Factor XIII val34leu and the risk of myocardial infarction

BACKGROUND AND OBJECTIVE: Recent studies have suggested an association between a genetic variation in the coagulation factor XIII (FXIII Val34Leu) and decreased risk of vascular thrombosis. DESIGN AND METHODS: We investigated the frequency of the FXIII Val34Leu polymorphism in 150 consecutive, unrelated and relatively young (<55 years) survivors of myocardial infarction (MI) with angiographically-proven severe coronary atherosclerosis and in 150 age-, gender- and race-matched controls. RESULTS: FXIII Val34Leu was detected in 54/150 patients and 73/150 controls, yielding an overall odds ratio (OR) for MI of 0.6 (CI95: 0.4-0.9). Homozygosity for FXIII Val34Leu was found in 4/150 patients and in 12/150 controls, yielding an OR for MI of 0.26 (CI95: 0.08-0.9). The OR for heterozygotes was 0.65 (CI95: 0.4-1.1). FXIII Val34Leu carriership decreased the risk of MI related to metabolic risk factors (RF) (hypertension, diabetes, dyslipidemia, and obesity): non-carriers in the presence of a metabolic RF had a 13.9-fold higher risk of MI, whereas in carriers with a metabolic RF the risk was reduced to 6.8. FXIII Val34Leu also attenuated the risk of MI among smokers. Non-carrier smokers had a 6.1-fold higher risk (CI95: 3.1-11.9), whereas the risk among smokers carrying FXIII Val34Leu was 3.9 (CI95: 1.9-8.1). INTERPRETATION AND CONCLUSIONS: FXIII Val34Leu confers a significant protective effect against the occurrence of MI in relatively young patients. FXIII Val34Leu exhibits a gene dosage effect: the protective effect was particularly strong in homozygous carriers, and heterozygosity conferred moderate protection. Finally, FXIII Val34Leu seems to reduce the risk of MI related to major cardiovascular risk factors.     

Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males

Factor XIII is a transglutaminase that crosslinks fibrin in the last steps of the coagulation process. A few polymorphic sites have been identified in this gene, one of them being a point mutation (FXIII Val34Leu), leading to an amino acid change of valine to leucine. Recently, in British patients, FXIII 34Leu allele was suggested to be associated with a decreased incidence of myocardial infarction (MI). PAI-1 4G/4G genotype seemed to lessen the beneficial effect of FXIII 34Leu allele. The aim of our study was to further investigate the possible protective role of the FXIII 34Leu allele against MI and its suggested interaction with the PAI-1 4G/5G polymorphism. We carried out genotype analyses for FXIII Val34Leu using solid-phase minisequencing in two independent Finnish study groups. In our study, the FXIII 34Leu allele was associated with a lower risk of MI (P = 0.009), however, the PAI-1 4G allele showed no interaction with this polymorphism. To establish the population frequency of the FXIII 34Leu allele and to study the possible variations in Finland four DNA pools from different geographical areas of Finland were genotyped. No significant differences in the allele frequencies were observed (21-28%) except in the Eastern Kainuu area (13%), an area with an increased risk of mortality from coronary artery disease (CAD), supporting the results presented above. The association of FXIII 34Leu variant with a lower incidence of myocardial infarction suggests a new role for FXIII in a polygenic thrombotic disease.     

The association between factor XIII Val34Leu polymorphism and early myocardial infarction.

BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSION: Our findings support the hypothesis that Val34Leu polymorphism in FXIII gene has a protective effect against myocardial infarction.     

The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction

Factor XIII catalyzes the formation of covalent bounds between fibrin monomers, thus stabilizing the fibrin clot and increasing its resistance to fibrinolysis. The frequency of a frequent Val34Leu polymorphism in the FXIII A-subunit gene has been shown to be lower in patients with myocardial infarction or venous thrombosis than in controls, whereas it was higher in patients with hemorrhagic stroke than in controls. Our aim was to study the relation between brain infarction (BI) and the FXIII Val34Leu polymorphism in 456 patients consecutively recruited with a BI confirmed by MRI, and 456 matched controls. The distribution of genotypes was different in cases (63. 2% Val/Val; 30.9% Val/Leu; 5.9% Leu/Leu) compared with controls (49. 8% Val/Val; 42.8% Val/Leu; 7.4% Leu/Leu; P <.001). Carrying the Leu allele was associated with an OR of 0.58 (95% CI = 0.44-0.75). A similar association was observed in cases and controls free of previous cardiovascular or cerebrovascular history (OR = 0.51; 95% CI = 0.36-0.73). No heterogeneity of this association was observed after stratification on the main BI subtypes. Adjustment for traditional vascular risk factors did not modify these findings. In addition, the effect of smoking was modified by the polymorphism (P =.05); the effect of smoking was weaker among Leu carriers than among noncarriers. In conclusion, there was a negative association of the FXIII Val34Leu polymorphism with BI, thus suggesting a protective effect of the Leu allele against thrombotic cerebral artery occlusion. In addition, our results suggest that among Leu carriers, the protective effect of the polymorphism outweighed the effect of smoking. (Blood. 2000;95:586-591)     

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

OBJECTIVES: 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). BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.     

The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure

Factor XIII on activation by thrombin cross-links fibrin. A common polymorphism Val to Leu at position 34 in the FXIII A subunit is under investigation as a risk determinant of thrombosis. Because Val34Leu is close to the thrombin cleavage site, the hypothesis that it would alter the function of FXIII was tested. Analysis of FXIII subunit proteolysis by thrombin using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-performance liquid chromatography showed that FXIII 34Leu was cleaved by thrombin more rapidly and by lower doses than 34Val. Mass spectrometry of isolated activation peptides confirmed the predicted single methyl group difference and demonstrated that the thrombin cleavage site is unaltered by Val34Leu. Kinetic analysis of activation peptide release demonstrated that the catalytic efficiency (k(cat)/K(m)) of thrombin was 0.5 for FXIII 34Leu and 0.2 (micromol/L)(-1) x sec(-1) for 34Val. Presence of fibrin increased the catalytic efficiency to 4.8 and 2.2 (micromol/L)(-1) x sec(-1), respectively. Although the 34Leu peptide was released at a similar rate as fibrinopeptide A, the 34Val peptide was released more slowly than fibrinopeptide A but more quickly than fibrinopeptide B generation. Cross-linking of gamma- and alpha-chains appeared earlier when fibrin was incubated with FXIII 34Leu than with 34Val. Fully activated 34Leu and 34Val FXIII showed similar cross-linking activity. Analysis of fibrin clots prepared using plasma from FXIII 34Leu subjects by turbidity and permeability measurements showed reduced fiber mass/length ratio and porosity compared to 34Val. The structural differences were confirmed by electron microscopy. These results demonstrate that Val34Leu accelerates activation of FXIII by thrombin and consequently affects the structure of the cross-linked fibrin clot.     

Factor XIII Val34Leu polymorphism,factor XIII antigen levels and activity and the risk of deep venous thrombosis

Varying results on the effect of factor XIII (FXIII) Val34Leu on venous thrombotic risk have been reported. The probability of a true association between this polymorphism and venous thrombotic risk would be enhanced by a laboratory phenotype associated with this polymorphism and with the thrombotic risk. The aim of this study was to assess the effect of FXIII Val34Leu, FXIII activity and subunit levels on venous thrombotic risk in a large case-control study, The Leiden Thrombophilia study (LETS). We found higher FXIII activity for 34Leu carriers (Leu/Leu: 158.0, Val/Val: 95.0). FXIII subunit levels were not associated with genotype. Higher FXIII activity was associated with a slightly decreased thrombotic risk [Odds ratio (OR): 0.8, 95% confidence intervals (CI): 0.5-1.3]. This effect was not present for elevated FXIII subunit levels. Higher FXIII activity was also associated with a higher dissociation index (percentage A2B2 complex dissociated after activation by thrombin for a fixed time interval). This index was higher for FXIII 34Leu carriers. The risk of deep venous thrombosis was slightly decreased for carriers of the 34Leu allele [OR: 0.9 (95%CI: 0.7-1.1)]. For homozygous 34Leu carriers the OR was 0.7 (95%CI: 0.4-1.3). This finding, suggesting a weak protective effect, was completely restricted to men. An overall estimate of thrombotic risk was calculated by using earlier reports on the risk of FXIII Val34Leu. The overall risk estimate for homozygous 34Leu carriers was 0.8 (95%CI: 0.6-1.0). In this study, a weak protective effect against venous thrombosis was found, of FXIII 34Leu as well as of increased FXIII activity.     

Is the factor XIII 34Val/Leu polymorphism a protective factor for cerebrovascular disease?

A frequent polymorphism in the factor XIII (FXIII) A-subunit gene, leading to a Val to Leu amino acid exchange at position 34, suggested to affect clot stability, has been associated with a decreased risk for venous thromboembolism and myocardial infarction. Its role in the development of stroke is still under investigation. Ninety-four patients with primary arterial intracerebral haemorrhage (mean age +/- standard deviation: 69 +/- 14 years; 48 men, 46 women), 718 patients with ischaemic stroke (63 +/- 14 years; 395 men, 323 women) and 369 healthy control subjects (59 +/- 14 years; 299 men, 170 women) were analysed for FXIII Val34Leu. No differences in genotype distribution between all three groups were observed. Also, no significant differences in the genotype distribution were found between subgroups of patients stratified according to age, sex, aetiology, history of hypertension, antiplatelet or anticoagulant medication and other vascular risk factors. In contrast to previously reported findings in smaller collectives, our data suggest that an association of the FXIII Val34Leu polymorphism with a decreased risk of ischaemic stroke or an increased risk of intracerebral haemorrhage is highly unlikely. Thus, screening for the FXIII Val34Leu polymorphism will not contribute significantly to the risk prediction of cerebrovascular disease.     

Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease

Altered fibrin clot structure has been reported both in patients with coronary artery disease (CAD) and those with type 2 diabetes mellitus (DM2). The aim of the present study was to evaluate plasma fibrin clot permeability and susceptibility to lysis in patients with DM2 and CAD. We studied 132 consecutive CAD patients, including 67 subjects with DM2, scheduled for elective coronary artery bypass grafting surgery. Ex vivo plasma fibrin clot permeability (K_s) and lysis time (t_50%) induced by 1 μg/mL recombinant tissue plasminogen activator (tPA), along with plasma levels of plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tPA, von Willebrand factor (vWF), P-selectin, soluble CD40 ligand (sCD40L), were measured. Diabetic and non-diabetic patients did not differ in regard to demographics and remaining cardiovascular risk factors. Concomitant DM2 was associated with higher glucose (+24.3 %, p < 0.001), fibrinogen (+9.0 %, p = 0.037), PAI-1 (+58.7 %, p < 0.001), tPA (+24.0 %, p < 0.001) and P-selectin (+12.2 %, p < 0.001). Compared with the non-diabetic group, the CAD patients with DM2 had lower K_s (-6.1 %, p = 0.02) and prolonged t_50% (+5.1 %, p = 0.04). Multiple regression analysis of the whole study group showed that vWF, PAI-1, fibrinogen and DM2 were the independent predictors of t_50% (R ² = 0.58, p < 0.001), while only vWF was an independent predictor of K_s (R ² = 0.22, p < 0.001). This study indicates that DM2 is potent enough to unfavorably affect plasma fibrin clot characteristics despite abnormal clot phenotype typically observed in CAD. Of note, platelet and endothelial markers appear to contribute to fibrin clot properties in CAD concomitant with DM2.     

Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia

Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) is located in the activation peptide (AP) just 3 amino acids away from the thrombin cleavage site. This mutation has been associated with a protective effect against occlusive arterial diseases and venous thrombosis; however, its biochemical consequences have not been explored. In the current study it was demonstrated that the intracellular stability and the plasma concentration of FXIII of different Val34Leu genotypes are identical, which suggests that there is no difference in the rate of synthesis and externalization of wild-type and mutant FXIII-A. In contrast, the release of AP by thrombin from the Leu34 allele proceeded significantly faster than from its wild-type Val34 counterpart. By molecular modeling larger interaction energy was calculated between the Leu34 variant and the respective domains of thrombin than between the Val34 variant and thrombin. In agreement with these findings, the activation of mutant plasma FXIII by thrombin was faster and required less thrombin than that of the wild-type variant. Full thrombin activation of purified plasma FXIII of different genotypes, however, resulted in identical specific transglutaminase activities. Similarly, the mean specific FXIII activity in the plasma was the same in the groups with wild-type, heterozygous, and homozygous variants. Faster activation of the Leu34 allele hardly could be associated with its presumed protective effect against venous thrombosis. No such protective effect was observed in a large group of patients with familial thrombophilia.     

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.     

alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism

The Aalpha-fibrinogen Thr312Ala polymorphism, which occurs in a region involved in factor XIII (FXIII)-dependent cross-linking processes, is associated with poststroke mortality in subjects with atrial fibrillation, suggesting an influence either on intraatrial clot formation or embolization. We have determined the association of Thr312Ala with deep vein thrombosis (DVT) and pulmonary embolism (PE) and have assessed the interaction of Thr312Ala with the FXIII Val34Leu polymorphism in 122 patients with DVT, 99 patients with PE, and 254 healthy control subjects. The genotype distribution of patients with PE (TT = 49%, TA = 36%, AA = 15%), but not DVT (TT = 50%, TA = 42%, AA = 8%), differed significantly from healthy control subjects (TT = 60%, TA = 34%, AA = 6%, P =.02). A significant interaction of Thr312Ala and Val34Leu was also identified (P =.01), indicating an inverse association between Leu34 and Ala312. These results support the hypothesis that Thr312Ala alters FXIII-dependent cross-linking, making formed fibrin clot more susceptible to embolization.     

Thrombelastography does not predict clinical response to rtPA for acute ischemic stroke

Thrombelastography (TEG) measures coagulation in venous blood. We hypothesized that TEG, by reflecting clot subtype and ex vivo fibrinolysis, might predict fibrinolytic response to tPA as reflected by rapid clinical improvement or hemorrhagic transformation of the infarct. 171 acute ischemic stroke patients treated with tPA were prospectively enrolled. Venous blood for TEG was drawn before and 10 min after tPA bolus. We measured rapid clinical improvement (RCI = 8 point improvement on NIHSS or total NIHSS of 0, 1 at 36 h), Hemorrhagic transformation (HT = any blood on imaging within 36 h), and hyperdense middle cerebral artery sign (HDMCA = biomarker for erythrocyte-rich clot). Multivariable regression models compared TEG parameters after adjusting for potential confounders. No differences in pre- or post-tPA TEG were found between patients with or without RCI. Also, there was no correlation between TEG and HDMCA. Clotting was slightly prolonged in patients with HT (p = 0.046). We failed to find a robust association between TEG and clinical response to tPA. It is likely that arterial clot lysis is determined by factors unrelated to coagulation status as measured by TEG in the venous circulation. It is unlikely that TEG will be useful to predict clinical response to tPA, but may help predict bleeding.     

The factor XIII Val34Leu polymorphism: is it protective against idiopathic venous thromboembolism?

The substitution of leucine for valine at amino acid position 34 of the factor XIII gene is commonly referred to as FXIII Val34Leu polymorphism. The homozygous leucine/leucine genotype has been reported to confer protection against venous thromboembolism, but previous studies have not evaluated a population limited to those with idiopathic venous thromboembolism. The primary objective of the study was to determine whether the FXIII Val34Leu polymorphism is independently associated with the occurrence of idiopathic venous thromboembolism. We prospectively enrolled consecutive patients with at least one objectively confirmed idiopathic venous thromboembolism. Friends of cases were recruited as controls and matched to cases by sex, ethnicity, and age. All participants were tested for the FXIII Val34Leu polymorphism in addition to several well-known thrombophilias. Data from 309 cases and 306 controls were analyzed. The FXIII leucine/leucine genotype was present in 4.9% of cases and 6.5% of controls. An adjusted odds ratio of 0.59 (95% confidence interval, 0.25-1.38) was found for the recessive model and 0.69 (95% confidence interval, 0.46-1.02) for the dominant model. Our results do not support an independent association of the FXIII Val34Leu polymorphism with idiopathic venous thromboembolism in our Caucasian Canadian study population.     

Association of CYP1B1 Leu432Val Polymorphism and Lung Cancer Risk: An Updated Meta-Analysis

Background

Cytochrome P4501B1 (CYP1B1) a phase I enzyme, is involved in the activation of a broad spectrum of procarcinogens. Impacts on the catalytic activity of the CYP1B1 enzyme, as well as an association of the Leu432Val polymorphism with the risk of lung cancer, have been described; however, the results remain controversial.

Methods

We conducted a meta-analysis of all available studies to clarify the effects of the Leu432Val polymorphism on lung cancer risks basing on 2,543 lung cancer cases and 3,304 controls from ten separate comparisons. We also performed subgroup analyses by ethnicity (categorized as Caucasian, Asian and African-American), gender, smoking status ,and histological type. A pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated to estimate the strength of the association.

Results

A significantly increased risk was found in our meta-analysis in the overall population (Val/Val vs. Leu/Leu: OR = 1.371, 95 % CI 1.137–1.652, P = 0.001). In subgroup analysis, significant associations with lung cancer susceptibility were also found in Caucasians (Val/Val vs. Leu/Leu: OR = 1.312, 95 % CI 1.075–1.602, P = 0.008), females (Val/Val vs. Leu/Leu: OR = 1.472, 95 % CI 1.097–1.976, P = 0.010), and smokers (dominant model Leu/Val + Val/Val vs. Leu/Leu: OR = 1.257, 95 % CI 1.016–1.554, P = 0.035). Null results were noted in the subgroup analysis by histological type under different genetic models.

Conclusions

Our results suggest that the CYP1B1 Leu432Val polymorphism acts as a risk factor for the carcinogenesis of lung cancer.     

Factor XIII Val34Leu and the risk of venous thromboembolism in factor V Leiden carriers

A mutation in factor XIII (Val34Leu) was reported to protect against venous thromboembolism. We evaluated the effect of Val34Leu on thrombotic risk in 352 factor V Leiden carriers who were first-degree relatives of 132 thrombotic propositi carrying factor V Leiden. The total observation period was 2,594 years in 92 Val34Leu carriers and 7,444 years in 260 non-carriers. The annual incidence of a first episode of venous thromboembolism was 0.31% in Val34Leu carriers and 0.44% in non-carriers [relative risk (RR) for venous thromboembolism: 0.7, 95% CI 0.3-1.5]. Age-specific RR for venous thromboembolism were (for Val34Leu carriers and non-carriers respectively): 1.0 (95% CI 0.3-3.2) in the age group of 15-30 years, 0.4 (95%, CI 0.05-3.0) in the age group of 30-45 years, 0.6 (95% CI 0.1-2.9) in the group aged 45-60 years and 0.5 (95% CI 0.06-4.5) in relatives older than 60 years. In conclusion, the impact of FXIII Val34Leu on the venous thromboembolic risk is modest, suggesting that screening for this mutation in factor V Leiden carriers is not justified.     

A common F13A1 intron 1 variant IVS1+12(A) is associated with mild FXIII deficiency in Caucasian population

Mild factor XIII deficiency is an underdiagnosed coagulation disorder. Considering the large number of coding and non-coding polymorphisms identified in the F13A1 gene, there is a possibility that some of these might result in alterations of plasma FXIII levels and cause mild FXIII deficiency. Recently, a homozygous F13A1 gene intron 1 variant (IVS1+12C>A) was found in a patient with FXIII deficiency. In vitro expression studies for this variant demonstrated its lowering effect on FXIII levels. In order to determine the impact of this variant on a population level, we analysed the prevalence of this variant in three clinically and genetically defined population cohorts: an apparently healthy control cohort C1 (n?=?102), a mild FXIII deficiency cohort C2 with no detectable F13A1 or F13B gene mutations (n?=?183) and a mild FXIII-A deficiency cohort C3 exhibiting heterozygous F13A1 mutations (n?=?37). FXIII activity was determined using photometric assay on plasma samples. The F13A1 gene intron 1 variant was analysed by direct sequencing. The C1 cohort showed a normal distribution of FXIII activity (mean 114.1?±?20.86 %). Mean FXIII activity levels for the C2 and C3 cohorts were 54.45?±?11.12 % and 44.21?±?10.16 %, respectively. The frequencies of minor allele (A) were 0.07 in C1 cohort, 0.19 in C2 cohort and 0.11 in C3 cohort. The difference in minor allele frequencies for the C1 and C2 cohorts were highly significant (p?<?0.001). The greater frequency of the IVS1+12(A) variant among C2 cohort patients suggests that this polymorphism is associated with mild FXIII deficiency.     

Lack of association between clopidogrel responsiveness tested using point-of-care assay and prognosis of patients with coronary artery disease

Dual antiplatelet therapy is important treatment modality across the spectrum of coronary artery disease manifestations. However, a significant number of patients do not have a completely effective response to clopidogrel. This study assessed the impact of response after clopidogrel with Verify Now device on prognosis on patients undergoing coronary interventions. Consecutive patients following percutaneous coronary intervention were prospectively enrolled. A loading dose of 600 mg of clopidogrel was administered before or during PCI. Blood samples were drawn within 24 h after clopidogrel administration. The effect of clopidogrel was measured using VerifyNow. All patients were evaluated at 6 months. The primary end-point was the combination of death, MI and stroke. 378 patients (69.3 % men and 30.7 % women) were enrolled. The mean age was 67.2 ± 12.8 years, BMI 28.9 ± 17.7, and 116 patients had diabetes (30.7 %). During the 6-months follow-up 30 patients (7.94 %) experienced a monitored end-point: 12 patients (3.17 %) had MI; five patients (1.32 %) strokes and 15 patients (3.97 %) died. The remaining 248 patients (71.26 %) were end-point free. Factors associated with a poor prognosis were: leukocytes (OR 1.7 [1.2–2.4], p < 0.01), creatinine (OR 1.4 [1.1–2.5], p < 0.05) and at a borderline level the presence of AA allele of gene CYP2C19*2 (OR 2.5 [0.99–4.1], p = 0.052). The results using VerifyNow were similar between both groups (Group End-point: 208.5 ± 85.5, group No end-point 203.1 ± 91.3) and failed to show any prognostic value (OR 1.00 [0.992–1.007], p = 0.9). The measurement of clopidogrel efficacy using VerifyNow had no prognostic value for our unselected cohort of patients after PCI.     

Hyperhomocysteinemia in patients with pulmonary embolism is associated with impaired plasma fibrinolytic capacity

Hyperhomocysteinemia (HHcy) affects haemostasis and shifts its balance in favour of thrombosis. In vitro and in vivo studies suggested that HHcy may impair fibrinolysis either by influencing the plasma levels of fibrinolytic factors or by altering the fibrinogen structure. We investigated the influence of mild HHcy levels on plasma fibrinolytic potential by using clot lysis time (CLT) and fibrin susceptibility to plasmin-induced lysis in 94 patients with previous pulmonary embolism and no pulmonary hypertension. CLT was measured as lysis time of tissue factor induced clots exposed to exogenous tissue plasminogen activator (t-PA). The rate of in vitro plasmin-mediated cleavage of fibrin β-chain was assessed over a 6-h period on fibrin clots, which were obtained by exposition to thrombin of purified fibrinogen. Homocysteine plasma levels were measured by Abbott Imx immunoassay and we considered as altered the values above 15 μmol/L according to the literature. In 68 patients homocysteine levels were below 15 μmol/L (NHcy) and in 26 they were above (HHcy). Significant differences were observed between the two groups regarding plasma fibrinolytic potential (p = 0.016), TAFIact (expressed as clot lysis ratio) (p = 0.02), t-PA (0.008) and PLG (0.037), but not for the other assessed components. The HHcy-patients had a threefold higher risk to have an impaired fibrinolysis. Instead, a multivariate logistic regression analysis adjusted for significances of univariate showed that HHcy (OR 5.2 95 % CI 1.7–15.9; p = 0.003) and BMI (OR 5.0 95 % CI 1.6–15.9; p = 0.006) resulted independently associated with impaired fibrinolytic activity. HHcy affects TAFI-mediated hypofibrinolysis but not fibrin(ogen) structure or function as documented by fibrin degradation analysis.     

Increased coagulation factor XIII activity but not genetic variants of coagulation factors is associated with myocardial infarction in young patients

Journal of Thrombosis and Thrombolysis - The aim of the study was to investigate the possible role of coagulation factor XIII (FXIII) plasma activity and its gene (F13A1) Val34Leu variant as well...