Factor XIII-A: An Indispensable “Factor” in Haemostasis and Wound Healing

Abstract

Factor XIII (FXIII) is a transglutaminase enzyme that catalyses the formation of ε-(γ-glutamyl)lysyl isopeptide bonds into protein substrates. The plasma form, FXIIIA2B2, has an established function in haemostasis, with fibrin being its principal substrate. A deficiency in FXIII manifests as a severe bleeding diathesis emphasising its crucial role in this pathway. The FXIII-A gene (F13A1) is expressed in cells of bone marrow and mesenchymal lineage. The cellular form, a homodimer of the A subunits denoted FXIII-A, was perceived to remain intracellular, due to the lack of a classical signal peptide for its release. It is now apparent that FXIII-A can be externalised from cells, by an as yet unknown mechanism. Thus, three pools of FXIII-A exist within the circulation: plasma where it circulates in complex with the inhibitory FXIII-B subunits, and the cellular form encased within platelets and monocytes/macrophages. The abundance of this transglutaminase in different forms and locations in the vasculature reflect the complex and crucial roles of this enzyme in physiological processes. Herein, we examine the significance of these pools of FXIII-A in different settings and the evidence to date to support their function in haemostasis and wound healing.

Another piece of knowledge in the puzzle of procoagulant COAT platelets

“…This localizes important amounts of active FXIII-A directly at sites of thrombus formation. 4 Indeed, Mitchell et al 5 demonstrated that platelet FXIII-A exerts an antifibrinolytic function by cross-linking α2-antiplasmin into the fibrin network adjacent to platelet aggregates. Subsequently, Mattheij et al 20 showed that on the surface of the platelet subpopulation expressing negatively charged procoagulant phospholipids upon activation by collagen and thrombin, fibrinogen bound to activated αIIbβ3 and cross-linked by cFXIIIa is responsible for the formation of so-called "star-like fibrin fiber formation", 21 thought to be involved in the anchorage of these platelets within the thrombus and eventually stabilization of the platelet-fibrin clot.…”

Mechanisms Underlying Dichotomous Procoagulant COAT Platelet Generation—A Conceptual Review Summarizing Current Knowledge

“…Coagulation factor XIII (FXIII), a transglutaminase that stabilizes the fibrin mesh against mechanical stress and proteolysis, is present at high concentrations in platelet cytosol [ 63 ]. During convulxin/thrombin activation, platelet FXIII is externalized by a receptor-signaling dependent mechanism on the membrane of procoagulant COAT platelets [ 64 ], where it appears to serve several functions, such as cross-linking α2-antiplasmin into fibrin [ 65 ], promoting star-like fibrin fiber formation [ 62 ], and retaining α-granule proteins [ 36 ].…”

Current Application of Beta-Tricalcium Phosphate in Bone Repair and Its Mechanism to Regulate Osteogenesis

“…Plasma factor XIII, a 325.8 kDa heterotetrameric proenzyme which stabilizes fibrin, is composed of two catalytic A subunits (FXIII-A) and two inhibitory B subunits (FXIII-B) (Ashcroft et al, 2000;Muszbek et al, 2011;Singh et al, 2019). It is the last factor in the coagulation cascade and facilitates crosslinking between fibrin monomers, protects fibrin from shear stress, and guards clots from premature degradation (Duval et al, 2014;Vasilyeva et al, 2018;Alshehri et al, 2021). For factor XIII to react with fibrin monomers, it is converted to an activated transglutaminase and functions in the presence of thrombin and Ca 2+ .…”