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93 Cards in this Set
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platelet alpha-granules |
platelet specific proteins (PF4) adhesive glycoproteins - fibrinogen, vWF coagulation factors - V, XI, Protein S Mitogenic factors (PDGF-TGF-beta) |
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platelet delta (dense) granules |
non-protein agents: ATP, ADP, GTP, GDP serotonin (vasoconstricting) calcium ions phosphate (PPI & Pi) |
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non-specific platelet surface antigens |
HLA, ABO blood group antigens |
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specific platelet surface antigens |
human platelet antigens (HPA), CD109 (family of thioester- containing proteins), GPIIb-IIIa integrin complex |
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endothelial damage exposes |
extracellular matrix (ECM) - highly thrombogenic |
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when platelets bind to ECM... |
they activate! |
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activation of platelets |
incr. in cytoplasmic calcium -> release of alpha and dense-core (delta) granules |
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Platelet receptors (integrins) |
GPIa-IIa, GPIb-IX-V, GPIIb-IIIa |
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GPIa-IIa |
function = adhesion by directly binding any of 8 collagen types |
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GPIb-IX-V |
function = adhesion by binding vWF |
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GPIIb-IIIa |
function = aggregation- binds to non-cleaved fibrinogen, acts as cross-link b/t platelets (primary hemostatic plug) ADP induces conformation change |
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adhesion molecules w/ RGD (Arg-Gly-Asp) recognition site to bind integrins |
vWF, fibronectin, fibrinogen, thrombospondin, collagens |
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Bernard-Soulier syndrome |
lack GPIb/IX/V (vWF receptor) autosomal recessive inherited platelet disorder no vWF binding = lack of platelet binding |
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von Willebrand Dz |
inherited platelet disorder deficiency in vWF leads to bleeding tendency, most apparent in tissues w/ high blood flow shear in narrow vessels normal platelet count |
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vWF (von Willebrand factor) present in... |
in blood plasma produced in endothelium (Weibel-Palade bodies), megakaryocytes, found in subendothelial CT |
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vWF function |
not enzymatic fxn: binds to Factor VIII & platelet adhesion to wound sites, binds collagen when exposed |
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Factor VIII |
degrades when not bound to vWF released from vWF by action of thrombin |
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Type I von Willebrands |
AD; reduced quantity of circulating vWF |
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Type II von Willebrands |
AD; vWF formed is abnormal |
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Type III von Willebrands |
AR; extremely low functional vWF; severe, bleeding characteristics resemble hemophilia |
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alarm signals cause... |
exocytosis of Weibel-Palade bodies = release vWF, angiopoietin 2, IL-8 => regenerative & proinfl. processes |
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exogenous vWF binds to normal platelets... |
platelet is activated, stored vWF is released |
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formalin Rx |
does NOT block exogenous vWF and platelet aggregation DOES block response to vWF binding & release of stored vWF |
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how to measure vWF in plasma sample? |
formalin-preserved platelets incubated w/ ristocetin (AB for staph inf but toxic, so not used - causes platelet aggregation in presence of vWF) |
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activation of GPIIb-IIIa |
when platelets are stimulated by ADP, thrombin, collagen, epinephrine |
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clopidogrel |
ADP binding inhibitor = block activation of GPIIb-IIIa |
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Glanzmann's Thrombasthenia |
lack GPIIb-IIIa receptor Integrin expressed is mutated, so no effective binding to fibrinogen or synthetic RGD peptides |
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platelet phospholipase A2 activation |
arachidonic acid => liboxygenase & cyclooxygenase => eicosanoids (e.g. thromboxane-A2) => platelet aggregation |
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NSAIDs (non-steroidal anti-infl. drugs e.g. aspirin) |
block cyclooxygenase activity = block thromboxane-A2 production = prevent platelet aggregation |
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Thrombocytopenia |
below 100,000/microliter spontaneous bleeding when below 20,000/microliter prolonged bleeding time w/ normal PT, PTT |
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Causes of thrombocytopenia |
decr. production = hereditary & acquired incr. destruction = TTP, HIT, ITP, drug-induced sequestration in spleen = ITP, splenomegaly |
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drug-induced thrombocytopenia |
quinine, quinidine, sulfonamide ABs
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thrombocytopenia presentation |
purpura (non-blanching), mucosal hemorrhage, menorrhagic, prolonged bleeding petechiae (smaller, 1-2mm) ecchymoses (larger, >1cm) |
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Heparin Induced Thrombocytopenia (HIT) Type I |
transient drop in platelet count 10-20% of pts on heparin NOT immune |
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Heparin induced thrombocytopenia (HIT) Type II |
auto-immune reaction - Ab's vs. platelet factor 4 (PF4) or rarely NAP-2 when complexed with heparin (heparin-PF4 complex most common) |
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Type II HIT mechanism |
1) heparin binds PF4 = epitope exposed, becomes antigenic 2) causes thrombosis in 30-40% of these patients - clot is arterial & platelet rich ("white clot syndrome") 3) platelet activation -involves lower limbs, skin lesions & necrosis at site of heparin infusion |
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can you give heparin to a patient with HIT Ab's? |
NO!!! |
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Thrombotic thrombocytopenic purpura (TTP) |
aka Moschcowitz Dz deficiency of ADAMTS13 = Zn-metalloprotease that cleaves large multimers of vWF |
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TTP mechanism |
no ADAMTS13 = high MW multimers of vWF in plasma = platelet microaggregate formation |
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TTP patient presentation |
fever, thrombocytopenia w/ purpura, microangiopathic hemolytic anemia (helmets/schistosomes), transient neuro deficits, renal failure |
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what is TTP's clinical presentation like? |
HUS (hemolytic-uremic syndrome) caused by shiga-like toxin produced by E. coli O157:H7 ACUTE renal failure, children affected |
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transfusion of platelets in pt. with TTP, HIT II? |
not indicated unless pt is in danger of life threatening bleeding |
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Reactive Thrombocytosis |
iron deficiency, acute blood loss, splenectomy
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clonal hematopoietic disorders causing thrombocytosis |
myeloproliferative disorders, deletion of 5q, AML, ET (essential thrombocythemia) |
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Bleeding time (lab test) |
directly evaluates platelet fxn prolonged in thrombocytopenia & functional platelet disorders |
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Prothrombin time |
tests extrinsic & common coagulation pathways |
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Partial thromboplastin time |
tests intrinsic & common clotting pathways |
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gray platelet syndrome |
genetic disorder where alpha granules are not being made - seen on blood smear |
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platelet transfusions are indicated for: |
thrombocytopenia due to marrow failure - platelet count <10,000 and no add'n abn - platelet ct. b/n 10 and 20,000 w/ coag. abn or extensive petechiae or ecchymoses - bleeding at sites other than skin + ct <40-50,000 - pre-surgical when ct <50,000 |
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typical single donor platelet pheresis (SDP) |
incr. platelet count of typical 70kg man by 30-50,000/microliter |
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hemostasis |
clot formation at site of bv wall damage 1) vasoconstriction 2) platelet plug formation (temporary clot) 3) activation of coagulation system (permanent clot) |
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Tissue Factor (TF) |
procoagulation factor, membrane bound made in endothelium activate coagulation cascade (convert prothrombin to thrombin) |
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thrombin function |
convert soluble fibrinogen to insoluble fibrin, induce platelet recruitment & activation |
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secreted platelet factors |
ADP, TxA2, Calcium; procoagulative factors |
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coagulation factor w/ highest plasma concentration? |
fibrinogen |
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fibrin |
cross-linking fibers of mature clot |
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Factor V |
receptor for Xa, stored in alpha granules |
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Factor VIII antigen |
stored in alpha granules; platelet adherence to subendothelium, receptor for IXa |
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shortest lived coagulation factors? |
Protein C & Factor VII |
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Vitamin K-dependent zymogens |
Factors II, VII, IX, X, Protein C |
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Factor IX cofactor |
Factor VIII |
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Factor X cofactor |
Factor V |
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Protein C cofactor |
Protein S |
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Plasmin inhibitors |
alpha2-antiplasmin/macroglobulin, Plasminogen activator inhibitors |
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Protein C + Protein S |
inactivates Factor VIII and Factor V |
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Tissue factor pathway inhibitor (TFPI) |
inhibits Factor VIIa/TF complex (extrinsic pathway) = prevent Factor X activation |
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Antithrombin |
inhibits Factors IIa, Xa, VIIa, IXa, XIa, Kallikrein, and XIIa; facilitated by heparin |
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t-PA |
lysis fibrin, destroys the clot activates plasminogen |
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thrombomodulin |
blocks coagulation cascade |
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endothelial cell factors |
NO, prostacyclin, thrombomodulin, heparin, plasminogen activators prevent inappropriate coagulation & platelet activation |
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Extrinsic pathway (physiological coagulation) |
initiated by tissue thromboplastin (tissue factor) TF -> Factor 7 -> Factor 10 -> Factor 10 + Factor 5 -> common pathway Factor 7 + TF -> Factor 9 -> Factor 10 |
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Intrinsic pathway |
activated by foreign bodies w/ negatively charged surfaces, inflammation Factor 12 -> Factor 11 -> Factor 9 + Factor 8 -> Factor 10 -> common pathway |
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Common pathway |
Factor 10 + Factor 5 + Prothrombin (Factor 2) = prothrombin complex = prothrombin converts to thrombin |
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Factor 5 activation |
requires thrombin (IIa) |
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Clot formation |
Fibrinogen converted by thrombin to fibrin mesh, thrombin activates Factor 13 Factor 13 cross links Fibrin Mesh E domains w/ D domains (transglutamination rxn) |
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Clot degradation |
fibrinogen & fibrin broken down by plasmin fibrin mesh => D-dimers only fibrinogen => D & E fragments |
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sites of primary hemostasis bleeding |
skin, mucous membranes
skin, mucous membranes |
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sites of secondary hemostasis bleeding |
deep tissues - joint, muscle, CNS, retroperitoneal |
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primary hemostasis form of bleeding |
petechiae, ecchymosis |
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secondary hemostasis form of bleeding |
hematomas |
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clinical ex. primary hemostasis |
thrombocytopenia, platelet defects, von Willebrand, scurvy |
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clinical ex. secondary hemostasis |
factor deficiency, liver dz, acquired inhibitors |
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Prothrombin time (PT) |
tests extrinsic & common coagulation pathways add exogenous tissue thromboplastin & Ca2+ ions = plasma clots, measured in seconds |
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cause of prolonged prothrombin time |
deficiency/dysfunction of factor V, VII, X, prothrombin, fibrinogen |
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Partial thromboplastin time (PTT) |
intrinsic & common clotting pathways add kaolin, cephalin, and calcium ions = plasma clots, measured in seconds |
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Kaolin |
activates contact-dependent factor XII |
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cephalin |
sub for platelet phospholipids |
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cause of prolonged PTT |
deficiency/dysfunction of factors V, VII, IX, X, XI, XII, prothrombin, fibrinogen |
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D-dimer meaning |
did the patient for a clot? DVT, pulm. embolism |
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mixing studies |
pt w/ coag. factor deficiency plasma + normal donated plasma = normal clotting pt w/ immune defect (auto-Abs) + normal donated plasma = continued abnormal clotting |
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abnormal PTT alone |
w/ bleeding: VII, IX, XI defects not assoc. w/ bleeding: XII, prekallikrein (PK), high-MW kininogen, lupus anticoagulants |
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Abnormal PT alone |
Factor VII defects |
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combined abnormal PTT & PT |
anticoagulants, DIC, liver dz, vit K deficiency, massive tranfusion rarely dysfibrinogenemias, factors X, V, II defects |