Question 19

Outline the process of fibrinolysis (40% marks). Write short notes on the indications,
mechanism of action, pharmacokinetics and side effects of tranexamic acid (60% marks).

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College Answer

The relative allocation of marks and thus time to be spent on each component was delineated by the relative percentages in the question. The first part of the question required a step-by-step outline of the fibrinolytic pathway with mention of the regulatory processes. Tranexamic acid is an important drug in the practice of intensive care and the question provided the headings under which to answer the question. The detail surrounding the keys aspects of this drug with respect to its use in critical care were often vague and underappreciated.

Discussion

  • Fibrinolysis is the natural process of clot degradation which is mediated by circulating and endothelial proteolytic enzymes.
  • Tissue plasminogen activator and urokinase activate plasminogen
  • Plasminogen is activated into p​​​​​​lasmin
  • Plasmin degrades fibrin into fibrin degradation products
  • Several inhibitors regulate this pathway:
    • plasminogen activator inhibitor-1 and 2 (PAI-1,2): produced by the liver, inhibits tPA
    • 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

As for tranexamic acid:

Class Serine protease inhibitor
Chemistry Monocarboxylic acid (a synthetic derivative of the amino acid lysine)
Routes of administration IV, nebulised, topical, oral
Absorption 50% absorbed from the GI tract; bioavailability is about 30-35%. Most of it is not metabolised.
Solubility pKa of 10.22; highly water soluble, but minimally fat-soluble
Distribution VOD = 0.18 L/kg; minimally protein bound (3%, all of which is accounted for by its binding to plasminogen). After some loading (eg. several doses over 24-36 hrs), enough of it distributes to the tissues to continue having a sustained antifibrinolytic effect for many hours.
Target receptor Plasminogen
Metabolism Minimally metabolised
Elimination 95% of the dose is excreted unchanged in the kidneys; half-life is 2 hours
Time course of action Relatively short-acting, very rapid onset of effect
Mechanism of action Competitive inhibitor of plasminogen activation (by binding to the 5-lysine site on plasminogen). This inhibts the formation of plasmin and displaces plasminogen from the surface of fibrin.
Clinical effects Prevents the breakdown of fibrin, thus maintaing clot integrity. Numerous other effects (as it also inhibits other proteases), as well as indirect effects via plasminogen inhibition (eg. on complement activation, where by reducing plasmin activity it reduces the consumption of C1 esterase inhibitor)
Single best reference for further information Data sheet from medsafe.govt.nz

References

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

Pilbrant, Å., M. Schannong, and J. Vessman. "Pharmacokinetics and bioavailability of tranexamic acid." European journal of clinical pharmacology 20.1 (1981): 65-72.

Dunn, Christopher J., and Karen L. Goa. "Tranexamic acid." Drugs 57.6 (1999): 1005-1032.

McCormack, Paul L. "Tranexamic acid." Drugs 72.5 (2012): 585-617.