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PubMed2006

Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia.

INTRODUCTION: The objective of this study was to determine the effects of the administration of the coagulation factor XIII (F XIII) on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation during experimental endotoxemia. METHODS: In a prospective, randomized, controlled animal study 42 male Wistar rats were divided into three groups. Group 1 served as the control group. Groups 2 (lipopolysaccharide (LPS) group) and 3 (F XIII group) received endotoxin infusions (2.5 mg/kg/h for 2 hours). In group 3, 50 U/kg body weight F XIII was continuously administered during the first 30 minutes of endotoxemia. F XIII levels were measured in all animals. One half of the animals of each group were studied for intestinal functional capillary density (FCD) and leukocyte adherence on venular endothelium by intravital fluorescence microscopy (IVM). In the other half of each group, mesenteric plasma extravasation (FITC-albumin) was determined by IVM. RESULTS: The F XIII level was significantly increased in the F XIII treatment group. In the LPS group, endotoxemia led to a significant reduction of mucosal FCD (-18.5%; p < 0.01 versus control group). F XIII administration in the F XIII group attenuated the decrease in mucosal FCD (-3.7% compared to control; p < 0.05 versus LPS group). During endotoxemia, a significant increase of leukocyte adherence at the endothelium could be noted in the LPS group compared to the control group. Leukocyte adherence at the endothelium and plasma extravasation in the F XIII group did not differ significantly from the LPS group. CONCLUSION: Factor XIII protected mucosal capillary perfusion against endotoxin-induced impairment in an experimental sepsis model in rats, whereas leukocyte adherence and plasma extravasation remained unchanged.

Animals↗
PubMed1979

Genetic polymorphism of the A subunit of human coagulation factor XIII.

Utilizing a fluorescent technique for the localization of transglutaminase activity after electrophoresis on thin layer agarose gels, we observed a new polymorphism of coagulation factor XIII in both platelets and plasma. The electrophoretic pattern was that of a dimeric protein. Homozygotes gave a single band, while heterozygotes presented a three banded pattern. The polymorphism was found to be due to variation of the A subunit. Data from Australian blood donors indicate that the A subunit of factor XIII has an autosomal locus.

Australia↗
PubMed2004

Mapping of factor XIII solvent accessibility as a function of activation state using chemical modification methods.

The transglutaminase Factor XIII (FXIII) catalyzes the formation of covalent cross-links between adjacent noncovalently associated fibrin chains in blood coagulation. The resulting covalently cross-linked hard clot is much more mechanically stable and resistant to proteolytic degradation. FXIII is activated by the serine protease thrombin in the presence of calcium ions. Protein modification experiments involving the labeling of cysteine and lysine side chains of the enzyme were performed before and after activation of the enzyme in an effort to gain further insight into structural changes occurring during the activation of FXIII. The experiments revealed differences in the labeling patterns of nonactivated and activated FXIII. These differences result from the exposure or sequestration of specific cysteine or lysine residues when the enzyme is activated, either physiologically with thrombin or nonproteolytically by exposure to calcium. Of note is the acetylation of Lys 73 and Lys 221 upon activation. Both of these residues lie within possible substrate recognition regions of FXIII. The active site Cys 314 is consistently alkylated in the activated enzyme, as is Cys 409, located near the dimer interface. Within the beta-barrel 2 domain of FXIII, Cys 695 becomes alkylated in activated FXIII. Within the same domain, an acetylated Lys (677 or 678), which is observed in the zymogen, cannot be found in the activated enzyme. The results provide a more extensive view of FXIII activation than has been previously available.

Acetic Anhydrides↗
PubMed1976

Cross-linking of a major fibroblast surface-associated glycoprotein (fibronectin) catalyzed by blood coagulation factor XIII.

The surface proteins of cultured human skin fibroblasts were iodinated and then exposed to one or more of the following blood coagulation proteins: thrombin, fibrinogen, and factor XIII (plasma protransglutaminase). Radiolabeled polypeptides were analyzed by polyacrylamide gel electrophoresis in the presence of sodium dodecylsulfate. After exposure to physiological concentrations of activated factor XIII (XIIIa), the band of radioactivity corresponding to the major labeled surface protein (fibronectin, molecular weight = 2.2 x 10(5) daltons) was cross-linked to a very high molecular weight complex. The cross-linking reaction was inhibited by fibrin (which is known to bind the catalytic subunit of XIIIa). Cross-linking of labeled cell surface fibronectin to fibrin could not be demonstrated. The fibrillar pattern of surface fibronectin appeared unaffected by cross-linking when studied by immunofluorescence. Cross-linking of cell surface fibronectin by XIIIa requires highly specific enzyme-substrate and protein-protein interactions, and may be an important physiological reaction.

Cell Line↗
PubMed1999

A complete deficiency of coagulation factor XIII A-subunit due to a novel compound heterozygote of Ser 413 Leu missense and an nt 389 (ins G) frameshift mutation.

Coagulation factor XIII consists of two A- and two B-subunits, and either gene mutation can cause a complete deficiency. In a newborn patient with persistent bleeding from the umbilical cord stump, the plasma A-subunit protein was not detectable. Direct PCR sequencing revealed an nt 389 (ins G) frameshift mutation in exon 4 resulting in a new stop codon and a Ser 413 Leu missense mutation in exon 10 in either allele. His mother and father were heterozygous for the nt 389 (ins G) and the Ser 413 Leu, respectively, with about 50% reduction of the plasma A-subunit proteins. In all family members examined only those with either mutation showed the reduced subunit A protein levels. Thus, this complete deficiency of factor XIII was due to a novel compound heterozygous mutation in the A-subunit gene.

DNA Transposable Elements↗
PubMed2005

Congenital deficiency of factor XIII caused by two missense mutations in a Dutch family.

We present the clinical, biochemical and genomic findings of a family with congenital factor XIII (FXIII) deficiency. Congenital FXIII deficiency is a very rare autosomal recessive bleeding disorder, characterized by umbilical cord bleeding at birth and spontaneous intracranial haemorrhage. Routine clotting tests are normal, which may delay the diagnosis, leading to an increased chance of severe sequelae. The propositus and her brother, known with haemorrhagic diathesis, were found to be compound heterozygous with a known missense mutation (1050 G --> T transversion in exon 7, Val316Phe substitution) and a novel mutation 889 G --> A in exon 6, which predicts a Gly262Glu substitution. As these mutations were known in the family, DNA obtained from cord blood of the youngest sister was analysed for mutations in exons 6 and 7 only. We postulate that the diagnosis was facilitated by determining the two different mutations in the genotype of this family. The analysis showed that she was heterozygous for the exon 7 mutation. Hence, she was not at risk of experiencing haemorrhagic diathesis. This diagnosis avoided the administration of FXIII concentrate to the newborn.

Adult↗
PubMed1974

Calcium and the assays of human plasma clotting factor XIII.

1. A continuous fluorimetric assay for blood-clotting Factor XIII based on the incorporation of dansylcadaverine into casein was investigated. 2. Hammarsten casein was fractionated to yield the beta-casein, which was dephosphorylated and acetylated to give a substrate which itself did not bind calcium and which was not cross-linked by the activated Factor. 3. The modified beta-casein was used as substrate for a continuous fluorimetric assay and as substrate for the incorporation of radioactive glycine ethylester. 4. A linked fluorimetric assay for the zymogen is described. 5. The K(m) for calcium was redetermined and at 0.2mm was in the physiological range and much lower than the values reported by others using substrates which interact with calcium. 6. The K(m) for casein is about 14mum.

Acetylation↗
PubMed2005

Probing interactions between the coagulants thrombin, Factor XIII, and fibrin(ogen).

Thrombin cleaves fibrinopeptides A and B from fibrinogen leading to the formation of a fibrin network that is later covalently crosslinked by Factor XIII (FXIII). Thrombin helps activate FXIII by catalyzing hydrolysis of the FXIII activation peptides (AP). In the current work, the role of exosites in the ternary thrombin-FXIII-fibrin(ogen) complex was further explored. Hydrolysis studies indicate that thrombin predominantly utilizes its active site region to bind extended Factor XIII AP (FXIII AP 33-64 and 28-56) leaving the anion-binding exosites for fibrin(ogen) binding. The presence of fibrin-I leads to improvements in the K(m) for hydrolysis of FXIII AP (28-41), whereas peptides based on the cardioprotective FXIII V34L sequence exhibit less reliance on this cofactor. Surface plasmon resonance measurements reveal that d-Phe-Pro-Arg-chloromethylketone-thrombin binds to fibrinogen faster than to FXIII a(2) and dissociates from fibrinogen more slowly than from FXIII a(2). This system of thrombin exosite interactions with differing affinities promotes efficient clot formation.

Amino Acid Chloromethyl Ketones↗
PubMedDate not supplied

Coagulation factor XIII, endothelial damage and systemic sclerosis.

In the blood coagulation process, Factor XIII (F XIII) is responsible for the stabilization of the fibrin clot. The hypothesized ability of this blood coagulation factor to affect collagen synthesis and degradation led to its use in the treatment of scleroderma. However, the complex mechanism of action of F XIII remains unclear. The aim of our study was to assess possible effects of F XIII on endothelial damage, regarded as an early pathogenic event in systemic sclerosis (SSc). Thus, we measured plasma levels of von Willebrand factor antigen (vWF:Ag), a marker of endothelial cell injury, in 22 patients with SSc, 9 of whom were treated with F XIII and 13 who do not receive the drug. The plasma concentration of F XIII has also been analyzed. Interestingly, the vWF:Ag plasma levels within the group of SSc patients treated with F XIII were significantly lower than those of untreated SSc individuals (p < 0. 02). On the other hand, the highest mean value of vWF:Ag was found in a subset of untreated subjects having SSc with severe lung involvement, supporting a strict relationship between elevated levels of vWF:Ag and severity of the disease. In contrast, plasma concentration of F XIII resulted normal in all but 3 SSc patients, ruling out a deficiency of this blood coagulation factor as promoting the occurrence of SSc. These preliminary findings seem to support the hypothesis that F XIII may play an improving role on endothelial damage, other than the initially suggested action on collagen metabolism, in SSc.

Adult↗
PubMed2002

Delayed umbilical bleeding--a presenting feature for factor XIII deficiency: clinical features, genetics, and management.

OBJECTIVES: The objectives of this study were 1) to assess the importance of an early diagnosis for factor XIII (FXIII) deficiency, and 2) to investigate the molecular basis and mechanism(s) of disease in the patients under study. METHODS: The case histories of 6 FXIII-deficient patients were examined to assess the influence of early versus delayed diagnosis and replacement therapy. The nucleotide sequence of the FXIIIA gene was determined to identify the underlying mutations responsible for the bleeding diathesis in each patient. Molecular modeling was used to predict the mechanism(s) of disease causation for each mutation. RESULTS: All cases presented with umbilical hemorrhage. Patients 1 to 3 were diagnosed, and their prophylactic therapy was commenced in infancy. Diagnosis in patients 4 to 6 was considerably delayed and, as a result, they continued to suffer from many bleeding symptoms. The FXIIIA gene mutations identified in these patients were as follows: a homozygous GAA-->AAA mutation in codon 102 (Glu102Lys) in patient 1 and a homozygous AGC-->AGG mutation in codon 295 (Ser295Arg) in patients 2 to 6. These mutations segregate with disease and are absent from the normal population, suggesting that they are likely to be disease-causing sequence changes. Computer modeling indicates that both the Lys102 and Arg295 mutants are unable to fold correctly, and probably result in unstable FXIIIA molecules. CONCLUSIONS: We demonstrate the importance of recognizing delayed umbilical hemorrhage as a presenting feature for congenital FXIII deficiency, and the value of early diagnosis and prophylaxis. The bleeding disorder of patient 1 was attributable to a homozygous Glu102Lys mutation in FXIIIA. A homozygous Ser295Arg mutation in FXIIIA was responsible for FXIII deficiency in patients 2 to 6.

Factor XIII↗
PubMed1980

Genetic polymorphism of the B subunit of human coagulation factor XIII.

Genetic variation of the B subunit of human coagulation factor XIII has been observed after electrophoresis of plasma or serum samples on thin layer agarose plates and subsequent immunofixation with a specific antiserum. The F-XIIIB locus is autosomal and has three alleles. In Australian blood donors, the F-XIIIB1, F-XIIIB2 and F-XIIIB3 alleles have frequencies of .747, .084, and .169, respectively.

Electrophoresis, Agar Gel↗
PubMed1999

Transcriptional regulation of cell type-specific expression of the TATA-less A subunit gene for human coagulation factor XIII.

To study the mechanism of gene regulation for coagulation factor XIII A subunit (FXIIIA), we characterized its 5'-flanking region using a monocytoid (U937), a megakaryocytoid (MEG-01), and other cells. Our results confirmed that U937 and MEG-01 contained FXIIIA mRNA. A tentative transcription start site was determined to be 76 bases upstream from the first exon/intron boundary. Reporter gene assays revealed that a 5'-fragment (-2331 to +75) was sufficient to support basal expression in U937 and MEG-01 but not in the other cells. Deletion analysis confined a minimal promoter sequence from -114 to +75. DNase footprinting, electrophoretic mobility shift, and reporter gene assays demonstrated that promoter elements for a myeloid-enriched transcription factor (MZF-1-like protein) and two ubiquitous transcription factors (NF-1 and SP-1) in this region were important for the basal FXIII expression. It was also revealed that an upstream region (-806 to -290) had enhancer activity in MEG-01 but silencer activity in U937. DNA sequences for binding of myeloid-enriched factors (GATA-1 and Ets-1) were recognized in this region, and the GATA-1 element was found to be responsible for the enhancer activity. These transcription factors play a major role in the cell type-specific expression of FXIIIA, which differs from other transglutaminases.

Base Sequence↗
PubMed2004

The impact of factor XIII on coagulation kinetics and clot strength determined by thrombelastography.

Fibrinogen has been shown to be responsible for most protein-mediated clot strength via thrombelastography. However, factor XIII (FXIII) activity also plays a prominent role in the development of clot strength. Thus, we hypothesized that changes in FXIII activity would significantly increase clot strength. FXIII (0%, 1%, 6.25%, 12.5%, 25%, 50%, and 100% normal activity) was placed in a fixed volume of citrated FXIII-deficient plasma with 1% tissue factor and calcium chloride and underwent thrombelastography for 10 min. We measured the variables reaction time (R; a measurement of clot initiation), alpha (a measure of the rate of clot formation), amplitude (A; a measure of clot strength), and shear elastic modulus (G; a measure of clot strength). FXIII activity significantly decreased R in a pattern of exponential decay (R2 = 0.77; P < 0.001). FXIII activity significantly increased alpha, following a sigmoidal pattern (R2 = 0.88; P < 0.001). Finally, increases in FXIII activity significantly increased A and G in a sigmoidal pattern (R = 0.89; P < 0.001). We concluded that FXHI significantly affects R, alpha, A, and G. Thus, transfusion decision making with protein-mediated thrombelastographic patterns must account for the contribution of both fibrinogen and FXIII.

Blood Coagulation↗
PubMed1999

Prevalence of three common polymorphisms in the A-subunit gene of factor XIII in patients with coronary artery disease.

Activated blood coagulation factor XIII has an important role in the final stage of the clotting cascade by the covalent crosslinking of alpha- and gamma-fibrin chains. We have recently shown that a functional polymorphism in exon 2. codon 34 of the FXIII A-subunit gene is protective against myocardial infarction. To investigate the prevalence of three other common point mutations in the A-subunit gene (codon 564, C to T, 650 G to A and 651 G to C) and their association with FXIII activity and antigen levels, 275 patients with coronary artery disease and 196 controls were studied. There was no difference in the prevalence of the polymorphisms between patients and controls or between patients with or without MI. Only genotype at codon 564 was associated with FXIII activity with lower activities in subjects possessing the T allele. There was evidence of linkage disequilibrium between codon 34 and codon 564. These results suggest that FXIIIVal34Leu is the only common polymorphism in the coding region of the A-subunit gene of FXIII associated with coronary artery disease.

Analysis of Variance↗
PubMed2006

Prognostic role of factor XIII gene variants in nonhealing venous leg ulcers.

OBJECTIVE: Many factors impair healing of chronic venous ulcer (CVU), and many theories have been proposed to explain their pathogenesis. Coagulation factor XIII (FXIII) influences tissue regeneration and angiogenesis with effects on wound healing. Because FXIII properties depend upon its genetic variants, we investigated whether intragene polymorphisms may have modulating effects on the CVU area. METHODS: The study included 121 patients with nonhealing CVUs (CEAP clinical class C6) that included 67% with primary chronic venous disease (CVD), 26% with post-thrombotic ulcers, and 7% with mixed ulcer origin. Polymerase chain reaction was used to genotype them for Val34Leu, Pro564Leu, and Tyr204Phe variants in the FXIII-A subunit gene and for His95Arg variant in the FXIII-B subunit gene. The same variants were analyzed in 102 controls, healthy subjects who were case-matched by age and gender. RESULTS: Genotype distribution for all polymorphisms investigated was not significantly different between cases and controls. Conversely, our CVU cases had a mean ulcer area inversely related with the presence of both Leu34 and Leu564 alleles (ValVal, 12.3 +/- 22.4 cm2 vs LeuLeu, 3.9 +/- 2.6 cm2, P = .002; ProPro, 10.2 +/- 21.2 cm2 vs LeuLeu, 2.9 +/- 1.4 cm2, P = .002). In combined analysis, those cases who were wild-type for both variants (ValVal34/ProPro564) had a further increase in mean ulcer size compared with cases carrying both variants (Leu34/Leu564) (13.3 +/- 27.1 cm2 vs 5.2 +/- 5.6 cm2; P = .034). CONCLUSIONS: No correlation exists between FXIII genotypes and the prevalence of chronic venous ulcers, thus demonstrating that FXIII polymorphisms have no role in ulcer development. In contrast, FXIII-gene variants, in particular the non-wild-type alleles Leu34 and Leu564, were associated with a smaller venous ulcer surface and might have favorable effects on reparative processes.

Adult↗
PubMed1983

[Thrombin, factor XIII and fibronectin as regulators of the proliferation of tumor cells and vascular wall cells].

In culture fibroblasts, endothelial cells and smooth muscle cells from arterial wall are stimulated by thrombin and factor XIII, whereas fibronectin inhibits the proliferation of these cells. Experiments with tumor cells show growth stimulation of sarcoma cells and HeLa cells by thrombin and factor XIII. While growth of sarcoma cells is inhibited by fibronectin, HeLa cells are stimulated by fibronectin in physiological concentrations. Possible mechanisms of these effects and relations to in vivo-phenomena are discussed.

Animals↗
PubMed1999

Arg506Gln factor V mutation and Val34Leu factor XIII polymorphism in Finnish patients with inflammatory bowel disease.

BACKGROUND: Earlier studies have indicated that inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is associated with thromboembolic complications, whereas inherited disorders of coagulation occur less often than expected in IBD patients. The point mutation Arg506Gln of factor V (Factor V Leiden), resulting in resistance to activated protein C, is the commonest inherited form of thrombophilia. Alterations in circulating levels of factor XIII (FXIII) have been reported among IBD patients. We investigated whether Factor V Leiden or inherited Val34Leu polymorphism of FXIII would associate with IBD or its clinical outcome. METHODS: Factor V Leiden mutation and FXIII Val34Leu polymorphism were assayed in 328 unrelated Finnish patients with UC and 235 patients with CD by solid-phase minisequencing techniques. The control groups comprised 142 apparently healthy Finnish subjects and 120 Finnish blood donors. RESULTS: The frequency of Factor V Leiden mutation among IBD patients (4.5%) was not significantly different from that in subjects living in the same area (2.1%). No significant differences could be observed in the FXIII Val34Leu polymorphism allele frequencies between patients and controls. Clinical features of IBD, including the disease extent, requirement for immunosuppressive drugs, and occurrence of complications, seemed to be independent of these two clotting factor variants analyzed. CONCLUSIONS: Our data do not support an aetiologic or disease-modifying role for the factor V mutation or factor XIII Val34Leu polymorphism in IBD.

Adult↗