FXIIIα/F13A1: A Promising Therapeutic Target for Vascular Diseases

Background

• FXIIIa in Coagulation diseases

FXIIIa stabilizes the blood clot by cross-linking the α- and γ-chains of fibrin. It also protects the newly formed clot from plasmin-mediated fibrinolysis by cross-linking α2-antiplasmin to fibrin. Furthermore, FXIIIa is a major determinant of clot size and the clot's RBC content. Accordingly, FXIII(a) has been implicated in the risk of atherothrombotic diseases and venous thromboembolism (VTE). Inhibiting FXIIIa directly or indirectly leads to smaller clots with fewer entrapped RBCs and relatively more fragile clots that are more susceptible to hydrolysis by the action of proteolytic enzymes such as plasmin. Therefore, inhibitors targeting FXIIIa have been considered to develop a new generation of anticoagulants to prevent and/or treat venous thromboembolism.

Fig. 1 Factor XIIIa Inhibitors as Potential Novel Drugs for Venous Thromboembolism

• FXIIIa in degenerative bone diseases

It has been demonstrated that the FXIII, drives arthritis pathogenesis by promoting local inflammatory and tissue degradative and remodeling events. Thus, eliminating FXIIIa limits inflammatory arthritis and protects from cartilage and bone destruction in part through mechanisms linked to reduced RANKL-mediated osteoclastogenesis. In summary, therapeutic strategies targeting FXIIIa activity may prove beneficial in limiting arthropathies and other degenerative bone diseases.

Fig. 2 The role of FXIIIa in diseases

• FXIIIa in diseases of tissue repair dysregulation

Under infectious disease conditions, FXIII cross-links bacterial surface proteins to fibrinogen, resulting in immobilization and killing, while during wound healing, FXIII induces cross-linking of the provisional matrix. The latter process has been shown to influence the interaction of leukocytes with the provisional extracellular matrix and promote wound healing. Through these actions, there are good rationales for evaluating the therapeutic potential of FXIII in diseases in which tissue repair is dysregulated or perturbed, including systemic sclerosis (scleroderma), invasive bacterial infections, and tissue repair.

• FXIIIa in cardio- and cerebrovascular diseases

FXIII acts on endothelial cell VEGFR-2 and αvβ3 integrin, which ultimately leads to the downregulation of the antiangiogenic protein thrombospondin-1, promoting angiogenesis and neovascularization. Besides, there are studies that have indicated its cardioprotective effect as well as its potential contribution to vascular permeability and stabilization, and to the formation of amyloid β deposits in cerebral amyloid angiopathy and Alzheimer's disease.