What is the role of synthetic inhibitors in the pathophysiology of factor XIII (FXIII) deficiency?

Updated: Aug 01, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
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Answer

Several selective synthetic inhibitors have been shown to prevent the ability of FXIIIa to stabilize a clot, thereby reducing clot strength (clot stiffness, viscoelastic modulus) to approximately 20% of normal (values similar to those seen in patients with severe FXIII deficiency). Rapid lysis of these clots occurred following in vitro exposure to thrombolytic agents. [29] Imidazolium derivatives, a new class of compounds, specifically inhibit both FXIII-induced formation of a-chain polymers and the incorporation of a2 PI into the a chain of fibrin, resulting in accelerated clot lysis. [11, 56]

Specific monoclonal antibodies to FXIII have provided similar benefits by reducing the viscoelastic properties and by enhancing clot lysis. They also have been used to modify disease states. The beneficial effect of the absence of cross-linked fibrin on pathophysiologic processes was proven in an animal model of widespread thrombosis. FXIIIa deficiency induced in rabbits by pretreatment with a specific monoclonal antibody before induction of a generalized Schwartzman reaction protected them from the deleterious effects of widespread microvascular thrombosis. The protection resulted from the ability of the fibrinolytic system to effectively degrade non–cross-linked thrombi. [57] These data add support to the author's speculation many years ago of the potential use of drugs that inhibit cross-linking as a method of prophylaxis in venous thromboembolic disease.

The biochemical basis and potential for using modifiers of fibrin stabilization in improved thrombolytic therapies are discussed in a recent review by Lorand. [29] Similar ideas have been proposed by others, expanding on the importance of fibrin structure in thrombus formation and dissolution. [58] Prospective clinical trials must prove any thromboprophylactic efficacy of altering fibrin structure using specific drugs.


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