Hemostasis Flashcards
(26 cards)
Name the basic steps of hemostasis.
platelet adhesion
platelet secretion, vasoconstriction and aggregation
thrombin generation
(clot lysis with wound healing)
What components of the hemostatic system are important for formation of primary hemostatic plug and coagulation cascade?
platelets and vWF form primary hemostatic plug
coagulation cascade is important in formation of fibrin got (stabilizes and strengthens fibrin clot)
When is reduction in platelet count reach a clinically significant threshold?
typically below 20-30K, note about 30% are sequestered in the spleen (more if the spleen is enlarged)
megakaryocyte development under the influence of thrombopoietin
What structural features of platelets are important for the activation of clotting activity
granules: electron dense(ADP, Ca++, serotonin: recruit), a granules (proteins that participate in coagulation)
membrane glycoproteins: vWF and fibrinogen receptors
membrane phospholipids kept in check by “flippase”
Name the 3 most potent platelet activators.
thrombin
ADP
thromboxane
…each with corresponding platelet membrane receptor
additionally: prostacyclin, TPO, Epi, adenosine, sertonin, collagen
What are the function of platelets in intact vessels?
maintain vessel integrity by preventing RBC from leaking from uninjured vessels (petechiae)
effect is mediated by VEGF, angiopoietin, EGF
List common platelet inhibitors.
NO
prostacyclin
aspirin
clopidogrel
What is the function of vWF and where is it produced?
mediates platelet adhesion via GP Ib receptor released into the blood and subendothelium (adheres to sub endothelial matrix)
immobilization and unfolding of vWF increase adhesion, larger multimers are most effective; unfolding occurs under shear stress
What is the activity of ADAMTS13?
can regulate vWF multimer size by cleaving unfolded multimers; modulates the “stickiness” of vWF
autoimmune destruction of ADAMTS13 can cause TTP
How is thrombin clot formation initiated?
tissue factor triggers enzymatic cascade that results in formation of thrombin
thrombin converts fibrinogen to fibrin, fibrin polymerizes and polymers are cross linked to form stable clot
What types of cells express tissue factor?
TF is a ubiquitous membrane-associated lipoprotein that is expressed by most cells, not normally expressed by endothelial cells or leukocytes although expression can be induced in theses cells by inflammatory cytokines
there is high expression in the adventitia of blood vessels, brain, skin, an mucosal tissue
What factors are required for the generation of thrombin?
enzyme Xa, prothrombin (substrate), helper protein Va, phospholipid surface and calcium
both enzyme and substrate contain calcium binding regions that are vitamin K-dependent
What clotting and anticoagulant proteins require vitamin K?
II, VII, IX, X and protein C and S : vitamin K is needed to create calcium-binding sites (Warfarin is an antagonist of vitamin K)
What factor is initiated by tissue factor and how does the clotting cascade continue (just the initiation stage)?
tissue factor binds VIIa (7)
TF and 7 activate X and IX (9 and 10)
9 and 8 complex activate 10
10 and 5 activate II (2-prothrombin) to thrombin
TF and 7 complex quickly inhibited by tissue factor pathway inhibitor
Describe the amplification of of the clotting cascade.
prothombin sends positive feedback to XI, VIII and V (5,8 and 11)
Xa and prothrombin activate more VII (10 begets more 7)
IX/VIIIa generate more X (8/9 complex begets more 10)
5/10 complex makes more prothrombin that makes fibrin from fibrinogen, fibrin is cross linked by 8
How do deficits in one or several coagulation proteins effect the risk of bleeding?
a single factor doesn’t typically cause bleeding but trouble with more than one factor leads to additive effects
Clotting factor deficiencies are most impactful in which tissues?
articular cartilage and skeletal muscle have relatively little tissue factor, low tissue factor expression can be really important (esp in hemophiliacs)
Name the 3 components in the “contact system” and what is this system’s significance?
high molecular weight kininogen, prekallikrein, factor XII
pathways is only activated when plasma is exposed to a negatively charged surface, with end product of XII activation; this pathway has little if any role in physiologic coagulation (deficiency of contact factors does not cause bleeding)
What is a D dimer made up of?
and E region that connects to two D regions from different fibrin molecules
What anticoagulant proteins antagonize (slow the cascade) the clotting cascade and where do they act?
TFPI (tissue factor pathway inhibitor)- at tissue factor VIIa (7)
APC (activated protein C)- at IXa-VIIIa (8/9 complex) and X-V complex (5/10 complex)
AT3 (antithrombin 3) at X-V complex and thrombin
Discuss properties/molecules that have an antithrombic effect on the endothelium.
sequesters tissue factor from the blood
prostaglandin I- inhibitis platelet aggregation
heparin sulfate catalyzes antithrombin
thrombomodulin catalyzes activation of protein C
NO inhibitis platelet aggregation
ADPas inhibits platelet aggregation
What is the mechanism of anti-thrombin?
AT3 is a protease inhibitor that inhibits multiple coagulation enzymes, most significantly factors IXa, Xa and thrombin (IXa and Xa are protected from inhibition while incorporated in membrane-bound complexes, AT3 works largely as a scavenger of free proteases- localizing clotting)
AT3 activity is markedly accelerated by heparin
Prothrombin bound to thrombomodulin can activate protein C, what is the down stream effect in this activation?
activation of protein C is a negative feedback loop that goes on to degrade Va and VIIIa, to slow/stop the clotting cascade
What is the mechanism of TFPI, where does it bind and what does it inhibit?
TFPI bind activated Xa and together they bind to 7a/TF complex, stopping propagation of the clotting cascade
