Question 17

College Answer

The question was answered well overall. Better answers included detail of the platelet receptor and mediator interactions. Discussion of the role of the platelet in providing a phospholipid surface to enable the formation of the activated Xa complex was expected. Modulation of the coagulation cascade and prevention of clot propagation via protein C, nitric oxide, thrombomodulin and fibrinolysis was important to note in a comprehensive answer. The pharmacodynamic action of aspirin was generally understood.
Syllabus: J1,2c and J2, 2d
Recommended sources: Basic and Clinical Pharmacology, Katzung, Chp 34, 36

Discussion

Events of haemostasis:

• Initiation takes place when tissue factor (TF) and other basal lamina components are exposed to the bloodstream
  • Tissue factor 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 tissue factor and basal lamina components such as collagen, and involves several largely simultaneous steps:
  • Adhesion to the denuded surface collagen via VWF, as well as directly
  • Aggregation (platelet to platelet) mediated by fibrin and VWF
  • Activation, which means
    • Degranulation (release of vasoactive and platelet-activating mediators)
    • Shape change (flattening and extension of cellular projections)
    • Phosphatidylserine exposure on the platelet surface, which is essential for clotting factor binding
• 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
  • This leads to the formation of a large amount of 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

Mechanism of action of aspirin:

• By inhibiting the activity of COX-1 isoenzyme, aspirin decreases the synthesis of thromboxane-A2, which is a potent platelet activator.
• The result is a decrease in platelet activation and aggregation.
• This inhibition is irreversible (acetylation)

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