maturing cells.
What is Hematopoiesis?
Process by which blood cells are produced and released into the peripheral blood
So, putting the intrinsic, extrinsic, and common pathway together. What starts first? How do they interact (besides the common final pathway)
Process starts with the extrinsic path when the TF is released from the subendothelium. TF does the following: - converts F10 -> F10a - - F9 -> F9a (this has the ability to activate a small amount of prothommbin to thrombin) The initial thrombin burst is sufficient to cleave F8 from vWF and help activate F9 and F11. Therefore, extrinsic path help start extrinsic path.
What is the hallmark of an inflammatory response? What are common clinically used biomarkers of an inflammatory response.
Production of *acute phase proteins* is a hallmark of an inflammatory response. CRP, fibrinogen are common clinically used biomarkers of an inflammatory response.
How does TPO affect progenitor, megakaryocyte, and platelet cells respectively?
Progenitor: TPO results in these cells producing more megakaryocytes Megakaryocytes: TPO results in these cells producing more platelets Platelets: Platelets internalize it but there is no biochemical effect. Just helps to regulate how much free (active) TPO there is.
What are the symptoms of hemophillia?
Prolonged PTT. Normal PT. - Hemarthritis -- Present first year of life (when baby starts to walk) -- Knees and elbows > ankles > shoulders > hips --Without preventative treatment, leads to total joint destruction requiring replacement - will see massive muscle bruises, mucocutaneous bleeding, -intra-cranial bleeds (including neonatal period) - Post dental bleeding post surgincal bleeding (can be delyaed by days) *NOT* after minor cuts or abrasions
What does the megakaryocyte erythroid progenitor differentiate into?
Promegakaryoblast which them turns into the immature, mature, and finally, late megakaryocyte
How does fever act as a systemic sign of acute inflammation?
Prostaglandin and IL-1 Effect thermoregulation by the hypothalamus, associated with increased pulse rate.
Soluble factor produced by macrophages promote recruitment of additional cells to the inflammatory site. Which of the following factors is LEAST directly involved with leukocyte recruitment? A. Prostaglandins B. TNF-alha C. IL-8 D. IL-12 E. Leukotrienes
Prostaglandins and LT both play a role in vasoilation and expression of adnesion, same with TNF-alpha. IL-8 recruites neutrophils to site. We didn't really talk about IL-12, this is the answer
Why can inhibition of prostanoids (COX path) lead to beneficial and adverse effects?
Prostanoids carry out a diverse array of biochemical functions!
What is the heparin Anagonist?
Protamine Sulfate Arginine rich, extremely +ve, Ion pairs with heparin to make inactive complex Short heparin chains don't make complex
What does the CD19 mean in the CD nomenclature?
Protein expressed by B lymphocytes. If a cell is CD19+, it is a B cell.
How do you measure bleeding time? Why would it be elevated?
Pump BP cuff to 40mm, making a 1cm cut 1 mm in depth, blotting every 30 seconds until bleeding stops Normal is less than or equal to 8 minutes It can be elevated either because: platelets aren't functioning properly, or Thrombocytopenia
If there is failure to respond to iron therapy for iron deficient anemia, what can you do? What comes first, the symptomatic improvement of increase in Hb?
Question diagnosis, compliance, associated illness, ongoing blood loss and malabsorption -symptomatic response preceds increase in Hb; retic count increased after 5-10 days of Rx - Usually the Hb returns to normal after 2 months of therapy -Continue therapy to replenish iron stores
What do macrocytic anemias encompass? What is the difference?
RBC MCV >100 fl IT encompasses both megaloblastic and non-megaloblastic anemias. The term megaloblast refers to the characterisc bone marrow RBC precursors with specific chromatin changes; impaired DNA synthesis. Therefore, Megaloblastic = changes in BM Non-megaloblastic anemias do NOT have impaired DNA synthesis and RBC precoursors are normal
What are RBC called a histological ruler? What is their size?
RBC can be used as a measure toll for looking for other cells. usually 6-8um long
What may falsely elevate the MCV?
RBC clumping may falsely elevate the MCV, also dehydration (increase), and hydration (decrease)
What is the main protein component of RBC and what is the function of this?
RBCs contain mostly hemoglobin (Hb) as a major protein component (95%). Hemoglobin (HB) can carry both oxygen and carbon dioxide through the circulatory system
What is an important mechanism for neutrophil killing?!
ROS production
What is the function of rac and rho?
Rac and rho also regulate cytoskeletal changes. This is important for regulating cell-cell interaction and for cell migration and movement.
What is the function of Ras?
Ras promotes MAP kinase (e.g. ERK) activation and activation of transcription factors (e.g. AP-1)
What are examples of small G proteins? How are they regulated?
Ras, rac, rho Regulation by guanine nucleotide exchange factors (GEFs) and GTPases
What is the calculation for the corrected reticulocyte count?
Raw reticulocyte % x (patient's hematocrit/ mean normal hematocrit)
when do you not screen VTE pts?
Recent major surgery/trauma/immobilization - active malignancy - central line associated - SLE, IBD, MPN, HIt - Retinal vein thrombosis - Upper limb VTW - asymptomatic women undergoing fertility tx - Women with prior pregnancy complication (don't screen until numerous issue)
What should you do to avoid glucocorticoid withdrawal of therapy?
Recovery accomplished by slowly tapering the dose!
Which immune cells involved with acute inflammation are recruited? Which ones are constitutive in tissues?
Recruited: Neutrophils Constitutive: Macrophages, Dendritic cells
What is RDW?
Red cell distribution width: mathematical expression of the degree of variation in the volume (size) of individual RBCs in a population,
What are the approved indications for direct inhibitors (factor 10a and 2a)?
Red clot AF not due to mechanical heart valve (MHV): (MHV: increase stroke/MI in Dabigatran trials) Tx/PPx of DVT/PE
What is a red clot? What abotu a white clot? How do you treat them?
Red clot is predominately RBC and fibrin Tx: anticoagulants White Clot is platelets and fibrin Tx: Antiplatelets (+ or - anticogulants)
What is the definition of anemia? How is it measured?
Reduction in the total circulation RBC mass, which results in reduction in the oxygen carrying capacity Decrease in hematocrit (packed RBC volume), hemoglobin concentration, and/or RBC count.
Describe the second step in the healing and repair process
Regenreation of native tissues - Activated macrophages --> products that promote healing growth factors (EGF, HGF, TGFa) that induce proliferation of epithelial and other native cells capable of mitosis - Remaining tissue must be able to support recovery: architecture sufficeintly preserved to provide strucutre, tissue resources (blood flow, oxygen,...) sufficient to allow for recovery of native cells.
Why are children with sickle cell disease at risk for cognition abnormalities?
Related to CNS involvement: - Stroke (CVA), - Silent stroke
What are the general tests for hemolytic anemias?
Release and degradation of hemoglobin: -serum haptoglobin (low = hemolytic anemia) -plasma free hemoglobin - urine hemoglobin -urine sediment hemosiderin - serum conjugated (indirect) bilirubin -Urine urobilinogen Other: serum lactate dehydrogenase -LDH(is high in hemolytic anemia)
What do mast cells look like? What is their activated function?
Release of granules containing histamine and active agents tissue resident cell. Associated with allergic inflammatory responses.
Remodeling of scar occurs in the late wound organization in granulation tissue. Explain this process.
Remodeling of scar: requires metalloproeinases (An-dependent collagenase, stromelysin) produced by macrophages and fibroblasts, regulated by TGF-beta - induced inhibitors (TIMP)
What is the therapy for TTP
Removal of antibody and clearance of multimers (vWF) Plasma exchange (plasmapheresis) -- plasma is removed and exchanged with someone else's plasma Additional therapy: ASA, steroids
Describe the first step in Healing and repair.
Removal of edema and debris, lymphatics absorb edema, macrophage phagocytosis removes cell and tissue debris.
What is washing? What is the purpose?
Removal of plasma from cellular blood products. Purpose: prevent hyperkalemia in pediatric pathiest, reccurent allergic reaction or IgA deficiency, remove incompatible antibodies
What does resolution of inflammation mean?
Resolution is an active biological process and it requires decreased production of prostaglandins and leukotrienes and synthesis of anti-inflammation and pro-resolving lipid mediators.
What are the adenoids (pharyngeal tonsils)?
Respiratory (pharyneal -- makes sense!) - Ciliated pseudostratified epithelium -Incompletely encapsulated -no crypts
Describe the structure of reticulocytes. When are they released into circulation? How long does it take? What is the lifetime of RBCs? What drives this processes?
Reticulocytes have no cellular organelles but retain ribosomes to maximized hemoglobin synthesis. These cells are released into circulation where they mature into RBC. The whole process takes about 1 week. RBCs have a lifetime of appx 120 days EPO dries this provess
What are the drugs that block GP IIB/IIIA receptor? What is the mechanism?
Reversibly block GP-11b/IIIa binding to: Fibrinogen, vWF, other adhesion molecules
What is the Rh system? What is RhD negative? Why do we routinely type for RhD? Why is anti0D dangerous.
RhD negative person has no naturally occurring anti-D D antigen highly immunogenic Routinely type for RhD and transfuse RhD negative red cells to RhD negative patients to prevent them from forming anti-D Anti-D is clinically significant antibody and is a major cause of hemolytic disease of the fetus newborn
So is the NK in adaptive or innate immunity? What is its role?
Role of NK cells in innate immunity Clearance of intraceullar pathogens (like viruses) by killing host cells!! Containment!! Also associated with tumor immune response.
What protein allows the neutrophil to roll on the endothelial surface? What allows it to adhere? What about transmigration (moving b/w the endothelial cells)?
Roll: selectins on the endothelial surface bind to Sialyl-Lewis X receptors Adhere: Beta1-2 integrins (LFA, MAc-1) bind to VCAM-1 or ICam-1 on endothelial Transmigration: Beta1-integrins bind to PECAM
What temperature are platelets stored at? What is their shelf life?
Room temp! (20-24 C) -- can be an issue because much higher risk of bac. growth Shelf life: 5-7 days
Compare the Serum Iron, TIBC, S. Ferritin, and sTFR (transferrin --transports iron) levels in iron eficiency and anemia of chronic disease
S.iron: both low BUT THEN TIBC: Iron def. = high, ACD = low S.Ferritin: Iron def = low, AC = high sTFR = Iron def: high ACD: low
How does the endothelial function to modulate vascular resistance (BP)?
Secretion of vasoconstrictors: Endothelin, Angiotensin converting enzyme (ACE) Vasodilators: NO, prostacyclin
What population of people are beta thalassemias seen in?
Seen in Italians, greeks, arabs, blacks
What happens to leukocyte trafficking during normal circumstances (when no inflammation)?
Selectin-mediated adhesion to leukocyte sialyl leqis is weak, and allows leukocytes to roll along the vascular endothelial surfacy -- leukocytes will not leave the blood.
What are the different types of exudates of inflammation?
Serous: -clear, few cells -fluid Purulent (supportive) - pus: cell rich (PMNs and necrotic tissues, common with bacteria, Empyema - within a body cavity Fibrinous- fibrin-rich, common in serous sacs (pleura,...) Mucinous: mucin-rich, common in mucinous epithelial Sangunious (rich in blood): hemorrhagic, common with necrosiis
Which is more reliable, serum or RBC folate levels?
Serum folate is labile, reflects recent intake Low serum RC folate concentration
What are iron studies?
Serum iron, TIBC, serum ferritin
What is used to analyze "chemistries" or "metabolic" panels?
Serum is usually used It has a bunch of ish - electrolytes (Na,K, Cl, HCO3), BUN, creatinine, glucose etc.
What are the studies for megaloblastic anemias?
Serum vitamins B12 (cobalamin) (goof reflection of B12 stores) - Serum and RBC folate, serum level is a good measure of folate stores, but may be LABILE; RBC level may be better measure of total body stores. - Intrinsic Factor Blocking Antibody : positive in about 75% of patients with autoimmune pernicious anemia, high specificity, when positive in patient with low serum B12, diagnostic of autoimmune pernicious anemia
When should platelets be transfused? When should they not be transfused?
Should: Treat thrombocytopenia, platelet function disorders Shouldn't: Pre-procedure prophylaxis to prevent serious bleeding, expand intravascular compartmen.
What does the photo on the other side of the card show?
Shows a bunch of platelets -together
How is signal 2 regulated?
Signal 2 is regulated by the microenvironment because expression of B7 usually requires the APC to receive some kind of activation signal either from pathogen itself or another T cell, or some other inflammatory stimulus
What are eosinophils?
Similarly to neutrophils (but fewer in number), circulate in blood and migrate to tissues during certain kinds of inflammatory responses. especially associated with alergic patterns of inflammation to provide host response to eukaryotic parasite (e.g. worm) infections
Where does the energy production in the RBC stop? Do RBC's need the enzyme Lactate dehydrogenase? why? What happens to the lactic acid produced.
Since RBCs have no mitochondria, energy metabolism stops at the end of glycolysis, *pyruvate*. RBCs do contain LAD, which converts pyruvate + NADH --> lactate + NAD+. This NADH is the source of reducing power for voncersion of met-Hb (HbM) back to HbA. LAD is also a method for the regeneration of Oxidized NAD+ so that RBc glycolysis may continue glycolysis at the G3PDH stage (this needs it). Lactate is lost from the RBC to circulation, it is pucked up by the liver, and is subjected to gluconeogenesis to resynthesize glucose.
Why is maintenance of the "folate pool" critical to single carbon metabolism?
Single carbon metabolism engages carbons of three oxidation states; formic acid, formaldehyde and methanol. These are toxic so they are handled by a carrier, tetrahydrofolate (THF)
Are sinusoids found in Bone marrow? What is their function?
Sinusoids are commonly found in hematopoietic tissues and are discontinuous type of vasculature with opn pores that allow the exchange of gasses and nutrients
How many hemoglobins are produced?
Six normal hemoglobins, three in adult life, all are tetrameric structure
What are the 4 things in a peripheral blood smear examination that describe RBC morphology?
Size, Hemoglobin concentration, Number of immature RBC, shape
What are the medullary cords and medullary sinus?
So obviously we are talking about the medulla. Cellular processes of supporting reticular cells span the spaces of the meullary and other sinuses in the node. B-cells, macrophages, and plasma cells may all be found in the medullary cords and surrounding tissues.
What is the purple (lavender) tube top for?
Sodium EDTA as an anti-coagulant and is mostly used to analyze cellular components of blood (e.g., complete blood count)
Why are there residual risks when transfusion despite all the of the steps we take beforehand?
Some tests have limitations If someone is tested right after exposure, levels may be too low to be detected (window period!) Residual risk depends on the test sensitivity. Some tests have a longer window than others
What is found in platelet specific alpha granules?
Specific alpha granules: growth factor, fibrinogen, factor V, vWF, fibronectin, B-thromboglobulin, PFR, thrombospondin
How is folate deficiency related to spina bifida?
Spina bifida is a neural tube defect in developing fetuses. Women of child bearing year, and especially those trying to become pregnant should assure adequate folate in their diets (fresh leafy greens, enriched grain). This is especially true for the first trimester. Many women do not know they are pregnant and by the time they find out it may be too late for diet modification, which could lead to an increased chance of neural tube defect
What are the stages of iron deficiency? What are the trends of this?
Stage I: prelatent Stage II: Latent Stage III: Anemia As you move from stage I to stage III, s.ferritin decreases, then you lose BM iron, and you become symptomatic
What are the three components of hematopoiesis?
Stem cells, growth factors, and microenvironment
What are the ways that the RBC that are damaged are removed from circulation?
Still an active area of research: one hypothesis --> When you change the shape of the RBC, this causes the RBC to get stuck in the fenestrae, this is how they get out of the system another hypothesis: as the RBC ages, it will express some sort of antigen/protein which will cause it to get into the fenestration to die
What is the function of thromboxanes (AX2)?
Stimulate platelet aggregation, clot formation and thrombosis.
How is cryoprecipitate stored ?
Storage (freezer): up to one year After Thaw: only 4-6 hours!!
How is plasma stored? How long is its shelf life?
Storage: freezer! (good to be frozen for a year) BUT after it thaws it will only last for 5 days
What are the symptoms of anemia based on?
Symptoms depend on severity of anemia, rapidity of delvelopment and cardiopulmonary status of patient.
What are the clinical manifestations of iron deficiency?
Symptoms of anemia (previously discussed) -pica-craving for peculiar food or non-doof substances e.g. ice, dirt, chalk - restless legs -koilonychia - spooning of nails - Dysphagia, esophageal web (plummer vinson or patterson-kelly Sx)- very rare
What is the diagnosis for Pulmonary embolism? What are the symptoms?
Symptoms: pleuritic chest pain, SOB, tachycardia, cough Diagnosis: emergent --> send to ER for imaging
What is TACO? What about TRALI?
TACO = circulatory overload Transfusion-associated circulatory overload (TACO) is a common transfusion reaction in which pulmonary edema develops primarily due to volume excess or circulatory overload. TRALI = acute lung injury Transfusion-related acute lung injury (TRALI) is a serious blood transfusion complication characterized by the acute onset of non-cardiogenic pulmonary edema following transfusion of blood products
What is Tissue factor pathway inhibitor (TFPI)? How does heparin affect this?
TFPI inhibits 10a and TF:7a. It circulates at a low concentration. The concentration is increase when heparin is given though.
How is THF released from storage?
THF can only be released from storage form through the reaction that regenerates methionine from homocysteine - homocysteine methytransferase -- which happens to be one of the only two enzymes that required V12 With B12 deficiency, homocysteine is not readily reconverted into methionine and N5methyl-THF builds up. This acts as a folate trap in the liver resulting in diminished one carbon chemistry.
What is tetrahydrofolate used for?
THF is used for 1) purine synthesis 2) serine, glycine and methionine synthesis 3) the final step of thymidine synthesis
List two examples of pattern recognition receptors?
TLR, NOD,
What are the pro-inflammatory cytokines?
TNF alpha, IL-1: activate macrophages, induce selectins,... IL-1: fever IL-8: Chemotaxin for PMNs
What is repressed by glucocorticoids?
TNF and COx 2 are both repressed w/ GC
Does TNF play a role in inflammation?
TNF plays a central role in induction of inflammation - produced by macrophages, lymphocytes, NK cells, activates many cell types: macrophages, neutrophils
Which cytokine mediated Platelet differentation?
TPO -Thrombopoietin
What are the more serious (less common) transfusion reaction?
TRALI = acute lung injury due to neutrophil activation by donor antibodies TACO: cardiac overload due to rapid transfusion Sepsis (especially bacteria) -- screening process in place for platelets.
T/f: Leukocytes polarize in gradients of chemoattractants, then crawl to the source
TRUE
T/f: Macrophages are present before birth.
TRUE the cells derive from the yolk sac (or sometimes from fetal liver) they migrate to develop into tissue specific macrophages.
T/f: macrophage subsets can have different functions
TRUE, come are pro-inflammatory, some are anti-inflammatory
T/f: Sickle Cell disease is the most common genetic disorder in the US?
TRUE, they do universal newborn screen
T/f: bilirubin, being of minimal solubility, tends to accumulate in fatty tissues and tissues with poor perfusion
TRUEE
Describe how TF starts the clotting cascade?
Tf binds to Factor 7 (FV11) forming TF-factor7a (TF-FVIIa complex). This has the ability to convert a small amount of prothrombin to thrombin, resulting in a initial thrombin burst sufficent to cleave factor 8 from vWF and to generate an amplification loop through activation of clotting factors.
How does linked recognition explain the hapten-carrier concept?
The B cell receptor recognizes the hapten and then presents peptides from the carrier to the T cell. the T cell is then stimulated and provides "help" to the hapten specific B cell and hapten specific antibody is produced.
Where does the iron go when the RBC are broken down?
The Fe is released in the macrophage when borken down. It is then either stored in the macrophage as ferritin or it is released to circulation by ferroportin to bind with transferrin for transport to tissues with an iron demand.
What si the mean corpuscular hemoglobin concentration (MCHC) -- value? what does this mean? what does it mean for someone with sickle cell?
The MCHC: is 33%, -- this amount of hemoglobin is very near its solubility limit and barely stays in solution. A single mutation can generate sickle cell anemia -- which is quite literally, deoxy-hemoglobin precipitating out of solution.
Which chromosome is the alpha globin gene on? What about the beta gene?
The alpha globin is on chromosome 16 The beta is on chromosome 11
What are the anchoring filaments for in the lympatic capillary/blood capillary sac?
The anchoring filaments attach the endothelial cells of the lymphatic capillaries to the surrounding CT to prevent the lumen from collapsing (the luman is literally one endothelial cell
What can the appearance of jaundice be diagnostic for?
The appearance of jaundice can be diagnostic for hemolytic anemia, hepatitis bile duct obstruction, gallstones or, liver or pancreatic cancer.
what are the tissue requirements for complete healing?
The architectural structure of the tissue must remain. Native cells must have the capacity to regenerate No inhibitory factors to healing may be present including: persistence of the causative agent, poor blood supply, defects in leukocytes, protein deficiency, malnutrition, vitamin C deficiency - inhibits collagen synthesis, suppressed immune response or steroids (can't produce cytokines)
What is the bethesday titer? What will happen with a strong inhibitor?
The bethesda titer is when the lab makes serial dilutions of plasma from a patient from normal poo and then checks for factor 8 activity. Dilution of patient plasma that results in 50% factor 8 activity is defined as 1 bethesda unit The stronger the inhibitor, the more dilutions are required to get 50% activity.
What gives color to our wastes?
The bilirubin diglucuronide . This compound is very soluble and it is lost to the bile, the intestinal track, its associated bacterial processing, partial reabsorption and eventually run "out of town" through both the kidney and bowel. IT gives color to varios waste materials "pee yellow" and "poo brown - various intesnsities "
What happens if formed elements (clotting elements and platelets are removed)?
The clear supernatant free of clotting factors and formed elements (platelets) is serum.
What is the clotting cascade divided into? Whu are they names this? What are the PTT and PT?
The clotting cascade is divided into intrinsic and extrinsic. Which come together to form the final common pathway. Intrinsic is named as such because all of the components are already circulating in the blood. Extrinsic pathways requires at least one component from the tissue (the tissue factor) Extrinsic is measured by PT (prothrombin time) Intrinsic is measured by PTT time (Partial thromboplastin time)
What is the cortex of the lymph node diveded into? Why is this the case?
The cortex is divided into an *outer cortex*, in which are found *B-cell-dependent lymphoid follicles (nodules)*, and then an inner cortex or paracortex which is a T-cell dependent zone The lymphoid follices seen here are secondary or active folliclesm distinguished from primary or inactive follices by the presence of a pale-staining central region called the germinal center. .
What is the CD (cluster of differentiation) nomenclature system?
The different lymphocyte subsets (e.g. T and B cell subsets) are usually not distinguishable by morphologic examination. cell subsets are characterized by different patterns of protein expression, often using the CD nomenclature system. For example, this system is sued to characterize major types of lymphocyte subsets (T, B, and NK cells).
How do you tell the eosinophil lineage from the basophilic lineage?
The eosinophil lineage will have eosinophillic (red) granules, and basophil lineage will have large basophillic (blue) granules
Why are alpha thalessemias fatal? What about beta thalessemias
The expression of delta-globin can be enhanced to compensate for reduced levels of HbA1. Delta-globin can combine with alpha globin to make HbA2. Maintaining HbF and HbA2, can occur to offset HbA1 deficiency in beta thalessemias There is NO alternative globin for alpha-thalessemias. There, lethal
What are the steps in the extrinsic pathway? How is it really started?
The extrinsic pathway starts the cascade. It starts upon trauma, the subendothelium is exposed, which releases tissue factor which binds to circulating factor 7a this activates factor 10. Trauma also released TF. so trauma both changes F7 to 7a AND releases TF. Tf binds to small amounts of circulating 7a and this complex activates F10. This then goes into the final pathway.
Why is Histidine 146 important in the bohr affect?
The formation of one of the salt brides depends on the prescence of an added proton on histidine B146. The proximity of the negative charge on aspartate 94 favors protonation of histidine 146 in the deoxy state. This results in the estabilishing of two additional salt-bridges (one for each beta-subunit.
What is the function of MHC 1?
The function of MHC molecules is to bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T cells.
What is the function of the myoglobin monomers? What about the hemoglobin tetramers?
The function of myoglobin monomers is to function as oxygen storage proteins while hemoglobin tetramers function as oxygen transport and delivery proteins. On the graph you can see that myoglobin holds tightly to its bound oxygen until the partial pressure of oxygen in the tissues is extremely low [p50 = 1mm Hg for myoglobin], while hemoglobin has much less affinity for its oxygen load and releases oxygen at much high partial pressures of oxygen [p50 = 26 mm Hg for HbA]. This oxygen tension is fairly conserved win functionally operating tissues. It is the working oxygen pressure in most tissues... steady state dynamic equilibrium! Why the difference? Structure - Funciton!!
How are the gene clusters arranged on the chromosome? What is interesting about this?
The gene clusters are arranged in the order of their relative expression throughout embryonic growth and development. For example, - the alpha-globin gene starts out as a zeta globin in early fetus development and shifts to alpha-globin later in fetal development. This is maintained postnatally. -beta globin starts as epsilon globin and quickly changes into fetal gamma globin and then beta.
When does the healing response occur after inflammation?
The healing response occurs after acute inflammation reaches it's peak. Acute response beings in seconds, healing in hours or days
Describe the structure and function of the heme binding pocket.
The heme binding pocket lies between helixes E,F, and G. It consists of predominatly hydrophobic cleft to associate with the planar heme ring and two central histidines; one covalently binds to the Fe2+ in the heme (proximal histidine - f8_ and the other protect s the oxygen binding side of the heme Fe2+ (distal histidine- E7. these are important to the quarternary structure and function of Hb isoforms
What is hereditary thrombophillia?
The hereditary thrombophilias are a group of inherited conditions that predispose to thrombosis. Heritable deficiencies of the endogenous anticoagulants protein C, protein S, and antithrombin have been recognized for some years, but their prevalence, even among patients with familial thrombosis, is low
How long do liver stores of b12 last?
The liver normally stores months to years worth of B12. However, with elderly patients who are no longer motivated to maintain a reasonable diet, B12 deficiency can and does commonly occur.
What is the lower limit of hb for males and females?
The lower limit for males is 13g/dl and the lower limit for females is 12 g/dl
What are agranular (non granular leukocytes)? Are they really agranular?
The lymphocytes (T,B, NK) The monocyte no, all cells have lysosomes (granulars)
What is usually the largest cell in the bone marrow niche? What is the process that they use to get to their size? What do they give rise to?
The megakaryocyte! They grow this large because you have the cell cycle, but not cytokinesis (occurs about 7x to achieve the size). This process is called *endoreplication*. They give rise to platelets
What is the most severe complication for NAIT? what is the treatment for NAIT
The most severe complication is intracranial bleeding. 10-50% occurs in utero. Tx: infusion of washed maternal platelets -Antenatal Tx: early C-section, IVIg, prednisone, intrauterine platelets
What is the difference between hypocellular, normocellular, and hypercellular? What does this all mean?
The number of cells here. Notice we aren't really counting fat cells Hypocellular can happen if a person is fat or old Hypercellular is often seen in leukemia -- everything is occupied by cells.
What does an iron stain look like in a bone marrow biopsy
The one on the right shows where the iron is
What are the two stable structures of HbA? How do they switch from one to the other? What is this process called?
The oxygenated form and the deoxygenated form are the two stable structures. As oxygen pp increases in solution (lungs), oxygen forces itself into one of the globin protein and binds to the iron in the heme. this causes a conformational change simultaneously shifting all the subunits from the deoxy to the oxy conformation. Thisnow increases the binding efficiency (300x)!! This process is caleld cooperativity!
What occurs to the structure of heme when it is oxygenated
The oxygenation of heme pulls on the iron of heme and to the covalently bound proximal histidine (F8) to change the conformation of Hb from the deoxygenated form to the oxygenated form. Movement of the histidine pulls on the globin monomer helix and reorganizes all the alpha and beta subunit interactions.
What is the red pulp and white pulp in the spleen? How do they look like in a histology slide?
The red pulp (red arrows) consist of large numbers of sinusese and sinusoids filled with blood and are responsible for the blood filtration function of the spleen - The while pulp (blue arrows) consist of aggregates of lymphoid tissue and are responsible for the immunological function of the spleen
What is contained in the red pulp?
The red pulp has a complex system of blood vessels within it, arranged to facilitate removal of old or damaged red blood cells from the circulation. A small proportion of splenic blood flow passes through more rapidly without undergoing filtration.
Describe how iron is uptaken into l'body?
The reduced Fe2+ form is transported into the enterocyte by DMT1 (ivalent metal transporter 1) and again out of the enterocyte into the circulation by ferroportin. Fe3+ is not transported through membranes. Excess Fe3+ is stores in intracellular ferritin complexes. When needed, Fe3+ in ferritin is reduced to Fe2+ and exported to the circulation. Once in circulation, Fe2+ is rapidly oxidized back to Fe3+ with the help of copper containing, Hephaestin. This is essential because the circulatory transporter of iron, Transferrin, will only bind to 2Fe3+ 2Fe3+Tf will bind to Transferrin receptor (Tfr). These are found on the cell membranes of tissues with an iron requirement; liver, proerythrocyes, muslce.
Compare the immature, mature, and late megakaryocyte. How can the stage of megakaryopoiesis be determined?
The stage can be determined by the absundance and appearance of the cytoplasm, and shape of nuclei
What does the bohr effect look like in the lungs?
The system demonstrates its reversibility by eliminating acid and carbon dioxide to the lungs and picking up oxygen for deep tissues delivery. Extremely large oxygen tensions (20% of atmopspheric pressure) overcomes the deoxy stabilizing salt-bridges driving the formation of oxy-form Hb. Note: the reversal of the chroride shift. Elevated bicarbonate levels are converted to carbonic acid (carbonic anhydrase) and then CO2 which is lost to the lungs. Shift of circulatory HCO3- into RBC induced export of CL- to maintain osmotic electrochemical balance
What is the difference between thrombosis and hemostasis?
The term 'haemostasis' refers to the normal response of the vessel to injury by forming a clot that serves to limit haemorrhage. Thrombosis is pathological clot formation that results when haemostasis is excessively activated in the absence of bleeding ('hemostasis in the wrong place').
Describe the general structure of the thymus?
The thymus gland is subdivided into lobules. It is arranged into an outer cellular cortex and an inner medulla, apparent in each lobule.
How does the size of the thymus change over life?
The thymus gradually enlarges during childhod but after puberty it undergoes a process of involution (size reduction) resulting in a reduction in the functioning mass of the gland. However, it continues to function throughout life. This is because we aren't dependent on the thymus as musch as we grow older -- so it shrinks. As we get older our immune system grows so we get less dependent BUT it is always gonna be there because we still need T cells in life
Where is the thymus located on the body?
The thymus is found in the thorax (superior mediastinum).
What is the role of the thymus?
The thymus is the site where lymphoid cells undergo maturation and education into T cells prior to release into circulation
Where are the tonsils located? What is an infection of the tonsils called?
The tonsils are areas of lymphoid tissue on either side of the throat. An infection of the tonsils is called tonsillitis.
What divides the lymph node into lobules?
The trabeculae subdivides the lymph node into lobules
How does Bradykinin play a role in inflammation?
The usual vasodilation/permeability AND PAIN
What are the effects of glucocorticoids? What is an example of a natural glucocortisol?
Their main effects = anti-inflammatry ex. cortisol
What is the function of the cytokines with the lowercase b ending?
Their role is binding (remember b is for binding hehe), binds cells to walls. It is an opsonin
Which of the two HbA states is more stable why?
There are 8 individual salt bridges that stabilize the deoxy (or T) form. There are only 6 for the oxy (or R) form. The deoxy is more stable.
How does the tetrameric heme structure stay together?
There are highly specific subunit interactions that are stabilizes by hydrogen bonds, electrostatic interactions and hydrophobin interactions between amino acid R-groups as well as the polypeptide backbone itself
Is it beneficial to purposefully delay children's entry to kindergarten?
There is alck of evidence supporting purposeful delay of children's kindergarten entry
Which molecules neutralize factor 8
These are IgG molecules.
what are the exogenous PAMPs? What about the endogenous DAMPS?
These are chemotaxins! Exogenous: bacterial products (LPS): pathogen-associated molecular patterns (PAMPs) Endogenous: (DAMPs) - damage associated molecular patterns: - Necrotis cells and fibronopeptides - C5a (complement 5a) - LTB4 (leukotriene B4) --chemokines : - IL-8 (CXC chemokine for PMNs) - MCP-1 (monocyte chemoattractant)
What are Hematopoietic growth factors?
These are cytokines Many cell types produce these, and other, cytokines, and multiple cell types respond to the same cytokines in a cell-specific manner -- There will be a summary table with all needed posted on blackboard
What is GALT, MALT, SALT?
These are lymphoid tissues associated iwth other organs GALT = gut associated lymphoid tissue SALT = skin associated lymphoid tissue MALT = mucosal associated lymphoid tissue
What is the mechanism of action of Desirudin and Bivalirudin?
These are the Hiruden derivatives (remember that leeches thing): the "rudens" They both are highly specific for thrombin, directly bind 2a actite (essentially irreversible -- suicide inhibitor), create 1:1 inactive complex active on both soluble and fibrin bound 2a.
What does the CD4 and CD8 nomenclature mean?
These are used to distinguish T cell subsets If CD3+CD4+, it is a CD4 T cell, if a cell is CD3+CD8+, it is a CD8 T cell. BUT CD8, and CD4 can be expressed on non-T cells as well. therefore, you need BOTH CD4/CD8 and CD3 to tell i it is a T cel.
What are the WBC that are present in the tissues?
These are vary rare in the blood - Macrophages, Dendritic cells, plasma cells, mast cells
When do factor 8 inhibitor autoantibodies occur?
These can occur - post-partum, -in lupus, RA, lymphoprolifferative disease (CLL) malignancy, allergic reactiosn
What are the systemic eggects of inflammatory cytokines?
They affect cell mobilization (for more efficienct phagocytosis) Temperature, protein and energy metabolism (for decreased bac. and viral replication) Make acute phase proteins for activation of complement and opsonization
What are all leukocytes, erythrocytes and platelets derived from? What do they give rise to?
They are all derived from pluripotent hematopoietic stem cells which give rise to both myeloid and lymphoid progenitor cells.
Where are the adrenal corticosteroid synthesized? Does this organ have its own blood supply?
They are all synthesized in the adrenal glands (cortex) Yes! They do have their own blood supply
What are neutrophils?
They are also known as polymorphonucleueocytes (PMNs). - Phagocytic cells with anti-microbial function. Increased production and increased release from bone marrow into circulation as a result of inflammatory signals. Immature forms in blood referred to as "bands" migrate to tissue sites during inflammation
What is the difference between the splenic cords and the splenic sinusoids?
They are both in the red pulp Splenic cords: bunches of cells, clustering together -- high density Splenic sinusoids -- open space Surrounding the sinusoids are populations of lymphocytes, plasma cells, macrophages, and reticular cels, among others, that form the splenic cords (of billroth)
Where are TLR expressed and what doe they do?
They are expressed on plasma membrane and recognize extracellular molecules as well as in endosomal compartments. Different TLRs recognize different PAMPs
What are blood capilaries surrounded by in the connecting capillary/lympathic vessel sac?
They are surrounded by basal lamina
When is the reticulocyte count increased?
They are the immature, non-nucleated RBCs that contain mRNA and are increased when the marrow responds to stress.
What are mast cells?
They are tissue resident cells that upon stimulation release "granules" that contain histamine and other bioactive molecules that act in the local microenvironment to mediate an inflammatory response.
What are dendritic cells?
They are very efficient at sampling tissue microenvironment at barrier sites. In response to extracellular signals (similarly to macrophages), will produce cytokines that regulate the development of immune and inflammatory response. Critical cell in interacting with and stimulating T lymphocyte activation, by presented "antigen" to T cells
Are corticosteroids well absorbed? How are they metabolised?
They are well absorbed - oral, iv, im, inhaled topical presentation - minimal systemic absorption unless skin abraded/broken Liver metabolism, inactive metabolites in urine (so they can test urine to see if they are present)
What is the significance of Myelocytes?
They can make the granulocytes. IGNORE PIC
Do glucocorticoids and mineralocorticoids bind equally to the mineralocorticoid receptor (MR)? How is specificity determined?
They do bind equally, Specificity is due to the clucocorticoid-degrading enzyme, 11beta hydroxysteroid dehydrogenase type 1 (11b-HSD2), which prevents glucocortisoids from interacting with receptor (converts cortisol to cortisone-inactive)
What do the lymphatic vessels include?
They include lymphatic capillaries, small lymphatic vessels, major lymph-collecting vessels - Notice that it goes from small to large -- opposite of CV system
What part of the vascular system do endothelial cells line?
They line the ENTIRE vascular system, including the HEART
What are the results of products from 5-LOX? Which conditions/diseases are they seen in?
They play a role in inflammation, asthma, CV disease and anaphylactic shock.
What are pattern recognition receptors?
They recognize broad molecular patterns present on microbes and not on healthy eukaryotic tissue. Neutrophils and macrophages express several calsses of receptors that promote phagocytosis of microbes (and also trigger signal transduction pathways that regulate gene transcriptional programs)
What do natural killer cells look like? what are they for?
They release lytic granules that kill some virus-infected cells
Why is it a problem when two hemes are close to one another?
They stack up which causes free radical buildup
How do type 1 and 2 cytokines work? (Signal 3 for T cells?
They utilize the JAK/STAT signaling pathway. This is another example of a receptor-associated kinase pathway.
Describe the structure of endothelium lining the vascular system
Thin, simple squamous epitherlium Centrally located flat nucleus Smooth lining (the smoother it is, the more the flow) so that's why. Endothelial long axis is oriented parallel to direction of blood flow
What are palatine tonsils? What about lingual tonsils? What kind of structure do they have?
Think of palate: therefore palatine tonsils = GI tract Lingual is the tongue The following apply to both Non-keratinized startified squamous epithelium (like the rest of the GI) - Incompletely encapsulated (one side is attached to the GI tract) - have crypts (which increase the surgace area for antigen sampling by the abundant lymphoid tissue beneath the epithelium)
A 36 y/o man had chest pain while joggin. It imporved with rest, but did not resolve. He died 30 hours later. Slide on other side
This coagulative necorisis: flat pink mummified look, neutrophils are there because of DAMPs that are released from ded cells, there are chemoattractants
Case report: 70 yo male, hypertension diagnosed 4 year previously and worsened over the last year. He ate A SHIT LOAD of licorice every day (*first of all we need to get judge him*). Turns out, lots of licorice can lead to hypertension. Why?
This diagram shows active cortisol being inhibited by 11b-HSD2 and inactive cortisol being activated by 11B-HSD1 Licorice inhibits 11B-HSD2
What is the result of increased regional carbon dioxide in tissues?
This induces an increase in RBC proton/acid levels, via the action of carbonic anhydrase, modifying Hb with both H+ and CO2 to increase stability of deoxy-conformation with multiple new stabilizing salt bridges induced. More oxygen is released to metabolizing tissues while trying to maintain the local partial pressure of oxygen.
What is complement?
This is a family of proteins produced by the lier and other cells at high concentrations in the blood.
What is keloid?
This is a inherited deficiency/disorder in wound healing.
What are defensins? How do they work? What secretes them?
This is a type of antimicrobial protein / peptides (AMP) (very old immunity - found in plants!) Defensins expressed mainly by *epithelial cells and neutrophils* that disrupt the bacterial membrane, leading to pathogen death. They go way back many lineages. Can be constitutively produced (also induced by normal flora) and induced upon infection. They work through electrostatic interactions and then make a pore
How does Prostaglandin (PG) act as a cell-derived mediator of acute inflammation?
This is an arachadonic acid metabolite (cyclo-oxygenase) --> Vasodilation > permeability, (occurs during *fever, pain* (PGE2)
What are the congenital and accquired bleeding disorders?
This is another way to divide the disorders (the other way was the tests) Congenital (hereditary): -platelet function defect - hemophilia A: factor 8 deficiency, hemophilia B: factor 9 deficiency - von willebrand disease - Deficiencies in factor 7, 11, 5, 2, or fibrinogen (rare) -- wont really touch on this Acquired: -Thrombocytopenia, liver disease, vitamin K defieincy, factor 8 inhibitor, DIC, inhibitors to factors.
Why is LDH a marker for hemolysis?
This is because LDH is contained in RBC
Why can water access to internal hydophilic amino acids be strongly denaturing to the hemoglobin overall structure?
This is because there are internal orientated salt links, H-bonds, and disulfide bonds which stabilize the Hemoglobin. These need to be protected from competion with the polar aqueous enviornment by the surrounding protein stucture.
What does it mean that tissue suffers as "innovent bystander" in phagocytosis?
This is like a battlefield and is nor complelely contained, enzymes can get released.
What is macrocytic normochromic anemia?
This is megaloblastic anemia!! Macrocytic = large Normochromatic - normal color - Low hematocrit - not so many RBCs (<40%) - RBCs are larger than normal with normal amounts of hemoglobin - Inhibited cell division (larger cells) with normal protein synthesis.
What is the chloride shift/
This is observed and is measurable in the blood/RBCs. As CO2 increases, then H2CO3 and HCO3- increases, higher levels of HCO3 in the RBC flow out of the cell into th circulation. To avoid osmotic lysis, the cell compensates by bringing in Cl-, no net electrochmical gradient is generated, but circulatory CL- levels decrease with an increase in circulatory HCO3- . This is reversible!
Image on other side!
This is showing neutorphil emigration at a post-capillary venule. You can see neutrophils accumulating in an extravascular space, you can also see them squeezing between the endothelial
anotha one!
This is showing neutrophile tissue infiltration. This is acute inflammation because you see a lot of neutrophils and they are first responders.
What gets absorbed by the lymphatic capilarries in the "blind sac"?
This is the connection between the capillary and the lymphatic system - Most of the fluid and proteins in the interstitial space are reabsorbed back into the venous end of the capillary. About one tenth of this fluid enters the lymphatic capillaries, in particular *large proteins!*
What is the therapeutic use of fludocortisone?
This is the drug of choice tp replace aldosterone it is potent GC and MC activity -most widely used Dosage too small to have significant anti-inflammatory or anti-growth
What is thrombocytopenia? What will be the PT an PTT if this is the only problem?
This is the most common acquired bleeding disorder. If this is the only problem PT and PTT will be normal.
What is the clear colored supernatant after blood has been centrifuged?
This is the plasma
What does it mean to apheresis blood components?
This is the selective collection of individual components using specialized equipment (RBCs, platelets, plasma)
What is Hgb H disease?
This is three nonfunctional alpha genes You will have: unstable hemoglobin, ineffective erythopoiesis, brisk hemolysis
Why are 2 glucuronic acids attached to propionate resides on bilirubiin in the hepatocyte?
This is to increase solubility so that it can be lost to bile (feces) and urine.
What is the result of enchanced thrombin generation in patients with prothrombin gene mutation?
This may lead to increased activation of TAFI, resulting in inhibition of fibrinolysis and increased thrombotic risk.
How does folate deficiency lead to megaloblastic anemia?
This occurs because diminished folate concentrations lead to deficiency in thymisine production, slowing DNA synthesis and replications. The cells do not divide BUt, they accumulate cytosol and protein materials, predominately hemoglobin, to support cell division... so they grow and apprear larger.. but they do not divide due to nucleotide imbalance.. Result = megaloblastic anemia (fewer but bigger cells)
why does cooperativity occur?
This occurs because the conformation shift in one subunit is transferred to the other subunits through salt-bridge (electrostatic interactions) between the subunit interfaces.
What is the symptomology of Carbon-Monoxide poisoning?
This shows the concentration gradient from top to bottom 50ppm to 1500ppm -light headed and dizzy (exposure = hours) - Minor headache, loss of judgement (exposure = hours) - Memory loss and confusion (exposure = minutes - Severe frontal heeadache, dizzy, nausea (exposure = minutes) -Convulusions and unconsciousness (exposure = minutes) -Coma and death
Where is the connection btw the circulatory system and the lymphatic system?
Thoracic duct, right lymphatic duct collect lyph after it is filtered through the lymph nodes - Lymph drains into venous system via these large vessels .
What does the federal maternal child health bureau define children with special health care needs as?
Those who have or are at increased risk for a chronic physical, developmental, behavioral, or emotional condition and who also require health and related services of a type or amount beyond that required by children generally
What are lymphocytes?
Three major classes of lymphocytes: T cells, B cells, NK cells. Most lymphocytes are present in lymphoid tissue (e.g. lymph nodes, spleen, mucosal associated lymphoid tissue). Recuriculate through lymphatic tissues via lymphatic circulation and blood circulation. Inly about 2% of lymphocytes are circulating in blood at any time. Participate in host defense and regulate immune and inflammatory responses.
What are the three complement pathways?
Three pathways: Classical = discovered first (antibody dependent activation) Alternative (antibodye independent activation Lectin pathway (most recently described, byt may be most importnat)
How are thrombocytopenia, preeclampsia and HELLP associated?
Thrombocytopenia is well recognized when preeclampsia is complicated by the hemolysis, elevated liver tests, low platelet count (HELLP)
How does the endothelial function to control thrombosis? What is thrombosis?
Thrombosis is the formation of a clot or thrombus inside a blood vessel, which obstructs the flow of blood as long as you have an intact barrier, you will have a non-thrombogenic barrier -- no clotting. The endothelial functions to create a non-thrombogenic barrier by producing 1. Anti-thrombogenics (prevents primary hemostasis) -- *prostacyclin (inhibits platelet aggregation) -- *tissue plasminogen activator (fibrinolytic) 2. Production of anti-coagulants (inhibits secondary hemostasis) -- *theombomodulin (binds/inhibits thrombin activity --> inhibits coagulatino cascade
What is the black box warning that all NSAIDs (except for aspirin) carry?
Thrombotic events: Can occur with short term (weeks) therapy - Risk increases with time on drugs and people who have heart disease - Likely due to inhibition of PGI2 in vessel endothelium: which inhibits platelet aggregation and induces vasoilation
What is the time to release, number of progeny, and survival of erythropoesis?
Time to release = 5 days # progeny = 16 Survival = 120 days
What is the megakaryocytic time to release, number of progeny, and survival?
Time to release = 5 days Progeny # = hundreds Survival = 8-11 days
What is the granulocytic time to release, # of progeny, and survival?
Time to release =14 days Progeny # = 16-32 Survival 1-4 days
What is the result of Aspirin/Salicylate poisoning?
Tinnitus (ringing in ear) - Acid-base balance: *At therapeutic doses* get a respiratory alkalosis (stimulation of respiratory center/medulla) followed by renal compensation and increased excretion of bicarbonate, sodium and potassium *at toxic doses* - get a respiratory and metabolic acidosis due to accumulation of (lactic) acid products due to uncoupling oxidative phosphorylation and mitochondrial toxicity.
How does the tissue factor-factor 7a-factor 10a complex activate platelets? What is the purpose of fibrinogen?
Tissue Factor:factor 7a:factor10a complex also activates platelets which leads to exposure of phospholipids on the platelet surface which help support the assembly of pro-coagulant enzyme complexes. The clotting cascade then takes off and more and more prothrombin is activated and turned into thrombin. Thrombin converts fibrinogen into fibrin which leads to clot stabilization. The fibirin acts as the scaffolding for the platelet rich thrombus
What starts secondary hemostasis (clotting cascade)?
Tissue factor starts the clotting cascade in which there is a sequential activation of a series of pro-enzymes (inactive precursors proteins) to active enzymes, resulting in stepwise response amplifaction.
What is the total iron binding capacity (TIBC)?
Total capacity of the serum to bind iron, reflection of serum transferrin level -- think about it as how much the body wants iron (if alot, the TIBC is high)
What is serum iron?
Total iron present in serum
What type of surgery is related to increased risk of clotting?
Total joint replacement -- hip and knee especially (also large cancer and abdominal), some surgeons may even put em on anticoagulants as prophylaxis after surgery.
What is the treatment of iron deficiency anemia? What is the problem with this?
Treat underlying cause -Pral Rx: ferrous sulfate is cheap and effective; - 200 mg - compliance is hard because of nausea/vomit/constipation
What is the treatment for type 1 vWD? What about Type 2 or 3?
Treatment of Type 1: DDAVP (desmopressin). It is a vasopressin analog that released vWF and VII from storage sites in the endothelial cells. - Intermediate purity - Factor 8 concentrates that contain vWF Treatment of Type 2 and 3 vWD: intermediate purity factor 8 concentrates that contain vWF.
How do you treat acute prophyria?
Treatment with hemin mimics feedback inhibition of ALA synthase preventing ALA synthesis
T/f: we have lymphocytes over the body and not just in lymph nodes
Trrruee
T/f: Stem cells produce both other stem cells and more differentiated cells?
Trrrueee
T/f: PGE2 mediates pain response peripherally
Trrrueeee, drug target
T/f: it can be hard to differntiate TACO from TRALI
Trruee
T/f: a vitamin B12 deficiency can be masked as a folate deficiency
True -- b12 is needed to get folate out o fstorage.
T/f: The immune system is important in pathogenesis and regulation of most human diseases
Truee
T/f: skin dendritic cells sample and respond to barrier environment and migrate to lymph nodes where they initiate adaptive immune response.
Truee
T/F: Hwmoglobin acts as a molecular environmental sensor or bio-computer
Trueee, going from oxy to deoxy state
T/f: clinically used corticosteroids are aynthetic derivatives of endogenous counterparts and bind the same receptors
Trueeee
What are the three layers of endothelium in the vascular system? Describe Them!
Tunica Intima: simple squamous epithelium (*endothelium*). Loose CT; occasional smooth muscle cells and/or internal elastic lamina may be present Tunica Media: *Concentrically* arranged *smooth muscle* and varying amounds of CT (elastic laminae, collagen) Tunica Adventitia: *Longitudinally* arranged *connective tissue*; smooth muscle in large veins!; *circumferential* external elastic lamina in arteries *nervi vascularis* and *vasa vasorum* in larger vessels.
What are the three types of vW diseases and what do they mean?
Two main ones: Type 1 - partial deficiency of vWf == (autosomal dominant) - AD, vWF antigen low and vWF activity similarly low. Factor 8 level low. Type 2 - qualitative defect in vWF (vWF activity), vWF activity lower than vWF antigen level. FVII normal or low. Type 3 - total deficiency of vWF (rare severe) - AR
What are high endothelial venules? What's the importance?
Typically endothelial cells are simple squamous (flat). these in the lymph node are a little bit thickened (look a big cuboidal). Therefore, they are called high endothelial venules (HEV) The HEVs represent an important site of lymphocyte entry into the lymph node and the site at which blood-borne lymphocytes can re-enter the lymphatic circulation
What occurs when the ITIM is activated
Tyrosines iwthin the ITEM get phosphorylated upon receptor ligation and recruit tyrosine phosphatases to the receptor. These phosphatases then can inhibit tyrosine phosphorylation cascades initiated by an activating immune receptor.
What does UV light therapy do for neonatal jaundice?
UV light is used because it drives the Bilirubin to regenerate Biliverdin (i.e., that double bond so that it doesn't fold up). This makes a more soluble compound (although still not v soluble).
What are the three types of heparins? And what is their structur?
Unfractionated Heparin (mixture of long chains) LMW heparin (mixture of short chains) - enoxaparin Fondaparinux (pure pentasaccharids)
What is the mechanism of action of heparin?
Unfractionated Heparin - AT neutralizes Xa and IIa Short chain neutralizes Xa >>>> IIa Pure neutralizes only Xa
What is the difference between a hemodynamically unstable and a hemodynamically stable PE? What is the treatment of each?
Unstable: massive PE, hypotension, left ventricular dysfunction Tx: ICU admission, thombolysis (tPA) to dissolve clot followed by anticoagulation. stable: symptomatic, hospital admission, anticoagulation - incidentally noted, hospital admission vs outpatient management, anticoagulation
What are the adverse effects of Glucocorticoids?
Unusual for administration of less than 2 weeks. Occurs due to either: - Cessation of therapy -abrupt withdrawl (adrenal has involuted due to long term use of high doses and cannot produce sufficient hormone or Continued use of supraphysiological ( amounts greater than normally found in the body) doses for inflammation: mimics cushing syndrome
What is the managment of Deep venous thrombosis include? What can you use is suspicion is low? What is the gold standard?
Urgent evaluation in ER or urgent care. Ddimer can be used if suspicion is low (if ddimer is normal, rules out clot) -- BUT like if you know then dont do this (you can't just send them home because ddmier is normal if something else is suggesting clot) Gold standard: ultrasound leg... prevent clot extension, prevent PE, reduce risk of recurrent thrombosis.
What are examples of DAMPs?
Uric acid, ATP, stress-induced proteins (heat shock proteins), nuclear proteins
How do hyperkalemia and irradiation relate? What should you do?
Urradiation substatially increases plasma K+ due to RBC damage, High potassium levels can lead to cardiac arrest Measures to reduce the risk: anticipating and replacing blood loss before significant hemodyanmic compromise occurs Checking and correcting electrolyte abnormalities frequently -Irradiation closer to transfusion time.
What are the therapeutic principles for GC use?
Use the lowest dose possible to achieve the desired result Chronic glucocorticoid therapy should never be withdrawn abruptly.
What are the usual components in a complete blood count (CBC)?
Usual components: - WBC count (total) - WBC differential count (% and absolute #) - Hematocrit - Hemoglobin - RBC count - RBC indicies: MCV, MCH, MCHC, RDW - Platelet count
What are the usual indications for a bone marrow examination?
Usual indications (after less invasive tests have been exhausted) - Anemia, neutropenia, and/or thrombocytopenia - Leukemia evalution - Metastatic neoplasms (part of staging w/u) - Search for seleccted infectious agents (e.g. mycobacteria, fungi)
How long does recovery from Glucocordicoid withdrawal usually take?
Usually several week to months/years (significant patient variability)
How does platelet activating factor (PAF) as a cell-derived mediator of acute inflammation?
Vasodilation/permeability, platelet activation with multiple effects
What is virchow's triad?
Venous stasis Vascular injury Hypercoagulability This describes the balance of the three properties of blood flow that contribute to clotting.
What is used to treat cyanide poisoning? Why do fire fighters need this?
Vit B12!! combustion of synthetic fibers (house fires) releases CN into the air, they carry b12
What is a drug interaction you should be aware of in regards to warfarin?
Vitamin K - large doses can reverse warfarin action; reestablishment of the normal activity of clotting factors
How do we ensure blood safety? How do we prevent transfusion- transmitted infection diseases?
Volunter donors Questionnaire (lol) Infectious disease screening Leukoreduction Prevent transfusion-transmitted infectious diseases: Basically see where they have travelled to and then ask them general questions. Then can do laboratory screening and pathogen reduction
What is Von willebrand disease? What Do Weibel-Palade bodies look like on an EM?
Von Willebrand disease is a congenital absence: Prolonged coagulation time and excessive bleeding after injury. More common and usualyl milder than hemophillia
What are the ways that we reduce the problem of free radicals?
WE use vitamin E, GSH, dismutase, and catalase.
Is Warfarin contraindicated in HIT? What could you use?
Warfarin IS contraindicated in HIT Preferred treatment: fondaparinux or argatoban (a direct thrombin inhibitor) so smal lthat it does not create P4 complexes
Why are warfarin effects delayed?
Warfarin effects are delayed until existing functional clotting factors turn over
What are the effects of mineralocorticoids? What is an example of one?
Water, electrolyte balance ex. aldosterone
Where do we get omega 3 and 6 fatty acids from?
We get them from our diet! They are essential fatty acids
Is it always better to transfuse patients? Should we use restrictive or liberal transfusion?
We shouldn't just give patients transfusions willy nilly!! there was a study comparing liberal (giving lots a blood) vs restrictive (deliverately making them a bit more anemic). There was actually little difference, in fact, restrictive transfusion actually did slightly better!
unfortunately// graph on other side?
What are the cells in the lower left quadrant? T cells (Cd3- and CD4-) What is the percentage of the cells marked with the X? What about the Y? Since we know that cells that are CD3+ are either CD8+ or CD4+, we can answer this question. We have been told on the left graph that 25% of the cells are CD3+/CD4-. Therefore 25% are CD3+/CD8+ (X). We have also been told on the left graph that 40% of the cells are CD3+/CD4+. Therefore, 40% are CD3+/CD8- (Y)
When should school readiness tests be used?
When child's development lags, this info should be used to plan for the special attention the child may need. Parent can encourage their child's cognitive, physical, and emotional development before they enter school
What is plasminogen activator inhibitor (PAI-1)? How is released? What is it released with? What happens if you are deficient in this?
When endothelial cells release tPA, it also releases type plasminogen activator inhibitor PAI-1. Deficiency causes bleeding problems because it doesn't stop fibrinolysis. PAI-1 inhibits tPA
How do lys residues keep the process of fibrolysis going?
When fibrin clots are being lysed, it exposes more and more lys residues (which is where tPA and Plasminogen bin).
What is neonatal jaundice? When does neonatal jaundice become a concern?
When the bilirubin gets to the liver, you are supposed to form conjugated billirubin. If the poop is not brown (like if it is grey/clay), you are not making enough of the bilirubin byproduct (sterobillin). Therefore, there could be a block or dysfunction An infant does not have active enough UDP glucuronosyl transferase. This should start working in the first weeks or so. If it doesn't you will get prolonged exposure of bilirubin -- hyperbilirubinemia- in neonates could lead to neurological issues known as *kernicterus*. If left untreated -- death or mental retardation
Someone comes to your clinic and says that a yellow bruise on their leg happened just yesterday. how do you know that they are lying?
When there is a bruise, capillaries and vessels have been broken. The RBCs lose oxygen and turn blue -- that's why someone says the bruise starts as black and blue As macrophages get there, it makes billiverdin which is green. Then it makes billirubin, which is yellow. A bruise recieved just yesterday would not have had enough time to be yellow!
What is the role of the PGE2 prostanoid? What is it made from?
When you get sick!! - It increases body temperature - Made from COX-2 - Pro-inflammation - Protective against peptic ulcers - Bronchodilation -Promotes patency of fetal ductus
What are the two types of platelet products? How does it differ in volume/pooled?
Whole blood: 4-6 donors combined to make 1 unit Apheresis: Single donor, equivalent to 4-6 pooled units.
Why do irradiation? How do you do it? What is a potential risk?
Why: emilitate T lymphocytes in RBC, PLT, and WBC products to prevent engraftment How: Gamma source irradiation: cesium or Xray Whatra th risk: Storage lesion exaggerated (potassium that is usually in the RBC is released) --> potassium release.
What is the Complete blood count?
Will provide information of blood. It is NOT recommended that this test be used on health people, but only be used when there is clinical suspicion of disease
What is the histopathology of keloid?
Wound repair - excessive collagen matrix --> increase in irregular collagen bundles, tendency to recur despite excision - excessive raised scar - dense collagen in irregular bundles Notes: lack of skin appendages in area of scar (as in any dermal scar) rises above skin surface (scars generally do not
How is hemophilia A and B passed on?
X-linked recessive females are carriers. No to mild symptoms. Only males affected
How are the 10a and 2a (thombin) mechanisms different in regards to heparin>??
Xa neutralization is pentasaccharide dependent -Pentasaccradie increase AT affinity for Xa IIa neutralization is long chain dependent. Long chain bridge At and IIa
Are mutations to the hemoglobin distal histidine residue categorically letha?
YES
Do larger lymphatic vessels have valves?
YES
T/f: any increase in estrogen also increases chance of clotting?
YES
Do lymph nodes have orientation?
YES They have a hillum, where the lymph sypply in entering and leaving
Can Acute Ches Syndrome be lethal?
YES!
Can receptor signaling negatively regulate cell activation? What motid is common in these?
YES! Often these receptors have immune receptor tyrosine inhibitory motifs (ITIM) in the cytoplasmic domain.
T/f: Fondaparinux use for HIT is currently off label.
YES! Expect labelled indications for LMW heparin and Fondaparinux to increase over time as more data accumulates
Is the lymphatic capilary more permeable than blood capillaries?
YES! They are more permeable -- no zona occludentes junctions; discontinuous BM
Is there a large difference between life span in a sickle cell and non sickle cell patient?
YES! but this gap is decreasing
T/f: there is a progressive increase in F8 and F9 activation as 10a and thrombin are formed.
YES! thrombin helps forms F8 (remember it cleaves it from vWF). As well as increasing F
Does the risk of hereditary thrombophillia go up a lot if you are homozygous?
YES, also this is autosomal dominant
The other side shows a gross specimen of meningitis!
YOU seethe suppurative exudate!! (i.e. pus)?? huh??
Can B cells get a second signal independently of CD40-ligand/CD40 interaction?
Yes! For example, T independent antigens can use bacterial patterns to activate pattern recognition receptors (e.g. TLR9) on B cells. This results in limited B cell activation and is not typically sufficient to mediate isotype switching and somatic hypermutation.
T/f: TXA2 and PGI2 are opposing
Yes! TRUE TXA2 tries to aggregate platelets PGI2 inhibits platelet aggregation
Can you use Hb electrophoresis for alpha thalassemias? What about beta?
You CANNOT use Hb electrophoressi for alpha thalassemias. Each adult hemoglobins are going to be affected the same way because each of the adult hemoglobins don;t have the alpha being made. (HbF - alpha 2, gamma 2, HbA (alpha2, beta 2), HbA2 (alpha2, delta2) will look the same -- there is no way of distinguishing them You can use for beta thalasemias For alpha: instead you should use HPLC
What are the ways to decrease production of prostaglandin/LT products via the glucocorticoid receptor?
You can decrease COX-2 synthesis (decrease prostaglandin) Or Increase Annexin A1 (lipocortin 1) production which decreases Arachidonic acid production (in turn decreases prostaglanding and LT) note: Annexin A1 blocks phopholipase A2 production (therefore AA blocked)
What is the anticoagulant BBW (black box warning)?
You can get bleeding around spinal cord (hematoma) -- this can cause paralysis, monitor neurologic status
What do you need to know if a patient is suffering from a clot stroke or hemorrhage stroke?
You can't give anticoagulant for a hemorhage stroke (because htey will just keep bleeding) BUT you should give for clot stroke
What occurs in sickle cell in the vasculature?
You have polymerized hemoglobin = decreased RBC deformability Occlusion in microcirculation, hemolysis Tissue hypoxia --> pain --> necrosis
Why is it important to know where your sample came from?
You need to know if it was a solid or liquid sample becuase the staining and morphology will look slightly different - a tissue section is likely slicing some cells in half, and will cause the nuclei to stain slightly more pale and the nucleoli/chromatin clumping will be more visible - an aspirate will spread whole cells across the slide and will cause the nuclei to stain slightly more dark and nucleoli/chromatin climping may be less visible.
Know this A 12 yo boy has Hbg SS presents to the ER with 101.5. profound lethargy. His Hgb is 5gm/dl (normal for him is 8.5 gm/dl). Last week his Hgb was 7 gm and today's retic count is 0.1. LDH is 275 (slightly elevated). What should you do?
You next should order PAROVIRUS B19 This is because, typically even in sickle cell crisis, the retic count is high, because you have chronic disease. Parovirus B19 causes red cell aplasia - fitz disease. It is pretty common. What happens if a ss patient not crisis is affected by a virus that turns off red cell production. The hb crashes! So, (esp. in kids) you have to look at the retic count. If a reti count is at 0.1, the patient is not making new red cells. In a sickle cell patient this can be catastrophic. tx with transfusions, this will give oxygen carrying capacity . Parovirus is a temporary thing but can really affect patient
What is iron overload? How do you test for it? How do you treat? How do you avoid?
You transfuse a lot of blood and they will eventually get broken down and increase the amount of iron in the body. Test: ferritin level Tx: iron chelation therapy (watch out for patient compliance) Mitigation: avoid unnecessary RBC transfusions, dietary restriction of iron intake.
What is found in platelet lysosome?
acid hydrolases
How are prostanoids synthesized from PGH2? (general)
additional isomerases and transdferases are involved ( eg. Thromboxane synthase)
keep going with l'case 7
after initiation anticoagulation, you should stop her bitch control pills and screen for hereditary thrombophillia
What are the common causes of non-megaloblastic anemias?
alcohol, liver disease
where are the pro-enzymes in the clotting cascade synthesized?
all of the pro-enzymes are synthesized in the liver except vWF (sunthesized in megakaryocytes and endothelial cells) and factor 8 (produced by endothelial cells)
What are acanthocytes?
also spiked (like burr cells) but not uniform and look differently ya feel
Describe the steps in the common pathway.
factor 10 binds with Factor 5a to form an enzyme on the platelet phospholipid surface that converts one molecule of prothrombin to a molecular of thrombin. This helps convert fibrinogen to fibrin monomer which will get crosslinked. Fibrin monomer acts as the scaffolding for the platelet plug.
Why is vit k and liver disease associated with the extrinsic pathway?
factor 7 is more sensitive to vit k deficiency an liver disease , so long PT first
What is the key/hallmark of iron transport?
ferro-oxidases and ferro-reductase - reversible oxidation-reduction reactions.
When do you give HU treatment for Sickle Cell Anemia?
give in Adults, some children, when there have been two or more painful episodes yearly, history of acute chest syndrome, other severe disease complications, severe anemia, CVA prevention when transfusion is not possible.
What do fragmented cells ("helmet" cells or schistocytes look like)?
helmet on the left, bite cells on the right.
What type of hemoglobin is made as a result of alpha thalassemia? What is the result of this?
hemoglobin barts: gamma 4 - death Hemoglobin H: Beta-4: baby is born and all of a sudden there is enough beta around and they can get B4 sometimes they don't get to this point and die in utero. So we can try to keep them alive until this point You will also see Hemoglobin H for patients with alpha thal major (3/4 genes are not functioning)
What happens to hemoglobin from lysed RBC (normally)?
hemoglobin from lysed RBCs is normally complexed to haptoglobin synthesized by the liver and released into the circulation, protects kidney filtration. The haproglobin-hemoglobin complex is targeted to the reticuloendothelial system where Hb is metabolized (liver, spleen, macrophages)
What is the inflammatory result of a high omega 6:omega 3 ratio? What about a low one?
high: strong response low: weak response
How do you tell the difference between a folate and b12 deficiency?
in both homocysteine will be high but ONLY in b12 will the L-methylmalonyl acid be high
If testing reveled, severe protein C defieincy. Presuming no other risk factors for clotting were present, how long do you treat for?
indefinetly
What is the Bohr Effect?
local envrionmental factors such as 1) increased proton generation (decreased pH), 2) increased CO2 generation and 3) decreased oxygen tension are seen in actively metabolizing tissues. These tissues have a higher demand for oxygen. So hemoglobin acts as a molecular environmental bio computer and senses these metabolic changes by *binding both H+ and CO2* to hemoglobin generating *4 additional deoxy-conformation stabilizing salt-brides (2 for each beta-subunit)*
What are the lab features of b12 deficiency?
low B12 in serum high methylmalonic acid and homocystein concentrations -anti-IF antibodies - pernicious anemia
What does the HMP sunt and the RL shunt in the RBC do with it's leftovers?
note shunts perform chemical modifications and then return their "leftovers" to glycolysis for energy generation.. little waste here.
What is the differential for isolated prolonged PTT?
note the lupus anticoagulnt is a pro-coagulant that increases PTT (it doesn't make sense but just believe and you will recieve)
The next photo has the structure of bone marrow. Should probs knw!
notice that there is vasculature all around the bone marrow. there is also a network of trabeculae. There is also adipose cells here. Interesting!!
I'm going to show you a picture of the thymus. Know it, love it
okay, maybe this image is not that important, notice the cortex, medulla, and lobules.
What is one hypothesis about why hassall's corpuscles exist? Why?
older person will have more hassalls corpuscle than younger person. Hypothesis is that it is an accumulation of dead things you get over time
How does the afificnity and concentration of oxygen help transport?
pO2 is high in the lung, so O2 passes from the lungs into the RBc. As O2 enters the RBC it binds to deoxy-Hgb forming ocy-Hgb. - Oxy-Hgb is a stronger acid than deoxy-Hgb (strong acid has a strong preference to donate a proton), so it releases a proton which shifts the equilibrium between bicarbonate/carbonic acid towards carbonic acid. - Carbonic acid dissociated into CO2 and water. This reaction is catalyzed by *carbonic anhydrase*. - Because of the low pCO2 the CO2 leaves the RBC and passes into the lung where it is expired. - there is a bicarbonate/chroride antiport which moves blood bicarbonate into the RBC as chloride moves out of the cell
What is the differential diagnosis for isolated prolonged PT (think of that chart
recall vitamin K is reqired for the modification of themany factors. also factors are made in the liver
What is the purpose of IL-8?
recruits neutrophils
What is ibuprofen? What happens when you get toxic levels?
reversible inhibitor of both COX 1 and COX 2 (nonselective) Toxicities: co-administration with aspirin may decrease cardio protective and anti-inflammatory effects
What is the EM on the other side of the card showing?
secondary hemostasis
How does the endotheliam function to modulate the immune and inflammatory response?
secretes leukocyte adhesion molecules and receptors to stimulate diapedsis of lymphocytes, monocytes, neutrophils - Secretion of interleukins regulate lymphocyte migration.
What does the EM on the other side of the card show?
shows platelets adhering to surface, change shape
What do burr cells look like? What is another name for them?
spikes here, echinocytes, (they are usually artifact actually)
What is parental iron? When is it used?
t is IV iron used for people who are intolerant, non-cmpliant or have malabsorption of oral iron
What is the function of Stem Cells?
the function of stem cells is delfrenewal and differentiation
What is the difference between the walls of lymphatic capillaries and the walls of blood capillaries?
the walls of lymphatic capillaries are more permeable than the walls of blood capillaries --> large molecules (Ag, cells) enter more readily
How do cells move toward increasing chemotaxin concentration?
they bind to fibrin matrix and move toward increasing chemotaxing concentration
How were toll-like receptors identified?
they were identified in the fruit fly they mutated a gene in the fly and got a fungal infection, indicating that it was important in defense. They then looked for homologs in uk and found a whole fam! They also characterized TLR-4 in mice and showed it recognized LPS
How does TF:F7a:F10a complex interact with platelet?
this complex helps activate platelets which leads to exposure of phospholipids on the platelet surface which help support the assembly of these pro-coagulant enzyme complexes
Describe the bone marrow niche
this has bone marrow cells as well as supporting Osteoclasts = breaking bone Osteocyte = mature cell " " -blast = building bone A lot of other cells too
What is the fucntion of trabeculae in the spleen?
trabeculae provide internal support for the spleen, and carry the blood vessels into the spleen.
How does Vit B12 result in megaloblastic or macrocytic anemia?
vit b12 allos folate to be removed from its trap, without this, folate will be stuck in trap (inactive form). this means that one carbon chemistry cannot take place. In the case of erythroblasts committed to divide, and busily building up their protein stores and cytoplasmic volumes for RBC generation, the DNA synthesis is put on hold and the cells swell up but do not divide... this results in megablastic or macrocytic anemia.
