Fibrinogen and Factor XIII in Venous Thrombosis and Thrombus Stability

Abstract

As the third most common vascular disease, venous thromboembolism is associated with significant mortality and morbidity. Pathogenesis underlying venous thrombosis is still not fully understood. Accumulating data suggest fibrin network structure and factor XIII-mediated crosslinking are major determinants of venous thrombus mass, composition, and stability. Understanding the cellular and molecular mechanisms mediating fibrin(ogen) and factor XIII production and function and their ability to influence venous thrombosis and resolution may inspire new anticoagulant strategies that target these proteins to reduce or prevent venous thrombosis in certain at-risk patients. This article summarizes fibrinogen and factor XIII biology and current knowledge of their function during venous thromboembolism.

Keywords: anticoagulant; fibrinogen; hemostasis; red blood cell; venous thrombosis.

Figure 1.. Fibrinogen and FXIII in hemostasis and venous thrombosis.

(A) FXIII-A- and B-subunits are synthesized in bone marrow and liver, respectively and assembled in plasma. Fibrinogen is also synthesized in the liver. FXIII-A₂B₂ circulates in plasma bound to fibrinogen. FXIII-A₂ also circulates in platelets and leukocytes. (B-C) Vessel injury (hemostasis, B) or endothelial dysfunction associated with blood stasis (venous thrombosis, C) triggers the activation of coagulation and results in the production of thrombin which cleaves fibrinogen into fibrin and activates FXIII to FXIIIa. FXIIIa catalyzes crosslinks between fibrin molecules and between fibrin and antifibrinolytic proteins (i.e., α₂-antiplasmin [α₂-AP]). Crosslinking provides mechanical and biochemical stability to the clot and promotes retention of red blood cells within contracted clots. Controlled clot formation seals the injury site during hemostasis and facilitates wound healing, whereas formation of large intravascular thrombi occludes the vessel and leads to venous thrombosis.

Figure 2.. Platelet FXIII-A activation and externalization.

In unstimulated platelets, FXIII-A exists in the cytoplasm in a diffuse distribution. After platelet activation, increased intracellular Ca²⁺ nonproteolytically activates FXIII-A to FXIII-A° which crosslinks cytoskeletal proteins and contributes to cytoskeletal rearrangement and platelet conformational change. After stimulation by strong dual agonists (convulxin + thrombin), two populations of FXIII-A-exposing platelets are formed: spread platelets with FXIII-A in a diffuse distribution, and ballooned procoagulant (phosphatidylserine-exposing) platelets with FXIII-A on a protruding “cap”. FXIII-A is also exposed on extracellular vesicles (EVs).