Haemostasis — Aspirin & Haemostasis

Cell-based model of coagulation

Initiation

• Small amounts of Factor VII, X and prothrombin leak into interstitium from intravascular space
• Factor VII interacts with Tissue Factor leading to activation of extrinsic pathway
  • Activation of Factor X
  • Small amounts of prothrombin converted to thrombin

Amplification

• At onset of tissue damage and vessel disruption
  • Platelets exposed to thrombin generated in initiation phase, together with collagen via GPIa
  • Platelet activation and release of α and dense granules, and morphological change
  • Factor XII activated, leading to consequent activation of factors XI and IX
  • Formation of Xase complex on platelet surface
    • Amplified activation of factor X

Propagation phase

• Increased activated factor X causes “thrombin burst”
• Fibrinogen activated to fibrin
• Further propagation of platelet activation and aggregation

Modulation of coagulation response

• Circulating proteins C and protein S bind and inactivate factors V and VIII
• Antithrombin 3 binds to thrombin, as well factors IX and X and inhibit these
• Thrombomodulin on intact endothelium binds thrombin → anti-coagulant effect and increased protein C activation
• Plasminogen converted to plasmin → degradation of fibrin and therefore thrombolysis

Effect of aspirin

• Non-selective COX inhibition
• At low doses
  • Irreversibly inhibits platelet COX in the portal circulation → inhibits platelet production of thromboxane (TXA)
  • TXA stored in α granules and augments the activation of surrounding platelets, therefore aspirin reduces platelet activation in response to coagulation cascade
• At high doses
  • Aspirin overcomes hepatic first pass metabolism and escapes to systemic circulation
  • Inhibits systemic COX → inhibits endothelial production of prostacyclin
  • Prostacyclin inhibits platelet aggregation and adherence, therefore increases clot formation and strength

Sakurai 2016

Answer by Sakurai