The HR2 Haplotype of Factor V Is not Associated with the Risk of Myocardial Infarction

SummaryThe HR2 haplotype of the factor V gene, which contains the histidine to arginine substitution at position 1299, has been reported to be associated with reduced factor V levels. Because high factor V levels have been found to be associated with an increased risk of myocardial infarction, we examined how the presence of the R2 allele affected the risk of myocardial infarction in the case-control “Study of Myocardial Infarctions Leiden”.Among 560 men with a first myocardial infarction before the age of 70 years, 9.5% were heterozygous carriers of the R2 allele. The control group consisted of 646 men, in which 9.9% were heterozygous and 0.2% homozygous carriers of the R2 allele. The risk of myocardial infarction in the presence of the R2 allele was not increased (odds ratio, 0.9; 95% confidence interval 0.6 to 1.4). Exclusion of factor V Leiden carriers did not change this result. The risk was 4.4-fold increased for smokers who carried the R2 allele compared to non-smoking noncarriers. No synergy was found between metabolic risk factors and the presence of the R2 allele.We conclude that the risk of myocardial infarction for men in the presence of the R2 allele of the His1299Arg polymorphism is neither increased nor decreased.

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FV Leiden Mutation and Deep Venous Thrombosis in Vojvodina: A Case-Control Study

Journal of Medical Biochemistry ◽

10.2478/v10011-010-0050-7 ◽

2011 ◽

Vol 30 (1) ◽

pp. 51-54

Author(s):

Iva Salatić ◽

Katarina Kiralj ◽

Gorana Mitić ◽

Igor Veselinović ◽

Dušan Vapa

Keyword(s):

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Case Control Study ◽

Factor V Leiden ◽

Case Control ◽

Factor V ◽

Increased Risk ◽

Fv Leiden ◽

Heterozygous Carriers ◽

Control Study

FV Leiden Mutation and Deep Venous Thrombosis in Vojvodina: A Case-Control StudyBetween September 2007 and February 2010, the occurrence of symptomatic deep venous thrombosis (DVT) was investigated in a cohort of 79 consecutive patients. A case-control study inclu ded 71 healthy controls matched with cases for sex and age. The prevalence of factor V G1691A mutation genotype was analyzed. Eighteen cases (22.79%; 95% confidence interval (CI) 13.53% to 32.03%) and four controls (5.63%; 95% CI 0.27% to 10.99%) were heterozygous carriers of FV Leiden (p= 0.025). The odds ratio for DVT was 4.94 (95% CI 1.58 to 15.42) and the relative risk 4.04 (95% CI 1.44-11.38) compared with FV 1691G carriers. Four cases were homozygous carriers of FV Leiden, giving a prevalence of 5.06% (95% CI 0.23 to 9.89%) and no controls, therefore OR and RR calculation was based on the prevalence of homozygotes in the general Caucasian population. The OR for DVT was 47.28 (95% CI 0.04 - 52167.3) and the RR 45.57 (95% CI 0.04 to 49540.77; p=0.025) compared with FV 1691 G carriers. Our study confirms that factor V Leiden carriers in Vojvodina, as in similar studies previously carried out in other populations, have an increased risk of developing DVT. The evaluated risk of DVT in heterozygous carriers of the mutation is four- to five-fold higher, whereas for homozygous carriers it is 45- to 48-fold higher than in non-carriers. These results confirm that patients with DVT and their relatives should undergo screening for FV Leiden mutation.

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Prevalence of Factor V Leiden in Patients with Myocardial Infarction and Normal Coronary Angiography

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613927 ◽

2000 ◽

Vol 83 (06) ◽

pp. 822-825 ◽

Cited By ~ 55

Author(s):

Antoine Da Costa ◽

Stéphane Munier ◽

Bernard Mercier ◽

Brigitte Tardy ◽

Claude Ferec ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Coronary Angiography ◽

Coronary Artery Stenosis ◽

Factor V Leiden ◽

Artery Stenosis ◽

Factor V ◽

Significant Coronary Artery Stenosis ◽

Increased Risk ◽

Normal Coronary Angiography

SummaryFactor V Leiden is associated with an increased risk of venous thrombosis and myocardial infarction in young women, but not in men in this latter case. The aim of this study was to evaluate the prevalence of this mutation in patients with myocardial infarction but normal coronary angiography.We compared 3 groups of patients: one group consisted of 107 patients with premature myocardial infarction but no significant coronary artery stenosis; another group of 244 patients with myocardial infarction and significant coronary artery stenosis; a third group of 400 healthy controls.Factor V Leiden was found in 13 patients (12.1%) who had a myocardial infarction without significant coronary artery stenosis, 11 patients (4.5%) who had a myocardial infarction with significant coronary artery stenosis (p = 0.01) and in 20 controls (5%) (p = 0.01). Odds ratio associated with factor V Leiden were respectively 2.93 (CI95 : 1.18-7.31) and 2.63 (CI95 : 1.19-5.78) when we compared myocardial infarction patients without significant coronary artery stenosis to controls or to patients with significant coronary artery stenosis.In myocardial infarction patients without significant coronary artery stenosis, prevalence of factor V Leiden is significantly higher than in controls. This new finding supports the hypothesis that thrombosis plays a key role in this selected situation.

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Risk of Pregnancy-related Venous Thrombosis in Carriers of Severe Inherited Thrombophilia

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616134 ◽

2001 ◽

Vol 86 (09) ◽

pp. 800-803 ◽

Cited By ~ 64

Author(s):

Cristina Legnani ◽

Paolo Bucciarelli ◽

Elvira Grandone ◽

Valerio De Stefano ◽

Pier Mannuccio Mannucci ◽

...

Keyword(s):

Venous Thrombosis ◽

Gene Mutations ◽

Factor V Leiden ◽

Study Cohort ◽

Factor V ◽

Thrombotic Risk ◽

Increased Risk ◽

Prothrombin Gene ◽

Heterozygous Carriers ◽

Anticoagulant Prophylaxis

SummaryHomozygous carriers of factor V Leiden have an approximately 80-fold increased risk of venous thrombosis. Also double heterozygous carriers of both the factor V Leiden and the prothrombin gene mutations are at high thrombotic risk. The magnitude of the risk of venous thrombosis in pregnant women with the two severe thrombophilic conditions has not been estimated so far. We performed a multicenter retrospective family study in women with homozygous factor V Leiden, double heterozygous factor V Leiden and the prothrombin gene mutation, and women with normal coagulation. Only relatives of index patients with thrombosis formed the study cohort. Fifteen homozygous and 39 double heterozygous women were compared to 182 women with normal coagulation. Venous thrombosis occurred in 3 of 19, 2 of 50 and 1 of 221 pregnancies, respectively. One thrombotic episode occurred in the third trimester, the remaining 5 in the postpartum. The prevalence of venous thrombosis was 15.8% (95% CI 3.4-39.6) for homozygotes, 4.0% (95% CI 0.5-13.7) for double heterozygotes and 0.5% for women with normal coagulation. The relative risk of pregnancy-related venous thrombosis was 41.3 (95% CI 4.1-419.7) for homozygous and 9.2 (95% CI 0.8-103.2) for double heterozygous carriers. In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period. On the basis of these findings we recommend that these women receive anticoagulant prophylaxis at least in the postpartum, that should perhaps be extended to the whole pregnancy in homozygous carriers.

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Factor V Leiden Is Associated with Premature Myocardial Infarction.

Blood ◽

10.1182/blood.v112.11.1817.1817 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1817-1817

Author(s):

Flora Peyvandi ◽

Marta Spreafico ◽

Luisa Foco ◽

Luisa Bernardinelli ◽

Stefano Duga ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Meta Analysis ◽

Large Population ◽

Factor V Leiden ◽

Coagulation Factor ◽

Factor V ◽

Gain Of Function ◽

Increased Risk ◽

Meta Analyses

Abstract Plasma levels of haemostatic proteins involved in coagulation and fibrinolysis may represent an important intermediate phenotype for cardiovascular diseases (because increased levels of these proteins have been associated with an increased/reduced risk of thrombosis). However, investigation in arterial diseases of gain-of-function polymorphisms of genes encoding coagulation factor V (F5 G1691A) and prothrombin (F2 G20210A), established risk factors for venous thrombosis, have generally indicated weak or no associations in a number of conflicting and inconclusive reports [Ye et al., Lancet2006;367:651–8]. These negative results might be due to the sample size, too small to reliably assess relatively small genetic effects. Recently, a meta-analysis of 4,944 patients and 7,090 controls on the association of the F2 G20210A and ischemic heart disease [Burzotta et al, Heart2004;90:82–6], and a meta-analysis of 66,155 cases and 91,307 controls on the association of haemostatic genetic variants and coronary artery disease (CAD) [Ye et al, Lancet2006;367:651–8], found that either F2 G20210A and F5 G1691A polymorphisms were associated with a moderately increased risk of CAD. Results from these meta-analyses, large but based respectively upon 19 and 100 different studies all of rather small size, should be taken cautiously. Considering that genetic factors play a particularly important role in CAD occurring in the young, with usually less coronary atherosclerosis and a high prevalence of normal or near-normal coronary angiograms, we chose to replicate the meta-analysis results by investigating an adequately large population of 1,864 Italian patients who developed myocardial infarction (MI) before the age of 45 yrs (1,655 men and 209 women) and 1,864 age- and sex-matched controls. Genotyping was performed by Sequenom MassARRAY platform. Statistical analysis was performed fitting a conditional logistic model with STATA 9.2 software. Our results showed that the minor A allele of F5 G1691A (2.6% frequency in cases and 1.7% in controls) was associated with a moderately increased risk of MI (OR:1.59; 95% CI:1.14–2.20; P=0.006). The association remained statistically significant after adjustment for traditional risk factors, including diabetes, smoking, hypertension, and hypercholesterolemia (OR:1.81; 95% CI:1.14–2.87; P=0.012). The minor A allele of F2 G20210A (2.4% frequency in cases and 1.9% in controls) was not associated with the risk of MI (OR:1.27; 95% CI:0.93–1.74; P=0.133), even after adjustment (OR:1.19; 95% CI:0.77–1.85; P=0.429). In conclusion, results of the previous meta-analyses are replicated only partially in this cohort of young MI patients, the largest investigated so far, as only the gain-of-function variant F5 G1691A (but not F2 G20210A) was associated with an increased risk of MI. Our results suggest that anticoagulant drugs might be considered for secondary prophylaxis of MI in patients with the F5 gene variant, who carry a procoagulant phenotype.

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Association of factor V gene polymorphisms (Leiden; Cambridge; Hong Kong and HR2 haplotype) with recurrent idiopathic pregnancy loss in Tunisia

Thrombosis and Haemostasis ◽

10.1160/th05-07-0525 ◽

2006 ◽

Vol 95 (04) ◽

pp. 612-617 ◽

Cited By ~ 18

Author(s):

Walid Zammiti ◽

Nabil Mtiraoui ◽

Eric Mercier ◽

Nesrine Abboud ◽

Sarra Saidi ◽

...

Keyword(s):

Hong Kong ◽

Pregnancy Loss ◽

Fetal Loss ◽

Factor V Leiden ◽

Factor V ◽

Inherited Thrombophilia ◽

Factor V Gene ◽

Fv Leiden ◽

Clinical Risks ◽

Control Study

SummaryInherited thrombophilia has been shown to be linked with fetal loss. We performed a case-control study on the association between thrombosis-related polymorphisms in the factor V (FV) gene (Leiden, Cambridge, Hong Kong; HR2 haplotype) and idiopathic recurrent pregnancy loss (RPL) in Tunisian women. A total of 348 women with RPL, and 203 control women were studied, corresponding to 1,250 pregnancy losses and 1,200 successful pregnancies. FV Leiden was seen in 19.4% of patients (4.3% in the homozygous state) and in 5.5% of controls. The prevalence of the FV HR2 haplotype was similar in patients and controls, but with 7 homozygous patients for 1 control. FV Cambridge and Hong Kong were absent from both patients and controls. The study of all pregnancy losses evidenced that the frequency of the factor V Leiden polymorphism was zero in women who had miscarried before7 weeks of gestation, and then sharply increased to a plateau. After categorization of pregnancy losses (before8 weeks of gestation; weeks 8 and 9; weeks 10 to 12; from the 13th week of gestation onwards), heterozygous and homozygous factor V Leiden polymorphisms, and homozygous FV HR2 haplotype, were associated with significant and independent risks of pregnancy loss during weeks 8 and 9, which increased during weeks 10 to 12, then culminated after week 12. In Tunisian women with idiopathic RPL, factor V Leiden polymorphism and homozygous FV HR2 haplotype are not a risk factor for very early pregnancy loss, before 8 weeks of gestation, but are thereafter associated with significant clinical risks, which gradually increase from the 8th week onwards.

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Review of Management and Outcomes in Women with Thrombophilia Risk during Pregnancy at a Single Institution

ISRN Obstetrics and Gynecology ◽

10.1155/2014/381826 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Alhossain A. Khalafallah ◽

Abdul-Rauf O. Ibraheem ◽

Qiong Yue Teo ◽

Abdul-Majeed AlBarzan ◽

Ramanathan Parameswaran ◽

...

Keyword(s):

Pregnant Women ◽

Anticoagulation Therapy ◽

Factor V Leiden ◽

Protein S ◽

Obstetric Complications ◽

Obstetric Outcomes ◽

Control Group ◽

Factor V ◽

Protein C Deficiency ◽

Increased Risk

Pregnancy is a hypercoagulable state associated with an increased risk of venous thromboembolic disease (VTE). We retrospectively studied 38 Caucasian pregnant women with thrombophilia risk and compared their obstetric outcomes with a matched cohort without known thrombophilia risk during the period between January 2007 and December 2010. There were (2) cases with factor V Leiden, (6) prothrombin gene mutation, (1) antithrombin III deficiency, (2) protein C deficiency, (3) protein S deficiency, (10) MTHFR mutation, (7) anti-cardiolipin antibodies, and (1) lupus anticoagulant. Patients without thrombophilia who presented with recurrent unprovoked VTE were considered as high risk (6 cases). Most patients received anticoagulation (34/38) with aspirin only (6), enoxaparin (27), and warfarin (1). Twenty-six out of thirty-eight pregnant women (68.4%) with an increased risk of thrombophilia experienced one or more obstetric complications defined as hypertension, preeclampsia, placenta abruptio, VTE, and oligohydramnios, compared with 15 out of 40 (37.5%) pregnant women in the control group (OR 3.6; 95% CI 1.42, 9.21, P<0.001). The incidence of obstetric complications was significantly higher in the thrombophilia group compared to the controls. However, these complications were the lowest among patients who received full-dose anticoagulation. Our study suggests that strict application of anticoagulation therapy for thrombophilia of pregnancy is associated with an improved pregnancy outcome. The study was registered in the Australian and New Zealand Clinical Trials Registry under ACTRN12612001094864.

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Inherited Thrombophilia and First Venous Thromboembolism during Pregnancy and Puerperium

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613085 ◽

2002 ◽

Vol 87 (05) ◽

pp. 791-795 ◽

Cited By ~ 115

Author(s):

Valerio De Stefano ◽

Emanuela Taioli ◽

Katia Paciaroni ◽

Elena Rossi ◽

Mannucci Pier ◽

...

Keyword(s):

Venous Thromboembolism ◽

Factor V Leiden ◽

Protein S ◽

First Episode ◽

Factor V ◽

Inherited Thrombophilia ◽

Vein Thrombosis ◽

Increased Risk ◽

Prothrombin Mutation ◽

Heterozygous Carriers

SummaryVenous thromboembolism is a rare but threatening complication of pregnancy. Little conclusive information is available on the actual risk of venous thromboembolism during pregnancy or puerperium in women with inherited thrombophilia, particularly in carriers of factor V Leiden and of the G20210A prothrombin gene mutation. To determine the pregnancy-related and puerperium-related risk of venous thromboembolism in women with inherited thrombophilia, we performed a case-control study on 119 women who had a first episode of deep vein thrombosis and/or pulmonary embolism during pregnancy or puerperium and 232 healthy women who had at least one pregnancy without thrombosis. Inherited thrombophilia was diagnosed in 47 patients (39.5%) and 15 controls (6.5%). The relative risk of venous thromboembolism was 10.6 (95% CI, 5.6-20.4) for heterozygous carriers of factor V Leiden, 2.9 (95% CI, 1.0-8.6) for heterozygous carriers of the prothrombin mutation and 13.1 (95% CI, 5.0-34.2) for those with antithrombin, protein C or protein S deficiency taken together. Sixty-eight of the 119 women (57%) had thrombosis after delivery, confirming the puerperium as a particularly high-risk period. When women were divided into two groups of those with antenatal or postnatal thrombosis, the relative risks associated with each type of inherited thrombophilia were of similar magnitude. In conclusion, women with inherited thrombophilia have an increased risk of venous thromboembolism during pregnancy. Among thrombophilic abnormalities, the prothrombin mutation was the weakest risk factor. Thrombosis occurred more frequently in puerperium than in pregnancy, whether or not thrombophilia was diagnosed.

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Prevalence of Venous and Arterial Thrombosis Among 268 Heterozygous and 111 Homozygous Factor V Leiden Carriers: a Single-Center Cross-Sectional Study

Blood ◽

10.1182/blood.v124.21.1536.1536 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1536-1536

Author(s):

Juliana Perez Botero ◽

Wayne D. Ormsby ◽

Aneel A Ashrani ◽

Robert D McBane ◽

Waldemar E Wysokinski ◽

...

Keyword(s):

Arterial Thrombosis ◽

Factor V Leiden ◽

Cross Sectional Study ◽

Categorical Variables ◽

Factor V ◽

Sectional Study ◽

Cross Sectional ◽

Increased Risk ◽

Heterozygous Carriers ◽

The Mean

Abstract Background: While Factor V Leiden is associated with an increased risk of thrombosis, the magnitude of that risk among homozygous carriers is uncertain. Methods: In a cross-sectional study of Mayo Clinic patients referred to the Special Coagulation Laboratory for a thrombophilia profile (n=379) over the 18-year period, 1996-2013, the prevalence of venous and arterial thrombosis was estimated for patients found to be Factor V Leiden carriers based on leukocyte genomic DNA genotyping. T tests and chi-square tests were used for continuous and categorical variables, respectively. Results: Among homozygous (n=111) and heterozygous (n=268) carriers, the mean age at testing (50.3 and 50.5 years, respectively; p=0.9) and the proportion of females (50% and 54%, respectively; p=0.5) did not differ significantly. Of 29 asymptomatic carriers at the time of testing, 14 were homozygotes. Of the remaining 350 carriers, the mean age at first venous or arterial thrombosis (42 vs 43.8 years; p=0.5) among homozygous and heterozygous carriers, respectively, did not differ significantly. Thirty-five (33%) and 83 (31%) homozygous and heterozygous carriers, respectively, had at least one recurrent venous or arterial thrombosis (p=0.72). The prevalence of deep venous thrombosis (DVT) was 61% and 46% in homozygous and heterozygous carriers, respectively (p=0.008); the prevalence of pulmonary embolism was 18% and 20%, respectively (p=0.69). The prevalence of arterial thrombosis (mainly stroke and/or TIA) was higher in heterozygous (23%) compared to homozygous carriers (8%). Conclusion: In the largest sample of homozygous Factor V Leiden carriers reported to date, thrombosis penetrance and phenotype did not appear to differ among homozygous vs. heterozygous carriers with the exception of a higher prevalence of DVT among homozygous carriers. These data should be interpreted with caution due to the potential for referral bias. Disclosures No relevant conflicts of interest to declare.

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Frecuencia aumentada del alelo D y el genotipo DD del gen de la enzima convertidora de angiotensina en pacientes con un primer evento coronario

Universitas Scientiarum ◽

10.11144/javeriana.sc15-1.ifot ◽

2010 ◽

Vol 15 (1) ◽

pp. 77

Author(s):

Nelsy Loango ◽

Ramiro Vargas ◽

José H. Osorio ◽

Martha L. Gallego ◽

Patricia Landázuri

Keyword(s):

Myocardial Infarction ◽

Enzyme Activity ◽

Clinical Evidence ◽

Enzyme Inhibitor ◽

Control Group ◽

Activity Levels ◽

Coronary Syndrome ◽

Increased Risk ◽

Polymerase Chain ◽

First Myocardial Infarction

Objective. To evaluate the genotypic and allelic frequencies of the I/D polymorphism of the ACE gene and the enzymatic activity in a group of Colombian patients with myocardial infarction (MI) and in a group of healthy subjects. Materials and Methods. We examined 41 patients diagnosed MI and admitted consecutively in the San Juan de Dios Hospital, and 39 subjects with no clinical evidence of coronary syndrome. ACE genotypes were determined by means of the polymerase chain reaction and the enzyme activity using spectrophotometry. Results. Polymorphism distribution among the patients was II 30.8%, ID 28.2%, and DD 51.2%, whilst in the control group it was II 30.8%, ID 28.2% and DD 41.0%, without significant differences between groups. ID and DD subjects were combined and after adjustment for other variables, their risk of MI was 3.5 times higher than in those subjects with the I allele (95% IC: 1.2-10.4 p=0.02). Enzyme activity was higher in subjects with the D allele, except in patients with enzyme inhibitor medication. Conclusions. Results show a higher frequency of the D allele and the DD genotype in patients with a first myocardial infarction, besides confirming a variation in the ACE activity levels influenced by the I/D. Our findings provide evidence of an increased risk of MI in Colombian subjects with the D allele. Key words: angiotensin-converting enzyme, hypertension, myocardial infarction, polymorphism, risk factors.

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