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PubMed1988

Primary structure of human coagulation factor XIII.

The complete primary structures of the a and b subunits of human factor XIII were determined by a combination of cDNA cloning and amino acid sequencing. The a subunit is composed of 731 amino acids including an activation peptide (37 amino acids), an active site (-Tyr-Gly-Gln-Cys-Glu-), a putative calcium binding site(s), and a thrombin-inactivation site. The functional regions of the a subunit appear to be located in separate exons of its gene. The b subunit consists of 641 amino acids including ten tandem repeats that are homologous with those in at least 13 other proteins. Each GP-I structure in the b subunit is probably encoded by a separate exon.

Amino Acid Sequence↗
PubMed2004

Probing thrombin's ability to accommodate a V34F substitution within the factor XIII activation peptide segment (28-41).

In blood coagulation, thrombin helps to activate factor XIII (FXIII) by cleaving the activation peptide (AP) at the R37-G38 peptide bond. The common polymorphism V34L yields a FXIII that is more easily activated than the wild type enzyme. Peptides based on the FXIII (28-41) (28TVELQGVVPRGVNL41) sequence serve as an important model system to evaluate the substrate specificity of thrombin and thus how to regulate FXIII activation. Our previous kinetic and nuclear magnetic resonance (NMR) studies have suggested that the P4-P1 amino acids on this FXIII segment provide key anchors to the thrombin active site surface. Furthermore, the most effective amino acid to have at the P4 position is a leucine. In the current work, a peptide containing V34F was examined to probe the ability to accommodate an aromatic residue at this position. Kinetic parameters for thrombin-catalyzed hydrolysis of FXIII AP (28-41) V34F are comparable with that of the wild type V34. One-dimensional proton line-broadening studies reveal that the 34FVPR37 segment encompassing the P4-P1 positions makes the most contact with the thrombin surface. Two-dimensional transferred-nuclear overhauser effect spectroscopy (NOESY) studies indicate that when the peptide is bound to thrombin, the F34 aromatic ring is oriented to promote P4-P2 interactions with P36. This characteristic has been viewed as a hallmark for V34L. An ability to generate this interaction may promote the ability of FXIII AP (28-41) V34F to remain a viable substrate for thrombin.

Amino Acid Sequence↗
PubMed1988

Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration.

We investigated the migration of oil-induced, guinea pig peritoneal macrophages in three-dimensional fibrin matrices, with particular attention to variables which modified fibrin gel structure and/or its adhesive properties for cells. The variables studied were fibrin concentration, gel cross-linking, and fibronectin and glycosaminoglycan content. Macrophage migration was an inverse linear function of fibrinogen concentration. Little or no fibrinolysis accompanied macrophage migration; rather, macrophages migrated through fibrin gels by an active process associated with marked distortions of cell shape and specialized plasma membrane contacts with fibrin strands. Fibrin matrices prepared from fibrinogen that had been depleted of clotting factor XIII and/or fibronectin provided a superior matrix for macrophage migration. Both the number of migrating cells and distance of migration were reduced when the gel matrix included fibronectin and was cross-linked by factor XIII. A hexapeptide containing the fibronectin cell-binding RGDS sequence reversed this migration inhibition, suggesting that fibronectin immobilized by cross-linking to fibrin may have bound macrophages and restricted cell migration. Hyaluronic acid, heparin, and heparan sulfate inhibited macrophage migration in cross-linked fibrin-fibronectin gels over a range of concentrations. These data are relevant to an understanding of macrophage migration in vivo where cross-linked fibrin-fibronectin gels containing variable amounts of glycosaminoglycans are deposited in tissues in immunologic reactions and in many other types of pathology.

Animals↗
PubMed1989

Immunohistochemical detection of factor XIII subunit a in histiocytes of human uterus.

As spontaneous abortion is a frequent finding in females with Factor XIII (FXIII) deficiency it has been presumed that this clotting factor is essential to normal pregnancy. FXIII subunit a (FXIII A) has been demonstrated in the homogenate of human uterus, but no information on its cellular distribution has been published, so far. In the present study first FXIII A was detected in paraformaldehyde-fixed, paraffin-embedded sections of human uterus by immunoperoxidase technique. Cells containing FXIII A were localized between collagen fibrils stained by Picrosirius Red F3B in the connective tissue. To characterize them the immunofluorescent detection of FXIII A was combined by the visualization of different marker antigens of monocytes and macrophages recognized by Leu-M3, RFD7, anti-HLA-DR and DAKO-anti-macrophage monoclonal antibodies on frozen sections. The coexpression of FXIII A with monocyte and macrophage differentiation marker antigens clearly proves that cells containing FXIII A in the uterus are monocyte-derived tissue macrophages. The results well agree with our previous findings demonstrating FXIII A in human monocytes and different types of macrophages. On the basis of these results, the presence of FXIII A does not seem to be a specificity of the uterus but a characteristic of monocyte/macrophage cell line including tissue macrophages, in general.

Adult↗
PubMed1990

Factor XIII in scleroderma: in vitro studies.

The administration of Factor XIII (FXIII) produces a beneficial effect on the skin lesions in about 50% of the treated patients with progressive systemic sclerosis (PSS). The effect of FXIII on various skin fibroblast functions (proliferation, attachment, biosynthetic activity and mechanical properties) was investigated in vitro using normal and PSS strains. In cell culture, most of the PSS fibroblast strains synthesized excessive amounts of collagen. Other cell functions such as adhesion to collagen I or III, to fibronectin, retraction of collagen lattices, proliferation in low serum concentration and degradation of newly synthesized collagen were not significantly different. The addition of FXIII (I U/ml) inhibited the synthesis of collagen by normal fibroblasts and reduced it in PSS fibroblasts to a level similar to that of normal fibroblasts. This effect was observed for cells cultured on plastic or in a collagen lattice. In the latter, an increased amount of collagen degradation was observed. No significant effect of FXIII on the other cell functions was noted. Excessive collagen production by PSS fibroblasts can be repressed by FXIII in vitro by at least two distinct mechanisms: a reduction of collagen synthesis and an increased degradation of the newly synthesized collagen.

Adult↗
PubMed1989

Hemopoietic origin of factor XIII A subunits in platelets, monocytes, and plasma. Evidence from bone marrow transplantation studies.

Factor XIII A subunit (FXIIIA) is found in plasma, platelets, and monocytes. The hemopoietic contributions to FXIIIA in these components were studied in patients transplanted with marrows from donors with different FXIIIA phenotypes. In three patients with successful engraftment (by DNA genotyping, red cell phenotyping, and cytogenetic studies) platelet and monocyte FXIIIA changed to donor phenotypes with hematologic recovery. Thus, FXIIIA in platelets and monocytes is synthesized de novo and/or from their progenitor cells. Plasma FXIIIA phenotype change after transplantation was more complex. Patient I changed from phenotype 1-1 (one electrophoretically fast band) to 1-2 (three bands) in 115 d; patients 2 and 3 did not change completely from phenotype 1-2 to 1-1 in up to 458 d, but did show enrichment of the fastest band. Thus, while there is a definite contribution of donor hemopoiesis to plasma FXIIIA, another source of recipient FXIIIA appears to be present to delay or prevent the phenotype change.

Adult↗
PubMed2002

Genetic and phenotypic polymorphisms of the A subunit of Coagulation factor XIII in Japanese population.

To clarify whether genetic polymorphisms in exon 14 of Coagulation factor XIII A-subunit gene (FXIIIA) affect phenotype expressions, we studied genetic polymorphisms in exon 14 of FXIIIA in a Japanese population and the relationship between the genetic polymorphisms and phenotype expression. Genetic polymorphisms in exon 14 of FXIIIA of 144 unrelated Japanese were analyzed by single-strand conformation polymorphism. Plasma FXIIIA antigen concentrations, FXIII activities, and phenotype were also determined by two-dimensional electrophoresis. The frequencies of the three genotypes, the homozygote (AD), the homozygote (BC) and the heterozygote (AD/BC), were 77.1, 0.7, and 22.2%, respectively. The gene frequencies of AD and BC were 0.88 and 0.12. We detected AD (GTT x GAG) and BC (ATT x CAG) at codon 650 and 651 of exon 14. There were no significant differences of FXIIIA antigen concentrations and FXIII activities between these genotypes. We detected three pl differences among them as being pls of 5.3, 5.6, 5.8 in the homozygote (AD) and the heterozygote (AD/BC), and a pl of 5.8 in the homozygote (BC). These polymorphisms affected isoelectric mobility, but did not affect protein levels, enzyme activities, or the molecular weight of FXIII.

Electrophoresis, Gel, Two-Dimensional↗
PubMed1991

Organization of the gene for human erythrocyte membrane protein 4.2: structural similarities with the gene for the a subunit of factor XIII.

Human erythrocyte band 4.2 is a major membrane-associated protein with an important, but still undefined, role in erythrocyte survival. We previously sequenced the complete cDNA for band 4.2 and showed that the protein has a strong sequence identity with the transglutaminase family of proteins but lacks transglutaminase activity. Here we have analyzed the genomic organization of band 4.2. The band 4.2 gene is approximately 20 kilobases, consisting of 13 exons and 12 introns. Reticulocytes contain two different sized messages for band 4.2, and our results show that the major, smaller, message is produced by alternative splicing within band 4.2 exon I. The upstream region of the gene has several prospective promoter elements arranged in a pattern similar to that of two other erythroid genes, beta-globin and porphobilinogen deaminase. Alignment of the band 4.2 amino acid sequence with that of the a subunit of human coagulation factor XIII and division of the sequences into exons reveal a remarkable correspondence, and in most cases identity, in the sizes of the paired exons. Moreover, each corresponding intron of the two genes is of an identical splice junction class. These and other similarities suggest that the gene for band 4.2 is closely related to and possibly derived from that for the a subunit of factor XIII and that the proteins may share common structural and functional properties.

Amino Acid Sequence↗
PubMedDate not supplied

Effectiveness of coagulation factor XIII concentrate for reversing loss of tensile strength of rat intestinal anastomoses.

BACKGROUND: Blood coagulation factor XIII (F-XIII) promotes cross-linking of fibrin during blood coagulation. Impaired clot stabilization in patients with genetic deficiencies of F-XIII is associated with marked pathologies of wound healing. METHODS: 60 rats given carbon tetrachloride underwent ileal anastomosis after which they received albumin (Alb animals) or F-XIII concentrate (F-XIII animals) immediately after surgery and daily thereafter until day 2 or 4 and were euthanized on day 3 or 5, respectively, or until day 5 and were euthanized on day 7, 10, or 21. We measured the plasma F-XIII activity and anastomotic tensile strength, followed by immunohistochemical localization of F-XIII subunit A within anastomoses. RESULTS: On day 3, there were no significant differences between Alb and F-XIII animals for plasma F-XIII activity and tensile strength, and both groups of animals showed little immunostaining for F-XIII on anastomoses. Plasma F-XIII activities did not differ between Alb and F-XIII animals on day 5 (115.8 +/- 16.8 vs. 137.3 +/- 14.9%). Although the tensile strength in both groups was increased compared with that of day 3, that in F-XIII animals (129.8 +/- 3.3 gf) was significantly higher than that in Alb animals (100.8 +/- 5.3 gf, p = 0.014). F-XIII animals showed de novo collagen fibers and intense immunoreactivity of F-XIII in the extracellular matrix around the anastomoses. Similar differences occurred on day 7 but not days 10 and 21. CONCLUSIONS: F-XIII concentrate may accelerate the early healing process of intestinal anastomosis because of the protein's accumulation in situ.

Anastomosis, Surgical↗
PubMed2001

Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angiography.

Possession of the coagulation factor XIII Val34Leu (FXIIIVal34Leu) polymorphism is associated with protection against myocardial infarction (MI) in Caucasians, in the absence of features of insulin resistance. The role of this polymorphism in the UK Asian population, with its high prevalence of insulin resistance and ischaemic heart disease, is unknown. We investigated the frequency of genotypes at this polymorphism, and measures of circulating FXIII in a group of UK Asians attending for coronary angiography. Genotype at the FXIIIVal34Leu polymorphism was not associated with MI. FXIII B-subunit levels correlated with waist: hip ratio (r = 0.19, p <0.005), HbA1c (r = 0.18, p <0.05), fasting triglycerides (r = 0.21, p <0.005), total cholesterol (r = 0.29, p <0.0005) and PAI-1 antigen (r = 0.24, p <0.005). An association between FXIIIVal34Leu and FXIII cross-linking activity was confirmed in these subjects (one-way ANOVA p <0.0005). This evidence does not support the hypothesis that FXIIIVal34Leu is protective against MI in the UK Asian population. FXIII B-subunit levels are strongly linked to risk factors for cardiovascular disease, suggesting an underlying association with insulin resistance.

Adult↗
PubMedDate not supplied

Factor XIII V34L polymorphism modulates the risk of chronic venous leg ulcer progression and extension.

Low Factor XIII (FXIII) activity has been reported in the blood of patients with chronic venous leg ulcer (CVU). In vivo studies have described increased wound healing in CVU patients treated with FXIII concentrate, and in vitro studies have shown increased regenerative capacity in FXIII-treated fibroblasts. In addition, a common G-to-T polymorphism in the FXIIIA-subunit gene (V34L) significantly increases the activity and modifies the cross-linking properties of the FXIII molecule and this variant has been investigated as a protective factor against thrombosis, a recognized risk factor for CVU establishment. Therefore, the role of FXIII levels, FXIII V34L, FVR506Q, and FIIG20210A, common gene polymorphisms in the pathogenesis of CVU was investigated. Ninety-one patients with CVU and 195 healthy controls (91 of them sex- and age-matched) were PCR-genotyped for the FXIIIV34L, FVR506Q, and FIIG20210A substitutions and FXIIIA-subunit levels were determined by immuno-electrophoresis. The extent of the venous ulcer surface in patients was measured by computer software. The allele frequency and the genotype distribution of the FXIII polymorphism did not show significant differences between the whole group of cases and controls as well as prothrombin variants did. On the contrary, the FVR506Q variant (FV Leiden) allele was more frequent in patients, yielding a significant OR value of 5.93 (95 percent CI, 1.83-19.17; p= 0.003). Considering only CVU cases secondary to a post-thrombotic syndrome (n= 24), FV Leiden yielded a greater OR value of 16.08 (95 percent CI, 4.33-59.6; p < 0.0001). When the CVU cases were stratified by the three possible FXIII genotypes, a significant trend toward a lower mean value of the ulcerated area was clearly evident as the number of the polymorphic alleles (L34) increased in the genotype of patients (VV = 11.9 cm(2,)+/- 23.6; VL = 6.1 cm(2,)+/- 6.9; LL = 4.1 cm(2,)+/- 2.8; p= 0.01). On the other hand, FXIIIA antigen levels were similar between CVU cases and matched controls, but 11 percent of cases had FXIII deficiency (FXIIIA </= 0.65 U/ml; p= 0.003) and they showed a greater mean extension of the lesion if compared with the remaining cases without FXIIIA deficiency (14.5 cm(2), +/- 20.2 vs. 9.0 cm(2), +/- 6.3; p= 0.08). We conclude that FXIII antigen levels and FXIII V34L polymorphism may play a crucial role in the complex cascade of CVU pathophysiology, being significantly related to the CVU progression and extension because of the direct effects they have on the FXIII molecular activity.

Aged↗
PubMed1999

[Factor XIII].

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Factor XIII↗
PubMed2003

Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages.

To understand the molecular pathology of factor XIII (FXIII) deficiency in vivo, its A subunit (FXIIIA)-knockout (KO) mice were functionally analyzed. Although homozygous FXIIIA female KO mice were capable of becoming pregnant, most of them died due to excessive vaginal bleeding during gestation. Abdominal incisions revealed that the uteri of the dead mice were filled with blood and that some embryos were much smaller than others within a single uterus. A series of histologic examinations of the pregnant animals suggested that massive placental hemorrhage and subsequent necrosis developed in the uteri of the FXIIIA KO mice on day 10 of gestation. This was true regardless of the genotypes of fetuses. These results are reminiscent of spontaneous miscarriage in pregnant humans with FXIII deficiency and indicate that maternal FXIII plays a critical role in uterine hemostasis and maintenance of the placenta during gestation.

Abortion, Veterinary↗
PubMed2002

[Role of coagulation factor XIII in cardio- and cerebrovascular diseases].

In the final step of the clotting cascade coagulation factor XIII (FXIII) is activated by thrombin. The activated enzyme (FXIIIa) has an important role in the final stage of blood coagulation in cross-linking soluble fibrin to a stable insoluble clot. The role of FXIII in cardio- and cerebrovascular diseases has been investigated recently. The widespread Val34Leu polymorphism in the gene coding for the FXIII subunit A (FXIII Val34Leu) has been shown to protect against myocardial infarction and ischemic stroke, but is also associated with an increased risk for hemorrhagic stroke. Additionally, FXIII Val34Leu is supposed to be protective against pulmonary embolism and deep vein thrombosis. As possible mechanisms for the antithrombotic effect, premature depletion of the mutant protein from circulation and altered fibrin structures of clots cross-linked by the mutant FXIIIa are under discussion. The connection between FXIII and the insulin resistance syndrome also attracts attention, i.e. the interaction between a component of the coagulation cascade and thus a thrombotic risk factor and classical atheromatous risk factors. Therefore, FXIII must be considered as another coagulation factor contributing to complex interactions between genes and environment important for the pathogenesis of cardio- and cerebrovascular and thromboembolic diseases.

Capillary Permeability↗
PubMed1990

Human recombinant factor XIII from Saccharomyces cerevisiae. Crystallization and preliminary x-ray data.

Crystals of human recombinant factor XIII from the yeast Saccharomyces cerevisiae have been grown from solutions of ammonium sulfate at pH 5.8. The crystals are orthorhombic, with space group P2(1)2(1)2 and unit cell dimensions gamma a = 101.2, b = 182.7, and c = 93.4 A. The asymmetric unit consists of one a2 dimer of molecular mass 166 kDa. A 3.5-A resolution data set for the native protein has been collected. Practical resolution limits for these crystals have not been determined, but reflections have been observed to a Bragg spacing of 2.8-A resolution.

Crystallization↗
PubMed1989

Factor XIII of blood coagulation modulates collagen biosynthesis by fibroblasts in vitro.

The effect of activated factor XIII (FXIIIa), the transglutaminase of blood coagulation, on some cellular functions was studied in skin and lung fibroblasts in vitro. FXIIIa repressed the overall protein synthesis and mainly collagen synthesis in a concentration-dependent manner and induced modifications in the proportion of the different types of newly synthesized collagen. The repression of collagen synthesis occurred in cells cultured on plastic (-40%), on coated fibronectin (-53%), on coated collagens (-38%) and within a collagen lattice (-16%). Preincubation of the cells with FXIIIa and labelling in its absence also resulted in such an inhibition. However, when embedded into a fibrin lattice cross-linked by FXIIIa, fibroblasts displayed a higher biosynthetic activity than in untreated fibrin gel. These results suggest that FXIIIa acts through a modulation of the cell-matrix interactions.

Animals↗