Module 1 Flashcards
What are the haemostatic functions of Protein C and Protein S?
What activates them?
- Protein C and protein S act to combat factor Va and Factor VIIIa respectively to modulate the clotting cascade
- Activated by thrombin/thrombomodulin complex, combines with thrombomodulin/protein C receptor and protein S to inactivate above
What are the acquired causes of protein C and S deficiency
- Autoimmune
- Medication: eg. Warfarin
- Vit K deficiency
- Liver disease
- Pregnancy: protein S deficiency
What is Factor V Leiden?
What are the results of its inheritance
- Specific inherited genetic mutation: one of the sites that are bound by protein C/protein S complex
- Factor Va is inactivated eventually, but the process occurs more slowly
Prolonged activation of Va, predisposes to increased clotting
What is TFPI? What activates it? What does it do?
- TFPI inactivates protein VII/TF/Xa complex to inhibit clotting
- activated by thrombin
- uses protein S as a cofactor
Decreases clotting and fibrin formation
Where and how is plasminogen activated?
tPA or uPA co-localise on exposed lysine residues on fibrin clots to activate plasminogen into plasmin
What are 3 key regulatory mechanisms of fibrinolysis?
- PAI-1 (inhibits tPA) or PAI-2 (inhibits uPA)
- Antiplasmin: inhibits plasmin
- Pharmacologic
- TAFI: clips lysine residues off fibrin so plasminogen/tPA can’t co-localise
- TXA: lysine analogue competes with plasminogen to bind to fibrin
What is the natural mechanism of action of endogenous heparin?
Heparan sulfate is a glycosaminoglycan that enhances the activity of
antithrombin, in turn inhibiting thrombin and fXa
What are the key proteins involved in adhesion of platelets to sites of injury?
VWF binds platelets through their GP Ib/IX/V membrane receptor
What are the key proteins involved in aggregation of platelets at the site of injury?
GP IIb/IIIa receptor allows binding of fibrinogen, fibronectin and vWF
What are the components of large granules of platelets?
What are the components of dense granules of platelets?
alpha-granules
- b- thromboglobulin
- FV
- FXI
- Protein S
- fibrinogen
- vWF
- PF4
dense granules ADP(activates neighboring platelets) ATP Calcium Serotonin (vasoconstrictor)
What is the prothrombinasae complex made of? What does it do?
Prothrombinase complex is factor Xa and its cofactor Va, bound to the surface of platelets.
Prothrombinase cleaves
prothrombin to the active enzyme thrombin
Where does thrombomodulin come from and how does it regulate coagulation?
Constitutively expressed on ECs. Combines with thrombin to
- activate protein C which in turn inactivates Va and VIIIa
- inactivates thrombin
- activates TAFI
What are some of the consequences of the initial thrombin generated in the initiation phase of the cell-based model of coagulation?
Exposure of TF triggering the formation of the extrinsic X-ase complex
Small amounts of thrombin generated via the VIIa/TF pathway which
(1) activates platelets through cleavage of protease activated receptors PAR-1 and PAR-4
(2) activates factor V released
from platelet a-granules
(3) activates factor VIII and dissociates it from VWF
(4) activates factor XI, the intrinsic accessory
procoagulant that activates more factor IX
(5) splits fibrinogen peptides A and B from fibrinogen and forms a preliminary fibrin network
Describe propagation as it relates to the cell based model of coagulation
Occurs on platelets
IXa generated in the initiation phase
binds to VIIIa on the platelet membrane to form the intrinsic X-ase complex IXa:VIIIa.
More factor IXa is also generated by platelet-bound factor XIa.
Factor Xa binds to Va to form the prothrombinase complex, which activates prothrombin and generates a burst of thrombin
What are 4 key actions of thrombin?
- Cleaves fibrinogen into a fibrin clot
- activates factor XIII to stabilize the clot
- binds to thrombomodulin to activate the protein C control pathway
- activates TAFI to inhibit fibrinolysis
