Factor XIII Val34Leu Research Articles

Genetic Polymorphisms of Hemostasis Genes and Primary Outcome of Very Low Birth Weight Infants

Recent investigations have reported an influence of thrombophilic mutations and antithrombotic risk factors with development of intraventricular hemorrhage. It was our objective for this study to investigate the impact of genetic polymorphisms of hemostasis genes on the primary outcome measures of sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia in a large cohort of very low birth weight infants. There were 586 very low birth weight infants enrolled prospectively in a multicenter trial between September 2003 and July 2005, and an additional 595 very low birth weight infants, who had been recruited in a previous prospective trial, were studied. DNA samples were taken by buccal swab, and genotypes of factor V Leiden mutation, prothrombin G20210A mutation, the factor VII-323 del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. In contrast to data published previously, the frequency of intraventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate and a longer period of hospital care compared with noncarriers. The factor VII-323 del/ins polymorphism was found to be a potential protective factor against bronchopulmonary dysplasia. We could not confirm previously reported associations of hemostasis gene variants and development of intraventricular hemorrhage in very low birth weight infants. To better understand gene-disease associations in very low birth weight infants, the prospective development of large-scale cohorts with well-defined phenotypes and corresponding DNA samples is essential.

Prevalence of the coagulation factor XIII polymorphism Val34Leu in women with recurrent miscarriage

Background Recurrent miscarriage (RM) syndrome is not an uncommon obstetrical problem of multifactorial etiology. We investigated the role of the coagulation factor XIII (FXIII) Val34Leu polymorphism in RM. Methods We recruited 80 subjects (40 normal and 40 with history of RM; of each group 20 pregnant and 20 non-pregnant) and analyzed the prevalence of this polymorphism. The women recruited for the present study had similar age and did not have history of any hemostatic disorders. FXIII levels and activity and the rate of fibrin cross-linking by FXIII genotype Val34Val and Val34Leu were studied. Results Genotype analyses of patients and normal revealed that the frequencies distribution of Val/Val and Val/leu were statistically similar ( P < 0.05): 62.5% and 60%, and 37.5% and 40%, respectively; no Leu/leu genotype was found. The FXIII-A subunit levels and activity were also found similar between Val/Val and Val/leu genotypes in the different groups, pregnant and non-pregnant, normal or with RM. The rate of FXIII α and γ-chains fibrin cross-linking was not different between the 2 genotypes. Conclusion From our results we conclude that FXIII Val34Leu polymorphism does not appear to be associated to RM.

The Association Between Factor XIII Val34Leu Polymorphism and Early Myocardial Infarction

Activated factor XIII (FXIII) cross-links between fibrin monomers, thus increasing the clot stability and resistance to fibrinolysis. Congenital FXIII deficiency causes severe bleeding diathesis. Recently, a common polymorphism of the FXIII A subunit (FXIII Val34Leu) has been identified as a protective factor against both arterial and venous thrombosis. The aim of this study was to investigate the role of FXIII Val34Leu polymorphism in coronary artery thrombosis, especially in young patients. One hundred and thirty patients under than 60 years of age with a history of myocardial infarction (%) and 130 healthy control subjects in the same age group were included to our study. Genomic DNA was extracted from venous blood samples and the polymerase chain reaction method was used to genotype FXIII Val34Leu polymorphism. Coronary risk factors such as obesity, diabetes mellitus, hyperlipidemia and smoking were compared between the groups with chi-square test and logistic regression analysis. The Leu allele frequency was significantly lower in patient group compared to control group (7.69% vs 19.23%, p=0.0001, chi-square). This difference was extremely significant in patients younger than 50 years-old (5.26% vs 19.64%, p<0.0001, chi-square). Our findings support the hypothesis that Val34Leu polymorphism in FXIII gene has a protective effect against myocardial infarction.

Factor XIII Val34Leu Polymorphism and the Risk of Myocardial Infarction: A Meta-Analysis.

Genetic factors involving blood coagulation are thought to contribute to the pathogenesis of myocardial infarction. A common polymorphism of Factor XIII, Factor XIII Val34Leu, may be protective against developing an acute myocardial infarction, but various studies show conflicting results. We performed a meta-analysis to determine whether the Factor XIII Val34Leu polymorphism is associated with a decreased risk of myocardial infarction. 93 articles were reviewed after a MEDLINE search of the literature (1966 through April Week 1 2005) and 12 case-control studies were selected. We included studies involving patients with objectively diagnosed myocardial infarctions (according to the WHO criteria) provided Factor XIII genotyping data were available. Inclusion decisions, quality assessment and data extraction were conducted by two reviewers. Hardy-Weinberg equilibrium was verified in all studies. Hypothesizing that the Leu allele was protective we performed 3 analyses with the Val/Val genotype as the reference group. Pooled odds ratios and their 95% confidence intervals were determined using the method of DerSimonian-Laird. Prior to pooling, heterogenity testing was performed using the I2 statistic. Funnel plots ruled out the possibility of publication bias. These studies included a total of 8743 patients, of which 3663 were MI patients and 5080 were healthy controls. Using the random effects methods, protective effects were seen with the Leu/Val genotype alone (OR for MI 0.79, 95% CI 0.68–0.93) and with Leu/Val and Leu/Leu genotypes (OR 0.79, 95% CI 0.68–0.93). There was also a protective effect with the Leu/Leu genotype alone, but this was not statistically significant (0.83, 95% CI 0.61–1.12) likley due to the low frequency of this genotype. Removing the first published study (Kohler 1998) due to potential publication bias assocaited with the first study evaluating a genotype did not significantly change the results. Our analysis found that the Factor XIII Leu allele confers a small but significant protective effect against myocardial infarction. The polymorphism may be useful in profiling an individual's susceptibility for arterial thrombosis. It remains to be elucidated whether or not routine testing for the FXIII Val34Leu polymorphism will be clinically relevant.

Analysis of prothrombotic mutations and polymorphisms in children who developed thrombosis in the perioperative period of congenital cardiac surgery

In this study, we investigated some of the prothrombothic mutations and polymorphisms in 15 children with congenital cardiac malformations who developed severe thrombosis in the perioperative period following surgical repair. The mutations and polymorphisms included in the study were Factor V Leiden, prothrombin G20210A, methylentetrahydrofolate reductase C677T, endothelial nitric oxide synthase intron 4 VNTR, alpha-fibrinogen Thr312Ala, Factor XIII Val34Leu, and insertion or deletion of angiotensin 1 converting enzyme. Compared to the healthy Turkish subjects, our patients had a similar rate of mutation of Factor V Leiden, Factor XIII Val34Leu, and endothelial nitric oxide synthase a/b polymorphisms, but higher frequency of the prothrombotic angiotensin 1 converting enzyme deletion/deletion genotype, and lower frequency of the antithrombotic alpha fibrinogen Thr/Thr genotype. None of the patients exhibited mutations involving prothrombin G20210A or methylentetrahydrofolate reductase C677T. The results of our study suggest that, in addition to prothrombotic mutations such as Factor V Leiden, single-nucleotide polymorphisms should be considered in all children with congenital cardiac malformations who develop thrombosis. Malformations of the heart are the most common of all serious lesions that are present at birth, with an incidence of 4 to 8 cases per 1,000 live births. If needed, corrective surgery is usually the optimal treatment for these anomalies, but perioperative morbidity and mortality still remain high due to several factors. Arterial or venous thrombosis, or both varieties of thrombosis, is among these factors. Prior to surgery, the most frequent time at which these children develop thrombosis is during cardiac catheterization. Postoperative thrombosis in this group of patients is a more complex disorder, which can affect both small and large vessels, and is associated with a high morbidity and mortality. Recent studies indicate that both point mutations and single-nucleotide polymorphisms of genes that encode proteins involved in the coagulative and anticoagulative cascades are important risk factors for development of thrombosis. Patients with these risk factors are most likely to develop thrombosis when triggering elements, such as placement of catheters, prolonged immobilization, or surgery, are also present. In this study, we investigated some of the above-mentioned mutations and polymorphisms in children who developed thrombosis in the perioperative period after correction of congenital cardiac malformations.

Polymorphisms of haemostasis genes as risk factors for preterm delivery

Clinical trials evaluating the potential benefit of anticoagulant treatment in pregnant women with inherited thrombophilia are based on the observation that a genetic predisposition to thrombosis is associated with frequent abortions and preterm birth. It was the aim of our study to delineate the impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth in a large cohort of very-low-birth-weight (VLBW)-infants and their mothers. We examined the factor V Leiden and the prothrombin G20210A mutation, the factor VII 121del/ins and the factor XIII Val34Leu polymorphism in preterm very-low-birth-weight (VLBW, n=593) and term-born-infants (n=278) and their mothers (n=785). The primary outcome was preterm vs.term birth. From all polymorphisms tested, the maternal factor VII-121del/ins polymorphism (26.2 vs. 17.6 %; p=0.009) and the infant's factor VII-121del/ins polymorphism (29.0 vs. 20.0 %; p=0.009) were more frequent in singleton VLBW and their mothers compared to term infants and their mothers. Furthermore, the frequency of the factor XIII-Val34Leu polymorphism was significantly lower in singleton VLBW than in term infant controls (5.1 vs. 9.6%, p=0.025). In a multivariate regression analysis, previous preterm delivery (OR=3.8, 95% CI: 1.7-8.4), the maternal carrier status of the factor-VII-121del/ins polymorphism (OR=1.7, 95% CI: 1.12-2.5, p=0.007) and the lower frequency of infant's factor-XIII-Val34Leu polymorphism (OR=0.53; 95% CI: 0.29-0.96; p=0.038) were found to be independently associated with preterm delivery. InVLBW mothers with pathological CTG as cause of preterm delivery, the frequency of factor V Leiden mutation was significantly increased compared to VLBW mothers without pathological CTG (14.1 vs. 6.1%, p=0.01). The investigated haemostasis gene polymorphisms have a much lower impact on subsequent preterm delivery than known risk factors such as previous preterm birth. The reported association of the factor-VII-121del/ins polymorphism on preterm delivery and its clinical relevance needs to be further elucidated.

A pharmacogenetic effect of factor XIII valine 34 leucine polymorphism on fibrinolytic therapy for acute myocardial infarction

The aim of this study was to evaluate the pharmacogenetic role of the factor XIII (FXIII) valine 34 leucine (Val34Leu) polymorphism in the fibrinolytic therapy of acute myocardial infarction (MI). Fibrinolytic therapy is an established treatment for acute MI, but up to 40% of treated patients do not achieve optimal tissue reperfusion. The FXIII Val34Leu polymorphism is one of the most relevant functional polymorphisms described in the haemostatic system. The common Leu34 allele associates with an increased FXIII-transglutaminase activity, which results in an increased and faster rate of fibrin stabilization. We genotyped this polymorphism in 293 consecutive MI patients (62 +/- 12 years; 231 males) from two different European populations. All patients were treated with standard doses of fibrinolytic drugs. Noninvasive assessment of the efficacy of coronary fibrinolysis was evaluated by serial electrocardiograms and creatine kinase time-activity curves. The clinical outcome was also re-evaluated at 24 h (death, reinfarction, or urgent revascularization). Multivariate analysis showed that Leu34 carriers displayed a significantly less efficient fibrinolysis than carriers of Val/Val genotype (p = 0.021; odds ratio [OR] 1.90, 95% confidence interval [CI] 1.10 to 3.28). At 24 h, Leu34 allele carriers had the worst outcome (p = 0.006; OR 2.14, 95% CI 1.25 to 3.68). Interestingly, the combination of the Leu34 allele and nonsmoking status increased the risk of non-reperfusion criteria (p = 0.003, OR 3.77), and worse outcomes at 24 h (p = 0.001, OR 4.55). In a large cohort of nonselected and consecutive acute MI patients from two different European populations, we show clinical evidence that the presence of the Leu34 allele reduces the efficacy of fibrinolytic therapy.

Factor XIII Val34Leu Polymorphism Is Protective Against Venous Thromboembolism; a Meta-Analysis.

Controversy over whether the factor XIII Val34Leu polymorphism confers protection against venous thromboembolism (VTE) is a persistent debate in the current thrombosis literature. If an accurate estimate of the protective effect were established, routine screening for this mutation in patients with VTE could provide more precise individual risk-profiling, but presently, it remains undetermined whether it is worthwhile to screen for this polymorphism. We performed a meta-analysis to determine whether the 34Leu allele of the factor XIII gene is associated with a decreased risk of VTE. Studies were identified by searching MEDLINE (1966 through to June Week 2 2004) followed by a manual search of reference lists from previously retrieved articles, symposia proceedings, and abstracts from major thrombosis conferences. Studies were selected for review if they involved unselected objectively diagnosed VTE patients with factor XIII Val34Leu genotypes reported and were a case-controlled study. Inclusion decisions, quality assessment and data extraction were conducted by two reviewers and consensus was achieved by discussion or by a third independent reviewer. Hardy-Weinberg equilibrium of the study control populations were verified. Four of the studies did not report whether they had verified Hardy-Weinberg equilibrium (Balogh, Catto, Margaglione, and Zidane). Authors were contacted for missing data. Forty-five studies were reviewed for eligibility and ten studies met the inclusion criteria. Pooled Odds Ratios and their 95% confidence intervals (CI) were determined using the method of DerSimonian-Laird. Prior to pooling, heterogeneity testing was performed using the Breslow-Day statistic and was insignificant (p = 0.06) which validated testing our FXIII 34Leu recessive model using the random effects model. Funnel plots ruled out the possibility of publication bias. The random effects model gave a combined odds ratio of 0.75 (95% CI= 0.55 to 1.01). Testing our dominant model using a random effects model gave a combined odds ratio of 0.86 (95% CI=0.76 to 0.98). Heterogeneity testing was insignificant (p=0.16). Our meta-analysis found significantly lower odds of VTE with the presence of FXIII 34Leu allele using a dominant model (i.e. the presence of at least one Leu allele). This polymorphism should be given consideration as part of routine risk profiling in patients at risk for VTE.

New Interactive Effects Involving Factor XIII Gene Polymorphisms in Venous Thrombotic Disease.

Venous thrombosis (VT) is considered to be a multifactorial disorder in which several genetic and acquired risk factors interact dynamically. Coagulation factor XIII (FXIII) is an enzyme that participates in the final steps of the coagulation cascade. A number of gene variations have been described in both FXIII A and B subunits. FXIIIA Val34Leu, Tyr204Phe and Pro564Leu polymorphisms have been associated to increased specific activity of FXIII, and FXIIIA Val34Leu has been claimed to be protective against VT in several studies. In the FXIII B subunit, two common polymorphisms (His95Arg and G30899A) have been also reported, but its association with VT is uncertain. In addition, possible interactive effects between these polymorphisms and between these polymorphisms and the two most prevalent mutations associated with VT, factor V Leiden (FVL) and factor II (FII) G20210A mutations, have not been explored. In the present study, we determined the prevalence of the five above-mentioned FXIII polymorphisms in 418 consecutive patients with an objective diagnosis of VT and in 418 age-, gender- and race-matched controls in the BRATROS (Brazilian Thrombosis Study) case-control investigation. Genotyping for Val34Leu, Pro564Leu, His95Arg and G30899A was performed by PCR amplification followed by MseI, BstUI, NsiI and BspHI restriction digestion analysis, respectively. Genotyping for Tyr204Phe was performed by single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing of samples showing mobility shifts. Odds ratios (OR) as a measure of relative risks of VT, and 95% confidence intervals (CI95), were calculated. Stratified analyses were performed to search for interactions between the FXIII polymorphisms and between the FXIII polymorphisms, FVL and FII G20210A. Overall OR for VT linked to Val34Leu was 0,78 (CI95: 0,59–1,03); OR for heterozygotes (HT) was 0,85 (CI95: 0,64–1,13) and for homozygotes (HM) the OR was 0,33 (CI95: 0,15–0,71). Overall OR linked to G30899A was 1,06 (CI95: 0,81–1,39); OR for HT was 0,96 (CI95: 0,72–1,28) and for HM the OR was 1,58 (IC95: 1,00–2,49). No impacts over the risk of VT were observed, related to the other three polymorphisms investigated. When stratified analyses were performed to search for interactions, a trend towards increased risk of VT was detected when the Val34 allele was co-inherited with the Arg95 allele (OR 1,45; CI95: 0,97–2,18), and a trend towards decreased thrombotic risk was verified when the Leu34 and Leu564 alleles were co-inherited (OR 0,63; CI95: 0,40–1,00). Furthermore, increased risk for VT was observed when the mutant A30899 allele was co-inherited with FII G20210A, pointing to a notable interaction effect (OR 18,29; CI95: 2,41–138,87). The data confirm that homozygosity for FXIII Val34Leu is protective against the occurrence of VT in our population. In addition, the findings point to a previously unknown increased risk of VT related to homozygosity for FXIIIB G30899A of the order of 58%. Lastly, an impressive interactive effect (18-fold increased risk of VT) between FXIIIB G30899A and FII G20210A is reported for the first time. Taken together, the findings from the present investigation strengthen the clinical significance of FXIII in vascular thrombosis and reinforce the concept of VT as a multigenic disease.

Prevalence of factor XIII Val34Leu polymorphism in patients affected by spontaneous subconjunctival hemorrhage

Purpose To verify the prevalence of Val34Leu polymorphism in factor XIII A-chain gene (FXIII Val34Leu) in patients with spontaneous subconjunctival hemorrhage (SCH). Design Nonrandomized case-control study. Methods One hundred seven white patients suffering from one or more episodes of idiopathic SCH and 107 healthy subjects were matched for age and gender, and genotyped for FXIII Val34Leu. Anamnestic, ophthalmologic, cardiovascular, and serologic examinations were performed. Results Frequency of FXIII mutated allele (Leu34) was significantly higher in SCH patients than in controls. Computing together heterozygotes (Val/Leu) and homozygotes (Leu/Leu), genotype distribution was statistically different. In a conditional logistic regression model, the comparison of the three separated genotypes, performed among 25 patients with recurrent idiopathic SCHs and controls, gave significant differences for both Val/Leu and Leu/Leu variables. Conclusion Both homozygosity and heterozygosity for FXIII Val34Leu predispose to idiopathic SCH, emphasizing the role of Leu34 allele as inherited risk factor for spontaneous, especially recurrent, SCHs.

Factor XIII Val34Leu polymorphism modulates the prothrombotic and inflammatory state associated with atrial fibrillation

Atrial fibrillation (AF) has been shown to confer a prothrombotic or hypercoagulable state, which could be related to inflammation. Factor XIII (FXIII) catalyses the cross-linking of fibrin monomers, increasing clot resistance; specifically, a common polymorphism, Val34Leu, in the FXIII-A subunit gene has been associated with more rapid FXIII activation. We hypothesised a role for this polymorphism in the prothrombotic state and inflammation in AF, and tested this hypothesis by measurement of indices of coagulation (tissue factor (TF) and fibrinogen), inflammation (interleukin-6 (IL6)) and platelet activation (soluble P selectin (sPsel)). Methods. – We studied 90 stable outpatients (73 ± 8 years) with persistent AF. The FXIII Val34Leu polymorphism was determined by polymerase chain reaction–allelic specific restriction assay (PCR–ASRA). Prevalence of Val34Leu polymorphism of patients was compared to 585 unrelated subjects from the same geographical area. Plasma fibrinogen (Clauss), TF, IL6 and sPsel (all ELISA) were quantified in patient group. Research indices were compared to 74 controls in sinus rhythm with similar clinical characteristics. Results. – There were no statistical differences in FXIII polymorphism prevalence between AF patients and controls. Patients carrying the Leu34 allele had higher plasma levels of TF, IL6 and sPsel (all P < 0.05) compared to controls. Plasma IL6 and TF levels were significantly correlated (Spearman coefficient, r = 0.33, P < 0.01). On multivariate analysis, the Leu34 allele was independently associated with IL6 levels ( P < 0.01), whereas TF levels were only associated with IL6 concentrations. However, sPsel and fibrinogen levels were not related to Leu34 allele. Conclusion. – FXIII Val34Leu polymorphism was independently associated with IL6 levels in AF. The Leu34 allele may potentially influence the prothrombotic state in these patients by modulating the inflammatory state.

Turkish population data on the factor XIII Val34Leu,glycoprotein (GP)Ibalpha Kozak and P-selectin glycoprotein ligand 1 (PSGL-1) loci.

We determined the allele and genotype frequencies of three PCR-based gene polymorphisms factor XIII (FXIII) Val34Leu, glycoprotein (GP) Ibalpha Kozak and P-selectin glycoprotein ligand 1 (PSGL-1) in the Turkish population (n = 126 for FXIII Val34Leu, n = 110 for GPIbalpha Kozak and n = 203 for PSGL-1). To detect these polymorphisms, DNA was extracted from venous blood. Genomic DNA samples were replicated and analysed by a polymerase chain reaction (PCR) method. PCR products were digested by restriction endonuclease enzymes for FXIII Val34Leu and GPIbalpha Kozak. PSGL-1 was analysed by variable number of tandem repeats (VNTR). Allele frequencies of V (Val) and L (Leu) were found to be 0.805 and 0.195 respectively for the FXIII Val34Leu polymorphism. No significant difference was observed between French and Turkish populations for FXIII Val34Leu. Allele frequencies of T and C were calculated to be 0.873 and 0.127 for the GPIbalpha Kozak polymorphism and no significant difference was found between Turkish and French populations. In contrast, the difference between Turkish and Japanese populations was statistically significant (p<0.0001). In the PSGL-1 group, allele frequencies of A, B and C were calculated as 0.818, 0.160, 0.022 respectively. For the PSGL-1, although the difference between Turkish and French populations was not significant, the difference between the Turkish and Japanese was extremely significant (p<0.0001). In conclusion, a Turkish population database has been established for three gene polymorphisms.

Factor XIII Val34Leu polymorphism does not contribute to the prevention of thrombotic complications in patients with antiphospholipid syndrome.

The effect of thrombophilic mutations in the development of thrombosis in patients with antiphospholipid syndrome (APS) has been extensively investigated. Factor XIII (FXIII) Val34Leu polymorphism is a newly described polymorphism which is located in the three amino acids away from the thrombin activation site of the FXIII-A subunit. It has been reported that the Leu allele decreases the risk of both arterial and venous thrombosis. In the present study, we examined the association between the FXIII Val34Leu polymorphism and the development of thrombosis in patients with APS. Sixty APS patients with arterial and venous thrombosis, 22 antiphospholipid antibody (aPLA) positive patients with first trimester abortus and/or thrombocytopenia, 126 healthy controls, and 60 healthy subjects who were age- and sex-matched with thrombotic APS group were included into the study. FXIII Leu allele frequencies in the APS patients with thrombosis, aPLA-positive patients without thrombosis, healthy controls, and matched controls were 13.3, 16, 19.5, and 18.3%, respectively. When we compared Leu allele frequencies between APS patients with thrombosis and aPLA-positive patients without thrombosis, healthy controls or matched controls, we could not find any difference (chi2, p = 0.43, and P = 0.09, P = 0.67, respectively). Our results showed that the FXIII Leu allele has no protective effect in the development of thrombosis in APS.

POLymorphisms and Risk of Ischemic Stroke (POLARIS) Study: Rationale and Design

Twin and family-based studies indicate that genetic factors might be involved in the risk of transient ischemic attack (TIA) and ischemic stroke (IS). Identification of genetic risk factors for new vascular events after cerebral ischemia may target secondary prevention. The overall aim of POLARIS is to study which polymorphisms predispose to new vascular events after TIA/IS and to assess their predictive value. Patients who have had a TIA or IS of presumed arterial origin are included. The study design is twofold. In part one the prevalences of polymorphisms will be compared between 300 long-term survivors of the Dutch TIA Trial (average follow-up 10 years) and 820 patients with recent TIA/IS. In part two a cohort of 820 patients with recent TIA/IS will be followed for the occurrence of vascular events for an average of 3.5 years. Several polymorphisms of interest will be genotyped, including factor V Leiden, prothrombin 20210A, 5,10-methylenetetrahydrofolate reductase, HR2 haplotype factor V and factor XIII Val34Leu.

Role of Genetic Factors in Vascular Access Thrombosis in Hemodialysis Patients

Vascular access thrombosis is a frequent complication in hemodialysis (HD) patients. Genetic mutations, inflammation, and changes in the vascular wall are some factors that are thought to increase thrombosis risk. In this study, we tested for possible relationships between vascular thrombosis and some known thrombophilic mutation/polymorphisms in coagulation factors [factor V Leiden (FVL), prothrombin (Pt) G20210A, methylene tetrahydrofolate reductase (MTHFR C677T), factor XIII (F‐XIII) Val34Leu, alpha‐fibrinogen (AF) Thr312Ala, factor VII (F‐VII) R353Q] and angiotensin I converting enzyme (ACE) gene in our HD patients. Patients who had experienced at least 3 episodes of AVF thrombosis composed of the study group, and patients who had never encountered this complication composed of the control group. None of the patients in either group had a history of diabetes mellitus, atherosclerosis, dialysis‐related amyloidosis, or vasculitis. In order to find the frequency of F‐XIII Val34Leu, AF Thr312Ala, and F‐VII R353Q polymorphisms in our population, we also searched persons without renal disease or history of thrombosis (normal group). Results are summarized in Table. There was a tendency toward thrombotic mutation/polymorphisms in the study group for FVL, Pt G20210A, ACE I/D, and AF Thr312Ala. We suggest that patients who develop recurrent AVF thrombosis should be screened for the above‐mentioned factors and investigated for other possible risk factors. This screening would allow more effective focus on prophylaxis. Genetic mutation/ polymorphism Study group Normal group Control group FVL/heterozygous 13 (n = 46) 7 (n = 81) 24.5 (n = 44) Pt G20210A/ heterozygous 8.7 (n = 46) 2.7 (n = 182) 20 (n = 44) MTHFR C677T/ heterozygous 0 (n = 44) 28.8 (n = 66) 22.3 (n = 44) ACE I/DD/D 44.5 (n = 44) 28.8 (n = 138) 26.2 (n = 29) I/D 36.3 (n = 44) 47.2 (n = 138) 23.1 (n = 29) I/I 18.2 (n = 44) 15.4 (n = 138) 27 (n = 29) F‐XIII/ Val34LeuVal/Val 44.8 (n = 29) 71.5 (n = 112) 52 (n = 25) Val/Leu 51.8 (n = 29) 27.6 (n = 112) 48 (n = 25) Leu/Leu 3.4 (n = 29) 0.9 (n = 112) 0 (n = 25) AF Thr312AlaAla/Thr 83 (n = 24) 58 (n = 119) 83.3 (n = 30) Thr/Thr 12.5 (n = 24) 32.6 (n = 119) 10 (n = 30) Ala/Ala 4.5 (n = 24) 8.4 (n = 119) 6.7 (n = 30) F‐VII R353QR/R 39 (n = 18) 74.5 (n = 98) 31.8 (n = 22) R/Q 34 (n = 18) 23.5 (n = 98) 68.2 (n = 22) Q/Q 27 (n = 18) 2 (n = 98) 0 (n = 22) Values are percentages and numbers in parenthesis represent the number of patients/persons studied.

Rapid detection of the factor XIII Val34Leu (163 G-->T) polymorphism by real-time PCR using fluorescence resonance energy transfer detection and melting curve analysis.

The Val34Leu polymorphism in the A subunit of blood coagulation factor XIII (FXIII-A) is located in the activation peptide, just three amino acids upstream of the thrombin cleavage site. The Val-->Leu replacement accelerates the rate of the proteolytic activation of FXIII and it seems to provide protection against myocardial infarction. Methods available for the assessment of the FXIII-A Val34Leu polymorphism are rather time-consuming, laborious and not easily applicable for large-scale studies. In this study a new method based on real-time PCR with fluorescence resonance energy transfer (FRET) detection and melting curve analysis was developed. The rapid, simple method was adapted to the widely used real-time PCR instrument, LightCycler (Roche Diagnostics). The results showed 100% coincidence with those obtained by the traditional PCR-restriction fragment length polymorphism (RFLP) assay and fluorescent DNA sequencing. Using this method, an allele frequency of 24.2% was obtained (n=113), which well agrees with the allele frequency obtained by PCR-RFLP on a different group of the same ethnic Hungarian population (25.9%).

Plasminogen activator inhibitor 1 4G/5G polymorphism and coagulation factor XIII Val34Leu polymorphism: impaired fibrinolysis and early pregnancy loss.

A successful outcome of pregnancy depends on proper placental formation. In the very beginning of this process, trophoblast invasion and fibrin deposition into the wall of the decidual veins play an important part. Two polymorphisms, coagulation factor XIII (FXIII) Val34Leu and plasminogen activator inhibitor 1 (PAI-1) 4G/5G, interfere with fibrin cross-linking and regulation of fibrinolysis and may therefore contribute to early pregnancy loss. We enrolled 49 unrelated Caucasian women with a history of two consecutive or three to six nonconsecutive early pregnancy losses and 48 unrelated parous healthy controls without a history of pregnancy loss and evaluated them for the following genetic variants: the factor V Leiden and prothrombin G20210A gene mutations, the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms, and the PAI-1 4G/5G and FXIII Val34Leu polymorphisms. For the isolated occurrence of PAI-1 4G/5G or FXIII Val34Leu, we found no statistically significant difference between cases and controls. For homozygosity of either or compound carrier status of both mutations, the overall relative risk for early pregnancy loss was significantly increased (odds ratio = 2.4; 95% confidence interval, 1.1-5.5; P = 0.032). We observed no statistically relevant association of any of the other tested mutations with early pregnancy loss. Homozygosity for PAI-1 4G or FXIII 34Leu polymorphisms as well as compound carrier status is associated with early pregnancy loss.

Association between factor XIII Val34Leu polymorphism and risk of ischemic stroke in young patients

Association between factor XIII Val34Leu polymorphism and risk of ischemic stroke in young patients

Role of factor XIII Val34Leu polymorphism in patients

Role of factor XIII Val34Leu polymorphism in patients <45 years of age with acute myocardial infarction

Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk

Polymorphisms in the fibrinogen and factor XIII genes are associated with atherothrombotic risk, but clinical studies have produced inconsistent results and laboratory studies have not explained these findings. We aimed to investigate interactions between polymorphisms in the factor XIII and fibrinogen genes, fibrinogen concentrations, and other cardiovascular risk factors in relation to fibrin structure and function. We used permeation analysis and electron microscopy to investigate interactions between fibrin structure, factor XIII Val34Leu, fibrinogen Aalpha Thr312Ala, fibrinogen Bbeta Arg448Lys, and fibrinogen concentrations in plasma and purified systems. Increased fibrinogen concentrations were associated with decreases in permeability, with tighter clot structures in the presence of factor XIII 34Val alleles compared with those in the presence of 34Leu alleles. Findings were confirmed by scanning electron microscopy of fibrin. Similar changes in permeability were noted for Aalpha fibrinogen 312Ala compared with that for 312Thr. Our results show interactions between coding polymorphisms in fibrinogen and factor XIII and fibrinogen concentrations that modify fibrin and explain the apparent paradox between epidemiological studies of factor XIII 34Leu and reported in-vitro effects on fibrin structure and function. We suggest a potential complexity of gene-gene and gene-environment interactions in determining cardiovascular risk.