Factor XIII: A Coagulation Factor With Multiple Plasmatic and Cellular Functions

Abstract

Factor XIII (FXIII) is unique among clotting factors for a number of reasons: 1) it is a protransglutaminase, which becomes activated in the last stage of coagulation; 2) it works on an insoluble substrate; 3) its potentially active subunit is also present in the cytoplasm of platelets, monocytes, monocyte-derived macrophages, dendritic cells, chondrocytes, osteoblasts, and osteocytes; and 4) in addition to its contribution to hemostasis, it has multiple extra- and intracellular functions. This review gives a general overview on the structure and activation of FXIII as well as on the biochemical function and downregulation of activated FXIII with emphasis on new developments in the last decade. New aspects of the traditional functions of FXIII, stabilization of fibrin clot, and protection of fibrin against fibrinolysis are summarized. The role of FXIII in maintaining pregnancy, its contribution to the wound healing process, and its proangiogenic function are reviewed in details. Special attention is given to new, less explored, but promising fields of FXIII research that include inhibition of vascular permeability, cardioprotection, and its role in cartilage and bone development. FXIII is also considered as an intracellular enzyme; a separate section is devoted to its intracellular activation, intracellular action, and involvement in platelet, monocyte/macrophage, and dendritic cell functions.

Factor XIII and inflammatory cells

“…FXIIIa, a transglutaminase (TG), catalyzes an acyl transfer reaction, resulting in ε(γ-glutamyl)lysyl cross-links between peptide chains [1,2]. The main hemostatic function of FXIIIa is to cross-link fibrin chains and covalently attach the main inhibitor of plasmin, α 2 -plasmin inhibitor (α 2 PI), to fibrin.…”

“…The cross-linking of fibrin considerably enhances its stiffness and rigidity and makes it more resistant against shear stress. α 2 PI to fibrin cross-linking has the predominant role of protecting newly formed fibrin from elimination by the fibrinolytic enzyme, plasmin [1,6,7]. The importance of these mechanisms is underlined by the severe bleeding diathesis of non-substituted FXIII-A deficient patients [8,9].…”

“…The two subunits form a tight tetrameric complex (FXIII-A 2 B 2 ) in the plasma; practically all FXIII-A is in complex, while about 50% of FXIII-B circulates in free form. A cellular dimeric form of FXIII-A (cFXIII) is also present in the cytoplasm of platelets and monocytes/macrophages [1,2].The concerted action of thrombin and Ca 2 + is required for the activation of pFXIII (Fig. 1).…”

“…Then, in the presence of Ca 2 + , FXIII-B dissociates and the remaining FXIII-A dimer assumes an enzymatically active configuration (FXIIIa). The activation of pFXIII occurs rapidly on the surface of fibrin, which accelerates the activation process 80-100-folds [1,2]. The activation of cFXIII in the cytoplasm occurs through a nonproteolytic mechanism and the rise of intracellular Ca 2 + concentration seems sufficient to bring about the active configuration [3][4][5].…”

“…The activation of pFXIII occurs rapidly on the surface of fibrin, which accelerates the activation process 80-100-folds [1,2]. The activation of cFXIII in the cytoplasm occurs through a nonproteolytic mechanism and the rise of intracellular Ca 2 + concentration seems sufficient to bring about the active configuration [3][4][5].FXIIIa, a transglutaminase (TG), catalyzes an acyl transfer reaction, resulting in ε(γ-glutamyl)lysyl cross-links between peptide chains [1,2]. The main hemostatic function of FXIIIa is to cross-link fibrin chains and covalently attach the main inhibitor of plasmin, α 2 -plasmin inhibitor (α 2 PI), to fibrin.…”