Blood coagulation factor XIII (FXIII) is a protransglutaminase that becomes activated by the concerted action of thrombin and Ca2+ in the final stage of the clotting cascade. In addition to plasma, FXIII also occurs in platelets, monocytes, and monocyte-derived macrophages. While the plasma factor is a heterotetramer consisting of paired A and B subunits (A2B2), its cellular counterpart lacks the B subunits and is a homodimer of potentially active A subunits (A2). The gene coding for the A and B subunits has been localized to chromosomes 6p24-25 and 1q31-32.1, respectively. The genomic as well as the primary protein structure of both subunits has been established, and most recently the three-dimensional structure of recombinant cellular FXIII has also been revealed. Monocytes/macrophages synthesize their own FXIII, and very likely FXIII in platelets is synthesized by the megakaryocytes. Cells of bone marrow origin seem to be the primary site for the synthesis of subunit A in plasma FXIII, but hepatocytes might also contribute. The B subunit of plasma FXIII is synthesized in the liver. Plasma FXIII circulates in association with its substrate precursor, fibrinogen. Fibrin(ogen) has an important regulatory role in the activation of plasma FXIII. The most important steps of the activation of plasma FXIII are the proteolytic removal of activation peptide by thrombin, the dissociation of subunits A and B, and the exposure of the originally buried active site on the free A subunits. The end result of this process is the formation of an active transglutaminase, which cross-links peptide chains through epsilon(gamma-glutamyl)lysyl isopeptide bonds. Cellular FXIII in platelets becomes activated through a nonproteolytic process. When intracytoplasmic Ca2+ is raised during platelet activation, the zymogen--in the absence of subunit B--assumes an active configuration. The protein substrates of activated FXIII include components of the clotting-fibrinolytic system, adhesive and contractile proteins. The main physiological function of plasma FXIII is to cross-link fibrin and protect it from the fibrinolytic plasmin. The latter effect is achieved mainly by covalently linking alpha 2 antiplasmin, the most potent physiological inhibitor of plasmin, to fibrin. Plasma FXIII seems to be involved in wound healing and tissue repair, and it is essential to maintaining pregnancy. Cellular FXIII, if exposed to the surface of the cells, might support or perhaps take over the hemostatic functions of plasma FXIII; however, its intracellular role has remained mostly unexplored.

Summary. Development of autoantibody against coagulation factor V (FV) is a rare clinical condition with hemorrhagic complications of varying severity. The aim of this study was to establish the pathomechanism of an acquired FV deficiency and characterize the FV inhibitor responsible for the clinical symptoms. A 78-year-old female was admitted to hospital with severe gastrointestinal bleeding. General clotting tests and determination of clotting factors were performed by standard methods. FV antigen and FV containing immune complexes were measured by ELISA. The FV molecule was investigated by Western blotting and by sequencing the f5 gene. The binding of patient's IgG to FVand activated FV (FVa) was demonstrated in an ELISA system and its effect on the procoagulant activity of FVa was tested in clotting tests and in a chromogenic prothrombinase assay. Localization of the epitope for the antibody was performed by blocking ELISA. FV activity was severely suppressed both in plasma and platelets. FV antigen levels were normal by ELISA using polyclonal anti-FV antibody or monoclonal antibody against the connecting region of FV, but depressed when HV1 monoclonal antibody against the C2 domain in the FV light-chain was used as capture antibody. The FV molecule was found intact. An IgG reacting with both FV and FVa was present in the patient's plasma and its binding to FV was inhibited by HV1 antibody. FV-containing immune complexes were detected in the patient's plasma and platelet lysate. The patient's IgG inhibited the procoagulant function of FVa. An anti-FV IgG was present in the patient's plasma and platelets. The autoantibody reacted with an epitope in the C2 domain of FV light chain and neutralized the procoagulant function of FVa.Keywords: factor V, factor V inhibitor, hemorrhagic diathesis, platelets.Human coagulation factor V (FV) is a single-chain glycoprotein with a Mr of 330 kDa. Its plasma concentration is approximately 20 nmol L À1 (7 mg mL À1 ) [1]. Approximately 25% of whole blood FV is compartmentalized in the a-granules of platelets and becomes secreted during activation [1,2]. The principal site of FV biosynthesis is the liver [3,4], but it is still unclear whether platelet FV originates from the uptake of exogenous FV via endocytosis by megakaryocytes or megakaryocytes themselves can synthesize FV [5][6][7]. Single chain FV has a structure consisting of three homologous A domains and two homologous C domains connected by a heavily glycosylated B domain in the order of A1-A2-B-A3-C1-C2 [8,9]. The gene for human FV has been localized to chromosome 1q21-25, it spans approximately 80 kilobases of DNA and consists of 25 exons and 24 introns [10]. Proteolytic cleavage of FV by a-thrombin results in the removal of B-domain and converts the pro-cofactor into active cofactor (FVa) that enhances factor Xa (FXa) À catalyzed activation of prothrombin by several thousand-fold [11,12]. FVa contains a heavy chain (HC; Mr 105 kDa) and a light chain (LC; Mr 71 or 74 kDa) associated via calcium bond [13]. The HC is ...

Blood coagulation factor XIII (FXIII) exists both in plasma and also in the cytoplasmic compartment of platelets, monocytes, their bone marrow precursors and monocyte-derived macrophages. FXIII present in the plasma is of tetrameric structure consisting of two potentially active A subunits and two carrier/inhibitory B subunits. In contrast, the cellular form of FXIII is a dimer of A subunits. Recombinant variants of the cellular form have also been produced [see review articles 1-4].The terminology and abbreviations used in the literature by different authors to designate different forms and subunits of FXIII have hitherto been rather variable and cause for confusion. At the ISTH SCC Subcommittee on FXIII meeting in Florence in 1997, a first proposal for unifying the nomenclature was presented. Members of the Subcommittee discussed the proposals, made several comments, and finally agreed upon a terminology and its use by Members of the Subcommittee. Since that time a number of scientists have been using the terminology proposed by the Subcommittee. However, the recommendations on nomenclature have never been published and have not been easily available. In consequence, the nomenclature used in the literature is still far from being unified, causing misunderstanding, and editors/publishers of scientific journals have not been aware of the recommendations.The main function of FXIII in plasma, upon activation by thrombin, is to cross-link fibrin and hence increase the stability of the clot. The field of FXIII research has, however, extended beyond the borders of hemostasis; for example, demonstration of FXIII in cells by immunohistologic and flow cytometric techniques became a marker reaction for the monocytic lineage, which has been proposed for the diagnosis or classification of malignant diseases [5][6][7]. It is of high importance therefore that a unified nomenclature on FXIII be used for these research areas as well, making it timely to update the original proposal and to publish the nomenclature in the official journal of ISTH. The recommendations presented here were unanimously approved by members of the FXIII Subcommittee at the 51st annual SSC meeting in Sydney, 2005, and relate to terms and abbreviated terms of different forms of FXIII, and its subunits, as well as intermediaries and end-products of FXIII activation. Recommended terms and abbreviations to designate different forms of FXIII zymogenBlood coagulation FXIII in general without specifying its form Recommended term: coagulation FXIII or FXIII. Recommended abbreviation: FXIII. FXIII normally present in the plasma (tetramer)Recommended term: plasma coagulation FXIII or plasma FXIII.

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