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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.

Factor XIII-A (FXIII-A) is present in the cytosol of platelets, megakaryocytes, monocytes, osteoblasts, and macrophages and may be released from cells by a nonclassical pathway. We observed that plasma FXIII-A levels were unchanged in thrombocytopenic mice (Bcl-x Plt20/Plt20 and Mpl ؊/؊ ), which implicates nonclassical secretion from nucleated cells as the source of plasma FXIII-A. We, therefore, examined the intracellular targeting of FXIII-A in the THP-1 (monocyte/macrophage) cell line and in human monocyte- IntroductionCoagulation factor XIII-A (FXIII-A) is an 83-kDa protransglutaminase that is present in plasma as an A 2 B 2 heterotetramer and present in the cytoplasm of platelets/megakaryocytes, monocyte/macrophages, chondrocytes, and osteoblasts 1,2 as an A 2 heterodimer. The best-characterized function of plasma FXIII-A is to cross-link fibrin clots after thrombin activation, 1 but extracellular FXIII-A has also been implicated in bone calcification, 2 angiogenesis, 3 and tissue repair. 4 The intracellular roles of FXIII-A remain poorly defined, as is the mechanism by which it is secreted into the plasma or extracellular matrix (ECM).FXIII-A does not contain an identifiable endoplasmic reticulum (ER) signal sequence and is excluded from the classical ER-Golgi pathway in nucleated cells 5 ; hence, FXIII-A synthesized de novo in megakaryocytes cannot be delivered to ␣-granules in nascent platelets. However, certain leaderless proteins, including interleukin-1␤ (IL-1␤), IL-18, and fibroblast growth factor-2 are secreted by nonclassical mechanisms, some of which may be specific to hematopoietic cells. [6][7][8] In some contexts (eg, cartilage deposition), FXIII-A may be nonselectively released into the ECM on cell death and lysis. 9 However, it also seems probable that FXIII-A will be actively released from cells by one or more nonclassical pathways. Furthermore, the homologous protein transglutaminase-2 TG2 may be actively released under conditions of cell stress 10 under the direction of an amino-terminal peptide motif. 11 The outcome of bone marrow transplantation protocols in humans has implicated platelets in releasing plasma 13 Activated platelets release procoagulant microparticles containing FXIII-A, 14 and the constitutive low level release of microparticles 15 could mediate secretion of FXIII-A if these particles burst and release their cargo in plasma. If platelets maintain the plasma pool, then changes in plasma FXIII-A concentrations might be predicted in thrombocytopenia. Several studies have measured FXIII-A levels in human subjects with thrombocytopenia, both idiopathic [16][17][18] and iatrogenic, secondary to chemotherapy. 18,19 However, these studies have generated conflicting results and are difficult to interpret because of the differences between the patients and the treatments involved. In the present study, we used 2 distinct mouse lines that display thrombocytopenia as a result of unrelated single-gene mutations. In Bcl-x Plt20/Plt20 mice, a homozygous missense mutation in the gene e...

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