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PubMed2000

Factor XIII Val34Leu polymorphism in primary intracerebral haemorrhage.

INTRODUCTION: Recently, the common Val34Leu polymorphism of the A-chain factor XIII gene, associated with high factor XIII activity, has been identified as a protective genetic factor against occlusive arterial and venous diseases. Moreover, this polymorphism has been suggested to be the first one to increase the risk of cerebral haemorrhage in a small number of Caucasian patients. The aim of our study was to investigate the role of this polymorphism in patients with primary intracerebral haemorrhage from a distinct population. MATERIAL AND METHODS: Patients with non-traumatic primary intracerebral haemorrhage (n=116), age-, race-, sex- and risk factor-matched controls (n=116), and individuals from the general population (n=465) were genotyped for the factor XIII Val34Leu polymorphism by polymerase chain reaction and allele specific restriction assay. The relationships of the Val/Leu genotype with distinct intracerebral haemorrhagic risk factors and with early mortality associated with the haemorrhagic episode were also analysed. RESULTS: No statistical difference in terms of prevalence was detected between patients (P=0.190) and controls (P=0.181). The frequency of the FXIII Leu34 allele was similar in the general population (P=0.191). CONCLUSION: The results suggest that the Leu 34 allele of the A-chain factor XIII gene has a minor role in the development of non-traumatic primary intracerebral haemorrhage. Moreover, the simultaneous presence of the Leu 34 allele with selected risk factors for this disease does not increase the risk of developing this disease.

Aged↗
PubMed2006

Effect of four missense mutations in the factor XIII A-subunit gene on protein stability: studies with recombinant proteins.

Four missense mutations in the factor XIII A-subunit gene, Arg260Leu, Ala318Val, Thr398Asn and Gly210Arg, were previously reported by us in patients with severe factor XIII deficiency. The objective of our study was to discern the effect of all four mutations on the stability and intracellular localization of the factor XIII A-subunit by their expression in COS cells. In-vitro mutagenesis, transient expression of the mutants in COS cells and subsequent pulse-chase analyses were carried out. Intracellular localization of wild-type and mutant proteins was analyzed by immunohistochemistry using a monoclonal antibody against factor XIII A-subunit. Pulse-chase analyses of metabolically labeled proteins demonstrated rapid intracellular degradation of each mutant protein as compared with wild type. Immunocytochemical and immunofluorescence analyses disclosed that wild-type and all four mutant factor XIII A-subunit proteins were diffusely distributed within the cytoplasm but not in the endoplasmic reticulum of the COS-7 cells. The Arg260Leu, Ala318Val, Thr398Asn and Gly210Arg mutations in FXIII A-subunit cause rapid intracellular degradation of the corresponding mutated protein.

Animals↗
PubMed2002

Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction.

We hypothesized that possession of either of 2 functional coagulation factor XIII polymorphisms, one within subunit A (Val34Leu) and one within subunit B (His95Arg), might modulate the prothrombotic effects of estrogen and help to explain the variation in incidence of arterial thrombotic events among postmenopausal women using hormone replacement therapy. In a population-based case-control study of 955 postmenopausal women, we assessed the associations of factor XIII genotypes and their interactions with estrogen therapy on risk of nonfatal myocardial infarction (MI). The presence of the factor XIIIA Leu34 allele was associated with a reduced risk of MI (odds ratio [OR] = 0.70, 95% confidence interval [95% CI] = 0.51-0.95). The presence of the factor XIIIB Arg95 allele had little association with MI risk. Neither factor XIII polymorphism alone significantly modified the association between the risk of MI and current estrogen use. In exploratory analyses, however, there was a significant factor XIII subunit gene-gene interaction. Compared to women homozygous for both common factor XIII alleles, the Arg95 variant was associated with a reduced risk of MI in the presence of the Leu34 variant (OR = 0.36, 95% CI = 0.17-0.75) but not in the absence of the Leu34 variant (OR = 1.11, 95% CI = 0.69-1.79). Moreover, among women who had at least 2 copies of the variant factor XIII alleles and were current estrogen users, the risk of MI was reduced by 70% relative to estrogen nonusers with fewer than 2 factor XIII variant alleles (P value for interaction =.03). If confirmed, these findings may permit a better assessment of the cardiovascular risks and benefits associated with postmenopausal estrogen therapy.

Adult↗
PubMed1981

Plasma factor XIII levels in children with renal disease.

Plasma levels of coagulation factor XIII determined quantitatively were found to have a tendency to be decreased in more severely affected cases of acute poststreptococcal glomerulonephritis and Henoch-Schönlein nephritis, and found to be decreased in patients with rapidly progressive glomerulonephritis and chronic renal failure in comparison with normal controls. It seems that the degree of decrease in factor XIII reflects the intensity of glomerular damage. In contrast, the patients with the nephrotic syndrome showed significant elevation of plasma factor XIII levels and it was closely correlated with the increase in serum triglycerides. The elevation of factor XIII levels in the nephrotic syndrome is suggested to be mainly attributed to enhanced protein synthesis in connection with urinary loss of proteins.

Adolescent↗
PubMed2004

Factor XIII deficiency associated with valproate treatment.

PURPOSE: We present two children who developed a deficiency of factor XIII with valproate (VPA) treatment. This coagulation disorder has not been described in association with VPA treatment in children, and only very recently in one adult patient. RESULTS: Both patients showed recurrent epistaxis as major clinical sign of a combination of decreased coagulation parameters (factor XIII deficiency with thrombocytopenia and decreased von Willebrand factor, respectively). A few days after reduction or withdrawal of VPA treatment, clinical symptoms disappeared, and laboratory findings were within normal range. CONCLUSIONS: VPA is known to influence the synthetic function of the liver and the number and function of megakaryocytes. Therefore an alteration of the factor XIII level by VPA is conceivable. Our case reports suggest that bleeding symptoms during VPA treatment may be caused or aggravated by a decreased factor XIII activity. A determination of factor XIII activity should be considered before surgical procedures during VPA treatment to minimize the risk of (severe) postsurgical bleeding complications.

Anticonvulsants↗
PubMed1984

[Effect of anesthesia on blood coagulation factor XIII].

57 patients who had undergone surgical operations because of varicosis were examined for the influence of the mode of anaesthesia on the plasma levels of factor XIII. Within a randomized study the patients were given by alternate order halothane (NA) (n = 19), neurolept-analgesia (NLA) (n = 19) or peridural anesthesia (PA) (n = 19). Pre- and postoperatively as well as at the 1st, 3rd, 5th, and 7th p.o. day the plasma levels of factor XIII, fibrinogen (factor I) and fibrinogen-degradation-products (FDP) were measured. FDP were not found. The levels of factor XIII remained within the normal range. Fibrinogen showed an identical course: the postoperative findings were lower than the initial ones. 24 h later the levels were higher. At the 7th p.o. day the most important readings were found. In comparing the three methods of anaesthesia the most obvious differences in the data on factor XIII were in the peridural anesthesia-group, especially on the 3rd p.o. day with significant lower results than in the other groups. The modes of anaesthesia used had no visible influence on the range of factor XIII.

Adult↗
PubMedDate not supplied

Decreased factor XIII activity during severe Henoch-Schoenlein purpura -- does it play a role?

BACKGROUND: In patients with Henoch-Schoenlein purpura (HSP), particularly with severe gastrointestinal symptoms, an associated decrease of plasma factor XIII has been observed. PATIENT: The authors report a case of HSP in a boy and describe the development of factor XIII activities throughout the course of the disease. Every relapse of severe gastrointestinal manifestation was associated with a decrease of factor XIII. No improvement was seen after treatment with prednisone. The symptoms resolved each time factor XIII concentrate was administered. With the return of factor XIII to normal values eight weeks after admission abdominal symptoms ceased. CONCLUSION: The documented course supports the hypothesis that factor XIII activity correlates well with the severity of abdominal symptoms. Measuring factor XIII activity helps to identify those patients with severe gastrointestinal manifestation who may benefit from substitution therapy.

Child↗
PubMed1999

Low levels of fibrin-stabilizing factor (factor XIII) in human Plasmodium falciparum malaria: correlation with clinical severity.

Plasmodium falciparum malaria is associated with procoagulant activity but not with thromboembolism. We measured coagulation factor XIII, i.e., fibrin-stabilizing factor, in 45 patients with falciparum malaria over time. Of these, 22 had organ complications. The factor XIII antigen (subunits A and B) and plasma activity levels were abnormally low in those with falciparum malaria. They increased during antiparasitic therapy. In 14 of 22 patients with complications, but in no patient with mild disease (P < 0.001), subunit A and activity was < 50%. The factor X.III levels were inversely correlated with clinical severity, parasitemia, and human neutrophil elastase (HNE), but not with thrombin-antithrombin III levels. Thus, low factor XIII levels may reflect proteolysis by HNE, rather than procoagulant activity. One could speculate that factor XIII degradation in severe malaria prevents thromboembolism. On the other hand, factor XIII deficiency might reduce protection of the vascular endothelium against HNE and reactive oxygen species, which would promote organ damage.

Antithrombin III↗
PubMed1991

Hemorrhagic disorder due to an isoniazid-associated acquired factor XIII inhibitor in a patient with Waldenström's macroglobulinemia.

A case is described of a 75-year-old woman with a history of pulmonary tuberculosis and Waldenström's macroglobulinemia who developed an inhibitor of coagulation factor XIII while taking isoniazid. The patient presented with a subcutaneous hematoma of the abdominal wall that extended from the xiphoid process to the symphysis pubis and measured 20 cm in diameter. Results of routine coagulation studies were normal with the exception of an increased solubility of the patient's plasma clot in 5M urea consistent with a deficiency of factor XIII activity. Persistence of the deficiency following a 1:2 dilution of the patient's plasma in normal plasma indicated the presence of an inhibitor. A sample of the patient's plasma was depleted of IgG by streptococcal protein G adsorption. The IgG-depleted plasma did not inhibit factor XIII activity, indicating that the inhibitory activity was not attributable to the underlying IgM paraprotein. The patient's purified IgG, on the other hand, inhibited factor XIII activity and the inhibitory activity could be neutralized by anti-IgG antibody. The patient's IgG also inhibited factor XIII-mediated incorporation of fluorescent monodansylcadaverine into casein. Binding of the patient's IgG to factor XIII concentrate was demonstrated by enzyme-linked immunosorbent assay and the IgG that bound to the factor XIII was demonstrated to be polyclonal. Isoniazid was discontinued after the patient was admitted to the hospital. Cryoprecipitate infusion controlled bleeding and reduced the inhibitor titer by 50%. Treatment with cyclophosphamide and prednisone, followed by extracorporeal immunoadsorption over a staphylococcal protein A column, did not reduce the inhibitor titer further. Plasma exchange therapy reduced the inhibitor titer to undetectable levels but failed to restore factor XIII activity. Infusions of factor XIII concentrate reproducibly restored factor XIII activity and were not associated with an anamnestic rise in the inhibitor titer. This represents the seventh reported case of an acquired inhibitor to factor XIII associated with the ingestion of isoniazid.

Aged↗
PubMed1994

Butyrate, mesalamine, and factor XIII in experimental colitis in the rat: effects on transglutaminase activity.

BACKGROUND/AIMS: Butyrate and factor XIII may improve ulcerative colitis; they also affect tissue and serum transglutaminase levels. We investigated the therapeutic potential of sodium butyrate and factor XIII and the role of transglutaminase during mucosal repair in experimental colitis. METHODS: Rats with induced colitis were treated with sodium butyrate, mesalamine, sodium butyrate plus mesalamine, or saline enemas. Thromboxane B2 was monitored as index of inflammation. In a fifth group, the effectiveness of intravenous Factor XIII was assessed. RESULTS: Sodium butyrate, alone or plus mesalamine, reduced histological activity from 13.7 +/- 1.7 (saline) to 2.5 +/- 1.3 and 2.3 +/- 1.1 (P < 0.01), respectively. Transglutaminase, reduced in the colons of the saline group (783 +/- 157 vs. normal 1800 +/- 192 mU/g; P < 0.01), returned toward normal values in the sodium butyrate or sodium butyrate plus mesalamine groups (1390 +/- 228 and 1226 +/- 172 mU/g, respectively; P < 0.01 vs. saline). Furthermore, sodium butyrate plus mesalamine reduced thromboxane B2 levels by day 5 (0.92 +/- 0.16 vs. saline 1.85 +/- 0.34 ng/mL; P < 0.05). Factor XIII therapy improved the histological picture (2.7 +/- 2.1 vs. saline 13.8 +/- 1.7; P < 0.01) and increased transglutaminase levels both in serum (2.81 +/- 0.11 vs. saline 1.45 +/- 0.09 mU/mL; P < 0.01) and in colon (1503 +/- 127 vs. saline 747 +/- 103). CONCLUSIONS: Sodium butyrate and factor XIII improve colitis, sodium butyrate plus mesalamine reduce early thromboxane B2 synthesis, and transglutaminase(s) plays a role in ulcer healing.

Aminosalicylic Acids↗
PubMed1986

Molecular subunits and transamidase activity of factor XIII in patients with deep vein thrombosis.

Thrombin formed during the clotting process leads to the activation of factor XIII and then to its consumption. Transamidase activity of factor XIII and its concentrations of subunits "a" and "b" were measured in plasmas of patients with deep vein thrombosis of the calves. The patients revealed a significant decrease of both factor XIII activity and its concentration of subunit "a". A subsequent rise of transamidase activity and concentration of subunit "a" of factor XIII to the normal values was observed in two weeks' time. It is assumed that estimation of factor XIII activity and/or its concentration of subunit "a" may be an additional method for detecting venous thrombosis and monitoring its therapy.

Acyltransferases↗
PubMed1992

Microtiter assay for measurement of factor XIII activity in plasma.

A sensitive, reproducible and rapid quantitative microtiter assay for factor XIII activity is described. The assay is based on incorporation of a soluble amine substrate into casein attached to polystyrol microtiter plates and detection of bound substrate with a monoclonal antibody-enzyme conjugate. Defibrination of plasma samples is not required. The assay shows strong correlation with the immunologic assay for factor XIII catalytic subunit a (r = 0.94), the factor XIII dansylcadaverine assay (r = 0.83), and the factor XIII clot solubility test. Normal values detected in healthy blood donors were in the range of 74% to 117%, with a mean value of 96.9% and a median value of 97.8%; pooled normal plasma was used as a reference. Since the assay is performed in a single microtiter plate and requires few reagents and short incubation periods, it can be easily adapted for clinical use.

Caseins↗
PubMed1999

Association of a common polymorphism in the factor XIII gene with venous thrombosis.

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.

Adult↗
PubMed1997

Recombinant and nonrecombinant factor XIII and its effect on bone ingrowth and strength of fixation.

Thirty cylindrical, commercially pure, titanium fiber, porous-coated Ti6Al4V implants were inserted press-fit into the proximal humeral portion of 30 sheep humeri to determine the systemic effect of recombinant factor XIII and placenta-derived factor XIII concentrate on bone ingrowth and strength of fixation. For both the recombinant factor XIII and the factor XIII concentrate group, the volume of bone ingrowth and the strength of fixation were higher than for the control specimens. However, the difference was only significant for the factor XIII concentrate group.

Animals↗
PubMed1987

Factor XIII A is synthesized and expressed on the surface of U937 cells and alveolar macrophages.

Factor XIII A subunit was detected in U937 cells and human alveolar macrophages by immunohistology and Western blotting. U937 cells synthesize factor XIII A subunit de novo under serum-free, platelet-free conditions, as indicated by 35S-methionine labeling and immunoprecipitation. Thrombin-dependent activity was demonstrated to account for 98% of the total transglutaminase activity in U937 cells (1.5 micrograms per 0.5 X 10(6) cells/mL). Intact U937 cells and alveolar macrophages and homogenates from these cells cross-linked fibrin to form gamma-gamma and alpha-polymers. Factor XIII A was detected on the surface of intact U937 cells and macrophages by flow cytometry and 125I-labeling and immunoprecipitation. Cell surface expression of factor XIII A was augmented in the presence of several soluble macrophage activators; however, no concurrent increase in its biosynthesis was observed. The presence and cell surface expression of factor XIII A subunit within macrophages suggest new pathways by which these cells may function in clotting and in the remodeling of the extracellular matrix during inflammation and wound healing.

Blood Coagulation↗
PubMed1996

Plasma factor XIII binds specifically to fibrinogen molecules containing gamma chains.

The difference between peak 1 and peak 2 fibrinogen lies in their gamma chains. Peak 1 molecules contain 2 gamma A chains; peak 2 molecules contain 1 gamma A and 1 gamma chain, the latter of which contains a 20 amino acid extension (gamma 408-427) replacing the carboxyl-terminal 4 amino acids of the gamma A chain (gamma A 408-411). While the existence of gamma chains in plasma fibrinogen molecules has been known for many years, their function remains unknown. When fibrinogen is purified from plasma, the factor XIII zymogen (A2B2) copurifies with it and is found only in the peak 2 fibrinogen when this fraction is separated from peak 1 fibrinogen by ion-exchange chromatography on DEAE-cellulose. Factor XIII alone applied to the same DEAE column elutes at a position between peak 1 and peak 2. When mixtures of peak 1 fibrinogen plus factor XIII or peak 2 fibrinogen plus factor XIII are applied to DEAE columns, the peak 1/factor XIII mixture elutes in two peaks, whereas the peak 2/factor XIII mixture elutes in the peak 2 fibrinogen position. Gel sieving on Superose 6 of peak 1/factor XIII mixtures results in two protein peaks, the first of which contains the fibrinogen. Most factor XIII activity elutes in the second peak with a small amount of activity emerging with the trailing end of the fibrinogen peak. Gel sieving of mixtures of peak 2 and factor XIII results in a single protein peak with all factor XIII activity emerging with the leading edge of the fibrinogen peak. The interaction between peak 2 fibrinogen and plasma factor XIII appears to be through binding to the B subunit of factor XIII since placental or platelet factor XIII (A2), which does not contain B subunits, elutes independently from peak 2 fibrinogen on DEAE-cellulose chromatography. The results indicate that peak 2 fibrinogen gamma chains have a physiologically significant affinity for the B subunits of plasma factor XIII and that through this interaction fibrinogen serves as a carrier for the plasma zymogen in circulating blood.

Binding Sites↗
PubMed2001

Role of factor XIII Val34Leu polymorphism in retinal artery occlusion.

BACKGROUND AND PURPOSE: Factor XIII (FXIII) Val34Leu, a common polymorphism in the gene for factor XIII, has been associated with a lower risk of stroke, myocardial infarction, and deep vein thrombosis. Ineffective fibrin cross-linking has been suggested to be causative. The aim of the present case-control study was to investigate the role of FXIII Val34Leu polymorphism in patients with retinal artery occlusion. METHODS: A total of 108 patients with retinal artery occlusion and 313 age- and sex-matched controls were genotyped for the FXIII Val34Leu polymorphism. Factor XIII Val34Leu genotypes were determined by use of allele-specific polymerase chain reaction. RESULTS: Homozygous Leu genotype was found significantly more often in control subjects than in patients with retinal artery occlusion (P=0.018), with an odds ratio of 0.22 (95% confidence interval 0.07 to 0.74). Distribution of the Val/Val and Val/Leu genotypes did not differ significantly between groups. CONCLUSIONS: Because prevalence of homozygous Leu genotype was significantly higher in controls, we conclude that the Leu/Leu genotype is associated with a protective effect against retinal artery occlusion.

Adult↗
PubMed1985

Kinetic determination of blood coagulation Factor XIII in plasma.

We have designed a new kinetic assay for estimating Factor XIII in plasma. Plasma fibrinogen is removed by treatment with bentonite (colloidal aluminum silicate) before measurement. During the lag phase, Factor XIII is transformed by thrombin and Ca2+ into active transglutaminase (EC 2.3.2.13), which attaches the substrate ethylamine to a glutamine residue in acetylated, dephosphorylated beta-casein. During the reaction, ammonia is released, which can be continuously monitored in an NADPH-dependent indicator reaction catalyzed by glutamate dehydrogenase (EC 1.4.1.4). We determined the optimal concentrations of substrate and activator and found that, to eliminate the clottable fibrinogen from the plasma samples, bentonite treatment was more advantageous than the traditional heat treatment. Results by the method correlate well with those by the most widely used amine incorporation and immunoinhibition assays for Factor XIII. We established a reference interval of 12.1-22.7 U/L; at optimal conditions, the variance of the method was less than 3% within this range. The method has several theoretical and practical advantages over traditional determinations of Factor XIII.

Ammonia↗