Substrates of Factor XIII-A: roles in thrombosis and wound healing

Abstract

FXIII (Factor XIII) is a Ca²+-dependent enzyme which forms covalent ϵ-(γ-glutamyl)lysine cross-links between the γ-carboxy-amine group of a glutamine residue and the ϵ-amino group of a lysine residue. FXIII was originally identified as a protein involved in fibrin clot stabilization; however, additional extracellular and intracellular roles for FXIII have been identified which influence thrombus resolution and tissue repair. The present review discusses the substrates of FXIIIa (activated FXIII) involved in thrombosis and wound healing with a particular focus on: (i) the influence of plasma FXIIIa on the formation of stable fibrin clots able to withstand mechanical and enzymatic breakdown through fibrin-fibrin cross-linking and cross-linking of fibrinolysis inhibitors, in particular α2-antiplasmin; (ii) the role of intracellular FXIIIa in clot retraction through cross-linking of platelet cytoskeleton proteins, including actin, myosin, filamin and vinculin; (iii) the role of intracellular FXIIIa in cross-linking the cytoplasmic tails of monocyte AT1Rs (angiotensin type 1 receptors) and potential effects on the development of atherosclerosis; and (iv) the role of FXIIIa on matrix deposition and tissue repair, including cross-linking of extracellular matrix proteins, such as fibronectin, collagen and von Willebrand factor, and the effects on matrix deposition and cell-matrix interactions. The review highlights the central role of FXIIIa in the regulation of thrombus stability, thrombus regulation, cell-matrix interactions and wound healing, which is supported by observations in FXIII-deficient humans and animals.

Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

“…Fibronectin, an extracellular matrix protein involved in cell adhesion and migration, is cross-linked to fibrin -chains by FXIIIa, via its glutamine residues 3, 4 and 16 [37], although no lysine residue donors have yet been identified in fibrin. Cross-linking of fibronectin to fibrin has been shown to have no effect on clot rigidity, however those clots were denser, with smaller pores [37].…”

“…Cross-linking of fibronectin to fibrin has been shown to have no effect on clot rigidity, however those clots were denser, with smaller pores [37]. A more recent study by Ramanathan et al, in a purified system in the absence of FXIII, showed that fibronectin increases the initial rate of fibrin polymerisation, leading to the formation of denser clots [38], thought to be more resistant to fibrinolysis [39].…”

Provisional Matrix Deposition in Hemostasis and Venous Insufficiency: Tissue Preconditioning for Nonhealing Venous Ulcers

“…The detailed molecular mechanisms of the role that FXIIIa plays in this process have recently been reviewed. 21 Interestingly, recent evidence suggests that the release kinetics of fibrinopeptides is different between soluble and surface bound fibrinogen, with FpB being released at a higher rate than FpA from the surface bound configuration. 20 This may have important functional consequences in vivo because the FpB is a known chemoattractant for neutrophils and fibroblasts in vitro.…”

Treatment of spontaneous intracranial hypotension with intravenous factor xiii administration: initial clinical experience

“…However, there is a possibility of side effects and complications including back pain, radiculopathy, meningitis, and rebound intracranial hypertension (9). Coagulation factor XIII is well known as a clot-stabilizing factor and circulates in the blood in the form of a proenzyme (4,10). Thrombin and Ca 2+ convert Factor XIII to its active form.…”