Question 19

College Answer

The fibrinolytic pathway is a cascade largely made up of proteolytic enzmes and other factors synthesized in the liver that circulate in inactive precursor forms. Marks were awarded for description of the principal members of the cascade and the pathway relations between them. Endothelium is also important in the fibrinolytic pathway.
Regulation of the pathway to localise the site and size of clot as well as delayed onset of action of fibrinolysis is central to any description. Regulation of fibrinolysis by the coagulation cascade and a description of this area of interaction were expected. Many candidates provided a reasonable description of the fibrinolytic cascade. Marks were not awarded for description of the coagulation cascade that did not have relevance to fibrinolysis. Understanding of regulation of fibrinolysis and it’s interaction with coagulation was poorly answered. Most candidates were able to name two antifibrinolytic agents. Few were able to describe
mechanism of action.

Discussion

• Fibrinolysis is the natural process of clot degradation which is mediated by circulating and endothelial proteolytic enzymes.
• The main mediators of fibrinolysis are:
  • Tissue plasminogen activator (tPA):
    • serine protease found on all endothelial cells, plus circulating soluble version
    • Requires fibrin and plasminogen for its action
      • Plasminogen binds fibrin
      • tPA binds the plasminogen-fibrin complex and activates plasminogen
      • Activated plasminogen (plasmin) degrades fibrin into small peptide degradation product
  • Plasmin: a serine protease, the activated form of plasminogen. 
  • Urokinase is another serine protease
    • produced by monocytes, macrophages, and urinary epithelium
    • Also an activator of plasminogen
    • Affinity for plasminogen is lower than that of tPa, but then it does not require fibrin as a cofactor.
• 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

Antifibrinolytic agents? One could list several, but the best known ones are:

• Tranexamic acid
• Epsilon-aminocaproic acid
• Aprotinin

The mechanism of action for aprotinin is actually rather complicated, so it would be better to just go with the other two, considering this is only worth 20%. In short:

• These molecules resemble lysine
• Lysine residues on fibrin are the molecular target for plasminogen 
• Tranexamic acid binds to plasminogen at lysine binding-sites
• tPA can only activate plasminogen if it is bound to fibrin
• Thus, lysine derivatives can inhibit plasmin production

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Longstaff, Colin, and K. Kolev. "Basic mechanisms and regulation of fibrinolysis." Journal of Thrombosis and Haemostasis 13 (2015): S98-S105.

Yau, Jonathan W., Hwee Teoh, and Subodh Verma. "Endothelial cell control of thrombosis." BMC cardiovascular disorders 15.1 (2015): 1-11.

Ezihe-Ejiofor, J. Adanma, and Nevil Hutchinson. "Anticlotting mechanisms 1: physiology and pathology." Continuing Education in Anaesthesia, Critical Care & Pain 13.3 (2013): 87-92.

Ezihe-Ejiofor, J. Adanma, and Nevil Hutchinson. "Anticlotting mechanisms 2: pharmacology and clinical implications." Continuing Education in Anaesthesia, Critical Care & Pain 13.3 (2013): 93-97.

Chapin, John C., and Katherine A. Hajjar. "Fibrinolysis and the control of blood coagulation." Blood reviews 29.1 (2015): 17-24.