Hematology
Bernard-Soulier syndrome
(1) Autosomal recessive disease of platelet adhesion due to deficiency of GPIb-IX; (2) On PBS, platelets are abnormally large; (3) Platelet count Is mildly low low or normal PC, high BT low GP Ib-IX causes defect in platelet to vWf adhesion
hematocrit formula
(Red Blood Cell Level/Total Blood Level) x 100= Percent Red Blood Cell Volume= Hematocrit. ~40% = females ~45% = males ~55% = newborns
Apixaban
Eliquis DIRECTLY inhibits factor Xa; prevents clots & strokes Used to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE)
Fibrinolysis
Breakdown and removal of a clot
Coagulation factors that contain Gla residues
Factor 2, 9, 10, 2
Which factor holds fibrin together
Factor XIII (ca2+ dependent)
normal blood hemoglobin levels
Females: 14 g/dL Males: 15.5 g/dL
46 year old woman receives a non-T lymphocyte depleted, allogenic bone marrow transplant from a matched, unrelated donor. Immunosuppressive therapy with cyclosporine is started. One month later, she has a fever. Cytolytic destruction of the skin, GI tract and liver is seen, with associated dermatitis, enteritis and hepatitis. Which of the following best explains these findings? A. C3b deposition B. Cytomegalovirus infection C. Graft vs. host disease D. Tolerance induction E. Type I hypersensitivity
C. Graft vs. host disease
B cells
Cells manufactured in the bone marrow that create antibodies and immunoglobulins for isolating and destroying invading bacteria and viruses.
Blood is what type of tissue?
Connective
Factors/ condition that can cause eosinopenia
Cushing syndrome, corticosteroids
What drives the support and differentiation of stem cells in bone marrow?
Cytokines
Human Leukocyte Antigens (HLA)
-class I is expressed on all nucleated cells (everything but RBCs) -class II is a subset of immune--showing antigens to T cells -polygenic-multiple genes encode for class I and II -6 different HLA I molecules per individual
Plerixafor
-drug that allows for autologous bone marrow transplant -targets CXCR4--keeps hematopoietic stem cells within bone marrow -releases CXCR4:CXCL12 lock on stem cells--mobilized into peripheral circulation -target stem cells -eliminates concerns of GVHD--no donor T cells in bone marrow graft
Why is HLA polymorphism critical?
-ensures population won't succumb to new or mutated pathogen--if we had same, would all be wiped out -HLA molecules teach T cells
What hematopoietic defects can bone marrow correct?
-immune system disorders--Severe combined immunodeficiency (SCID) -sickle cell anemia -leukemias and lymphomas--ALL, CML
Blood function:
-transport and distribute--oxygen, nutrients, waste products, and hormones -maintenance and regulation--body temp and pH -protection--infection and loss of blood
Eosinophils make up ____% of leukocytes
1 - 3% of leukocytes
steps of primary hemostasis
1 vasoconstriction, 2 platelet adhesion to vWF on exposed collagen (GPIb receptor), 3 platelet degranulation (ADP/TXA2), 4 platelet aggregation (GPIIb/IIIa)
Clinical manifestations of bone marrow graft
1+ months post transplant -bright red rash -fever -diarrhea -swelling of abdomen, skin around eyes -hepatitis
Coagulation involves which 3 pathways
1. Extrinsic pathway 2. Intrinsic pathway 3. Common pathway
two causes of anemia?
1. underproduction of RBC (reticulocyte count < 2.5%) 2. destruction of normal RBC (reticulocyte count > 2.5%)
RBC lifespan
120 days
Normal platelet count
150,000-450,000 cells/uL ~10 day lifespan
Hemoglobin A2
2 alpha, 2 delta (2-3% of Hb found in adults) is elevated in beta-thalassemia as beta-globin chain underproduction leads to decreased hemoglobin A levels.
calcium dependent factors
2, 10, 13
Which factors are activated by thrombin?
5,7,8,11,13
HbF is replaced how many weeks after birth?
6 weeks post birth HbF is 2 alpha 2 gamma
Blood is how much of total body weight?
8%
RBCs are ________% hemoglobin
97% each RBC can bind 1 billion oxygen molecules
Granulocytes
A group of leukocytes containing granules in their cytoplasm; neutrophils, eosinophils, basophils (& closely related mast cells).
Agranulocytes
A group of leukocytes without granules in their nuclei; lymphocytes (B & T-cells), monocytes (macrophages).
Hypoxia-inducible factor (HIF)
A transcription afctor that activates genes for EPO (HIF can only survive in hypoxic environment)
ReoPro
Abciximab GP IIaIIIa antagonist. This is the only one with irreversible blockade (binds GP IIaIIIb for weeks due to high affinity); used after angioplasty to prevent blood clot Antibody therapy
lymphopenia
Absolute lymphocyte count < 1500 cells/mm3 [<3000 in children]
What proteins are in blood?
Albumin, immunoglobulins, clotting factors, and globins
Coumadins
Anticoagulants that inhibit vitamin K reductase enzymes Ex: Warfarin, Dicoumarol *not for use in placenta (teratogenic)
ATIII
Antithrombin III; inhibits Xa and II (thrombin)
Drugs that inhibit platelet activation by blocking thromboxane A2 production
Aspirin (irreversible NSAID) and reversible NSAID (e.g. ibuprofen, naproxen)
Factors/ condition that can cause lymphopenia
HIV, DiGeorge syndrome, SCID, corticosteroids, radiation, sepsis, postoperative
Only identical twins have the exact same set of:
HLA molecules
Ristocetin cofactor assay
In vitro platelet agglutination test for vWF. Ristocetin enhances vWF interaction with platelet GP Ib/IX. If ABNORMAL, no platelet aggregation occurs in assay
Thalassemia
Inherited defect in the ability to produce hemoglobin
Von Willebrand Disease
Intrinsic pathway coagulation defect: low vWF --> high PTT (vWF acts to carry/protect factor VIII). Defect in platelet plug formation: low vWF --> defect in platelet-to-vWF adhesion. 2 types: hereditary (Autosomal dominant) & acquired Mild but most common inherited bleeding disorder (mixed platelet/coagulation disorder). No platelet aggregation with ristocetin cofactor assay. Treatment: desmopressin, which releases vWF stored in endothelium & prednisone (with patients w/autoimmune diagnosis)
Aspirin
Irreversible COX inhibitor; long lasting anti-thrombotic; inhibit platelet activation
Immunoglobulin classes
MAGED mu, alpha, gamma, epsilon, delta
what electrolytes are in blood?
Na+, K+, Cl-, and HCO3-
Thromboxane synthase
PGH2 --> TXA2
Drug that inhibits platelet activation by blocking ADP receptors (preventing contact activation)
Plavix (clopidogrel)
Agents that inhibit coagulation by decreasing Ca2+
Prostacyclin (in vivo)- released by endothelium in vitro: EDTA chelates calcium sodium citrate forms insoluble Ca2+ salts
Anti-coagulation factors that contain Gla residues
Protein C and S
Phospholipase A2
Releases arachidonic acid from phospholipid membrane
Which Rh classification makes anti-D (Rh) IgG antibodies?
Rh negative
Erythropoiesis steps
ST-HSC-->CMP-->MEP-->BFU-E--> Proerythroblast (CFU-E) --> Basophilic erythroblast --> Polychromatic erythroblast --> Orthochromatic erythroblast --> Reticulocyte --> Erythrocyte
Koilonychia
Spoon nails; characteristic of iron deficient microcytic anemia
Normal RBCs
The number of RBCs in a whole uL of blood. 4.8 x 10^6/ uL = females 5.5 x 10^6/uL = males
Heparin inactivates
Thrombin (IIa), IXa, Xa, XIa
___________ is an essential co-factor for the production of amino acid gamma-carboxyglutamate (Gla)
Vitamin K
Agglutination test
What immunologic test checks for a reaction between Abs and a particular Ag? (hint: ABO typing)
Angina
a condition of episodes of severe chest pain due to inadequate blood flow to the heart
Hemophilia
a group of hereditary coagulation disorders in which a blood-clotting factor is missing (results in high PTT)
Endothelin-1 (ET-1)
a vasoconstrictor secreted by endothelial cells and triggered by thrombin
Thromboxane A2
a vasoconstrictor that is released from platelet granules; major product of COX-1 metabolism in platelets
eosinopenia
absolute eosinophil count <30 cells/mm^3
Neutropenia
absolute neutrophil count < 1500 cells/mm3
CD4 helper T cells
activate Ag-specific B cells that stay in the T cell areas
When are remaining organelles lost on an immature erythrocyte
after reticulocyte stage
Plavix
aka Clopidogrel blocks GP IIb/IIIa activation inhibits aggregation to exogenous ADP prevents amplification by othe ragonists non effect on cyclooxygenase (COX)
Celiac disease
an inherited autoimmune disorder characterized by a severe reaction to foods containing gluten, results in decrease of iron absorption
Heparin activates?
antithrombin (AT III)
Glanzmann's thrombasthenia
autosomal recessive disorder, Defect in platelet plug formation ⇓ GpIIb/IIIa → defect in platelet to platelet aggregation via fibrinogen Labs: blood smear shows NO platelet clumping. ⇑ BT, normal PC AVOID aspirin
neutrophil number increases during...
bacterial infections
rarest leukocyte
basophil (0.5 - 1%)
important for parasitic infections and allergies
basophils
Heme is broken down into this pigment, which is secreted in bile and excreted in urine.
bilirubin
GP Ia/IIa binds to
binds collagen beneath the vascular bed; binding activates platelets
GP Ib/IX
binds von Willebrand factor
At what stage of erythropoiesis is all hemoglobin finished being synthesized?
by end of orthochromatic stage (stage were nucleus is lost)
CXCL12/CXCR4
chemokine and receptor pair that keeps hematopoietic stem cells within bone marrow
Agents that decease Ca2+ inhibit ______________
coagulation
Protein S
cofactor of protein C
Thrombomodulin
complexes with II (thrombin) and keeps it from being activated into IIa Thrombin-throbomodulin complex activates protein C
intrinsic pathway is activated by
contact activation (e.g. activated platelets, collagen, basement membrane, negatively charged surface like glass)
COX 1
converts arachidonic acid to prostaglandin H2
Cytopenia
decrease in WBC numbers
hypovolemia
decreased blood volume; leakage of blood into vasculature due to not enough clotting
Alpha Thalassemia
deletions in alpha globins, leading to an excess of beta chains in adults or gamma chains in fetus
hemolytic reaction
destruction of RBCs when patient receives mismatched blood transfusion
Allogenic graft
donor & recipient differ genetically, similar HLA haplotype
Syngenic graft
donor & recipient identical twins, matched HLA haplotype
What do monocytes do?
eat invading pathogens, clean up dead neutrophils & RBCs
critical for defense against helminths and bacteria
eosinophils
Integrillin
eptifibatide antiplatelet agent, GP IIb/IIIa inhibitor shorter half-life than ReoPro given to patients with angina
Clotting cascade starts which which pathway
extrinsic pathway
Hemophilia B
factor IX deficiency x linked recessive prevalent in European royal families
Hemophilia A
factor VIII deficiency x linked recessive
Hemophilia C
factor XI deficiency; autosomal recessive disorder primarily affecting the Ashkenazi Jewish population
Secondary hemostasis begins with
fibrin aggregation at platelet plug
spleen function
filters and removes old erythrocytes
best time to measure peripheral blood smear
first thing in the morning (b/c counts may be elevated after meals)
SCID (severe combined immunodeficiency)
genetic disorder in which T cells and B cells are absent or inactive
Prednisone
given to patients with autoimmune vWD
Graft vs. Host Disease (GVHD)
graft recognizes pt's cells as foreign and tries to attack them; some GVHD indicates successful engraftment; try limit activity of donor T-cells w/ drugs w/o suppressing them to the extent that new cells stop grafting
G-CSF
granulocyte colony stimulating factor, promotes neutrophil differentiation
GM-CSF
granulocyte-monocyte colony stimulating factor -promotes neutrophil and monocyte differentiation
leukocytes divided into
granulocytes and agranulocytes
Basophils secrete
histamine, serotonin, and heparin
Desmopressin
hormone that stimulates production of vWf
Events that trigger EPO synthesis
hypoxia, severe anemia, high altitude hormones Hb that have high affinity for O2 (not deposited in tissues)
Sites of bone marrow harvest
iliac crest and sternum
Protein C
inactivates co-factors Va and VIIIa
Unfractionated Heparin
injected under skin or through intravenous infusion; anticoagulant -long, high MW
Transferrin
iron transport protein that controls level of free iron in blood fh
Where is EPO produced?
kidneys (90%) and liver (10%)
WBC and platelets make up ______% of total blood volume
less than 1%
Causes of iron deficiency
low dietary intake (vegetarians), malabsorption (celiac disease, gastrectomy - decreased acid production), increased demands (pregnancy and infancy), chronic loss of blood (heavy menstruation), peptic ulcer disease, colon cancer/polyps, hookworm infection)
MCHC
mean corpuscular hemoglobin concentration-the amount of hemoglobin per unit volume in a single red blood cell (avg. concentration of Hb in a packed volume of RBCs normal = 35 g/dL or RBCs The difference between MCH and MCHC is that the MCHC measurement takes the volume or size of the red blood cell into account while MCH does not.; when MCHC is low, the cell is hypochromic
MCH
mean corpuscular hemoglobin-average amount of hemoglobin per cell (avg. mass of each cell); RBCs are mostly Hb normal = 30 picograms/cell
MCV
mean corpuscular volume-average volume or size of a single red blood cell; when MCV is high, the cells are macrocytic, and when low, the cells are microcytic normal = 80 - 100 femtoliters/cell
M-CSF
monocyte colony stimulating factor, promotes monocyte differentiation
first responders to damaged/infected tissues
neutrophils
most abundant leukocyte
neutrophils aka polymorphonuclear leukocyte 10^11 produced daily
GP IaIIa and GP IbIX are found
on the surface of platelets
All hemoglobin synthesized by the end of what stage
orthochromatic stage
PTT
partial thromboplastin time, time it takes for blood to clot (intrinsic & common pathway); tests for abnormalities in blood clotting 30 - 50 seconds; defect results in high PTT determines if blood thinning treatment is effective (monitors effect of heparin)
Where is bone marrow found?
pelvis, femur, sternum, ribs, and tibia
At what stage of erythropoiesis does globin synthesis begin?
pro-erythroblast stage (CFU-E)
Globin synthesis starts at what stage
pro-erythroblast stage (CFU-E)
Vitamin K deficiency causes
problems with coagulation & bleeding increase in PT & PTT; bleeding time= normal, decrease in activity of factors 10,9,7,2
PT
prothrombin time, time it takes for blood to clot (extrinsic & common pathway) 11 - 13 seconds; defect results in high PT most common test used to follow patients on warfarin (tests vitamin K status in blood) measures warfarin dosage
neutrophils are the major component of:
pus
GP Ia/IIa
receptor for collagen (beneath vascular bed)
Anemia
reduced oxygen flow to the body's organ & tissues
Thrombopoietin
required for platelet (megakaryocyte) development
Immature erythrocytes have no nucleus
reticulocyte
NSAIDs
reversible COX inhibitors; include ibuprofen and naproxen; inhibit platelet activation
Factors/ condition that can cause neutropenia:
sepsis, drugs (chemo), aplastic anemia, radiation
Platelets release
serotonin, thromboxane A2, ADP
these induce vasoconstriction
serotonin, thromboxane A2, endothelin-1
Function of fibrin
stabilizes platelet plug (clot)
SCF
stem cell factor, keeps stem cells pluripotent
low molecular weight heparin drugs
subcutaneous injection; anticoagulant; does not cross the placenta (good for use during pregnancy) delteparin, enoxaparin, nadroparin, tinzaparin (DENT)
IL-3
supports committed stem cells
Erythropoietin
supports differentiation and growth of RBCs
gastrectomy
surgical removal of part or all of the stomach
___________ activates intrinsic pathway
thrombin
TT
thrombin time; time it takes for clot to form in plasma containing anti-coagulant after excess of thrombin is added ; indicates abnormalities in conversion of fibrinogen to fibrin 12 - 19 seconds
Activation factors for platelets
thromboxane A2, ADP, thrombin, other activated platelets, collagen, vWf, serotonin
Extrinsic pathway is activated by
tissue factor
TFPI
tissue factor pathway inhibitor extrinsic pathway inhibitor; blocks protease activity of VIIa TFPI binds to and inhibits factor Xa. After binding o factor Xa, TFPI undergoes a conformation change. The TFPI/factor Xa complex then mediates feedback inhibition of tissue factor/factor VIIa
tPA
tissue plasminogen activator; a clot-dissolving drug used as therapy for stroke tPA released from endothelial cells
Thrombosis
too much fibrinogen causes blood clots to form in the bloodstream = bad
Integrins are
transmembrane proteins/receptors that attach cell cytoskeleton to ECM (e.g. GP IaIIa, GP IbIX)
What metabolites are in blood?
urea, bilirubin, and creatinine
VIII activity assay
vWf is a carrier protein for factor 8 & protects it from protease digestion; assay used to test for vWD Because factor VIII circulates in the body attached to vWF, a decreased amount of factor VIII can also mean a decreased amount of vWF
GP Ib/IX binds to
vWf on extra-vascular smooth muscle cells; binding activates platelets
The body contains how much blood?
~5 L of blood
