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PubMed1999

Effect of factor XIII on endothelial barrier function.

The effect of factor XIII on endothelial barrier function was studied in a model of cultured monolayers of porcine aortic endothelial cells and saline-perfused rat hearts. The thrombin-activated plasma factor XIII (1 U/ml) reduced albumin permeability of endothelial monolayers within 20 min by 30 +/- 7% (basal value of 5.9 +/- 0.4 x 10(-6) cm/s), whereas the nonactivated plasma factor XIII had no effect. Reduction of permeability to the same extent, i.e., by 34 +/- 9% could be obtained with the thrombin-activated A subunit of factor XIII (1 U/ml), whereas the iodoacetamide-inactivated A subunit as well as the B subunit had no effect on permeability. Endothelial monolayers exposed to the activated factor XIII A exhibited immunoreactive deposition of itself at interfaces of adjacent cells; however, these were not found on exposure to nonactivated factor XIII A or factor XIII B. Hyperpermeability induced by metabolic inhibition (1 mM potassium cyanide plus 1 mM 2-deoxy-D-glucose) was prevented in the presence of the activated factor XIII A. Likewise, the increase in myocardial water content in ischemic-reperfused rat hearts was prevented in its presence. This study shows that activated factor XIII reduces endothelial permeability. It can prevent the loss of endothelial barrier function under conditions of energy depletion. Its effect seems related to a modification of the paracellular passageways in endothelial monolayers.

Animals↗
PubMed2000

Factor XIII deficiency and postoperative hemorrhage after neurosurgical procedures.

BACKGROUND: Factor XIII is of physiological importance for hemostasis, especially in patients undergoing surgery. It catalyzes the enzymatic cross-linking of fibrin monomers into stable polymers and protects polymers from plasmatic and nonspecific degradation. Postoperative hemorrhage in patients with congenital and acquired Factor XIII deficiencies has been described in various surgical fields. However, there are no data about the incidence and clinical relevance of decreased Factor XIII after neurosurgical procedures. The objective of our study was to investigate the association between Factor XIII deficiency and postoperative hemorrhage after intracranial surgery. METHODS: A total of 1264 patients who underwent intracranial operations were reviewed retrospectively. Standard coagulation parameters were monitored during the perioperative course in all patients. Factor XIII testing was performed postoperatively in 34 patients in whom coagulopathies were suspected despite normal platelets, fibrinogen, prothrombin, and partial thromboplastin time. Data were analyzed to evaluate the association of Factor XIII deficiency and major postoperative hemorrhage. RESULTS: In this series of 1264 patients, a total of 20 patients (1. 6%) suffered from a major postoperative hemorrhage. Of the 34 patients with suspected coagulopathies and postoperative Factor XIII testing, 11 had a major postoperative hemorrhage. Normal levels of Factor XIII, defined as more than 60%, were found in 26 of the 34 patients. Factor XIII deficiency, defined as less than 60%, was found in eight patients. All patients with Factor XIII deficiency (n = 8) had a major postoperative hemorrhage. Of the remaining 26 patients with normal Factor XIII levels only three had a postoperative hemorrhage (p < 0.00001, Fisher's exact test). CONCLUSIONS: Decreased Factor XIII activity may be associated with an increased risk of postoperative hemorrhage after intracranial surgery.

Adult↗
PubMed1993

Analytical and clinical utility of a photometric assay for blood coagulation factor XIII.

A new photometric assay for factor XIII was evaluated for its analytical performance and clinical usefulness. The test showed good performance characteristics: intra-assay coefficients of variation between 0.83 and 2.68%, inter-assay coefficients of variation from 3.4 to 4.5%. The test can be conducted rapidly on an automated analyser such as the Cobas Bio. The reference values (mean +/- 2 SD) ranged from 67 to 147% and there was no gender difference. The comparability of the photometric test with a clot lysis factor XIII test showed an acceptable coefficient of correlation r = 0.87 (p < 0.0001). The diagnostic conformity of both tests was 76.7%. Factor XIII concentrations were assessed in seven patient groups. In liver cirrhosis, M. Crohn and during pregnancy noticeable percentages of lowered values were found: i.e. 18.2%, 11.8% and 10.0% respectively. Elevated values were seen in hypertensive patients (16%) and in the small group of patients with carcinoma of the ovarium (22.2%). These results show that the incidence of acquired factor XIII deficiencies is relative low. The clinical meaning of reduced or enhanced factor XIII needs to be clarified by more extensive patient studies.

Adult↗
PubMed1988

Increased resistance to plasmic degradation of fibrin with highly crosslinked alpha-polymer chains formed at high factor XIII concentrations.

We have previously demonstrated that increasing factor XIII concentrations above that present in plasma (1 U/mL) results in the formation of very high molecular weight alpha fate polyacrylamide and agarose gel electrophoresis (SDS-PAGE). In this report, we have examined the effect of such crosslinking on plasmic susceptibility of fibrin prepared from purified fibrinogen and from plasma in the presence of factor XIII concentrations between 0 and 10 U/mL. The crosslinking achieved with purified fibrinogen at 1 U/mL factor XIII increased resistance to plasmic degradation by 32% as measured in a radiolabeled clot lysis system. However, further increases in plasmic resistance occurred at factor XIII concentrations of 2 and 10 U/mL, the latter decreasing the lysis rate to 45% of that which occurred in the absence of factor XIII. To achieve the same rate of clot lysis with fibrin formed using 10 U/mL rather than 1 U/mL of factor XIII, an increase in plasmin concentration of up to 4.2-fold was required. Similar results were obtained using clots prepared from plasma in the presence of factor XIII concentrations greater than 1 U/mL. Since the alpha 2-plasmin inhibitor content was the same for fibrin at 1 or 10 U/mL factor XIII, the increasing plasmic resistance could not be attributed to increased binding of the inhibitor. We conclude that fibrin prepared in the presence of factor XIII at concentrations exceeding that in plasma shows increased resistance to plasmic degradation, which is likely explained by the formation of very high molecular weight alpha polymer chains.

Cross-Linking Reagents↗
PubMed1974

Calcium and thiol reactivity of human plasma clotting factor XIII.

1. The reaction of iodoacetate, 2-chloromercuri-4-nitrophenol and 5,5'-dithiobis-(2-nitrobenzoate) with thrombin-cleaved Factor XIII (i.e. Factor XIII(a)) was accompanied by enzyme inhibition. 2. The reaction with iodoacetate and 5,5'-dithiobis-(2-nitrobenzoate) was absolutely dependent on Ca(2+), and the rate of reaction increased with the Ca(2+) concentration up to very high, non-physiological concentrations. 3. 2-Chloromercuri-4-nitrophenol reacted with Factor XIII(a) in the absence of Ca(2+), but at a much slower rate. 4. Stopped-flow methods were used to quantify the reaction with 5,5'-dithiobis-(2-nitro-benzoate) because of the Ca(2+)-dependent dissociation of Factor XIII(a) (a'(2)b(2)) and subsequent aggregation of the a' chains into turbid precipitates. 5. The 3-carboxy-4-nitrothio-phenolate released was consistent with the reaction of 2 thiol groups/molecule of Factor XIII(a). The isolated b chains of Factor XIII did not react with either of the chromophoric reagents. This indicated that the a' chains of Factor XIII(a) were responsible for the thiol reactivity of the enzyme. 6. The Ca(2+) dependence of the enzyme inhibition by these thiol reagents was very dependent on protein concentration. This is discussed in relation to the Ca(2+)-induced dissociation of Factor XIII(a). 7. The acceptor substrate, casein, decreased the Ca(2+) concentration required for enzyme inhibition by both the mercurial and the aromatic disulphide compounds. Dansylcadaverine did not affect Ca(2+) dependence of inhibition.

Cadaverine↗
PubMed1989

Tb(III)-ion-binding-induced conformational changes in platelet factor XIII.

Ca(II) ions are crucial during proteolytic conversion of Factor XIII zymogen into the active enzyme Factor XIIIa. Factor XIII proteolyzed by thrombin or trypsin in the presence of 5 mM-EDTA resulted in rapid inactivation of transglutaminase activity. Factor XIIIa formed by thrombin or trypsin in the presence of 40 microM-Tb(III) ions, however, was indistinguishable from Factor XIIIa formed in the presence of 2-5 mM-Ca(II) ions with respect to molecular mass and transglutaminase activity. Thrombin treatment of Factor XIII in the presence of 1-5 microM-Tb(III) ions resulted in three fragments (76 kDa, 51 kDa and 19 kDa) with simultaneous loss of transglutaminase activity. Tb(III) ions at concentrations greater than 40 microM made platelet Factor XIII resistant to proteolysis by either thrombin or trypsin. Other lanthanide(III) ions [Ln(III) ions] tested [Ce(III), La(III) and Gd(III) ions] functioned similarly to Tb(III) ions during proteolytic activation of Factor XIII. Ln(III) ions (10-100 microM) were unable to replace the Ca(II) ions required for transglutaminase activity of Factor XIIIa. Tb(III) ions also inhibited in a non-competitive manner the transglutaminase activity of Factor XIIIa (Ki 71 microM) even when measured in the presence of 200-fold molar excess of Ca(II) ions. Factor XIII selectively bound to a Tb(III)-chelate affinity column, and could not be eluted by 100 mM-CaCl2. Binding of Tb(III) ions to Factor XIII was demonstrated by fluorescence emission due to Forster energy transfer. A 10(4)-fold molar excess of CaCl2, but not NaCl, partially quenched Tb(III) fluorescence. Low concentrations (5-20 microM) of Tb(III) ions also inhibited the binding of Factor XIII to des-A-fibrinogen by about 43%, whereas higher concentrations (40-100 microM) promoted binding. Conformational changes in Factor XIII consequent to the binding of Tb(III) ions could be responsible for the observed effects on protein structure and function.

Animals↗
PubMed1997

Coagulation factor XIII in pregnant smokers and non-smokers.

Human blood coagulation factor XIII is a transglutaminase zymogen. Two forms exist, an extracellular or plasma factor XIII and an intracellular form. Factor XIII occurs in platelets, blood, monocytes, megakaryocytes, the liver, the placenta, and the uterus. In obstetrics, factor XIII deficiency has been associated with fetal wastage. The interaction of smoking and the quantity of coagulation factor XIII during normal pregnancy was examined in 75 non-smoking and 118 smoking (> or = 20 cigarettes/day) women. A group of subjectively healthy, non-smoking, age-matched females served as a control group (n = 30). Smokers had a higher plasma concentration of factor XIII than non-smokers. Factor XIII declined during normal gestation. During the second half of gestation the plasma concentration of factor XIII was significantly higher in smokers than in non-smokers. In smokers the decline of factor XIII was less, possibly due to platelet activation and a relative polycythemia. The later decline of factor XIII in pregnant smokers remains unexplained. More extensive research with larger patient numbers is needed to address this matter.

Adult↗
PubMed1976

[The anticoagulant system following intravenous administration of factor XIII and thromboplastin].

The inactivated factor XIII does not change the functional state of the anticoagulating system. The i.v. administration of thromboplastin activates the anticoagulating system in rats which cannot be prevented by an artificial rise of the titre of the inactivated factor XIII in blood. The i.v. injections of the secondary adreanlin-heparin--fibrinogen complex with higher level of the factor XIII is followed by a sharp increase in the functional activity of the anticoagulating system.

Animals↗
PubMed1985

Factor XIII of blood coagulation in human monocytes.

The presence of Factor XIII subunit a was demonstrated in human monocytes by immunoperoxidase staining using specific antisera against Factor XIII and its subunits. This finding was verified by immunobiochemical techniques, as well. In an immunoblotting system after SDS polyacrylamide gel electrophoresis of denatured monocyte homogenate a protein band comigrating with Factor XIII subunit a showed positive reaction with antibodies against this subunit or whole Factor XIII. In contrast, no subunit b of Factor XIII could be detected by either of these methods in monocytes. Activity measurements were carried out by the dansylcadaverine incorporation assay in the absence and presence of anti-Factor XIII antibody with and without thrombin activation. The expression of transglutaminase activity required thrombin and was completely abolished in presence of anti- Factor XIII antibody, which clearly indicate that practically all the transglutaminase activity measured in monocytes comes from Factor XIII. Factor XIII of monocytes and macrophages might have a role in formation of focal fibrin thrombi as well as in organization of stable, fibrinolysis resistant fibrin clot at the site of inflammation or around tumor cells.

Acyltransferases↗
PubMed1993

Factor XIII: inherited and acquired deficiency.

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-Schönlein 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.

Amino Acid Sequence↗
PubMed2000

Interactions of human fibrinogens with factor XIII: roles of calcium and the gamma' peptide.

Plasma factor XIII is the zymogen of the transglutaminase factor XIIIa. This enzyme catalyzes the formation of isopeptide cross-links between fibrin molecules in nascent blood clots that greatly increase the mechanical stability of clots and their resistance to thrombolytic enzymes. We have characterized the solution interactions of factor XIII with two variants of fibrinogen, the soluble precursor of fibrin. Both the predominant fibrinogen gamma(A)/gamma(A) and the major variant gamma(A)/gamma' form complexes with a 2 fibrinogen:1 factor XIII ratio. The absence of detectable concentrations of 1:1 complexes in equilibrium mixtures containing free factor XIII and 2:1 complexes suggests that this interaction is cooperative. Factor XIII binds fibrinogen gamma(A)/gamma' approximately 20-fold more tightly than fibrinogen gamma(A)/gamma(A), and the interaction with fibrinogen gamma(A)/gamma' (but not fibrinogen gamma(A)/gamma(A)) is accompanied by a significant release of Ca(2+). Taken together, these results suggest that the strikingly anionic gamma' C-terminal sequence contains features that are important for factor XIII binding. Consistent with this notion, a synthetic 20-residue polypeptide containing the gamma' sequence was found to associate with factor XIII in a 2:1 molar ratio and act as an efficient competitor for fibrinogen gamma(A)/gamma' binding.

Binding, Competitive↗
PubMed1998

Significance of diminished factor XIII in Crohn's disease.

OBJECTIVE: Coagulation factor XIII is a plasma transglutaminase involved in crosslinking of fibrin, the last step of the coagulation system and a connective tissue factor contributing to the wound healing process. It circulates as a heterotetrameric molecule consisting of two identical proenzyme subunits (factor XIIIA) and two carrier protein subunits (factor XIIIS). The aim of this study was to determine the disease features associated with the diminution of factor XIII in Crohn's disease. METHODS: Factor XIIIA and factor XIIIS levels were assessed in patients presenting with Crohn's disease, ulcerative colitis, infectious colitis, or diverticulitis, in patients with rheumatoid arthritis, and in control subjects. Prothrombin fragment 1 + 2 assay, as a marker of the generation of thrombin and measurement of C-terminal telopeptide of type I collagen as an estimate of degradation of collagen type I, were performed. RESULTS: Factor XIIIA was significantly decreased in Crohn's disease, in ulcerative colitis, and in infectious colitis by comparison with subjects presenting with diverticulitis, normal, and rheumatoid subjects p = 0.0001). Factor XIIIS was unmodified in patients with Crohn's disease by comparison with controls but was reduced in those presenting with intestinal bleeding (p = 0.0002). In Crohn's disease, the lowest level of factor XIIIA was observed in patients with intestinal bleeding (p = 0.0003). Factor XIIIA was correlated with the Van Hees index (r = -0.5661; p = 0.0001) and with the C-terminal telopeptide of type I collagen (r = -0.4110; p = 0.0011) but not with prothrombin fragment 1 + 2. The multiple regression analysis showed that only Van Hees index and intestinal bleeding were independent variables for explaining the diminution of Factor XIIIA in Crohn's disease. CONCLUSIONS: Factor XIIIA subunit is an indicator of Crohn's disease activity. Our study suggests that a low factor XIIIA level is related to the presence of intestinal lesions and might be linked to intestinal repair mechanisms; loss in intestinal lumen could be also involved, especially in patients with intestinal bleeding.

Adolescent↗
PubMed2000

Identification of a new mutation (Gly420Ser), distal to the active site, that leads to factor XIII deficiency.

The molecular defects of the factor XIII A subunit gene were studied in a patient with factor XIII deficiency. Mutation analysis was performed on amplified DNA from each exon of this gene by single-strand conformation polymorphism (SSCP) and DNA sequencing techniques. A substitution of guanine by adenine at nucleotide 1258 in exon 10 of the coagulation factor XIII A subunit gene has been identified in the patient. The mutation results in the replacement of Gly420 by Ser in the core domain of the enzyme. Restriction enzyme analysis of amplified exon 10 DNA confirmed that the patient was homozygous for this mutation. A family study revealed that the mutation was inherited from both parents, who were first cousins. The potential effects of the mutation were predicted by molecular modeling of the amino acid substitution within the coordinates of the crystal structure. The substitution occurred within the core domain of the enzyme at a residue completely conserved among all known members of the transglutaminase family. The model of the mutant protein suggests that although the substitution of Gly420 by Ser causes only minor readjustment of the residues and does not appear to be particularly deleterious in terms of structure, the mutation is, however, likely to decrease the molecule's ability to undergo the conformational change that is thought to be required for full transglutaminase activity. Our data strongly support the previously published information about the functional significance of the residues surrounding, but not forming, the catalytic pocket in the A subunit of factor XIII.

Amino Acid Sequence↗