Clot Formation Flashcards
What are the two main parts of hemostasis?
coagulation cascade and platelet activation/aggregation
Damage to endothelium exposes the ECM which causes what to occur?
vMF is exposed and undergoes conformational change fro binding to platelets in circulation
How does vMF bind platelets?
via GP1b
A defect in vMF results in what disease?
Von Willebrand Syndrome
A defect in GP1b results what disease?
Bernard Soulier Disease
What happens when platelets bind to vMF on exposed endothelium?
they are activated, releasing the contents of their alpha and dense granules
and they undergo conformational change that allows them to bind fibrinogen to begin to aggregate and from a primary (weak) clot
What do platelet alpha granules contain?
TxA2, P-selectin, Fibrinogen, Factors V and VIII (main ones)
What do platelet dense granules contain?
ADP, Ca2+, histamine, serotonin, epinephrine
What is the significance of Ca2+ being released from dense granules?
activation of coagulation factors requires Ca2+
How does endothelial damage stimulate the extrinsic pathway?
It exposes TF
How else is TF up-regulated on damage endothelial surfaces?
cytokines TNF, IL-1 and bacterial endotoxins up-regulate TF expression
What does the exposed TF do?
binds factor VII, making the TF/VIIa complex
What inhibits the TF/VIIa complex formation?
tissue-factor pathway inhibitor
What else does TFPI do?
inactivates factor Xa
Where is TFPI expressed?
healthy endothelial cells only
What does TF/VIIa complex do?
activates Xa
How is the intrinsic coagulation pathway activated?
Kallikrein and ANY negatively charged surface can activated XIIa
What does XIIa do?
activate XIa, which activates IXa
What does activation of every coagulation require?
1) phospholipid surface
2) calcium
The enzymatic reaction that allows Ca2+ to bind to coagulation factors for activation requires what cofactor?
K+ (Coumadin is a drug that inhibits this)
What does IXa do?
binds with VIIIa to activate more Xa
What is VIII activated by once released from platelet alpha granules?
thrombin (also activates Va)
At this point, the extrinsic and intrinsic pathways combine as Xa. What happens next?
Xa and Va convert prothrombin (II) to thrombin (IIa)
What inhibits activation/function of VIIIa and Va?
Protein C
How is Protein C activated?
expressed on healthy endothelial cells and is activated via thrombomodulin
How does thrombomodulin activate protein C?
It changes the function of thrombin to activate Protein C instead of cleaving fibrinogen to fibrin
What cofactor does Protein C need to act?
Protein S (K+ dependent)
What does thrombin do (3 things)?
1) activates PAR on the surface of platelets, which with ADP and TxA2 enhance platelet aggregation
2) Converts fibrinogen in the primary clot to fibrin and
3) activates XIIIa to crosslink strands of platelet-fibrin-platelet chains to form the strong secondary clot
In the primary clot, how is fibrinogen connected to platelets?
via GPIIb/IIIa molecules
Defect in GPIIb/IIIa results in what disease?
Glanzmann thrombasthenia
How is fibrin inactivated to prevent overclotting?
plasmin cleaves it
How is plasmin activated? (4 things)
activated by:
1) factor XIIa
2) tissue plasminogen activator (tPA)
3) Urokinase-like plasminogen activator (uPA) in plasma
4) Streptokinase (bacterial product)
Where is tPA produced?
healthy endothelial cells
When is tPA most active? Why?
when attached to fibrin, which ensures that its mostly confined to sites of recent thrombosis
How is plasmin inactivated?
1) free plasmin rapidly complexes with a2-antiplasmin
2) plasminogen activator inhibitors (PAIs)
What are PAIs stabilized by?
vitronectin
What causes PAIs activation?
increased by inflammatory cytokines, especially IFN-y
What disease greatly reduces plasma a2-antiplasmin?
cirrhosis
How would you treat cirrhosis to prevent hemorrhaging?
caproic acid
