Coagulation Flashcards
What is the culminative event of coagulation?
The generation of thrombin
What is Thrombin’s function?
Turns soluble fibrinogen to Fibrin
What is the function of fibrin?
enmeshes the platelet aggregates at the sites of vascular injury and converts the unstable primary plug to firm definitive and stable haemostatic plug
Of all the enzymes of coagulation which is not a serine protease?
Factor VIII (8)
What are the three enzyme complexes that thrombin generation is dependent on?
1.Extrinsic case (VIIa, TF, PL, Ca2+)
2.Intrinsic case (IXa, VIIIa, PL, Ca2+)
These 2 pathways both generate FXa and the prothrombinase complex (Xa,Va,PL,Ca2+) generating thrombin
How does the generation of thrombin occur after tissue injury?
In two waves.
What happens during the initial wave?
Small amount generated which prepares the coag cascade for the second larger burst.
How does initiation occur?
Occurs by the interaction of membrane bound (TF) which is exposed and activated by an enzyme protein dislphide isomerase after vascular injury, with plasma factor VIIa.
What is TF?
The sole initiator of thrombin generation and fibrin formation. It is expressed on fibroblasts of the adventitia and small muscle of the vessel wall, and on non vascular cells.
What does Factor VIIa activate?
Activates both both Factor IX and Factor X
What inhibits the extrinsic pathway (extrinsic case)?
Tissue factor pathway inhibitor.
What does TFPI form?
A complex with VIIa, TF and Xa
What does this inactivation of extrinsic pathway lead to?
Dependence of thrombin generation on the intrinsic pathway.
What happens to the small amounts of Thrombin generated by the Extrinsic pathway?
It activates Factors VII and V to VIIIa and Va
How is the prothrombinase complex (Xa + Va) formed?
Xa is generated by IXa and VIIIa (Intrinsic Xase) in the presence of calcium Ca2+, which then combines with Va PL and Ca2+.
What does generation of prothrombinase yeild?
THROMBIN
What is the role of Factor XI?
- Does not seem to have a role in physiological initiation of coag.
- Appears to have a role in activation of Factor IX.
What is the role of Thrombin? How does it work?
Hydrolyzes fibrinogen releasing Fibrinipeptides A and B to form Fibrin monomers.
What Happens to The Fibrin monomers?
Bound spontaneously by hydrogen bonding to form loose insoluble fibrin polymer.
How is Factor XIII activated?
By Thrombin + Ca2+
What is a function of Xllla?
Stabilizes the fibrin polymers with formation of covalent cross links
Describe Fibrinogen
Heterodimer of 3 dissimilar sub units Alpha, Beta, and Gamma.
Which factors are dependent upon Vitamin K?
2, 7, 9, 10
Why is vitamin K important for these factors?
Carboxylates some terminal glutamic acid residues on those molecules.
Which 2* factors are not protease enzymes?
V and VIII
What 3 molecules produced by Endothelial cells have a inhibitory effect on platelets?
NO, CD39, and Prostacyclin
What 2 molecules released by platelets also have vasocontricive activity?
TXA2 and Fibrinopeptides.
What facilitates platelet adherence to exposed connective tissue?
GPIa and GPIb mediated via VWF
How does platelet aggregation and release accelerate the coagulation process?
By providing abundant membrane phospholipid
What molecules does TFPI inhibit?
Xa. VIIa, and Thrombin
How does TFPI work?
Forms a quaternary complex
What is another direct inactivator of thrombin and other serine proteases?
antithrombin-the most potent
What drug potentiates the action of antithrombin?
Heparin
What are some other thrombin and serine protease inhibitor
Heparin cofactor II (only thrombin), Alpha 2 macroglobulins, Alpha2-antiplasmin, C1 esterase inhibitor and a1-antitrypsin (only serine proteases)
What are proteins C & S?
These are inhibitors of Factors V and VIII
How is Protein C activated?
Thrombin binds to the endothelial cell surface receptor thrombomodulin
What other Vitamin K dependent protein enhances the activity of protein C?
Protein S.
It binds protein C to the platelet surface, and endothelial protein C receptor localizes protein C to the endothelial cell surface.
What else does activated protein C enhance?
Fibrinolysis
What else does Protein C inhibit?
TFPI and thus increases fibrinolysis
What is plasminogen?
A B-blobulin proenzyme in blood and tissue fluid that is converted to a serine protease plasmin by activating factors of both intrinsic and extrinsic pthwy
What is TPA?
A serine protease that binds to fibrin, enhancing its capacity to convert thrumbus bound plasminogen to into plasmin
How does Protein C affect TPA levels?
Protein C destroys plasma inhibitors of TPA
How does thrombin inhibit fibrinolysis?
By activating TAFI
What is the function of Plasmin?
Generation of plasmin at the site of injury limits the extent of the evolving thrombus
What is one of the functions of the split fibrin products?
Competitive inhibitors of thrombin and Fibrin polymerization
What inhibits most local free plasmin?
Alpha2-antiplasmin
What are two well known and characterized fibrin degradation products (used to test for DIC)?
Fragments D and E
What are the molecules that Plasmin is capable of digesting?
Fibrinogen, fibrin, Factors V and VII
What inhibits TPA?
PAI
What inactivates circulating plasmin?
Alpha2-antiplasmin and Alpha2-Macroglobulin
What does PT measure?
Factors VII, X, V, Prothrombin and Fibrinogen
PTT measures what?
VIII, IX, XI, XII, X, V, Prothrombin and Fibrinogen
How is defect of a factor checked?
By adding normal plasma to test plasma 50:50
If the test fails what is indicated?
The presence of an inhibitor of coagulation
What interaction intiates the platelets to degranulate?
Binding to Collagen
What is released on degranulation?
ADP TXA2
Deficiency of factor XIII leads to?
Normal clotting but clots are not stabilized and break down and bleeding continues
How does Factor XIII work?
It is a transaminase that covalently links fibrin polymers
What do haemophilia A patients lack?
Factor VIII
What do Haemophilia B patients lack?
Factor IX
What is the difference between serum and plasma?
Plasma contains unactivated clotting factors, serum contains used up clotting factors.
Factor XII deficiency causes?
Long PTT but patients won’t bleed out
Cannot fix clotting factor deficiency with?
Fresh frozen plasma.
Normal PT and PTT but still bleeding suggests?
Deficiency of factor XIII
What is the ratio of prothrombin 1.2 : thrombin after the cleavage by prothrombinase?
1:1
How does factor VIII exist in the circulation?
Bound to VWF
What is Anti-thrombin III?
An anti-serine protease, neutralizes the active site on a serine protease
How does heparin affect anti-thrombin III?
It binds at an allosteric site and makes it a much more effective anti serine protease.
What is a naturally occuring analogue of heparin that has the same effect on anti-thrombin III?
Haparan sulphate
What are D dimers specific for?
Cross-linked fibrin.
