A Common Prothrombin Variant (20210 G to A) Increases the Risk of Myocardial Infarction in Young Women

Abstract Using specimens from a population-based case control study among women ages 18 to 44 years in western Washington, we assessed the relationship between carriership of a genetic clotting factor II variant (20210 G→A) and myocardial infarction (MI). The factor II variant was previously shown to be present in 1% to 2% of the population, to increase the levels of factor II, and to be associated with venous thrombotic disease. Personal interviews and blood samples were obtained from 79 women with a first myocardial infarction and 381 control women identified through random-digit telephone dialing. Polymerase chain reaction (PCR) method was used to determine the factor II genotypes. The factor II 20210 G to A transition was present more often in women with MI (5.1%) than among control women (1.6%). The age-adjusted odds ratio for MI was 4.0 (95% confidence interval 1.1 to 15.1). The relative risk was high when another major cardiovascular risk factor was also present, such as smoking (odds ratio 43.3, 95% confidence interval 6.7 to 281), and the risk seemed limited to those with other risk factors. These results, in which the effect of major coronary risk factors is enhanced fourfold to sixfold by the prothrombin variant, are similar to those previously reported for another genetic clotting abnormality, factor V Leiden. We conclude that factor II 20210 G to A increases the risk of myocardial infarction in young women, especially in the women with other major risk factors for coronary heart disease.

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Examination of in Factor V Leiden and Prothrombin II Thrombophilic Mutations in Czech Young Women Using ddPCR—Prevalence and Cost–Benefit Analysis

Healthcare ◽

10.3390/healthcare9121656 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1656

Author(s):

Petra Riedlova ◽

Dagmar Kramna ◽

Silvie Ostrizkova ◽

Hana Tomaskova ◽

Vitezslav Jirik

Keyword(s):

Risk Factors ◽

Czech Republic ◽

Young Women ◽

Cost Benefit Analysis ◽

Factor V Leiden ◽

Cost Benefit ◽

Factor V ◽

Benefit Analysis ◽

The Czech Republic ◽

Factor Ii

Background: Thrombophilic mutations in genes for factor V Leiden and factor II prothrombin are among the most important risk factors for developing the thromboembolic disease (TED), along with the use of oral contraceptives (OCs) or smoking. Aim: This study aimed to investigate the occurrence of risk factors in young women using droplet digital PCR (ddPCR) and, based on the results of this investigation, to perform a cost–benefit analysis of ddPCR-based screening in young women starting to take OCs compared to the treatment costs of patients who develop preventable TED in the Czech Republic. Methods: In this cross-sectional study, female university students filled in a questionnaire and provided a blood sample for DNA isolation and ddPCR analysis of both aforementioned genetic risk factors. The results, along with data from literature and web search, were used for cost–benefit analysis valid for the Czech Republic. Results: Out of 148 participants, 30 (20%) were smokers and 49 (33%) took OCs. A mutation was confirmed in 6 women (4.1%) in the factor V gene and in 3 women (2%) in the factor II gene, respectively. A model calculation on a cohort of 50,000 women starting to use contraceptives in the Czech Republic every year showed that at maximum compliance, (i.e., non-use of OC and smoking cessation), screening could prevent 68 cases of TED over the course of the mean period of OC use (5.7 years). Economically, the costs of testing in this cohort (2.25 mil. USD) would be significantly lower than prevented treatment costs (16 mil. USD at maximum compliance); the cost–benefit break-even point would be at 14.1% compliance. Conclusion: The cost–benefit analysis based on our results indicates that screening for factor V Leiden and factor II prothrombin in young women before starting to use OCs would, in the conditions of the Czech Republic, likely be highly economically effective.

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Minor Events and the Risk of Deep Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613828 ◽

2000 ◽

Vol 83 (03) ◽

pp. 408-411 ◽

Cited By ~ 15

Author(s):

E. M. W. Eekhoff ◽

J. P. Vandenbroucke ◽

F. R. Rosendaal

Keyword(s):

Risk Factors ◽

Confidence Interval ◽

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Odds Ratio ◽

Factor V Leiden ◽

Common Disease ◽

Factor V ◽

Factor V Leiden Mutation ◽

Synergy Index

SummaryBackground Deep venous thrombosis is a common disease, with genetic and acquired risk factors. Many patients have a history of minor events (short periods of immobilisation such as prolonged travel, short illness, minor surgery or injuries) before onset of venous thrombosis. However, the role of these minor events has received little formal study. Also, we do not know how minor events might interact with the presence of genetic prothrombotic defects (factor V Leiden mutation, factor II mutation, protein C, S and antithrombin deficiency). Patients and Methods On the basis of case-control data from a thrombosis service in the Netherlands, we added a follow-up period for a casecross-over analysis of minor events as risk factors, and a case-only analysis for the interaction with factor V Leiden. A total of 187 patients with first, objectively diagnosed venous thrombosis of the legs, aged 15–70, without underlying malignancies and without major acquired risk factors entered the study. For the analysis of minor events in the case-cross-over analysis, we used a matched odds ratio; in the caseonly analysis, we used the multiplicative synergy index. Results In 32.6% of the 187 patients with deep venous thrombosis who did not have major acquired risk factors, minor events were the only external risk factors. Minor events increased the risk of thrombosis about 3-fold, as estimated in the case-cross-over analysis (odds ratio 2.9, 95% confidence interval 1.5–5.4). The synergy index between minor events and factor V Leiden mutation in the case-only analysis was 0.7 (95% confidence interval 0.3–1.5). Therefore, persons with factor V Leiden mutation who experience a minor event will have an estimated risk increase of about 17-fold, which exceeds the sum of the individual risk factors. Conclusions Minor events are likely to play an important role in the development of deep venous thrombosis, especially in the presence of genetic prothrombotic conditions.

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Factor V Leiden (Resistance to Activated Protein C) Increases the Risk of Myocardial Infarction in Young Women

Blood ◽

10.1182/blood.v89.8.2817 ◽

1997 ◽

Vol 89 (8) ◽

pp. 2817-2821 ◽

Cited By ~ 249

Author(s):

F.R. Rosendaal ◽

D.S. Siscovick ◽

S.M. Schwartz ◽

R.K. Beverly ◽

B.M. Psaty ◽

...

Keyword(s):

Myocardial Infarction ◽

Risk Factor ◽

Young Women ◽

Odds Ratio ◽

Protein C ◽

Genetic Defect ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation

AbstractFactor V Leiden (factor V Arg506Gln), the genetic defect underlying resistance to activated protein C, is the most common risk factor for venous thrombosis. The relationship between this genetic abnormality and arterial disease is still unresolved. To assess whether factor V Leiden increases the risk of myocardial infarction (MI), we conducted a population-based case-control study among women 18 to 44 years of age in western Washington state. We included 84 women with first MI and 388 control women, ie, women residing in the same area in the same age range without MI (n = 388). The control women were contacted by random digit dialing. Data on risk factor status were collected via personal interview, and data on the factor V genotype via polymerase chain reaction techniques. The factor V Leiden mutation was found more often in women with MI (10%) than among controls (4%). The odds ratio for MI was 2.4 [95% confidence interval (CI) 1.0 to 5.9]. The risk was increased fourfold (CIgs 1.2 to 12.1) when adjusted for major cardiovascular risk factors. Among nonsmokers the factor V Leiden mutation had little effect (odds ratio 1.1, CI95 0.1 to 8.5), whereas it had a large effect among smokers (odds ratio 3.6, CI95 0.9 to 14.4), which, because smoking was itself a strong risk factor for MI, led to an odds ratio for smoking carriers of the mutation that was 32-fold increased compared with nonsmoking noncarriers. We conclude that factor V Leiden increases the risk of MI in young women. This effect seems to be confined largely to current smokers.

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Combined Effect of Factor V Leiden and Prothrombin 20210A on the Risk of Venous Thromboembolism

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616136 ◽

2001 ◽

Vol 86 (09) ◽

pp. 809-816 ◽

Cited By ~ 193

Author(s):

Frits Rosendaal ◽

Marco Cattaneo ◽

Maurizio Margaglione ◽

Valerio De Stefano ◽

Tony Cumming ◽

...

Keyword(s):

Venous Thromboembolism ◽

Odds Ratio ◽

Large Population ◽

Factor V Leiden ◽

Pooled Analysis ◽

Factor V ◽

Case Control Studies ◽

Vein Thrombosis ◽

G20210a Mutation ◽

Factor Ii

SummaryFactor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-18.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.

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Geographic Distribution of the 20210 G to A Prothrombin Variant

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615049 ◽

1998 ◽

Vol 79 (04) ◽

pp. 706-708 ◽

Cited By ~ 418

Author(s):

C. J. M. Doggen ◽

A. Zivelin ◽

V. R. Arruda ◽

M. Aiach ◽

D. S. Siscovick ◽

...

Keyword(s):

Geographical Location ◽

Factor V Leiden ◽

Prevalence Estimate ◽

Clotting Factor ◽

Northern Europe ◽

Nucleotide Position ◽

Factor V ◽

Summary Estimate ◽

Factor Ii ◽

Prevalence Estimates

SummaryA variant in prothrombin (clotting factor II), a G to A transition at nucleotide position 20210, has recently been shown to be associated with the prothrombin plasma levels and the risk of both venous and arterial thrombosis. The purpose of this study was to investigate the prevalence of carriership of this mutation in various populations.We combined data from 11 centres in nine countries, where tests for this mutation had been performed in groups representing the general population. We calculated an overall prevalence estimate, by a precision-weighted method, and, since the distribution of the prevalences did not appear homogeneous, by an unweighted average of the prevalences. We examined differences in the prevalences by geographical location and ethnic background as a possible explanation for the heterogeneity.Among a total of 5527 individuals who had been tested, 111 heterozygous carriers of the 20210A mutation were found. The prevalence estimates varied from 0.7 to 4.0 between the centres. The overall prevalence estimate was 2.0 percent (CI95 1.4-2.6%). The variation around the summary estimate appeared more than was expected by chance alone, and this heterogeneity could be explained by geographic differences. In southern Europe, the prevalence was 3.0 percent (CI95 2.3 to 3.7%), nearly twice as high as the prevalence in northern Europe (1.7%, CI95 1.3 to 2.2%). The prothrombin variant appeared very rare in individuals from Asian and African descent.The 20210A prothrombin variant is a common abnormality, with a prevalence of carriership between one and four percent. It is more common in southern than in northern Europe. Since this distribution within Europe is very different to that of another prothrombotic mutation (factor V Leiden or factor V R506Q), founder effects are the most likely explanation for the geographical distribution of both mutations.

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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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Factor V Leiden Is Not a Risk Factor for Myocardial Infarction Among Young Women

Blood ◽

10.1182/blood.v93.4.1432.404a36b_1432_1433 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1432-1433

Author(s):

Lynn L. Amowitz ◽

Anthony L. Komaroff ◽

Joseph P. Miletich ◽

Paul M. Ridker

Keyword(s):

Myocardial Infarction ◽

Risk Factor ◽

Young Women ◽

Factor V Leiden ◽

Factor V

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Synergistic Effects of Prothrombotic Polymorphisms and Atherogenic Factors on the Risk of Myocardial Infarction in Young Males

Blood ◽

10.1182/blood.v93.7.2186 ◽

1999 ◽

Vol 93 (7) ◽

pp. 2186-2190 ◽

Cited By ~ 69

Author(s):

Aida Inbal ◽

Dov Freimark ◽

Baruch Modan ◽

Angela Chetrit ◽

Shlomi Matetzky ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Logistic Model ◽

Methylenetetrahydrofolate Reductase ◽

Synergistic Effects ◽

Factor V ◽

Current Smoking ◽

Young Males ◽

Factor Ii ◽

Control Study

Abstract Several recent studies evaluated a possible effect of the prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C → T, factor V (F V) nt 1691G → A (F V Leiden), and factor II (F II) nt 20210 G → A on the risk of myocardial infarction. In the present study, we analyzed the effect of these prothrombotic polymorphisms, as well as apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, on the risk of myocardial infarction in young males. We conducted a case-control study of 112 young males with first acute myocardial infarction (AMI) before the age of 52 and 187 healthy controls of similar age. The prevalences of heterozygotes for F V G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among cases and controls, respectively). In contrast, the prevalence of MTHFR 677T homozygosity and the allele frequency of Apo E4 were significantly higher among patients (24.1% v 10.7% and 9.4% v5.3% among cases and controls, respectively). Concomitant presence of hypertension, hypercholesterolemia, or diabetes and one or more of the four examined polymorphisms increased the risk by almost ninefold (odds ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5) and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed simultaneously by a logistic model, the combination of prothrombotic and Apo E4 polymorphisms with current smoking increased the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9).The presented data suggest a synergistic effect between atherogenic and thrombogenic risk factors in the pathogenesis of AMI, as was recently found in a similar cohort of women.

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