Genetic landscape in coagulation factor XIII associated defects – Advances in coagulation and beyond

Coagulation factor XIII (FXIII) acts as a fine fulcrum in blood plasma that maintains the balance between bleeding and thrombosis by covalently crosslinking the pre-formed fibrin clot into an insoluble one that is resistant to premature fibrinolysis. In plasma, FXIII circulates as a pro-transglutaminase complex composed of the dimeric catalytic FXIII-A encoded by the F13A1 gene and dimeric carrier/regulatory FXIII-B subunits encoded by the F13B gene. Growing evidence accumulated over decades of exhaustive research shows that not only does FXIII play major roles in both pathological extremes of hemostasis i.e. bleeding and thrombosis, but that it is, in fact, a pleiotropic protein with physiological roles beyond coagulation. However, the current FXIII genetic-epidemiological literature is overwhelmingly derived from the bleeding pathology associated with its deficiency. In this article we review the current clinical, functional, and molecular understanding of this fascinating multifaceted protein, especially putting into the same perspective its genetic landscape.