Hematology

Major Encapsulated Pathogens

"Some Killers Have Pretty Nice Capsules" Strep. pneumo Klebsiella pneumo Haemophilus influenza type B Pseudomonas aeruginosa Neisseria meningitidis Cryptococcus Neoformans (yeast(

Sickle cell vs Beta-thalassemia

rapid erythrocyte turnover(hemolytic anemia) can give a misleadingly low hemoglobin A1c

Schistocytes

seen in: HUS (Microangiopathic hemolytic anemia & Renal symptoms) TTP(Microangiopathic hemolytic anemia & CNS symptoms) DIC Malignant HTN Mechanical Damage = prosthetic valve or severely calcified valves

Chronic Myeloproliferative disorders

these include P. vera, Essential Thrombosis, and primary myelofibrosis. They often has a mutation in the cytoplasmic tyrosine kinase Jak2. This leads to constant activity and activation of STAT transcription factors.

Glucose-6-phosphate dehydrogenase deficiency (G6PD)

1. triggers include: -sulfonamide or antimalarial drugs -fava beans -infections 2. Blood smear shows -Bite cells and heinz bodies 3. X-linked recessive inheritance *Increased LDH, bilirubin and reticulocytes *Decreased haptoglobin and hemoglobin

Mantle Cell Lymphoma

B-cell malignancy associated with t(11;14) -translocation results in activation of cyclin D1 Overexpression of cyclin Dl promotes Gl/S transition in the cell cycle, facilitating neoplastic proliferation. "Fireplace with two "11" to hold up mantle, with bicycle on top (Cyclin D1), burning the fire for 5 nights for 20 minutes (CD5 & CD20)."

Familial erythrocytosis

Beta-globin mutation (histidine replaced by serine, normally histidine is paired with lysine) resulting in reduced binding of 2,3-bisphosphoglycerate

Hemophilia B

Factor 9 deficiency Laboratory findings include 1. INCREASE PTT; normal PT 2. DECREASE Factor 9 3. Normal platelet count and bleeding time

Hemoglobin

Hemoglobin is a tetrameric protein. There are a number of types of hemoglobins found in humans. The normal hemoglobins are HbA (2 alpha and 2 beta chains), HbA2 (2 alpha chains and 2 delta chains), and HbF (2 alpha and 2 gamma chains). A healthy individual's hemoglobin is largely composed of HbA, reflecting normal expression from the alpha- and beta- globin genes. All individuals express a small percentage (1-2%) of the fetal form (HbF) as well as HbA2. Example: The rise in HbF, along with a decreased level of the adult form (HbA), indicates that there is a defect in the ability to express normal levels of the beta-globin genes. This is explained by a (homozygous) point mutation in the promoter region of the beta-globin gene which produces more gamma chains that beta chains.

lead poisoning

Inhibition of delta-aminolevulinic acid and ferochelatase Presentation: - microcytic anemia w/ basophilic stippling - headache - memory loss - demyelination w/ foot and wrist drop - darkend gums - metal in epiphysis (XR) Rx: Adults: EDTA, dimercaperol Children: succomer ELEVATED WHOLE BLOOD LEVEL

Acute megakaryoblastic leukemia

Leukemia of Down Syndrome before the age of 5 proliferation of megakaryoblast and lack MPO

Anemia Evaluation (MCV)

Low: <80 Normal: 80-100 High: >100

Osteosarcoma (GROSS)

MCC via RB1 and TP53

Eculizumab MOA

Paroxysmal Nocturnal Hemoglobinuria (PNH): inhibits the formation of MAC, monoclonal ab to the complement component C5(terminal compliment inhibitor) *pts receiving complement therapy should be immunized against N meningitides and be given appropriate antibiotic prophylaxis (PCN)

Howell-Jolly bodies

Splenectomy (or nonfunctional spleen)

Ring sideroblasts

Trapped iron in mitochondria. Prussian-blue stain. Sideroblastic anemia via def ALA synthase(delta-aminolevulinate synthase)

Platelet plug formation

Triggered by exposure of platelets to collagen Platelets adhere to rough surface to form a plug

Sickle Cell anemia ($)

a genetic disorder in which erythrocytes take on an abnormal curved or "sickle" shape -Dactylitis (painful swelling of the hands and feet) is a common presentation in young children -sickling episodes result in hemolysis, which leads to increase indirect bilirubin and lactate dehydrogenase and decreased levels of haptoglobin (haptoglobin binds circulating hemoglobin and reduces renal excretion of free hemoglobin, preventing tubular injury) HbF protects against sickling; high HbF at birth is protective for the first few months of life. Treatment with hydroxyurea increases levels of HbF *HbS allows hydrophobic interaction among hemoglobin molecules -sickling occurs in low pH or increase 2,3-bisphosphoglycerate -substitution of valine in the place of glutamic acid at the 6th amino acid position of beta globin (GAG-->GTG) -at risk of having an aplastic crisis, often associated with parvovirus B19 infection, during which time erythropoiesis is suppressed. -aggregates in the deoxygenated state *Histopathologic evaluation of spleen will show fibrosis and atrophy *After autosplenectomy, patients are are disposed to infection with encapsulated bacterial organisms -Increased risk of infection with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae (most common cause of death in children); affected children should be vaccinated by 5 years of age. Increased risk of Salmonella paratyphi osteomyelitis MC COD in adults is Acute chest syndrome--vaso-occlusion in pulmonary circulation *Hydroxyurea (INHIBITS RIBONUCLEOTIDE REDUCTASE) can prevent painful occlusive crises in this disease. It is an anti-neoplastic agent, which causes an increase in fetal hemoglobin Gene is carried. by 10% of individuals of African descent, likely due to protective role against falciparum malaria. Patients with sickle cell disease often experience aplastic crisis after infection with parvovirus B19, which has a predilection for infecting rapidly dividing cell lines (e.g., bone marrow erythroid progenitor cells). Look for pancytopenia (anemia, leukopenia, and thrombocytopenia) with low reticulocyte count on peripheral blood smear after a febrile illness with or without joint pain and rash in children.

Essential thrombocytosis causes:

hyperproliferation of megakaryocytes in the bone marrow.

Epstein-Barr virus

identified in approximately 50% of systemic B-cell lymphomas and almost all primary lymphomas occurring in the setting of HIV infection. A high mitotic index is typical of Burkitt lymphoma.

Fanconi anemia

which is caused by mutation of DNA repair genes, manifests in most children between ages six and nine years. Patients with Fanconi anemia usually have short stature; café au lait spots; and anomalies involving the thumb, radius, and genitourinary tract. The disease is inherited in an autosomal recessive or X-linked fashion. These patients have aplastic anemia (characterized by pancytopenia—low white blood cells, red blood cells, and platelets—and bone marrow hypocellularity).

Beta Thalassemia major

(B0/B0=No B-globin production) is the most severe form of disease and presents with severe anemia a few months after birth with failure to thrive, cardiomegaly and bone marrow expansion; high HbF at birth is temporarily protective. DEFECT IN BETA-GLOBULIN mRNA FORMATION *Hemosiderin accumulation is the cardinal histologic finding 1. Unpaired a chains precipitate and damage RBC membrane, resulting in ineffective erythropoiesis and extravascular hemolysis (removal of circulating RBCs by the spleen). 2. Massive erythroid hyperplasia ensues resulting in (a) expansion of hematopoiesis into the skull (reactive bone formation leads to 'crewcut' appearance on x-ray) and facial bones ('chipmunk facies') (b) plastic crisis with parvovirus B19 infection of erythroid precursors. 3. Chronic transfusions are often necessary; leads to risk for secondary hemochromatosis *Iron overload (hemosiderosis is a common and serious complication of chronic hemolytic anemia and frequent blood transfusions) 4. Smear shows microcytic,hypochromic RBCs with target cells and nucleated red blood cells 5. Electrophoresis shows and HbF with little or no HbA, -asymptotic at birth via gamma-globins and HbF -switching to HbA production and the cessation of gamma globin precipitates the symptoms

Osteosarcoma

-Conventional x-ray --Signs of osteolysis adjacent to osteosclerosis (moth eaten appearance) --Sunburst appearance of lytic bone lesions and/or codman triangles -Most common primary bone malignancy . -Increased incidence in patients with retinoblastoma (Rb suppressor gene same as Osteosarcoma) and Li-Fraumeni syndrome (A risk factor for "BLANK" is retinoblastoma, which is caused by a defect in the Rb gene that inhibits the G1-to-S progression in the cell cycle, when it is not phosphorylated.)

Chondrosarcoma (HISTO)

*Hyaline cartilage matrix with small calcifications -made up of cartilage that permeates = surrounds and entraps bone (*hallmark of malignant cartilage tumor*) -sharp junction between cartilage and sarcoma

Thrombotic Thrombocytopenic Purpura (TTP) CNS sxs!

-ADAMSTS13 deficiency or autoantibody one of several primary thrombotic microangiopathies resulting in microangiopathic hemolytic anemia(INCREASED LDH, DECREASED haptoglobin) and thrombocytopenia (INCREASED bleeding time, normal PT/PTT), which are essential to the diagnosis. Plasma exchange has prompted more rapid diagnosis and is life-saving. -characterized by clotting in small blood vessels of the body, resulting in a low platelet count. -Patients with TTP have unusually large multimers of von Willebrand factor (vWF) in their plasma. Patients with TTP lack a plasma protease that is responsible for the breakdown of these ultra-large vWF multimers. *ADULTS and Neurological symptoms FAT RN: Fever Anemia Thrombocytopenia Renal failure (MC in HUS) Neurological symptoms

Beta Thalassemia Minor

-B-Thalassemia Minor (B/B+) -mildest form of disease -usually asymptomatic with inc RBC count -microcytic, hypochromic RBCS and target cells on blood smear** -Hb electrophoresis findings -slightly dec HbA -inc HbA2 to 5% (normal 2.5%)*** -inc HbF to 2%

Heparin-induced thrombocytopenia (HIT)

-Development of IgG antibodies against heparin- bound platelet factor 4 (PF4). -Antibody-heparin-PF4 complex activates platelets leading to thrombosis and isolated thrombocytopenia. Thrombosis is a feared complication -fragments of destroyed platelets may activate remaining platelets, leading to thrombosis *non-immune-mediated condition caused by platelet clumping generally 5-10 years s/p exposed to heparin therapy

Hemoglobin A/S/C (C has LYSINE)

-Hemoglobin C is caused by Missense mutation that results in a glutamate residue being substituted by lysine in the beta globin chain -this results in overall decrease in negative charge for the hemoglobin molecule -the speed of hemoglobin movement during gel electrophoresis is hemoglobin a > hemoglobin S > hemoglobin C

Hodgkin's lymphoma

-Hodgkin's lymphoma arises from germinal center B cells. -The disease is most common in young adults around 20-years-old and also in the elderly in the sixth decade of life. -The most common presentations include non-tender lymphadenopathy in the neck or mediastinum. -Hodgkin's lymphoma is defined by the presence of diagnostic Reed-Sternberg cells on histological examination. These are large cells with slightly basophilic cytoplasm that have a bilobed nucleus with eosinophilic inclusions of nucleoli -On cytological evaluation, the Reed-Sternberg cells express CD 15 and CD 30 positivity. --CD 15 is found on neutrophils and is responsible for the phagocytosis and chemotaxis of neutrophils. --CD 30 is a tumor necrosis factor receptor protein that leads to activation of NF-kappaB. NF-kappaB prevents apoptosis and promotes cell proliferation. --Hodgkin's lymphoma does not express the pan-B cell antigens CD 19 and CD 20 or the pan-T cell antigens CD 3 and CD 7. MC subtype is nodular and most aggressive is lymphocyte-depleted and best prognosis is lymphocyte rich Hodgkin lymphoma presents with nonspecific symptoms (fevers, night sweats, weight loss) and lymphadenopathy, particularly of the cervical and supraclavicular regions.

Acute Promyelocytic Leukemia (APL)

-M3 variant of AML APL is a cancer of the blood resulting in the accumulation of immature white blood cells (Promyelocytes) -can present with persistent infection and coagulopathy causing hemorrhagic signs and symptoms. classically reveals promyelocytes with intracytoplasmic Auer rods(rod-shaped intracytoplasmic inclusions that are deformed azurophilic granules found in the cytoplasm of myeloblasts that stain positively for myeloperoxidase). -t 15;17 causes fusion of retinoid acid receptor with promyelocyte leukemia gene (disruption in Retinoic Acid Receptor) -Treatment with all-trans-retinoic acid (ATRA), vitamin A derivative relieves the repression by PML-RARα and restores the differentiation of promyelocytes into mature leukocytes "Old guy with glasses working on apple (APL) computer, had a girlfriend named ATRA (All Trans Retinoic Acid), she had a DIC (Emergent condition), so he was a FAG GOT (Cell)."

Diffuse large B-cell lymphoma

-MC NHL -presents with enlarging nodal (neck, abdomen, mediastinum) or extra-nodal symptomatic mass -B symptoms: --fever, weight loss, drenching night sweats *arises sporadically or from transformation of a low-grade lymphoma Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and involves aggressive malignant transformation of B cells. DLBCL is diagnosed with lymph node biopsy revealing large lymphocytes that stain positive for B-cell antigens CD19, CD20, CD22, PAX5, and CD79a. "6 Big Chocolate Latte's with a Grandma (CD79a) and her two nieces (CD19 & CD 20)."

Factor V Leiden

-MC hereditary thrombosis/hypercoaguable state -is resistant to degradation by Protein C/S. -results in hypercoaguable state predisposes to deep vein thrombosis

Hematagenous Osteomyelitis

-MC in children and usually effects the metaphysis of long bone due to the slower blood flow and capillary fenestrae in this region

Follicular Lymphoma (Non-hodgkin Lymphoma)

-MC indolent non-hodgkin lymphoma in adults -B cell tumor made up of centrocytes -t(14;18) translocation -results in over-expression of BCL-2 (antiapoptotic gene product) *BCL-2 normally stabilizes the mitochondrial membrane, blocking release of cytochrome C *Disruption of BCL-2 allows cytochrome c to leave the mitochondria and activate apoptosis -histology is notable for cleaved and noncleaved follicle center cells *presents with painless waxing and waning lymphadenopathy Treatment is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab (anti-CI)20 antibody). "I went to the MaLL (MLL2 Mutation) in FALL (Follicular), to buy some transformers (Transforms to Diffuse Large Cell), they were cheap, only $10 (CD10), hollow on the inside (follicles without normal architecture) and had 2 Big Crusty Lesions (BCL-2)."

Phenytoin (anticonvulsant)

-MOA:inhibit sodium influx into neurons, thereby decreasing their ability for depolarization -inhibits intestinal conjugase, an enzyme necessary to convert folate into an absorbable form in the jejunum

Burr Cells, Helmet Cells (Schistocytes)

-Mechanical Red Cell Destruction or microangiopathic hemolytic anemia (HUS) -Pt's with Prosthetic Valves.

Warfarin and Heparin Overdose

-Warfarin treatment is Vitamin K or FFP *Rodenticides are superwarfarin -Heparin treatment is Protamine

Leukemoid reaction

-a benign leukocytosis (> 50,000) that occurs in response to underlying severe infection/hemorrhage, malignancy, or acute hemolysis. -Smear can show increased bands, early neutrophil precurors myelocytes, and granules (Döhle bodies) in the neutrophils.

Polycythemia Vera

-a myeloproliferative disorder characterized by uncontrolled erythrocyte production. -symptoms: --pruritis after bathing --eythromelalgia (erythematous, burning extremities) --facial plethora (reddish complexion) --splenomegaly --blurry vision and headache --INC DVT--> Budd chiari (Thrombosis in hepatic vein --> infarction of liver) MCC of budd chiari is PV -Virtually all patients with polycythemia have a mutation in JAK2, a (non-receptor) cytoplasmic tyrosine kinase associated with EPO receptor. Treatment is phlebotomy; second-line therapy is hydroxyurea. - Without treatment, death usually occurs within one year.

Pernicious Anemia ($)

-cell mediated,CD4+ mediated destruction, of parietal cells (normally secrete HCL and intrinsic factor(absorption of B12)) in the superficial upper glandular layer of the gastric body and fundus. - resulting in elevated intraluminal pH that leads to up-regulation of gastrin secretion

Ewing sarcoma ($)

-classic X-ray is concentric "onion-skin" layering of the periosteum. It is associated with a genetic translocation involving t(11;22), EWSR1 and FLI1 -composed of small anaplastic blue cells with hyperchromatic nuclei and scant cytoplasm and patches of necrosis and hemorrhage -2nd MC malignant bone tumor of childhood (after osteosarcoma) -MC involves lower extremity and pelvis and often mets to lung

Hairy Cell Leukemia

-commonly presents in males in the fifth decade of life. -Patients can present with splenomegaly and pancytopenia *Dry tap (unsuccessful bone marrow aspiration) -They can also have systemic complaints such as fatigue, weakness, and weight loss. Easy bruising and bleeding secondary to severe thrombocytopenia is also a prominent feature. -Physical examination would reveal splenomegaly via expanison of red pulp. Hepatomegaly and lymphadenopathy are not common features of "BLANK" -Laboratory results reveal an anemia, neutropenia, and thrombocytopenia. The malignant cell in hairy cell leukemia is a B lymphocyte that expresses the pan B-cell surface antigens CD 19, CD 20, and CD 22. The cell also expresses the surface antigen CD11c that is normally seen on neutrophils and macrophages. -The nuclei are often eccentric in position, with a reticular chromatin pattern without nucleoli. There is abundant cytoplasm with a pale blue color, and is often described as looking fluffy in appearance. The presence of the pathognomonic cytoplasmic projections on a peripheral blood smear gives the cell its hairy or ruffled appearance. -The diagnosis is confirmed with a tartrate-resistant acid phosphatase test (TRAP). Treatment: 2-CDA (cladribine), and ADA inhibitor leads to accumulation of adenosine and death of neoplastic b cell

Porphyria cutanea tarda (PCT)

-deficient enzyme: uroporphyrinogen decarboxylase -can be sporadic, acquired due to hepatitis, or ethanol abuse -symptoms: uroporphyrin III (ALONE) is formed and found in high levels in urine (red pee/pink/tea in fluorescent light), blood and skin, these are photosensitive and can form radicals upon exposure to light, this leads to blisters, poor wound healing and ulcers

Findings of systemic inflammation or infection

-dohle bodies -increased bands (left shift) -toxic granulation (image) -cytoplasmic vacuoles

Hemolytic Uremic Syndrome (HUS) Renal sxs!

-due to endothelial damage by drugs or infection. 1. Classically seen in children with E coli O157.H7 dysentery, which results from exposure to undercooked beef 2. E coli. verotoxin damages endothelial cells resulting in platelet microthrombi. Serious condition characterized by red blood cell breakdown and kidney failure -Decreased haptoglobin and hemoglobin -Increased LDH and unconjugated bilirubin levels *CHILDREN and RENAL FAILURE FAT RN: Fever Anemia Thrombocytopenia Renal failure Neurological symptoms (MC in TTP)

Chronic Myelogenous Leukemia (CML)

-due to the chromosomal translocation of t(9;22), which is known as the Philadelphia chromosome. *INCREASE IN NEUTROPHILS* -It results in the formation of the gene product BCR-ABL1 (tyrosine kinase activity). -Chronic myelogenous leukemia is suspected in a patient with the systemic complaints of fatigue, malaise, weight loss, and hepatosplenomegaly. -Laboratory findings reveal an elevated white blood cell count with an associated anemia, and thrombocytosis. There is an increase in mature dysfunctional granulocytes specifically BASOPHILS. These granulocytes have decreased apoptosis which results in accumulation of long-lived cells with low or absent enzymes, such as alkaline phosphatase. -myeloproliferative disorder Treatment: Imantinib that blocks tyrosine kinase activity *can transform to AML or ALL CML is distinguished from a leukemoid reaction (reactive neutrophilic leukocytosis) by: 1. Negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a leukemoid reaction are LAP positive) 2. Increased basophils (absent with leukemoid reaction) 3. t(9;22) (absent in leukemoid reaction) "At 9:22(Philadelphia chromosome), a Camel (CML) on top of clock, with a Liberty bell (Philadelphia chromosome and BCR-ABL) is waiting for Tires (Tyrosine Kinase, ABL encodes) and Basil (Increase in Basophils)." Chronic myelogenous leukemia is a myeloproliferative disorder that is characterized by granulocytosis with granulocytic immaturity, anemia, thrombocytosis, and splenomegaly. The most common presentation is with constitutional symptoms and abdominal fullness.

Heparin and LMWH heparin

-increases the effect of naturally occurring anticoagulant antithrombin III (ATIII) unfractioned heparin: -binds to anti thrombin 3 which acts to deactivate thrombin AND factor Xa low molecular heparin: -still activates anti thrombin 3 but acts to deactivate mostly factor Xa not so much thrombin!

acute lymphoblastic leukemia (ALL) ($)

-most common in adolescent and young adult males. *T-cell lymphoma -associated with Down syndrome after 5 years old -Patients are usually in their early twenties, and most commonly present with a mediastinal mass, lymphadenopathy, hepatosplenomegaly, fever, bleeding and bone pain. They may also present with SOB and cervical or supraclavicular lymphadenopathy. -"BLANK" is diagnosed if there are greater than 25% lymphoblasts in the bone marrow. The lymphoblasts replace the normal bone marrow elements, resulting in a decrease in the production of normal red blood cells and platelets. Consequently, anemia and thrombocytopenia occur. -On flow cytometry, the T-cell lymphoblasts are positive for CD3 and CD7. -The T-cell lymphoblasts stain positively for terminal deoxynucleotidyl transferase (TdT), a DNA polymerase, and negatively for myeloperoxidase. -The diagnosis of T-cell lymphoblastic leukemia is made based upon a bone marrow aspirate and biopsy. 6-Mercaptopurine (6-MP) is used in the maintenance phase of chemotherapy for acute lymphoblastic leukemia (ALL). The mechanism of action is through the inhibition of purine synthesis. 6-Mercaptopurine is a structural analog of the purine bases, adenine and guanine, and reduces de novo production of endogenous purines halting the DNA synthesis phase of the cell cycle. "Mr. T (TdT) went to ALLabama to sell CD's at 34 years old (CD34) and lost his hot rod (NO AUER RODS)."

Osteoclast differentiation

-nuclear factor kappa B (RANK)/RANK ligand (RANL-L) interaction is essential for the formation and differentiation of osteoclasts -Osteoprotegerin blocks RANK-L to RANK and reduces formation of mature osteoclasts -low estrogen causes osteoporosis by decreasing Osteoprotegerin production--> increasing RANK-L production and increasing RANK expression in osteoclast precursors

Aplastic Anemia

-pancytopenia with bone marrow hypocellularity with fat and stromal cells *NO splenomegaly Triad of: -low hemoglobin -thrombocytopenia -absent hematopoietic cells in the bone marrow *compensatory increase in circulating erythropoietin levels would be expected in individuals with "blank" and normal renal function The most common congenital form of aplastic anemia is Fanconi anemia, caused by a mutation of DNA repair genes. Patients present with short stature, repeated infections, and pancytopenia.

Vitamin B12 def (CHART)

-presents with megaloblastic anemia (impaired DNA synthesis) and neurologic deficits (impaired mylein synthesis). -Neurologic findings include subacute combined degeneration of the dorsal columns and lateral corticospinal tract. A. Dietary vitamin B12 is complexed to animal-derived proteins. 1. Salivary gland enzymes (e.g., amylase) liberate vitamin B12, which is then bound by R-binder (also from the salivary gland) and carried through the stomach. 2. Pancreatic proteases in the duodenum detach vitamin B12 from R-binder. 3. Vitamin B12 binds intrinsic factor (made by gastric parietal cells) in the small bowel; the intrinsic factor-vitamin B12 complex is absorbed in the ileum. B. Vitamin Bl2 deficiency is less common than folate deficiency and takes years to develop due to large hepatic stores of vitamin B12. C. Pernicious anemia is the most common cause of vitamin B12 deficiency 1. Autoimmune destruction of parietal cells (body of stomach) leads to intrinsic factor deficiency D. Other. causes of vitamin B12 deficiency include pancreatic insufficiency and damage to the terminal ileum (e.g., Crohn disease or Diphyllobothrium latum [fish. tapeworm]); dietary deficiency is rare, except in vegans. F. Subacute combined degeneration of the spinal cord i. Vitamin Bl2 is a cofactor for the conversion of methylmalonic acid to succinyl CoA (important in fatty acid metabolism). ii. Vitamin B12 deficiency results in increased levels of methylmalonic acid, which impairs spinal cord myelinization. iii. Damage results in poor proprioception and vibratory sensation (posterior column) and spastic paresis (lateral corticospinal tract).

Hepcidin and body iron regulation

-primary mediator is hepcidin (a peptide released from the liver that inhibits iron channels on enterocytes and reticuloendothelial macrophages Increased iron and inflammatory conditions--> increased hepcidin Hypoxia and increased erythropoiesis act to lower hepcidin levels Low hepcidin levels increase intestinal iron absorption and stimulate iron release by macrophages

Spherocytosis

-results from red cell cytoskeleton abnormalities, MC spectrin, ankyrin and band cells -Hemolytic anemia, jaundice and splenomegaly -mean corpuscular hemoglobin concentration (MCHC) is increased due to mild dehydration of the red blood cell. -Markers of hemolysis are often evident and include elevated lactate dehydrogenase, reticulocytosis and decreased haptoglobin

Acute Myelogenous Leukemia (AML)

-symptoms related to complications of pancytopenia. This includes generalized fatigue, shortness of breath, dyspnea on exertion, pallor, weakness, excess bleeding, easy bruising, gingival bleeding, ecchymoses, epistaxis, or menorrhagia. -Analysis of the peripheral blood will usually reveal an elevation in circulating myeloblasts. Myeloblasts are immature cells with large nuclei, prominent nucleoli, and a pale blue cytoplasm. Myeloblasts in acute myelogenous leukemia can be distinguished with a positive myeloperoxidase stain (most AML subsets). -Myeloperoxidase is an enzyme in the azurophilic granules of neutrophils and in the lysosomes of monocytes. Its major role is to aid in microbial killing. Myeloperoxidase catalyzes the conversion of hydrogen peroxide and chloride ions into hypochlorous acid for microbial killing. -Definitive diagnosis of acute myelogenous leukemia is made with bone marrow biopsy which displays greater than 25% myeloblasts. Myeloblasts have 1-4 nucleoli high nuclear-to-cytoplasmic ratios and often contain Auer rods (azurophilic, needle-shaped granules)The bone marrow is hypercellular due to replacement of the normal cellular components of the marrow by immature or undifferentiated cells, and thus results in an associated anemia and thrombocytopenia "Amelia RUN (RUNX1/RUNX1T1) home at 8:21 (translocation) to grab fishing RODS (AUER RODS PRESENT), she was going Down (Down Syndrome Trisomy 21) Benzene way (Benzene and Chemotherapy=risk factors with Down syndrome) to invite 16 CB to FB (Second Version of AML, inv(16) and CBFB-MYH11)." Acute myelogenous leukemia, or AML, is a hematopoietic malignancy characterized by overproduction of blast cells that accumulate in the marrow and lead to abnormal production of other blood cells. The clinical presentation of AML is related primarily to anemia and thrombocytopenia with symptoms of fatigue, weakness, and dyspnea as well as easy bleeding and bruising.

Burkitt's lymphoma

-translocation of the C-MYC gene (transcription activator) of chromosome 8, usually the Ig hevay chain region of chromosome 14[t(8:14)] translocation; associated with EBV -"starry sky" -highly aggressive but responsive to chemotherapy -growing masses in facial bone, jaw or abdomen "Ki-67 , a African boy, was singing (C-MYC) at the Apollo (REAL STARRY SKY) for 10 nights for 2-6 minutes (BCL-2/6). -TINGIBLE MACROPHAGES"

Paroxysmal Nocturnal Hemoglobinuria (PNH)

-triad of hemolytic anemia, hyper-coagulability and pancytopenia -aquired mutation in the PIGA gene that causes absence of the GP-1 anchor (glycosylphosphatidylinositol) -Chronic hemolysis can cause iron deposition in the kidney (hemosiderosis) -def in CD55 and CD59 complement inhibitor proteins A. Acquired defect in myeloid stem cells resulting in absentglycosylphosphatidylinositol (GP1); renders cells susceptible to destruction by complement 1. Blood cells coexist with complement. 2.Decay accelerating factor (DAF) on the surface of blood cells protects against complement-mediated damage by inhibiting C3 convertase. 3. DAF is secured to the cell membrane by Gpl (an anchoring glycolipid). 4. Absence of GPI leads to absence of DAE rendering cells susceptible to complement-mediated damage. B. Intravascular hemolysis occurs episodically, often at night during sleep. 1. Mild respiratory acidosis develops with shallow breathing during sleep and activates complement. 2. RBCs, WBCs, and platelets are lysed. 3. Intravascular hemolysis leads to hemoglobinemia and hemoglobinuria (especially in the morning); hemosiderinuria is seen days after hemolysis. or flow cytometry to detect lack of CD55 (DAF) on blood cells. D. Main cause of death is thrombosis of the hepatic, portal, or cerebral veins. 1. Destroyed platelets release cytoplasmic contents into circulation, inducing thrombosis. E. Complications include iron deficiency anemia (due to chronic loss of hemoglobin in the urine) and acute myeloid leukemia (AML), which develops in 10% of" patients.

Anemia of chronic disease (INC. Ferritin and DEC. TIBC)

-triggered by long-standing elevation in serum inflammatory cytokines -primary mediator is hepcidin (a peptide released from the liver that inhibits iron channels on enterocytes and reticuloendothelial macrophages), basically sequesters iron in storage sites and dec EPO production (on labs will show INC EPO) -Microcytic anemia with ↓ serum iron, ↓ total iron-binding capacity (TIBC), and normal or ↑ ferritin.

Warfarin

-vitamin K antagonist that blocks epoxide reductase in the liver --this depletes reduced form of vitamin K which is needed for vitamin K -dependent clotting factors (2,7,9, and 10) -Inhibits proteins C and S, which can lead to skin necrosis --if taking abx that target gram negative bacteria(metronidazole, macrolides, FQ) can develop supra-therapeutic INR via disruption of vitamin K-producing intestinal flora -therapeutic efficacy is delayed until preexisting clotting factors in the plasma are consumed -therapeutic effect does not occur until 3 days due to the long half-life of factor 2

Macrophages

1. Activated by gamma-interferon. 2. Can function as antigen-presenting cell via MHCII. 3. Name differs in each tissue type: -Kupffer cells in liver, -histiocytes in connective tissue -Langerhans cells in skin -Osteoclasts in bone -Microglial cells in brain. Important component of granuloma formation (eg. TB, sarcoidosis). Lipid A from bacterial LPS binds CD14 on macrophages to initiate septic shock.

Immunologic blood transfusion reactions

1. Delayed Hemolytic transfusion reaction are usually mild hemolytic reactions that occur>24 hrs s/p blood transfusion -type of anamnestic response (delayed immunologic response) that occurs in patients previously exposed to a minor RBC antigen (eg pregnancy or previous blood transfusion)

Nonmegaloblastic macrocytic Vs. Megaloblastic macrocytic anemia

1. Nonmegaloblastic macrocytic anemia:(neutrophils are not hypersegmented) -Alcoholism -chronic liver disease -myelodyplastic syndromes -hypothyroidism 2. Megaloblastic macrocytic anemia:(neutrophils are hypersegmented) -vitamin B12 and -folate deficiency.

Ewing Sarcoma (HISTO)

1. Small, round blue cells that resemble lymphocytes (confused w/ lymphoma, osteomyelitis esp. b/c it can cause *fever*)

Vitamin K deficiencies

1. Typically seen in fat malabsorption (cystic fibrosis) 2. Hemorrhage due to decrease vitamin K dependent clotting factors -neonatal hemorrhage (all neonate routinely given vitamin K injection at birth, b/c lack of GI colonization by bacteria that normally synthesize vitamin K) 3. Laboratory findings: -increased PT (most affected due to factor VII deficiency because it has shortest half life) *Vitamin K is necessary to gamma carboxylation of clotting factors II, VII, IX, X (produced in liver) and proteins C and S (these are anticoagulant proteins), VIA epoxide reductase *warfarin blocks epoxide reductase

Direct Coombs-positive hemolytic anemia

Penicillin, methylDopa, Cephalosporins P Diddy Coombs

Causes of endothelial cell damage include atherosclerosis, vasculitis, and high levels of homocysteine.

1. Vitamin B12 and folate deficiency result in mildly elevated homocysteine levels, increasing the risk for thrombosis. i. Folic acid (tetrahydrofolate, THF) circulates as methyl'THF in the serum. ii. Methyl is transferred to cobalamin (vitamin B12), allowing THF to participate in the synthesis of DNA precursors. iii. Cobalamin transfers methyl to homocysteine resulting in methionine. iv. Lack of vitamin Bl 2 or folate leads to decreased conversion of homocysteine to methionine resulting in buildup of homocysteine.

Lab characteristics of coagulopathies

1. aPTT -Intrinsic coagulation cascade -Factors 12, 11, 9, 8 -associated with heparin ( 30-60 seconds) 2. PT -Extrinsic Coagulation cascade -Factors 7 and 3 -associated with warfarin levels (INR 2-3) *Common pathway: -Factors 10, 5, 2 (thrombin), 1 (fibrin) and 13a (cross-linked fibrin clot)

charcteristic of anaplastic tumor

1. loss of cell polarity with disruption of normal tissue architectures 2. variation ins shape and size of cell and nuclei 3.Disproportionally large nuclei often deep staining (hyperchromic) w/ abundant coarsely clumped and large nucleoli 4. Giant multi-nucleated tumor cells 5. numerous, of abnormal mitotic figures

Fat embolus

A. "BLANK" is associated with bone fractures, particularly long bones, and soft tissue trauma. 1. Develops while fracture is still present or shortly after repair 2. Characterized by dyspnea (fat, often with bone marrow elements, is seen in pulmonary vessels and petechiae on the skin overlying the chest

Antithrombin III deficiency

A. "BLANK"ecreases the protective effect of heparin-like molecules produced by the endothelium, increasing the risk for thrombus and coagulation factors. 1. Heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors. 2. In ATI 11 deficiency, PTT does not rise with standard heparin dosing. i. Pharmacologic heparin works by binding and activating ATIII. ii. High doses of heparin activate limited ATIII; coumadin is then given to maintain an anticoagulated state.

Hemophilia A/EIGHT ($)

A. Genetic factor VIII (FVIII) deficiency 1. X-linked recessive (predominantly affects males) 2. Can arise from a new mutation (de novo) without any family history B. Presents with deep tissue, joint, and post surgical bleeding 1. Clinical severity depends on the degree of deficiency C. Laboratory findings include 1. INCREASE PTT; normal PT 2. DECREASE Factor 8 3. Normal platelet count and bleeding time D. Treatment involves recombinant FVIII. -Emicizumab-mimics factor 8 -deletions in enhancer sequence

Amniotic embolus

A. Amniotic fluid embolus enters maternal circulation during labor or delivery 1. Presents with shortness of breath, neurologic symptoms, and DIC (due to the thrombogenic nature of amniotic fluid) 2. Characterized by squamous cells and keratin debris, from fetal skin, in embolus

Sideroblastic anemia

A. Anemia due to defective protoporphyrin synthesis 1. DEC protoporphyrin —> DEC heme -> DEC hemoglobin -> microcytic anemia B. Protoporphyrin is synthesized via a series of reactions. 1. Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to aminolevulinic acid (ALA) using vitamin B6 as a cofactor (rate-limiting step). 2. Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen. 3. Additional reactions convert porphobilinogen to protoporphyrin. 4. Ferrochelatase attaches protoporphyrin to iron to make heme (final reaction; occurs in the mitochondria). C. Iron is transferred to erythroid precursors and enters the mitochondria to form heme. If protoporphyrin is deficient, iron remains trapped in mitochondria. 1. Iron-laden mitochondria form a ring around the nucleus of erythroid precursors; these cells are called ringed sideroblasts (hence, the term sideroblastic anemia) D. Sideroblastic anemia can be congenital or acquired. 1. Congenital defect most commonly involves ALAS (rate-limiting enzyme). 2. Acquired causes include i. Alcoholism—mitochondrial poison Lead poisoning—inhibits ALAD and ferrochelatase iii. Vitamin B6 deficiency—required cofactor for ALAS; most commonly seen as a side effect of isoniazid treatment for tuberculosis E. Laboratory findings include INC. ferritin, DEC. TIBC, INC serum iron, and INC % saturation (iron-overloaded state). Sideroblastic anemia is due to defective heme synthesis. Peripheral smear will reveal ringed sideroblasts (staining blue for iron on Prussian blue stains). Sideroblastic anemia is a result of pyridoxine deficiency (reversible causes are alcohol, isoniazid, and lead poisoning). The first step of treatment is pyridoxine replacement in addition to removing the offending agent.

Autoimmune Hemolytic Anemia (AHA)

A. Antibody-mediated (IgG or IgM) destruction of RBCs B. IgG-mediated disease usually involves extravascular hemolysis. 1. IgG binds RBCs in the relatively warm temperature of the central body (warm agglutinin); membrane of antibody-coated RBC is consumed by splenic macrophages, resulting in spherocytes. 2. Associated with SLE (most common cause), QlL> and certain drugs (classical^ penicillin and cephalosporins) i. Drug may attach to RBC membrane (e.g., penicillin) with subsequent binding of antibody to drug-membrane complex ii. Drug may induce production of autoantibodies (e.g., a-methyldopa) that bind self antigens on RBCs 3. Treatment involves cessation of the offending drug, steroids, IV1Q, and, if necessary, splenectomy C. IgM-mediated disease can lead to intravascular hemolysis. 1. IgM binds RBCs and fixes complement in the relatively cold temperature ofthe extremities (cold agglutinin). 2. RBCs inactivate complement, but residual C3b serves as an opsonin for splenic macrophages resulting in spherocytes; extreme activation of complement can lead to intravascular hemolysis. 3. Associated with Mycoplasma pneumoniae and infectious mononucleosis. D. Coombs test is used to diagnose IHA; testing can be direct or indirect. 1. Direct Coombs test confirms the presence of antibody- or complement-coated RBCs. When anti-IgG/complement is added to patient RBCs, agglutination occurs if RBCs are already coated with IgG or complement. This is the most important test for AHA. 2. Indirect Coombs test confirms the presence of antibodies in patient serum. AntiIgG and test RBCs are mixed with the patient serum; agglutination occults if serum antibodies are present.

Qualitative Platelet Disorders

A. Bernard-Soulier syndrome is lack of GP1b, which is vWF receptor so that platelet adhesion is impaired -enlarged platelets B. Glanzmann thrombasthenia is due to GPIIb/IIIa. platelet aggregation is impaired C. Aspirin inactivates cyclooxygenase, lack of TXA, impairs aggregation D. Uremia disrupts platelet aggregation and adhesion

Iron Deficiency Anemia (IDA) (DEC. Ferritin and INC. TIBC)

A. Due to decreased levels of iron LOW iron —> LOW heme -> LOW hemoglobin —> microcytic anemia B. Most common type of anemia 1. Lack of iron is the most common nutritional deficiency in the world, affecting roughly 1/3 of worlds population. C.Iron is consumed in heme (meat-derived) and non-heme (vegetable-derived) forms. 1. Absorption occurs in the duodenum. Enterocytes have heme and non-heme (DMT1) transporters; the heme form is more readily absorbed. 2. Enterocytes. transport iron across the cell membrane into blood via ferroportin 3. Transferrin transports iron in the blood and delivers it to liver and bone marrow macrophages for storage. 4. Stored intracellular iron is bound to ferritin, which prevents iron from forming { free radicals via the Fenton reaction. E. Iron deficiency is usually caused by dietary lack or blood loss. 1. Infants—breast-feeding (human milk is low in iron) 2. Children—poor diet 3. Adults (20-50 years)—peptic ulcer disease in males and menorrhagia or pregnancy in females 4, Elderly—colon polyps/carcinoma in the Western world; hookworm (Ancylostoma duodenale and Necator americanus) in the developing world 5. Other causes include malnutrition, malabsorption, and gastrectomy (acid aids iron absorption by maintaining the Fe2+ state, which is more readily absorbed than Fe3+). G. Clinical features of iron deficiency include anemia, koilonychia, and pica, I. Treatment involves supplemental iron (ferrous sulfate). J. Plummer Vinson syndrome is iron deficiency anemia with esophageal web and atrophic glossitis; presents as anemia, dysphagia, and beefy-red tongue INCREASED RED CELL DISTRIBUTION WIDTH

Von Willebrand Disease ($)

A. Genetic vWF deficiency 1. Most common inherited coagulation disorder B. Multiple subtypes exist, causing quantitative and qualitative defects; the most common type is autosomal dominant with decreased vWF levels. *vWF is a carrier protein for factor VIII, thus, the loss of factor VIII function results in prolonged PTT (50% of those affected). C. Presents with mild mucosal and skin bleeding; low vWF impairs platelet adhesion, but normal platelet count. D. Laboratory findings include 1. INCREASED bleeding time 2. INCREASED or normal PTT; normal PT—Decreased Factor 8 half-life (vWF normally stabilizes Factor 8); however, deep tissue, joint, and post-surgical bleeding are usually not seen. 3. Abnormal ristocetin test—Ristocetin induces platelet agglutination by causing vWF to bind platelet GPIb; lack of vWF--> impaired agglutination-->abnormal test. * vWF promotes platelet adhesion via cross linking platelet glycoproteins (GpIb) with exposed collagen underneath damaged endothelium & *vWF functions as a protective carrier protein for Factor 8 that increases its plasma half life E. Treatment is desmopressin (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells. -vWF also promotes platelet adhesion and plug formation, so a deficiency will lead to prolonged bleeding time

Herediatry Spherocytosis

A. Inherited defect of RBC cytoskeleton-membrane tethering proteins 1. Most commonly involves ankyrin, spectrin, or band 3 B. Membrane blebs are formed and lost over time. 1. Loss of membrane renders cells round (spherocytes) instead of disc-shaped. 2. Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages, resulting in anemia. C. Clinical and laboratory findings include 1. Spherocytes with loss of central pallor 2. INC RDW and INC mean corpuscular hemoglobin concentration (MCHC) 3. Splenomegaly, jaundice with unconjugated bilirubin, and increased risk for bilirubin gallstones (extravascular hemolysis) 4. Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors D. Diagnosed by osmotic fragility test, which reveals increased spherocyte fragility in hypotonic solution E. Treatment is splenectomy; anemia resolves, but spherocytes persist and Howell-Jolly bodies=spleen disfunction (fragments of nuclear material in RBCs) emerge on blood smear.

Thrombosis: Basic principles

A. Most common location is the deep veins (DVT) of the leg below the knee. B. Characterized by lines of Zahn (alternating layers of platelets/fibrin and RBCs) and attachment to vessel wall 1. Both features distinguish thrombus from postmortem clot. C. Three major risk factors for thrombosis are disruption in blood flow, endothelial cell damage, and hypercoagulable state (Virchow triad).

Adult T-Cell Leukemia/Lymphoma (ATLL)

A. Neoplastic proliferation of mature CD4+ T cells B. Associated with HTLV-I; most commonly seen in Japan and the Caribbean C. Clinical features include rash (skin infiltration), generalized lymphadenopathy with hepatosplenomegaly, and lytic (punched-out) bone lesions with hypercalcemia.

Mycosis fungoides/Sezary syndrome

A. Neoplastic proliferation of mature CD4+ T cells that infiltrate the skin, producing localized skin rash, plaques, and nodules. Aggregates of neoplastic cells in the epidermis are called Pautrier microabscesses. B. Cells can spread to involve the blood, producing Sezary syndrome. 1. Characteristic lymphocytes with cerebriform nuclei (Sezary cells) are seen on blood smear

Marginal Zone Lymphoma

A. Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone B. Associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis 1. The marginal zone is formed by post-germinal center B cells. C. MALToma is marginal zone lymphoma in mucosal sites. 1. Gastric MALToma may regress with treatment of H Pylori.

Disseminated Intravascular Coagulation (DIC) ($)

A. Pathologic activation of the coagulation cascade 1. Widespread microthrombi result in ischemia and infarction. 2. Consumption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces (bleeding from body orifices). B. Almost always secondary to another disease process 1. Obstetric complications—Tissue thromboplastin in the amniotic fluid activates coagulation. 2. Sepsis (especially with E Coli or N meningitidis)—Endotoxins from the bacterial wall and cytokines (e.g., TNF and IL-1) induce endothelial cells to make tissue factor. 3. Adenocarcinoma—Mucin activates coagulation. 4. Acute promyelocytic leukemia—Primary granules activate coagulation. 5. Rattlesnake bite—Venom activates coagulation. C. Laboratory findings include 1. DECREASE platelet count 2. INCREASE PT/PTT = consumption of clotting factors 3. INCREASE in bleeding time 4. DECREASE fibrinogen 4. Microangiopathic hemolytic anemia 5. Elevated fibrin split products, particularly D-dimer -Elevated D-dimer is the best screening test for DIC. -Deprived from splitting of cross-linked fibrin; D-dimer is not produced from splitting of fibrinogen. D. Treatment involves addressing the underlying cause and transfusing blood products and cryoprecipitate (contains coagulation factors), as necessary -subsequent increase in plasmin-->increased fibrinolysis to clear thrombi -lab shows low platelets(thrombocytopenia) and signs of excessive fibrinolysis(elevated D-Dimer)

Secondary Hemostasis

A. Stabilizes the weak platelet plug via the coagulation cascade 1. Coagulation cascade generates thrombin, which converts fibrinogen in the platelet plug to fibrin. 2. Fibrin is then cross-linked, yielding a stable platelet-fibrin thrombus. B. Factors of the coagulation cascade are produced by the liver in an inactive state. Activation requires: 1. Exposure to an activating substance i. Tissue thromboplastin activates factor VII (extrinsic pathway), associated with Warfarin/Coumadin ii. Subendothelial collagen activates factor XII (intrinsic pathway), associated with HEParin 2. Phospholipid surface of platelets 3. Calcium (derived from platelet dense granules)

Primary Hemostasis

A. Step 1—Transient vasoconstriction of damaged vessel 1. Mediated by reflex neural stimulation and endothelin release from endothelial cells B. Step 2—Platelet adhesion to the surface of disrupted vessel 1. Von Willebrand factor (vWF) binds exposed subendothelial collagen. 2. Platelets bind vWF using the GPlb receptor. 3. vWF is derived from the Weibel-Palade bodies of endothelial cells and alpha-granules of platelets. C. Step 3—platelet degranulation 1. Adhesion induces shape change in platelets and degranulation with release of multiple mediators. i. ADP is released from platelet dense granules; promotes exposure of GPIIb/IIIa receptor on platelets. ii. TXA2 is synthesized by platelet cyclooxygenase (COX) and released; promotes platelet aggregation D. Step 4—Platelet aggregation 1. Platelets aggregate at the site of injury via GPIIb/IIIa using fibrinogen (from plasma) as a linking molecule; results in formation of platelet plug 2. Platelet plug is weak; coagulation cascade (secondary hemostasis) stabilizes it.

Alpha thalassemia

A. Two genes deleted—mild anemia with INC. RBC count; cis deletion is associated with an increased risk of severe thalassemia in offspring (CIS is worse than TRANS). i. Cis deletion is when both deletions occur on the same chromosome; seen in Asians ii. Trans deletion is when one deletion occurs on each chromosome; seen in Africans, including African Americans B. Three genes deleted—severe anem ia; (3 chains form tetramers (HbH) that damage RbCs; HbH is seen on electrophoresis. C. Four genes deleted—lethal in utero (hydrops fetalis); Y chains form tetramers (Hb Barts) that damage RBCs; Hb Barts is seen on electrophoresis.

G6PD deficiency (CHART)

A. X-linked recessive disorder resulting in reduced half-life of G6PD; renders cells susceptible to oxidative stress 1. RBCs are normally exposed to oxidative stress, in particular 2. Glutathione (an antioxidant) neutralizes but becomes oxidized in the process. 3. NADPH, a by-product of G6PD, is needed to regenerate reduced glutathione. 4. DEC G6PD-->DEC NADPH -> DEC reduced glutathione --> oxidative injury by H2O2--> intravascular hemolysis B. High carrier frequency in both populations is likely due to protective role against falciparum malaria. C. Oxidative. stress precipitates Hb as Heinz bodies. 1. Causes of oxidative stress include infections, drugs (e.g., primaquine, sulfa drugs. and dapsone), and fava beans. 2. Heinz bodies are removed from RBCs by splenic macrophages, resulting in bite cells 3. Leads to predominantly intravascular hemolysis D. Presents with hemoglobinuria and back pain hours after exposure to oxidative stress

Leukemia (CHART)

ALL CLL HCL AML CML

Chronic Lymphocytic Leukemia (CLL)

An 80-year-old man presents with fatigue, lymphadenopathy, splenomegaly, and isolated lymphocytosis. Suspected diagnosis? *deletion of 13q -over-expression of BCL-2, anti-apoptotic protein on the mitochondrial membrane. -inhibitor of BCL causes cancer cell death by promoting cytochrome c release from the mitochondria-->activate caspases **CD20 and CD5 Transformation to diffuse B cell lymphoma (Richter Transformation), marked clinically by an enlarging lymph node or spleen "CaLL 13q14.3 for (Mr15/16) to meet you at the ATM at 11 pm, 17 people will be there trying to sell ZAP 70 (Poor Prognosis) Soccer Balls (Histo), and CD's for $23 but dropped down to $5 (CD5 &CD23)."

Immune Thrombocytopenic Purpura (ITP)

Autoimmune destruction of IgG antibodies against the platelet membrane glycoproteins GPIIb/IIIa Laboratory findings include 1. Normal PT/PTT 2. Decrease platelet count 3. Increase bleeding time *#1 cause of thrombocytopenia in children and adults *associated with SLE, causes secondary ITP

Acute Intermittent Porphyria (AIP)

Autosomal *dominant* mutation in *Porphobilinogen Deaminase* that often presents in puberty ↑Porphobilinogen ↑Delta-ALA ↑Coporphobilinogen (urine) ↓Heme 5 Ps: Painful abdomen, Purple (wine) urine, Polyneuropathy, Psychological disturbances, Precipitated by Puberty, drugs (P450 inducers), alcohol, starvation Treat with *glucose, heme*, which inhibit ALA synthase

Neutrophils

Hyper-segmented neutrophils (nucleus has 6+ lobes) are seen in vitamin B-12/folate deficiency Increase in band cells (immature neutrophils) reflect states of increased myeloid proliferation (bacterial infections, CML). Important neutrophil chemotactic agents: C5a, IL-8, LTB4, kallikrein, platelet-activating factor.

Drugs that cause aplastic anemia

Carbamazepine, Methimazole, NSAIDs, Benzene, Chloramphenicol, Propylthiouracil Can't Make New Blood Cells Properly

Drugs that cause agranulocytosis

Clozapine, Carbamazepine, Propylthiouracil, Methimazole, Colchicine, Ganciclovir Can Cause Pretty Major Collapse of Granulocytes

Types of Necrosis

Coagulative Liquefactive Caseous Fat Gangrenous

Primary myelofibrosis

Dacrocytes are common due to erythrocyte membrane damage during red blood cell production in the spleen or fibrotic marrow -associated with clonal expansion of megakaryocytes -bone marrow fibrosis accounts for most of the major manifestations: -hepatosplenomegaly -cytopenias (pancytopenia) -dacrocytes *Bone marrow aspiration is usually dry -*biopsy will show marked fibrosis(fibroblasts and collagen) with occasion clusters of atypical megakaryocytes Primary myelofibrosis is a disorder of fibrotic bone marrow that leads to extramedullary hematopoiesis and splenomegaly. The classic genetic mutation associated with myelofibrosis is a mutated JAK2 tyrosine kinase (very high yield for examinations). Symptomatic patients present with night sweats, fatigue, and unintentional weight loss. Bone marrow biopsy will reveal a fibrotic and dry marrow.

Erythropoietin Signal Transduction

EPO is produced by peritubular fibroblast cells in the renal cortex

cytoplasmic vacuoles

Findings of systemic inflammation or infection

Giant cell tumor of bone

Giant cell tumors are usually benign and are found in the epiphysis of the long bones. Patients at highest risk of developing these tumors are typically between the ages of 20 and 40 years. Clinical manifestations are progressively worsening pain and tenderness as well as swelling and decreased range of motion. Radiography will reveal a relatively aggressive tumor located within the epiphysis. As you can see in the exhibit, the tumor destroys bone and appears cystic. Radiologists describe this feature as a "soap bubble" lesion. Biopsy will reveal multinucleated giant cells.

Drugs that cause thrombocytopenia

Heparin, Vancomycin, Linezolid Help! Very Low platelets

Drugs that cause Hemolysis in G6PD deficiency

Isoniazid, Sulfonamides, Dapsone, Primaquine, Aspirin, Ibuprofen, Nitrofurantoin Hemolysis IS D PAIN

Heme synthesis

Maturing erythocytes lose their ability to synthesize heme when they lose their mitochondria, which are necessary for the 1st and final 3 steps of heme synthesis

Neonatal vitamin K deficiency

Newborns do not have intestinal flora (which synthesizes most vitamin K in adults), infants born in US hospitals are given a shot of vitamin K at birth. Vitamin K is necessary to gamma carboxylation of clotting factors II, VII, IX, X and proteins C and S (these are anticoagulant proteins). Neonates can get diffuse bleeding and easy bruising due to factor II, VII, IX, IX deficiencies. Protein C and S normally cleave factors Va and VIIIa and inactivates them. Normally prevent over-activation of the clotting cascade. *Patients with Cystic Fibrosis are also at risk for vitamin K def due to poor absorption of fat-soluble vitamins

Causes of Polycythemia

Polycythemia = erythrocytosis aka hematocrit >50% Primary causes: increase in RBC mass, increase in plasma volume, and low EPO levels Secondary causes: presence of leukocytosis, thrombocytosis and or splenomegaly *JAK2 mutation rendering hematopoietic stem cells more sensitive to growth factors

acute monoblastic leukemia

Subtype of AML Type of acute myeloid leukemia that involves gums. proliferation of monoblast and lack MPO

Key factors that promote angiogenesis in neoplastic and granulation tissue

VEGF and FGF

Warfarin vs Heparin

Warfarin is the anticoagulant most commonly used in the prophylaxis and treatment of thrombosis and thromboembolism, especially in patients with atrial fibrillation, cardiac valve replacement, deep vein thrombosis, pulmonary embolism, and a previous myocardial infarction. It inhibits the hepatic synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X). Adverse effects of warfarin are bleeding, osteoporosis, tissue necrosis, and purple toe syndrome. Vitamin K counteracts the effects of warfarin.

Drugs that cause megaloblastic anemia

You're having a mega blast with PMS: Hydroxyurea Phenytoin Methotrexate Sulfa drugs

AML is associated with what?

Young patients also often present with acute infection and high fever. Bone marrow biopsy will reveal auer rods within the cytoplasm of the leukemic blasts. AML is the most common leukemia in patients above the age of 30. When it presents in childhood, it is often associated with another illness or syndrome. One such congenital illness that can be associated with childhood AML is Fanconi anemia. AML is much more commonly diagnosed in the adult population, and it is in fact the most common leukemia in adults above age 30. When encountered in a child, especially on examinations, AML tends to be accompanying another childhood illness. Look for patients with a history of: -Bloom syndrome (short stature, history of other cancers) -Down syndrome (trisomy 21, cognitive impairment, short stature, slanted eyes, single palmar crease) -Neurofibromatosis (learning disabilities, multiple nervous tissue tumors) -Fanconi anemia.

Megaloblastic Anemia

a blood disorder characterized by anemia in which the red blood cells are larger than normal

integrin and fibronectin

adhesion of cells to extracellular matrix

microcytic hypochromic anemia

anemia characterized by small, pale red blood cells that lack adequate hemoglobin to carry oxygen with poikilocytosis; can be caused by deficiency of iron *can be to due to occult blood loss from the GI tract -Labs: -decreased RBC count -decreased hepcidin -increased transferrin -increased EPO, but not enough iron to efficiently generate erythrocytoses, therefore, reticulocyte count is low

Protein C and S deficiency

autosomal dominant decreases negative feedback on the coagulation cascade. 1. Proteins C and S normally inactivate factors V and VIII. 2. Increased risk for warfarin skin necrosis i. Initial stage of warfarin(blocks epoxide reductase) therapy results in a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, Vll, IX, and X ii. In preexisting C or S deficiency, a severe deficiency is seen at the onset of warfarin therapy increasing risk for thrombosis, especially in the skin.

Coarse erythrocytes basophilic stippling and microcytic hypochromic anemia are common peripheral blood smear findings in what?

common peripheral blood smear findings in lead poisoning. High-risk groups include young children ingesting paint chips and industrial workers inhaling particulate lead.

Chronic Granulomatous Disease (CGD)

defect in NADPH oxidase → ↑ susceptibility to infections with catalase + organisms (S. aureus, Aspergillus, etc...) *Nitroblue tetrazolium test is used to screen, remains color less if NADPH oxidase def

Aplastic anemia (BONE MARROW)

dry tap, Hypocellular, increased fat

Osteomyelitis

is an infection of the bone and surrounding soft tissue, often caused by the spread of a surface bacterial infection. Risk factors for osteomyelitis are recent trauma (often caused by motor vehicle accident on examinations), surgery, prostheses, immunosuppression, poor nutrition, or diabetes mellitus. Magnetic resonance imaging (MRI) is the most sensitive modality to capture the exact location and extent of damage to the bone marrow and soft tissue in osteomyelitis. MCC is Staph Aureus

Osteosarcoma (HISTO)

large pleomorphic spindle cells that are producing pink matrix = new osteoid

Folate deficiency & Vitamin B12 def ($$)

leads to a megaloblastic anemia due to decreased DNA synthesis. -It is characterized by a high mean corpuscular volume and hypersegmented neutrophils on peripheral smear -results in elevated levels of homocysteine and methylmalonic acid (Normal in MMA in folate and no neurologic dysfunction) *Neurologic dysfunction -INCREASE RISK FOR VESSEL THROMBOSIS Folate A. Dietary folate is obtained from green vegetables and some fruits. 1. Absorbed in the jejunum B. Folate deficiency develops within months, as body stores are minimal. C. Causes include poor diet (e.g., alcoholics and elderly), increased demand (e.g., pregnancy, cancer, and hemolytic anemia), and folate antagonists (e.g-> methotrexate, which inhibits dihydrofolate reductase).

Porphyria cutanea tarda (PCT) (GROSS)

photosensitivity presents as vesicle and blister formation

Extramedullary hematopoiesis

presence of erythroid precursors in organs such as liver and spleen, EPO stimulated hyperplastic marrow cell invasion of extramedullary organs -MC cause is from chronic hemolytic anemias (e.g. B thalassemia)

Drug-induced hemolytic anemia

red blood cell destruction due to drug-induced production of an autoantibody that recognizes red blood cell antigens MC triggers are penicillins and cephalosporins (ceftriaxone)

Hemolytic Anemia

reticulocytosis, spherocytes and nucleated RBC

EPO deficiency

via CKD and results in normocytic anemia -EPO is produced by peritubular fibroblast cells in the renal cortex in response to decreased renal oxygen delivery, and acts on erythrocyte precursors in the bone marrow to increase RBC production -tx is recombinant EPO --> HTN and thromboembolism