Factor XIII and Red Blood Cells in Venous Thrombosis

Blood coagulation culminates in the thrombin-mediated conversion of fibrinogen to fibrin and production of a fibrin network that stabilizes the clot. The transglutaminase factor XIII(a) [FXIII(a)] crosslinks fibrin and increases the clot’s resistance to fibrinolysis and mechanical disruption. Consequently, fibrin formation and crosslinking are essential for hemostasis. However, the formation of clots with abnormal fibrin network structure and/or stability (resistance to mechanical disruption or pharmacological dissolution) is a risk factor for both arterial and venous thrombosis. Improved understanding of fibrin formation and crosslinking during coagulation is essential for understanding the pathophysiologic mechanisms that promote thrombotic disease. We have shown that elevated levels of fibrinogen accelerate vessel occlusion and enhance thrombus stability in mice, demonstrating etiologic contributions of fibrin(ogen) to thrombosis. Recently, we discovered that FXIIIa transglutaminase activity also mediates venous thrombosis via its ability to promote red blood cell retention during clot contraction in whole blood. Genetic deletion of FXIII or pharmacologic inhibition of FXIIIa activity reduces red blood cell retention in clots and consequently, reduces thrombus size in vitro and in vivo. Furthermore, FXIII zymogen binding to soluble, circulating fibrinogen is necessary for normal FXIII activation and activity. The fibrinogen motif that mediates FXIII binding involves C-terminal residues in the fibrinogen gamma chain (gamma 390-396); mice that express a variant fibrinogen that has mutations within these residues show reduced binding of FXIII zymogen to fibrinogen, and delayed activation of FXIII. In venous thrombosis models, these mice phenocopy FXIII-deficient mice, producing smaller venous thrombi with reduced red blood cell content compared to thrombi from wild-type mice. Intriguingly, these mice do not exhibit bleeding or poor wound healing normally associated with FXIII deficiency. Collectively, these findings provide new insight into the pathophysiology of venous thrombosis, and expose the fibrin(ogen)-FXIII axis as a central determinant of venous thrombus formation and composition.