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.

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Factor XIII (FXIII) is a tetrameric zymogen (FXIII-A (2)B (2)) that is converted into an active transglutaminase (FXIIIa) by thrombin and Ca (2+) in the terminal phase of the clotting cascade. By cross-linking fibrin chains and alpha (2) plasmin inhibitor to fibrin, FXIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. Severe deficiency of the potentially active A subunit (FXIII-A) is a rare but severe hemorrhagic diathesis. Delayed umbilical stump bleeding is characteristic, and subcutaneous, intramuscular, and intracranial bleeding occurs with a relatively high frequency in nonsupplemented patients. In addition, impaired wound healing and spontaneous abortion in women are also features of FXIII deficiency. The extremely rare B subunit deficiency results in milder bleeding symptoms. FXIII concentrate is now available for on-demand treatment and primary prophylaxis. A quantitative FXIII activity assay is recommended as a screening test for the diagnosis of FXIII deficiency. For classification purposes, FXIII-A (2)B (2) antigen in the plasma is first determined, and if decreased, further measurement of the individual subunits is recommended in the plasma and FXIII-A in platelet lysate. Analytical aspects of FXIII activity and antigen assays are discussed in this article. There are no hot-spot mutations in the F13A1 and F13B genes, and the majority of causative mutations are missense/nonsense point mutations.

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Summary. Factor (F)XIII is a protransglutaminase that, in addition to maintaining hemostasis, has multiple plasmatic and intracellular functions. Its plasmatic form (pFXIII) is a tetramer of two potentially active A (FXIII-A) and two inhibitory/carrier B (FXIII-B) subunits, whereas its cellular form (cFXIII) is a dimer of FXIII-A. FXIII-A belongs to the family of transglutaminases (TGs), which show modest similarity in the primary structure, but a high degree of conservatism in their domain and sub-domain secondary structure. FXIII-A consists of an activation peptide, a bsandwich, a catalytic and two b-barrel domains. FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds. The structural elements of FXIII-A involved in the interaction with FXIII-B have not been elucidated; in FXIII-B the first sushi domain seems important for complex formation. In the circulation pFXIII is bound to the fibrinogen cÕ-chain through its B subunit. In the process of pFXIII activation first thrombin cleaves off the activation peptide from FXIII-A, then in the presence of Ca 2+ FXIII-B dissociates and FXIII-A becomes transformed into an active transglutaminase (FXIIIa). The activation is highly accelerated by the presence of fibrin(ogen). cFXIII does not require proteolysis for intracellular activation. The three-dimensional structure of FXIIIa has not been resolved. Based on analogies with transglutaminase-2, a three-dimensional structure of FXIIIa was developed by molecular modeling, which shows good agreement with the drastic structural changes demonstrated by biochemical studies. The structural requirements for enzyme-substrate interaction and for transglutaminase activity are also reviewed.

It has been known for a long time that blood coagulation factor XIII (FXIII) is essential for maintaining haemostasis, its deficiency leads to severe bleeding complication. Biochemical studies have revealed that FXIII is a key regulator of fibrinolysis and, in addition to its role in haemostasis, it has also been implicated in the pathology of arterial and venous thrombosis. Most recently, the polymorphisms in the FXIII subunit genes and their influence on the risk of thrombotic diseases have stirred a lot of interest. This review, besides including the basic biochemistry of FXIII, mainly concentrates on the biochemical and clinical aspects of the involvement of FXIII in fibrinolysis and thrombosis. Biochemical aspects: Basics on the structure and activation of plasma and cellular FXIII. The enzymological features of activated FXIII and its main substrates. The interaction of FXIIIa with fibrinogen/fibrin and with components of the fibrinolytic system. The impact of cross-linked fibrin clot formation on the fibrinolytic processes. The down-regulation of FXIIIa within the fibrin clot. FXIII polymorphisms and their biochemical consequences. Clinical Aspects: FXIII level and the risk of arterial thrombosis (coronary artery disease, peripheral artery disease, ischemic stroke). The effect of FXIII subunit polymorphisms on the risk of arterial thrombotic diseases. The interplay between FXIII polymorphisms and other factors influencing the risk of arterial thrombosis. FXIII and venous thromboembolism.

Plasma Factor XIII is a zymogen (plasma protransglutaminase) with the tetrametric structure A2B2, whereas the cellular protransglutaminase, i.e. Factor XIII in the platelet and monocyte/macrophage, consists exclusively of A subunits (A2). It is generally accepted that at Ca2+ concentrations comparable with that in plasma the proteolytic removal of an Nterminal activation peptide is the prerequisite for the Ca2+-induced formation of a catalytically active configuration of subunit A. In this study it was demonstrated that at high concentrations NaCl or KCI induced a non-proteolytic activation of cellular (placental macrophage) but not plasma protransglutaminase. The activation depended on time and salt concentration, and Ca2 , in the range 0-20 mm, greatly enhanced the activation process. At 1.25 M-NaCl maximal activation occurred within 60 min in the presence of 2 mM-CaC12, and even at physiological NaCl concentration a slow progressive activation could be observed in the presence of Ca2+. The specific activity of salt-activated Factor XIII was 1.5-2.0-fold higher than that obtained after thrombin activation. The non-proteolytic activation of cellular protransglutaminase was abolished by the addition of subunit B of plasma Factor XIII in stoichiometric amount, which suggests that (one of) the physiological function(s) of the B subunit in plasma Factor XIII is to prevent the slow spontaneous activation of A subunit that would occur in a plasmatic environment. INTRODUCTIONFactor XIII (FXIII) of blood coagulation present in the plasma is a zymogen (plasma protransglutaminase) of tetrameric structure (A2B2). The active site formed in the course of an activation process is located on the A subunit while subunit B remains enzymically inactive. The presence of FXIII has also been verified in platelets [1], monocytes and monocyte-derived macrophages [2][3][4][5][6][7]. In contrast with the plasma FXIII, however, this cellular protransglutaminase consists exclusively of A subunits (A2). The active transglutaminase (FXIIIa) formed from FXIII catalyses an acyl-transfer reaction in which the carboxamide group of a peptide-bound glutamine residue is the acyl

The high amount of pp60c‐src in platelets has led to speculation that this kinase is responsible for tyrosine‐specific phosphorylation of cellular proteins during platelet activation by different agonists, and is, therefore, implicated in signal transduction of these cells. Unlike pp60v‐src, the association of which with the cytoskeleton appears to be a prerequisite for transformation, pp60c‐src is detergent‐soluble in fibroblasts overexpressing the c‐src gene, and its role in normal cellular function remains elusive. To gain a better understanding of the function of pp60c‐src we have investigated the subcellular distribution of pp60c‐src and its relationship to the cytoskeleton during platelet activation. Quantitative immunoblotting and immunoprecipitation have revealed that pp60c‐src is detergent‐soluble in resting platelets, while 40% of total platelet pp60c‐src becomes associated with the cytoskeletal fraction upon platelet activation. We have also shown that a small pool of pp60c‐src is associated with the membrane skeletal fraction which remains unchanged during the activation process. The interaction of pp60c‐src with cytoskeletal proteins strongly correlates with aggregation and is mediated by GPIIb/IIIa receptor‐fibrinogen binding. We suggest that the translocation of pp60c‐src to the cytoskeleton and its association with cytoskeletal proteins may regulate tyrosine phosphorylation in platelets.