Newly-Recognized Roles of Factor XIII in Thrombosis

Abstract

Arterial and venous thromboses are major contributors to coagulation-associated morbidity and mortality. Greater understanding of mechanisms leading to thrombus formation and stability is expected to lead to improved treatment strategies. Factor XIII (FXIII) is a transglutaminase found in plasma and platelets. During thrombosis, activated FXIII cross-links fibrin and promotes thrombus stability. Recent studies have provided new information about FXIII activity during coagulation and its effects on clot composition and function. These findings reveal newly-recognized roles for FXIII in thrombosis. Herein, we review published literature on FXIII biology and effects on fibrin structure and stability, epidemiologic data associating FXIII with thrombosis, and evidence from animal models indicating FXIII has an essential role in determining thrombus stability, composition, and size.

Figure 1. FXIIIa crosslinking during fibrin formation

Fibrinogen is a hexamer composed of 2 Aα- (purple), 2 Bβ- (blue), and 2 γ-chains (green). During coagulation, thrombin cleaves N-terminal fibrinopeptides from the Aα- and Bβ-chains, producing fibrin monomers which polymerize into protofibrils and subsequently, fibers. FXIIIa increases clot stability by introducing ε-N-(γ-glutamyl)-lysyl crosslinks between residues in the γ- and α-chains of fibrin monomers within individual fibers. FXIIIa first introduces crosslinks between γ-chains (forming γ-γ dimers) and subsequently between γ- and α-chains (forming high molecular weight species [γ-multimers, α-polymers, and αγ-hybrids]).^,–

Figure 2. Contributions of FXIIIa to clot biochemical and mechanical stability

FXIIIa crosslinking of plasma proteins [i.e. α₂-antiplasmin, (α₂-AP)] increases the resistance of the clot to fibrinolysis. Crosslinking of the fibrin α- (purple) and γ-chains (green) stiffens fibrin fibers and increases the mechanical stability of the clot. Increased mechanical stability renders the clot more resistant to shear forces. α-chain crosslinking enables RBC retention during clot contraction.