Haematology 3 Coagulation Flashcards
(27 cards)
What function does thrombin have?
It’s formed by the activation of the coagulation cascade.
- enhances platelet activation and recruitment
- cleaves fibrinogen to fibrin
- fibrin network stabilises platelet clot (secondary haemostasis)
Coagulation factors
- mostly sarin proteases
- need to be activated (proenzymes)
- produced in liver
- stored in platelets and endothelial cells
Intrinsic and extrinsic systems of coagulation cascade
Intrinsic pathway:
- relevance unknown
- activated by surface contact (kvllikrein, HMWK
- Factors XII, XI, Prekallikrein, high weight molecular kininogen
Extrinsic pathway:
- triggers blood coagulation
- actives by tissue factor → activates F VII → activates F X
Coagulation cascade: intrinsic Tenase complex
F IXa and F VIIIa activate F X → binds to FVa → accelerates clotting
Coagulation cascade: Extrinsic Xase
Factor VIIa and Tissue Factor activate F X → accelerates clotting
Coagulation cascade: Josso-loop
Connection between intrinsic and extrinsic pathways: F VIIa can activate F IX and F X
Coagulation cascade: feedback activation by thrombin
Thrombin can activate F XI, F VIII, F V
Cell-based model of coagulation: Initiation
Tissue factor-expressing cells get into contact with plasma → FVII binds to TF and activates FX and F IX → F V attaches to FX and F IX → small amount of thrombin is released though prothrombin cleavage by F X (“ Thrombin spark”)
Cell-based model of coagulation: Amplification
Thrombin activates platelets → activates FV, FVII and FIX → perfect conditions for thrombin generation
Cell-based model of coagulation: Propagation
Tenase and Prothrombinase are formed → thrombin generation (“ Thrombin burst”) → coagulation occurs on platelet surface (localised)
What does F XIIIa do?
Induced crosslink of fibrin through transglutaminase reaction and guarantees fibrin stability
Activated (cleaved) by Thrombin, Fibrin and Ca2+
Haemophilia A
F8 gene defect → lacks factor VIII
Haemophilia B
F9 gene defect → lacks factor IX
Thrombin positive feedback loop
Thrombin activates F V, XI and VIII → increases Thrombin release
Thrombin binds to Thrombomodulin which activates TAFI (= Thrombin activated fibrinolysis inhibitor) → clot won’t resolve until coagulation is finished
Thrombin negative feedback loop
Protein C binds to Thrombin → inactivates F V and VIII
Inhibitors of coagulation
- Antithrombin II
- Tissue Factor Pathway Inhibitor (TFPI)
- Protein C/S System
What are Glycosaminoglycans? And how to they work?
Cofactors for Antithrombin III example: Heparin, Heparan sulfate → accelerate inhibition 1000x
Binding of Heparin → conformational change → higher affinity of antithrombin III to F Xa + detaches FVa from cell surface
“Template effect”: both Thrombin and Antithrombin use Heparin to get in contact with each other
Where can you find Heparin in humans?
What is Heparin made of?
In basophil granulocytes in blood and mast cells in tissue.
Polymer of glucuronic acid and glucosamine → has different lengths and molecular weight
What does Antithrombin III inhibit?
Thrombin (F IIa), F Xa, F IXa, XIa, XIIa, Kallikrein
What does TFPI (Tissue Factors Pathway Inhibitor) inhibit?
Binds to FXa → leads to an inhibitory complex that inhibits extrinsic Tase complex (VIIa + PL + Ca2+)
How does Protein C inhibit Thrombin?
Thrombomodulin binds to thrombin → activates Protein C (+ Cofactor Protein S) → inhibits FV and FIII
Fibrin structure
Dimer with two of each alpha, beta and gamma chains.
Fibrinopeptide A is on alpha chain
Fibrinopeptide B is on beta chain
Chains connected though disulfate bridges
How does Fibrinolysis work?
Plasminogen is cleaved by t-PA (tissue plasminogen activator, endothelial cells) or u-PA (urokinase plasminogen activator, kidney) to Plasmin → Plasmin dissolves fibrin clot
t-PA and u-Pa are activated once fibrin binds to them!
Inhibitors of fibrinolysis
- Alpha2-antiplasmin → Plasmin
- PAI 2 (Plasminogen activator inhibitor) → u-PA and t-PA
- TAFI (Thrombin actionable fibrinolysis inhibitor) → Plasminogen + proteolysis of fibrin
