scholarly journals Homozygous Cystathionine β-Synthase Deficiency, Combined With Factor V Leiden or Thermolabile Methylenetetrahydrofolate Reductase in the Risk of Venous Thrombosis

Blood ◽  
1998 ◽  
Vol 91 (6) ◽  
pp. 2015-2018 ◽  
Author(s):  
Leo A.J. Kluijtmans ◽  
Godfried H.J. Boers ◽  
Bert Verbruggen ◽  
Frans J.M. Trijbels ◽  
Irena R.O. Nováková ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Methylenetetrahydrofolate Reductase ◽  
Significant Risk ◽  
Factor V Leiden ◽  
Major Complication ◽  
Significant Risk Factor ◽  
Mthfr Gene ◽  
Factor V ◽  
Thromboembolic Complications ◽  
Thrombotic Complications

Abstract Severe hyperhomocysteinemia in its most frequent form, is caused by a homozygous enzymatic deficiency of cystathionine β-synthase (CBS). A major complication in CBS deficiency is deep venous thrombosis or pulmonary embolism. A recent report by Mandel et al (N Engl J Med 334:763, 1996) postulated factor V Leiden (FVL) to be an absolute prerequisite for the development of thromboembolism in patients with severe hyperhomocysteinemia. We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C→T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis. Thrombotic complications were diagnosed in six patients, of whom only one was a carrier of FVL. On the contrary, thermolabile MTHFR caused by the 677C→T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR. These data indicate that FVL is not an absolute prerequisite and probably not even a major determinant of venous thrombosis in homocystinuria, but, interestingly, thermolabile MTHFR may constitute a significant risk factor for thromboembolic complications in this inborn error of methionine metabolism.

scholarly journals Homozygous Cystathionine β-Synthase Deficiency, Combined With Factor V Leiden or Thermolabile Methylenetetrahydrofolate Reductase in the Risk of Venous Thrombosis

Blood ◽  
1998 ◽  
Vol 91 (6) ◽  
pp. 2015-2018
Author(s):  
Leo A.J. Kluijtmans ◽  
Godfried H.J. Boers ◽  
Bert Verbruggen ◽  
Frans J.M. Trijbels ◽  
Irena R.O. Nováková ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Methylenetetrahydrofolate Reductase ◽  
Significant Risk ◽  
Factor V Leiden ◽  
Major Complication ◽  
Significant Risk Factor ◽  
Mthfr Gene ◽  
Factor V ◽  
Thromboembolic Complications ◽  
Thrombotic Complications

Severe hyperhomocysteinemia in its most frequent form, is caused by a homozygous enzymatic deficiency of cystathionine β-synthase (CBS). A major complication in CBS deficiency is deep venous thrombosis or pulmonary embolism. A recent report by Mandel et al (N Engl J Med 334:763, 1996) postulated factor V Leiden (FVL) to be an absolute prerequisite for the development of thromboembolism in patients with severe hyperhomocysteinemia. We studied 24 patients with homocystinuria caused by homozygous CBS deficiency from 18 unrelated kindreds for FVL and for the 677C→T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and investigated their possible interaction in the risk of venous thrombosis. Thrombotic complications were diagnosed in six patients, of whom only one was a carrier of FVL. On the contrary, thermolabile MTHFR caused by the 677C→T mutation, was frequently observed among homocystinuria patients, especially among those with thromboembolic complications: three of six homocystinuria patients who had suffered from a thromboembolic event had thermolabile MTHFR. These data indicate that FVL is not an absolute prerequisite and probably not even a major determinant of venous thrombosis in homocystinuria, but, interestingly, thermolabile MTHFR may constitute a significant risk factor for thromboembolic complications in this inborn error of methionine metabolism.

A Case Control Study of Deep Venous Thrombosis in Relation to Factor V G1691A (Leiden) and A4070G (HR2 Haplotype) Polymorphisms.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4095-4095
Author(s):  
Wassim Y. Almawi ◽  
Lobna Borgi-Bouaziz ◽  
Hezard Nathalie ◽  
Nguyen Philipe ◽  
Mahjoub Touhami
Keyword(s):  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Activated Protein C ◽  
Significant Risk ◽  
Gene Mutations ◽  
Factor V Leiden ◽  
Significant Risk Factor ◽  
Factor V ◽  
Haplotype Allele ◽  
Fv Leiden

Abstract Activated protein C resistance (APCR) is a significant risk factor for venous thromboembolism (VTE), and the factor V (FV) gene mutations G1691A (FV-Leiden) account for the majority of inherited APCR cases. An additional FV gene mutation, the A4074G (FV-HR2), was recently reported to induce a risk of VTE by some but not all groups. The aim of this study was to determine the prevalence of single and combined SNPs in 126 patients with documented deep venous thrombosis (DVT), and 197 control Tunisian subjects. The frequencies of FV-Leiden A allele (p <0.001; OR = 5.031), and HR2 G allele (p = 0.014; OR = 2.463) were significantly higher among DVT patients. Genotype differences were found between FV-Leiden G/A (p <0.001; OR = 3.936) and A/A (p = 0.013; OR = 11.529), but not HR2 A/G genotypes (p = 0.862; OR = 1.166), between patients and controls. While no linkage disequilibrium was noted between the FV 1691A and 4070G or A alleles, higher prevalence of the 1691G/4070G (p = 0.002; OR = 5.189) and the 1691A/4070A (p = 0.007; OR = 3.670) were noted among DVT patients than in control subjects. Collectively, this indicates that FV-Leiden, and to a lower extent HR2 haplotype, are important independent risk factors for DVT, and that their coinheritance does not increase significantly the DVT risk imparted by either. Factor V-Leiden and HR2 Haplotype Allele and Genotype Analysis Cases Controls P OR Factor V-Leiden G 0.8492 0.9670 0.004 0.087 A 0.1508 0.0609 <0.001 5.031 G/G 0.754 0.939 <0.001 0.199 G/A 0.190 0.056 <0.001 3.936 A/A 0.056 0.005 0.013 11.529 HR2 Haplotype A 0.8913 0.9492 1.000 0.352 G 0.1087 0.0508 0.014 2.463 A/A 0.855 0.873 0.862 0.858 A/G 0.145 0.127 0.862 1.166 G/G 0.000 0.000

The Methylenetetrahydrofolate Reductase TT677 Genotype Is Associated with Venous Thrombosis Independently of the Coexistence of the FV Leiden and the Prothrombin

1998 ◽  
Vol 79 (05) ◽  
pp. 907-911 ◽  
Author(s):  
Maurizio Margaglione ◽  
Giovanna D’Andrea ◽  
Marina d’Addedda ◽  
Nicola Giuliani ◽  
Giuseppe Cappucci ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Methylenetetrahydrofolate Reductase ◽  
Factor V Leiden ◽  
Mthfr Gene ◽  
Factor V ◽  
Mthfr Genotype ◽  
Estimated Risk ◽  
Fv Leiden ◽  
Mild Hyperhomocysteinemia

SummaryA polymorphism, C→T677, in the methylenetetrahydrofolate reductase (MTHFR) gene has been identified as a cause of mild hyperhomocysteinemia, a risk factor for venous thrombosis. We have investigated the frequency of the TT genotype in 277 consecutive patients with confirmed deep venous thrombosis and 431 healthy subjects. The TT MTHFR genotype was more frequent in patients than in controls (25.6% vs. 18.1%; p = 0.016). The risk of thrombosis among carriers of this genotype was significantly increased [odds ratio: 1.6 (95% CI: 1.1-2.3)]. The estimated risk associated with the TT genotype was 2.0 (95% CI: 1.3-3.1) in subjects with (n = 122), and 1.3 (95% CI: 0.8-2.0) in those without (n = 155) predisposing (hereditary, acquired or circumstantial) risk factors for venous thrombosis. Factor V Leiden and prothrombin G→A20210 are known risk factors for venous thrombosis. After stratification for FV Leiden and prothrombin A20210 mutations, a significant association was also observed. After adjustment for sex, FV Leiden and prothrombin A20210 mutation, the estimated risk of venous thrombosis among carriers of the TT MTHFR genotype was 1.7 (95% CI: 1.2-2.6). The TT MTHFR genotype is independently associated with venous thrombosis, mainly among individuals with a high risk profile.

Factor V Leiden and Thrombotic Complications in Heparin-induced Thrombocytopenia

1998 ◽  
Vol 79 (01) ◽  
pp. 50-53 ◽  
Author(s):  
David Lee ◽  
Gregory Denomme ◽  
Danny Lagrotteria ◽  
John Kelton ◽  
Theodore Warkentin
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Factor V Leiden ◽  
Additional Risk Factor ◽  
Factor V ◽  
Skin Reactions ◽  
Local Skin ◽  
Additional Risk ◽  
Heparin Induced Thrombocytopenia ◽  
Thrombotic Complications

SummaryTo determine whether factor V Leiden is associated with thrombotic events in patients with heparin-induced thrombocytopenia (HIT), we evaluated 165 patients with serologically confirmed HIT for the presence of factor V Leiden and determined the incidence of venous or arterial thrombosis during the period of HIT. Factor V Leiden was detected in 16 of 165 HIT patients (9.7%). HIT-associated venous thrombosis occurred in 11 of 16 factor V Leiden positive subjects and 94 of 149 factor V Leiden negative subjects (69% vs. 63%; p = 0.79). Arterial thrombosis occurred in 1 of 16 factor V Leiden positive subjects and 21 of 149 factor V Leiden negative subjects (6% vs. 14%; p = 0.70). There was no difference in the incidence of proximal limb DVT, pulmonary embolism, venous limb gangrene, local skin reactions, hemorrhagic adrenal infarction, stroke, or myocardial infarction between the groups. No difference in the severity of venous thrombosis between Leiden positive and negative subjects was detected. Our data suggest that in the acute prothrombotic milieu of HIT, heterozygous factor V Leiden is not an important additional risk factor for thrombosis.

Evaluation Of Factor V Leiden, Prothrombin Mutations and The Homozygous mutation 677T In The MTHFR Gene In Patients With  Venous Thrombosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4798-4798
Author(s):  
Michele Pizzuti ◽  
Alberto Santagostino ◽  
Maria Antonietta Rizzo ◽  
Daniela Dragonetti ◽  
Maria Grazia Pietrafesa ◽  
...  
Keyword(s):  
At Risk ◽  
Venous Thrombosis ◽  
Pulmonary Thromboembolism ◽  
Factor V Leiden ◽  
Mthfr Gene ◽  
Homozygous Mutation ◽  
Factor V ◽  
Homozygous State ◽  
The Impact ◽  
Fvl Mutation

Over the last few years there has been increased interest in laboratory tests for thrombophilia. Testing is predominantly performed to identify asymptomatic individuals at risk for a first thrombosis or patients (pts) at risk of relapse. The results are not always concordant, and the impact on clinical practice is not yet defined, especially for heterozygous forms. We evaluated heterozygous and homozygous Factor V Leiden (FVL) and prothrombin (FII) mutations and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in 98 pts with venous thrombosis distinguishing idiopathic forms from forms that are secondary to malignancy, surgery, forced immobilization or hormone treatments. FII mutation was present in 17% of idiopathic and 5.8% of secondary forms. FVL mutation was present in respectively 17% and 15.8% and MTHFR homozygous state in 31.9% and 21.5%. At least one of FII or FVL mutations was present respectively in 31.9% and 19%, at least one of the three mutations examined was present in 57.4% and 36.2%. In pts with limb venous thrombosis (n-64), the percentages for each mutation are respectively: FII-23.5% and 6.6%, FVL-20.5% and 6.6%, MTHFR 35.2% and 16.6% .At least one mutation between FII and FVL is present respectively in 42.1% and 13.3% (P = 0,028) while at least one of the three mutations is present in 61.7% and 30.5% (P = 0,022) In our pts with pulmonary thromboembolism (n-36) FII mutation was absent while FVL mutation was present in 7.6% of idiopathic and 21.7% of the secondary thrombosis, MTHFR in 30.7% and in 30.4%. At least one of the three examined mutations was present in 38.4% and 47.8%. The mutations we have studied are generally more frequent in idiopathic forms. The difference reaches statistical significance in limb venous thrombosis where they seem to have a significant relevance, although in a heterozygous state, and to promote thrombosis even in absence of other causes. In pulmonary thromboembolism (PTE) pts FII mutation was absent, FVL mutation is less frequent in pts with idiopathic thrombosis and MTHFR homozygous state is equivalent between the two subgroups. Thus, they seem to not influence PTE pathogenesis that would be likely sought in different causes. Disclosures: No relevant conflicts of interest to declare.

The Influence of Hemostasis Genetic Features on Thrombosis Rates in Patients with Polycythemia Vera

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5180-5180
Author(s):  
Dzhariyat Shikhbabaeva ◽  
Vasily Shuvaev ◽  
Sergey Kapustin ◽  
Irina Martynkevich ◽  
Vera Udaleva ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Methylenetetrahydrofolate Reductase ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Hereditary Thrombophilia ◽  
Fibrinogen Receptor ◽  
Thrombotic Complications ◽  
Prothrombin Gene ◽  
Pai 1

Abstract Background. Thrombotic complications are the main cause of disability and mortality in Polycythemia Vera (PV) patients. Thrombosis in PV is a result of both inherited (genetic) and acquired predisposition under the external factors influence. Effective personalized prophylactic antithrombotic therapy is a key factor to save quantity and quality of life in PV patients. Objective. The objective of study was to assess the prevalence of hereditary thrombophilia genetic markers in PV patients in overall and groups with or without thrombotic complications. Materials and methods. 104 PV patients (60 females, 44 males, median age 58 years, range 31-82) were researched. Blood probes were examined by PCR for the presence of nucleotide polymorphisms in the following genes: FV (Leiden mutation), FII (prothrombin), methylenetetrahydrofolate reductase (MTHFR), fibrinogen (FI), plasminogen activator inhibitor (PAI-1), and platelet fibrinogen receptor type IIIA (GPIIIA). We studed the overall hereditary thrombophilia markers rate and the statistical significance between PV patients groups with (Thr+) or without thrombosis (Thr+). We used the next statistical methods: descriptive statistics, the significances of differences by gender and genes frequencies in the groups were evaluates with Fisher exact test, differences in age at the time of diagnosis were assessed with Mann-Whitney U test. Results. Thrombotic complications occurred in 20 (19.2%) of patients (16 arterial and 5 venous thrombotic episodes, 1 patient had both arterial and venous thrombotic episodes). Myocardial infarction was found in 7 (6.7%), cerebrovascular accident in 9 (8.7%) patients. The general PV population thrombophilia markers frequencies were: heterozygous (G/A) Leiden mutation in 4 (3,8%) patients; heterozygous mutation in prothrombin gene (G20210-A) in 4 (3,8%) patients; homozygous (T/T) mutation in MTHFR in 8 (7,7%) patients, heterozygous (C/T) mutation in 43 (41,3%) patients; homozygous (A/A) mutation in FI gene in 4 (3,8%) patients, heterozygous (G/A) mutation in FI gene in 43 (41,3%) patients; combination of mutations in FI and MTHFR was registered in 23 (22,1%) patients; homozygous (4G/4G) mutation in PAI-1 gene was revealed in 35 (33,7%) patients, heterozygous (4G/5G) mutation in 49 (47,1%) patients; mutation frequencies in GPIIIA gene were as follows: homozygous (A2/A2) in 5 (4,8%) patients, heterozygous (A1/A2) in 26 (25%) patients. The markers of hereditary thrombophilia was not identified only in one patient (1%).Characteristics and difference significances in the frequency of detection of thrombophilia genes between groups of patients with thrombosis (Thr+) and without their presence in history (Thr-) are shown in table 1. Table 1. Characteristics of PV patients with (Thr+) or without (Thr-) thrombotic complications. Thr+ (n=20) Thr- (n=84) p Age, median (range) 63 (36-73) 58 (32-82) 0.75 Gender, male/female 9/11 35/49 0.81 Factor V Leiden mutation, GA/GG 2/18 2/82 0.17 Prothrombin gene (G20210A) mutation, GA/GG 1/19 3/81 0.58 MTHFR mutation, (TT+CT)/CC 14/6 37/47 0.05 FI mutation, (AA+GA)/GG 6/14 41/43 0.14 PAI-1 mutation, (4G/4G+4G/5G)/(5G/5G) 17/3 67/17 0.76 GPIIIA mutation, (A2A2+A1A2)/A1A1 1/19 30/54 0.01 Conclusions. Various hereditary thrombophilia gene mutations were present in almost all PV patients. PV patients with and without thrombotic complications were significantly (p≤0.05) differed in frequencies of mutations in methylenetetrahydrofolate reductase gene (MTHR) and platelet fibrinogen receptor type IIIA (GPIIIA). We also observed statistical trends (p≤0.30) in differences of mutations frequencies in fibrinogen (FI) gene and Factor V Leiden mutation, for the confirmation of which the further research is required. Disclosures No relevant conflicts of interest to declare.

Factor V Leiden and Thermolabile Methylenetetrahydrofolate Reductase in Extreme Old Age

1997 ◽  
Vol 78 (05) ◽  
pp. 1357-1359 ◽  
Author(s):  
D C Rees ◽  
Y T Liu ◽  
M J Cox ◽  
P Elliott ◽  
J S Wainscoat
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Factor V Leiden ◽  
Premature Death ◽  
Mthfr Gene ◽  
Factor V ◽  
C677t Mthfr ◽  
C677t Mutation ◽  
Hardy Weinberg Equilibrium ◽  
Mthfr Mutation ◽  
The Uk

SummaryBoth factor V Leiden and the C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation are associated with premature vascular disease, and yet are found at surprisingly high allele frequencies in European populations, 2.7% and 35% respectively. We have investigated the prevalence of these mutations in 87 UK residents over the age of ninety, to look for any evidence of their association with premature death.Five factor V Leiden heterozygotes were found, giving an allele frequency of 2.9%, similar to that in the general UK population. The frequency of the thermolabile C677T MTHFR mutation was 36% with 11% homozygotes, again similar to that in the UK population; these genotypes are in Hardy-Weinberg equilibrium, suggesting that there is not strong selection against the homozygous state. One person was both heterozygous for factor V Leiden and homozygous for the C677T mutation. This study suggests that neither factor V Leiden nor thermolabile MTHFR are risk factors for premature death.

Comparison of three activated protein C resistance tests in the risk assessment of venous thrombosis in non-carriers of the factor V Leiden mutation

2006 ◽  
Vol 95 (04) ◽  
pp. 728-734 ◽  
Author(s):  
Felipe Guerrero ◽  
Catherine Arnaud ◽  
Francoise Nguyen ◽  
Bernard Boneu ◽  
Pierre Sié
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Significant Risk ◽  
Factor V Leiden ◽  
Factor V ◽  
Activated Protein C Resistance ◽  
Factor V Leiden Mutation ◽  
Risk Increase ◽  
Increased Risk

SummaryActivated protein C resistance (APCR), measured using the original assay described by Dahlbäck, is a risk factor for venous thrombosis independent of the factor V Leiden (FVL) mutation. This assay is based on the activated partial thromboplastin time (APTT) after plasma exposure to activated protein C (APC).As this assay was sensitive to numerous interferences, new assays have been developed for FVL screening. The objectives of the study were to investigate the association of second generation assays for APCR with venous thrombosis in FVL non-carriers. One hundred ninety-seven subjects with a history of venous thrombosis and 211 controls were explored using 3 APCR assays, the original APTT-based assay (test A), an APTT-based assay with factorV depleted plasma pre-dilution (test B) and a direct factorX activation-based assay with the same pre-dilution (test C).We found that subjects with results in the lowest quartile of the APTT-based assays are at increased risk, compared to those in the highest quartile (test A Odds Ratio = 6.39; 95%CI 3.23–12.63; test B OR=2.72; 95%CI 1.50–4.94). There was no significant risk increase associated with test C results. After adjusting for FVIII levels, the ORs of tests A and B were similar (test A OR=3.22; 95%CI 1.47–7.08; test B OR=3.10; 95%CI 1.54–6.21). In conclusion, APTT-based assays, but not direct factor X activation-based assays, effectively detect the risk for venous thrombosis independent of FVL. Pre-dilution in factor V depleted plasma is an effective way to directly assess the risk independent of FVIII levels.

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