Question 10

College Answer

This question was best answered in a chronological manner. Many candidates omitted initial vasoconstriction and its mechanism. The platelet plug and formation of the clot should have then been described followed by the fate of the clot, including in-growth of fibroblasts. Strictly, fibrinolysis is a system for repairing / limiting clot propagation after the fact. Anticoagulants refer to antithrombin III, heparin, thrombomodulin and protein C and S. An explanation of the interaction of these naturally occurring anticoagulants was expected. The clotting factors that are specifically inhibited was expected as part of the discussion. The glycocalyx and vessel wall also plays a role in preventing coagulation.

Discussion

Haemostatic events:

• simultaneous activation of clotting factors and platelets to prevent blood loss.
• Initiation:
  • tissue factor (TF)  is exposed
  • TF and Factor VIIa act to produce a small amount of thrombin (the extrinsic pathway)
  • Thrombin then activates platelets
• Platelet plug formation occurs when platelets are exposed to TF and collagen:
  • Adhesion to the denuded surface collagen via VWF, as well as directly
  • Aggregation (platelet to platelet) mediated by fibrin and VWF
  • Activation (degranulation, shape change, phosphatidylserine exposure on the platelet surface)
• Amplification
  • Intrinsic pathway activation by the available thrombin and other platelet granule content leads to the increase in available clotting factors in the region of the platelet plug
  • The available thrombin activates factor XI and leads to the activation of FXI
  • Activate platelet surfaces act as sites of attachment for FVIIIa and FVa
• Propagation
  • Platelet-bound Factors FVIIIa  FVa and FX activate thrombin (the "thrombin burst")
  • The large amount of thrombin made available allows the generation of a large amount of fibrin from fibrinogen
• Contraction of platelets occurs in later stages of clot maturation

Anticoagulation and fibrinolysis:

• Factors that prevent the initiation of thrombosis
  • Normal endothelium does not contain any clotting cascade activators (eg. TF)
  • Endothelial glycocalyx contains antithrombotic molecules:
    • Heparin-like oligosaccharides
    • Antithrombin-III
  • Blood flow produces shear stress which opposes regional clotting factor concentration and platelet aggregation
• Factors that prevent primary haemostasis
  • Extrinsic pathway inhibitors:
    • Tissue factor pathway inhibitor (TFPI) antagonises the TF-FVIIa complex and prevents extrinsic pathway activation
  • Platelet activation/aggregation inhibitors:
    • Prostacyclin (PGI2), via GS-protein-coupled receptor
    • Nitric oxide (less iCa²⁺, also inhibits TXA₂ receptor)
    • Fibrin degradation products (bind GPIIb/IIa receptors) 
• Factors that prevent secondary haemostasis
  • ​​​​​​​Antithrombin III antagonises the activity of thrombin
  • Protein C:
    • Activated by thrombin
    • Inhibits  thrombin,  Factor Va and Factor VIIIa
  • Protein S: co-factor for Protein C
  • Thrombomodulin:  co-factor for Protein C
• Factors which promote fibrinolysis
  • Tissue plasminogen activator and urokinase activate plasminogen
  • Plasminogen is activated into p​​​​​​lasmin
  • Plasmin degrades fibrin into fibrin degradation products

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