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Akitada Ichinose - One of the best experts on this subject based on the ideXlab platform.
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autoimmune acquired Factor XIII deficiency due to anti Factor XIII 13 antibodies a summary of 93 patients
Blood Reviews, 2017Co-Authors: Akitada IchinoseAbstract:Autoimmune acquired Factor XIII (F13) deficiency or autoimmune hemophilia-like disease (hemorrhaphilia) resulted from the generation of anti-F13 antibodies (AH13) is a severe bleeding disorder that occurs mainly in the elderly. Although rare, the number of patients diagnosed with AH13 has recently increased. To improve understanding of this disease, the author summarized 93 ever reported/diagnosed AH13 cases. About 50% of cases were idiopathic. In the remaining half of the patients, autoimmune diseases and malignancies were the most common underlying diseases. Intramuscular and subcutaneous bleeding were the most frequently reported symptoms. Hemorrhage was the cause of death in 13 patients. In 4 patients, the diagnosis was established after hemorrhagic death. Therefore, physicians/hematologists must raise the awareness of AH13 as a life-threatening disease. Most patients were treated with F13 concentrates to arrest bleeding and with prednisolone and cyclophosphamide to eradicate anti-F13 autoantibodies. AH13 cases tend to become chronic and intractable and require close follow-up over an extended period.
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recommendation for isth ssc criterion 2015 for autoimmune acquired Factor XIII 13 deficiency
Thrombosis and Haemostasis, 2016Co-Authors: Akitada Ichinose, Hans P Kohler, Helen PhilippouAbstract:Recommendation for ISTH/SSC Criterion 2015 for autoimmune acquired Factor XIII/13 deficiency -
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Spontaneous regression of the inhibitor against the coagulation Factor XIII A subunit in acquired Factor XIII deficiency
Thrombosis and haemostasis, 2010Co-Authors: Fumihiro Ishida, Masayoshi Souri, Kentaro Okubo, Toshiro Ito, Nobuo Okumura, Akitada IchinoseAbstract:Spontaneous regression of the inhibitor against the coagulation Factor XIII A subunit in acquired Factor XIII deficiency -
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physiopathology and regulation of Factor XIII
Thrombosis and Haemostasis, 2001Co-Authors: Akitada IchinoseAbstract:Factor XIII is a plasma transglutaminase. Transglutaminases are at least 8 enzymes which cross-link a number of proteins. This type of reaction not only enhances the original functions of substrate proteins, but also adds new functions to them. Factor XIII in plasma is a tetramer (A2B2 ), and the A subunit contains the active site. Although transglutaminases are homologous, the nucleotide sequences in their 5’-flanking region differ significantly. Accordingly, transcription Factors play a major role in the cell type-specific expression of each transglutaminase. A variety of missense and nonsense mutations, and deletions/ insertions with or without out-of-frame shift/premature termination and splicing abnormalities have been identified in the genes for A and B subunits in Factor XIII deficiency. In some cases, the mRNA level of the A or B subunit was severely reduced. Molecular and cellular bases have also been explored by expression experiments and by molecular modeling. In most cases, impaired folding and/or conformational change of the mutant A or B subunit leads to both intra- and extra-cellular instability, which is responsible for Factor XIII deficiency.
John W. Weisel - One of the best experts on this subject based on the ideXlab platform.
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Factor XIII topology organization of b subunits and changes with activation studied with single molecule atomic force microscopy
Journal of Thrombosis and Haemostasis, 2019Co-Authors: Anna D Protopopova, Andrea Ramirez, D V Klinov, Rustem I Litvinov, John W. WeiselAbstract:Essentials Factor XIII is a heterotetramer with 2 catalytic A subunits and 2 non-catalytic B subunits. Structure of active and inactive Factor XIII was studied with atomic force microscopy. Inactive Factor XIII is made of an A2 globule and 2 flexible B subunits extending from it. Activated Factor XIII separates into a B2 homodimer and 2 monomeric active A subunits. SUMMARY: Background Factor XIII (FXIII) is a precursor of the blood plasma transglutaminase (FXIIIa) that is generated by thrombin and Ca2+ and covalently crosslinks fibrin to strengthen blood clots. Inactive plasma FXIII is a heterotetramer with two catalytic A subunits and two non-catalytic B subunits. Inactive A subunits have been characterized crystallographically, whereas the atomic structure of the entire FXIII and B subunits is unknown and the oligomerization state of activated A subunits remains controversial. Objectives Our goal was to characterize the (sub)molecular structure of inactive FXIII and changes upon activation. Methods Plasma FXIII, non-activated or activated with thrombin and Ca2+ , was studied by single-molecule atomic force microscopy. Additionally, recombinant separate A and B subunits were visualized and compared with their conformations and dimensions in FXIII and FXIIIa. Results and Conclusions We showed that heterotetrameric FXIII forms a globule composed of two catalytic A subunits with two flexible strands comprising individual non-catalytic B subunits that protrude on one side of the globule. Each strand corresponds to seven to eight out of 10 tandem repeats building each B subunit, called sushi domains. The remainder were not seen, presumably because they were tightly bound to the globular A2 dimer. Some FXIII molecules had one or no visible strands, suggesting dissociation of the B subunits from the globular core. After activation of FXIII with thrombin and Ca2+ , B subunits dissociated and formed B2 homodimers, whereas the activated globular A subunits dissociated into monomers. These results characterize the molecular organization of FXIII and changes with activation.
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role of Factor XIII in fibrin clot formation and effects of genetic polymorphisms
Blood, 2002Co-Authors: Robert A S Ariens, Charles S Greenberg, John W. Weisel, Peter J GrantAbstract:Factor XIII and fibrinogen are unusual among clotting Factors in that neither is a serine protease. Fibrin is the main protein constituent of the blood clot, which is stabilized by Factor XIIIa through an amide or isopeptide bond that ligates adjacent fibrin monomers. Many of the structural and functional features of Factor XIII and fibrin(ogen) have been elucidated by protein and gene analysis, site-directed mutagenesis, and x-ray crystallography. However, some of the molecular aspects involved in the complex processes of insoluble fibrin formation in vivo and in vitro remain unresolved. The findings of a relationship between fibrinogen, Factor XIII, and cardiovascular or other thrombotic disorders have focused much attention on these 2 proteins. Of particular interest are associations between common variations in the genes of Factor XIII and altered risk profiles for thrombosis. Although there is much debate regarding these observations, the implications for our understanding of clot formation and therapeutic intervention may be of major importance. In this review, we have summarized recent findings on the structure and function of Factor XIII. This is followed by a review of the effects of genetic polymorphisms on protein structure/function and their relationship to disease.
Hans P Kohler - One of the best experts on this subject based on the ideXlab platform.
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recommendation for isth ssc criterion 2015 for autoimmune acquired Factor XIII 13 deficiency
Thrombosis and Haemostasis, 2016Co-Authors: Akitada Ichinose, Hans P Kohler, Helen PhilippouAbstract:Recommendation for ISTH/SSC Criterion 2015 for autoimmune acquired Factor XIII/13 deficiency -
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Factor XIII: Structure and Function
Seminars in Thrombosis and Hemostasis, 2016Co-Authors: Verena Schroeder, Hans P KohlerAbstract:Over the last two decades, it became evident that Factor XIII (FXIII) is not only a crucial determinant of clot characteristics but also has potentially important functions in many various fields such as bone biology, immunity, and adipogenesis. In this review, we aim to summarize the latest findings regarding structure and function of FXIII. In regard to FXIII structure, much progress has been made recently to understand how its subunits are held together. In the A subunit, the activation peptide has a crucial role in the formation of FXIII-A2 dimers. In the B subunit, Sushi domains that are involved in binding to the A subunit and in B2 dimer formation have been identified. In regard to FXIII function, interactions with immune cells and the complement system have been described. A novel function of FXIII-A in adipogenesis has been suggested. The role of FXIII-A in osteoblast differentiation has been further investigated; however, a novel double knockout mouse deficient in both FXIII-A and transglutaminase 2 showed normal bone formation. Thus, more research, in particular, into the cellular functions of FXIII-A is still required.
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identification of eight novel coagulation Factor XIII subunit a mutations implied consequences for structure and function
Haematologica, 2010Co-Authors: Vyatautas Ivaskevicius, Arijit Biswas, Verena Schroeder, Hans P Kohler, Carville G Bevans, Hannelore Rott, Susan Halimeh, Petro E Petrides, Harald Lenk, Manuele KrauseAbstract:Background Severe hereditary coagulation Factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous Factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer. Design and Methods We analyzed ten index patients and three relatives for Factor XIII activity using a photometric assay and sequenced their F13A and F13B genes. Additionally, structural analysis of the wild-type protein structure from a previously reported X-ray crystallographic model identified potential structural and functional effects of the missense mutations. Results All individuals except one were heterozygous for Factor XIIIA mutations (average Factor XIII activity 51%), while the remaining homozygous individual was found to have severe Factor XIII deficiency (<5% of normal Factor XIII activity). Eight of the 12 heterozygous patients exhibited a bleeding tendency upon provocation. Conclusions The identified missense (Pro289Arg, Arg611His, Asp668Gly) and nonsense (Gly390X, Trp664X) mutations are causative for Factor XIII deficiency. A Gly592Ser variant identified in three unrelated index patients, as well as in 200 healthy controls (minor allele frequency 0.005), and two further Tyr167Cys and Arg540Gln variants, represent possible candidates for rare F13A gene polymorphisms since they apparently do not have a significant influence on the structure of the Factor XIIIA protein. Future in vitro expression studies of the Factor XIII mutations are required to confirm their pathological mechanisms.
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association of a common polymorphism in the Factor XIII gene with venous thrombosis
Blood, 1999Co-Authors: Andrew J Catto, Hans P Kohler, M H Stickland, Julie Coore, Michael W Mansfield, Peter J GrantAbstract:We have shown an association between a common mutation in the Factor XIII a-subunit gene, coding for an amino acid change, 3 amino acids from the thrombin activation site (Factor XIII Val34Leu) that may protect against myocardial infarction and predisposes to intracranial hemorrhage. To investigate the possible role of Factor XIII Val34Leu in the pathogenesis of venous thromboembolism (VTE) and potential interactions with Factor V Leiden (FV:Q506) and prothrombin G → A 20210, we studied 221 patients with a history of VTE and 254 healthy controls. Patients with VTE showed an increased frequency of the FXIII Val/Val genotype (63% v 49%) and a lower frequency of the Val/Leu genotype (31% v 42%) than controls ( P = .007). FV:Q506 heterozygotes were more frequent in VTE patients (11%) than controls (5%; P = .04). The prothrombin G → A 20210 mutation was present in only 3 patients and no controls ( P = .10). In a logistic regression model for a history of VTE, the odds ratio (95% confidence interval) for FXIII Val/Leu or Leu/Leu genotype was 0.63 (0.38 to 0.82) and for possession of FV:Q506 2.40 (1.17 to 4.90). There was no evidence for an interaction between Factor XIII Val34Leu genotype and FV:Q506, prothrombin G → A 20210, sex, or age. It is concluded that possession of the Leu allele at Factor XIII Val34Leu is protective against deep venous thrombosis.
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Factor XIII val 34 leu a novel association with primary intracerebral hemorrhage
Stroke, 1998Co-Authors: Andrew J Catto, Hans P Kohler, Sally Bannan, M H Stickland, Angela M Carter, Peter J GrantAbstract:Background and Purpose—A common G-to-T point mutation (Val 34 Leu) in exon 2 of the α-subunit of the Factor XIII is strongly negatively associated with the development of myocardial infarction. This result suggests that Factor XIII Val 34 Leu is interfering with the formation of cross-linked fibrin. The role of Factor XIII Val 34 Leu in the pathogenesis of cerebral infarction and primary intracerebral hemorrhage is unknown. Methods—Six hundred twelve patients with acute stroke, defined by World Health Organization criteria and cranial CT, and 436 age-matched control subjects free of cerebrovascular disease were genotyped for the Factor XIII Val 34 Leu mutation. Venous blood was drawn for the determination of hemostatic variables and lipids. Factor XIII genotype was determined through a single-stranded conformational polymorphism technique and plasminogen activator inhibitor (PAI)-1 4G/5G promoter genotype by allele-specific polymerase chain reaction. Results—The mutation was more frequent in patients with...
Diane J Nugent - One of the best experts on this subject based on the ideXlab platform.
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developing the first recombinant Factor XIII for congenital Factor XIII deficiency clinical challenges and successes
Seminars in Thrombosis and Hemostasis, 2016Co-Authors: Manuel Carcao, Johannes Oldenburg, Aida Inbal, Bryce A Kerlin, Maylill Garly, Katsuyuki Fukutake, Riitta Lassila, Diane J NugentAbstract:Congenital Factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with potentially life-threatening consequences. FXIII is composed of two subunits (A and B), and a deficiency or dysfunction of either can result in FXIII deficiency. Traditionally, FXIII deficiency has been managed by infusing plasma-derived products containing FXIII (fresh frozen plasma, cryoprecipitate, and plasma-derived FXIII concentrates), all of which contain both subunits. Despite the increased safety of plasma-derived products, concern remains regarding potential viral safety issues. This review describes the development, from concept to clinical use, of a recombinant FXIII molecule (containing subunit A only; rFXIII-A2) for congenital FXIII-A subunit deficiency. Unmet needs and ongoing challenges in congenital FXIII deficiency are also discussed. Despite the challenges in developing a product for a very rare bleeding disorder, the information gathered on efficacy, safety, and pharmacokinetics of FXIII replacement therapy represents the largest dataset on congenital FXIII-A subunit deficiency in the world. It also provides evidence for the safety and efficacy of monthly prophylaxis with 35 IU/kg of rFXIII-A2 in patients with FXIII-A subunit deficiency. The issues encountered and overcome, along with lessons learned, may be applied to and encourage the development of new recombinant products for other rare bleeding disorders.
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recombinant Factor XIII a safe and novel treatment for congenital Factor XIII deficiency
Blood, 2010Co-Authors: Aida Inbal, Johannes Oldenburg, Manuel Carcao, Anders Rosholm, Ramin Tehranchi, Diane J NugentAbstract:Congenital Factor XIII (FXIII) deficiency is a rare, autosomal-recessive disorder, with most patients having an A-subunit (FXIII-A) deficiency. Patients experience life-threatening bleeds, impaired wound healing, and spontaneous abortions. In many countries, only plasma or cryoprecipitate treatments are available, but these carry a risk for allergic reactions and infection with blood-borne pathogens. The present study was a multinational, open-label, single-arm, phase 3 prophylaxis trial evaluating the efficacy and safety of a novel recombinant FXIII (rFXIII) in congenital FXIII-A subunit deficiency. Forty-one patients ≥ 6 years of age (mean, 26.4; range, 7-60) with congenital FXIII-A subunit deficiency were enrolled. Throughout the rFXIII prophylaxis, only 5 bleeding episodes (all trauma induced) in 4 patients were treated with FXIII-containing products. The crude mean bleeding rate was significantly lower than the historic bleeding rate (0.138 vs 2.91 bleeds/patient/year, respectively) for on-demand treatment. Transient, non-neutralizing, low-titer anti-rFXIII Abs developed in 4 patients, none of whom experienced allergic reactions, any bleeds requiring treatment, or changes in FXIII pharmacokinetics during the trial or follow-up. These non-neutralizing Abs declined below detection limits in all 4 patients despite further exposure to rFXIII or other FXIII-containing products. We conclude that rFXIII is safe and effective in preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency. This study is registered at http://www..clinicaltrials.gov as number NCT00713648.
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Factor XIII deficiency
Haemophilia, 2008Co-Authors: L Hsieh, Diane J NugentAbstract:Summary. Inherited Factor XIII (FXIII) deficiency is a rare bleeding disorder that can present with umbilical bleeding during the neonatal period, delayed soft tissue bruising, mucosal bleeding and life-threatening intracranial haemorrhage. FXIII deficiency has also been associated with poor wound healing and recurrent miscarriages. FXIII plays an integral role in haemostasis by catalysing the crosslinking of fibrin, platelet membrane and matrix proteins throughout thrombus formation, thus stabilizing the blood clot. The molecular basis of FXIII deficiency is characterized by a high degree of heterogeneity, which contributes to the different clinical manifestations of the disease. There have been more than 60 FXIII mutations identified in the current literature. In addition, single nucleotide polymorphisms have been described, some of which have been shown to affect FXIII activity, contributing further to the heterogeneity in patient presentation and severity of clinical symptoms. Although there is a lifelong risk of bleeding, the prognosis is excellent when current prophylactic treatment is available using cryoprecipitate or plasma-derived FXIII concentrate.
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safety and pharmacokinetics of recombinant Factor XIII a2 administration in patients with congenital Factor XIII deficiency
Blood, 2006Co-Authors: Amy E Lovejoy, Tom C Reynolds, Jennifer Visich, Michael D Butine, Guy Young, Melissa Belvedere, Rachelle C Blain, Susan Pederson, Laura M Ishak, Diane J NugentAbstract:Congenital Factor XIII (FXIII) deficiency is associated with a tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intracranial hemorrhage. This phase 1 escalating-dose study was developed to evaluate the safety and pharmacokinetics of a single administration of human recombinant FXIII-A2 (rFXIII-A2) homodimer in adults with congenital FXIII deficiency. Pharmacokinetics and activity of rXIII and changes in endogenous B subunit levels were assessed. Recombinant FXIII-A2 homodimer were complexed with endogenous FXIII-B subunits to form an FXIII-A2B2 heterotetramer with a half-life of 8.5 days, similar to that of endogenous FXIII. The median dose response was a 2.4% increase in FXIII activity based on unit per kilogram rFXIII administered. After the administration of rFXIII-A2, clot solubility normalized as measured by clot lysis in urea. Clot strength and resistance to fibrinolysis, as assessed by thromboelastography, also improved. Safety reviews were conducted before each dose escalation; no serious adverse events, including bleeding or thrombosis, were noted during the study. In addition, there was no evidence of the generation of specific antibodies to rFXIII or yeast proteins. Recombinant FXIII appears to be a safe and potentially effective alternative for FXIII replacement in patients with FXIII deficiency. (Blood. 2006;108:57-62)
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prophylaxis in rare coagulation disorders Factor XIII deficiency
Thrombosis Research, 2006Co-Authors: Diane J NugentAbstract:Factor XIII (FXIII) deficiency is a very rare form of haemophilia resulting in different manifestations of bleeding disorders, but characterised by umbilical stump bleeding in up to 80% of patients. Although originally described as the final enzyme in the clotting cascade, FXIII is now recognised to play a role throughout the clotting process. Treatment with FXIII concentrate (Fibrogammin P®, ZLB Behring) results in the re-establishment of a normal clotting pattern. Prophylaxis studies in France and the USA have demonstrated an excellent response following monthly prophylaxis with this plasma-derived, pasteurised concentrate. Patients with FXIII deficiency have good control of bleeding, with no development of inhibitors, or viral seroconversion. The development of registries such as that in the USA will enable the different manifestations of the disease to be explored.
Philip G Board - One of the best experts on this subject based on the ideXlab platform.
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new mutations causing the premature termination of translation in the a subunit gene of coagulation Factor XIII
Thrombosis and Haemostasis, 1996Co-Authors: S Kangsadalampai, A Fargesberth, S H Caglayan, Philip G BoardAbstract:The amplification of Factor XIII A subunit gene exons and heteroduplex analysis has been used to identify two new mutations that cause severe Factor XIII deficiency. One mutation in a family of French origin results from a 4 bp deletion and leads to a premature termination of translation. The other mutation occurred in a Turkish family and results from a C-->T transition that inserts a premature translation stop signal at codon 400. Both mutations alter restriction enzyme sites and can be readily detected in amplified exon DNA for genetic counselling or prenatal diagnosis. The new mutations reflect the extensive molecular heterogeneity of Factor XIII deficiency.
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Factor XIII inherited and acquired deficiency
Blood Reviews, 1993Co-Authors: Philip G Board, M S Lososky, K J A MiloszewskiAbstract:Abstract Factor XIII (XIII), an enzyme found in plasma (present as a pro-enzyme), platelets and monocytes, is essential for normal haemostasis. It may also have a role to play in the processes of wound healing and tissue repair. Inherited XIII deficiency results in a life-long, severe bleeding diathesis which, if untreated, carries a very high risk of death in early life from intracranial bleeding. XIII is a zymogen requiring thrombin and calcium for activation. In plasma, XIII has two subunits: the ‘a’ subunit, which is the active enzyme, and the ‘b’ subunit which is a carrier protein. Activated XIII modifies the structure of clot by covalently crosslinking fibrin through an e(γ-glutamyl)lysine link. It also crosslinks other proteins, including fibronectin and alpha-2-plasmin inhibitor (α-2PI), into the clot through the same link. Clot modified by XIII is physically stronger, relatively more resistant to fibrinolysis and may be a more suitable medium for the ingrowth of fibroblasts. Inheritance of Factor XIII is autosomal recessive. The majority of patients with the inherited defect show no XIII activity and absence of ‘a’ subunit protein in plasma, platelets and monocytes. At the molecular level, the defect is not a major gene rearrangement or deletion, but most likely a single point mutation which may be different in each family. Because of the severity of the bleeding diathesis, prophylaxis is desirable and has been shown to be very effective as the in vivo half-life of plasma XIII is long, and low plasma levels are sufficient for haemostatis. Acquired inhibitors have been reported in only two cases with inherited XIII deficiency. Acquired XIII deficiency has been described in a variety of diseases and bleding has been controlled by therapy with large doses of XIII in such conditions as Henoch-Schonlein purpura, various forms of colitis, erosive gastritis and some forms of leukaemia. Large dose XIII therapy has also been used in an endeavour to promote wound healing after surgery and bone union in non-healing fractures. The use of XIII in these conditions remains controversial. Very rarely a bleeding diathesis results from the development of a specific inhibitor to XIII arising de novo, often as a complication in the course of a disease or in association with long-term drug therapy. The bleeding diathesis in these patients is difficult to treat.
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Factor XIII inherited and acquired deficiency
Blood Reviews, 1993Co-Authors: Philip G Board, M S Losowsky, K J A MiloszewskiAbstract:Factor XIII (XIII), an enzyme found in plasma (present as a pro-enzyme), platelets and monocytes, is essential for normal haemostasis. It may also have a role to play in the processes of wound healing and tissue repair. Inherited XIII deficiency results in a life-long, severe bleeding diathesis which, if untreated, carries a very high risk of death in early life from intracranial bleeding. XIII is a zymogen requiring thrombin and calcium for activation. In plasma, XIII has two subunits: the 'a' subunit, which is the active enzyme, and the 'b' subunit which is a carrier protein. Activated XIII modifies the structure of clot by covalently crosslinking fibrin through an epsilon (gamma-glutamyl)lysine link. It also crosslinks other proteins, including fibronectin and alpha-2-plasmin inhibitor (alpha-2PI), into the clot through the same link. Clot modified by XIII is physically stronger, relatively more resistant to fibrinolysis and may be a more suitable medium for the ingrowth of fibroblasts. Inheritance of Factor XIII is autosomal recessive. The majority of patients with the inherited defect show no XIII activity and absence of 'a' subunit protein in plasma, platelets and monocytes. At the molecular level, the defect is not a major gene rearrangement or deletion, but most likely a single point mutation which may be different in each family. Because of the severity of the bleeding diathesis, prophylaxis is desirable and has been shown to be very effective as the in vivo half-life of plasma XIII is long, and low plasma levels are sufficient for haemostasis. Acquired inhibitors have been reported in only two cases with inherited XIII deficiency. Acquired XIII deficiency has been described in a variety of diseases and bleeding has been controlled by therapy with large doses of XIII in such conditions as Henoch-Schonlein purpura, various forms of colitis, erosive gastritis and some forms of leukaemia. Large dose XIII therapy has also been used in an endeavour to promote wound healing after surgery and bone union in non-healing fractures. The use of XIII in these conditions remains controversial. Very rarely a bleeding diathesis results from the development of a specific inhibitor to XIII arising de novo, often as a complication in the course of a disease or in association with long-term drug therapy. The bleeding diathesis in these patients is difficult to treat.
