Question 6

College Answer

(a) This part required candidates to demonstrate their knowledge of the fibrinolytic pathway with details of the relevant mediators and inhibitors. Candidates where then required to apply their knowledge of both the coagulation cascade and fibrinolysis, with detail of how the pathways are simultaneously activated by the same stimuli to ensure balance between bleeding and clotting. An example would be endothelial damage stimulating both the clotting cascade through collagen exposure and thromboplastin activation (faster response) as well as fibrinolysis through t-PA activation (slower response).

(b) This section of the question required a detailed description of the mechanism of action of alteplase, recombinant t-PA. A comparison to endogenous t-PA helped illustrate this action and the subsequent bleeding and the non-bleeding effects.

Discussion

a)

• Fibrinolysis is the natural process of clot degradation
• The main mediators of fibrinolysis are:
  • Plasminogen
  • Plasmin
  • Tissue plasminogen activator (tPA) - found on all endothelial cells, plus a soluble form
  • Urokinase,  which does not require fibrin as a cofactor.
• Process of fibrinolysis
  • Plasminogen binds fibrin
  • tPA binds the plasminogen-fibrin complex and activates plasminogen
  • Activated plasminogen (plasmin) degrades fibrin into small peptide degradation product
• Inhibitors of fibrinolytic pathways:
  • plasminogen activator inhibitor-1 and 2 (PAI-1,2): produced by the liver, inhibits tPA and urokinase
  • α2-antiplasmin: produced by the liver, a circulating serine protease inhibitor which inhibits plasmin directly by binding to it in a covalent manner
  • Thrombin Activatable Fibrinolysis Inhibitor (TAFI): a circulating inhibitor, activated by thrombin/thrombomodulin or plasmin; cleaves lysine residues on fibrin, preventing the binding of plasminogen to fibrin
• Activators of fibrinolytic pathways:
  • Thrombomodulin binds to thrombin and activates Protein C
  • Protein C then inactivates TAFI and PAI-1/2

ii)

• Mechanism of action of alteplase:
  • Recombinant analog of the tissue plasminogen activator (tPa)
  • Serum protease which has specific affinity for plasminogen in the presence of fibrin.
  • Catalyses the conversion of plasminogen to plasmin, which degrades fibrin strands
• Adverse effects of alteplase:
  • Thrombolytic effect extends into bleeding complications, which can be very serious.
  • Anaphylaxis, given that this is a recombinant protein

Collen, Désiré, and Roger H. Lijnen. "Thrombolytic agents." Thrombosis and haemostasis 93.04 (2005): 627-630.

Jerjes-Sánchez, Carlos, and H. David Rodriguez. "Pharmacokinetics and pharmacodynamics of fibrinolytic agents." Thrombolysis in Pulmonary Embolism. Springer, Cham, 2015. 19-39.

Vassalli, Jean-Dominique, A. P. Sappino, and Dominique Belin. "The plasminogen activator/plasmin system." The Journal of clinical investigation 88.4 (1991): 1067-1072.