The Risk for Venous Thrombosis in Patients with Increased Body Mass Index and Interactions with Other Genetic and Acquired Risk Factors: The MEGA Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1234-1234
Author(s):  
Daniel D. Ribeiro ◽  
Willem M. Lijfering ◽  
Frits R. Rosendaal ◽  
Suzanne C. Cannegieter
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Blood Group ◽  
Reference Group ◽  
Factor V Leiden ◽  
Factor V ◽  
Odds Ratios ◽  
Thrombosis Risk ◽  
Increased Risk ◽  
High Bmi

Abstract Abstract 1234 Background: Obesity (prevalence of 20–25% in Western populations), blood group non-O (present in 50% of Western populations) and factor V Leiden (present in 5% of Caucasian populations) are frequent prothrombotic risk factors and may therefore have a considerable impact on the overall incidence of venous thrombosis. We previously reported that the increased risk of venous thrombosis in individuals with a high BMI is mediated by factor VIII induced APC-resistance, and that the combination of blood group non-O with a high BMI or factor V Leiden leads to higher venous thrombosis risks than expected when these prothrombotic factors are analyzed separately (ASH Annual Meeting Abstracts. 2009;114:453). However, small numbers did not enable us to sufficiently study the risk of venous thrombosis for the combination of a high BMI with factor V Leiden and blood group non-O, or to study these effects in subgroups. Objectives: To investigate whether the presence of factor V Leiden with blood group non-O can modify the risk for venous thrombosis in individuals with different body mass index strata in a larger population based study than previously reported. To evaluate the presence of gene-environment interactions in specific subgroups. Methods: MEGA study: 4956 consecutive patients aged 18–70 years with a first episode of venous thrombosis, and 6297 age- and sex-matched controls were included. Information about BMI, blood group and factor V Leiden was available in 4062 patients and 4659 controls. Odds ratios for venous thrombosis and their 95% confidence intervals (95% CIs) were calculated for BMI tertiles with logistic regression and adjusted for age and sex (matching factors). An interaction analysis among the BMI tertiles, factor V Leiden and blood group non-O was performed. Subgroup analyses involved stratification by venous thrombosis place (i.e. deep vein thrombosis or pulmonary embolism), sex, and presence or absence of acquired venous thrombosis risk factors. Results: A progressive increase in BMI was associated with an increased risk for venous thrombosis, odds ratios 1.1 (95% CI, 0.9–1.3) for those with a BMI in the median tertile, and 1.9- (95% CI, 1.6–2.3) for those in the upper tertile, as compared to individuals in the first BMI tertile, blood group O, and no factor V Leiden (i.e. the reference group). The addition of factor V Leiden and blood group non O in the model increased the risk in all BMI tertiles; odds ratios for venous thrombosis were 3.8 (95% CI, 3.2–4.6) in the third BMI tertile of individuals with blood group non-O, and 5.4 (95% CI, 3.5–8.5) in the third BMI tertile of individuals with factor V Leiden, respectively. When both factor V Leiden and blood group non-O were present, odds ratios for venous thrombosis were 9.1 (95% CI, 5.9–14.0) in the first BMI tertile, 9.4 (95% CI, 6.6–13.5) in the second BMI tertile, and 12.5 (95% CI, 8.9–17.6) in the BMI third BMI tertile as compared to the reference group. Subgroup analyses revealed similar joint interactions of BMI with blood group non-O and factor V Leiden on venous thrombosis risk. Disclosures: No relevant conflicts of interest to declare.

The Risk of Venous Thrombosis Related to Increase in Body Mass Index Is Mediated by Factor VIII Induced APC-Resistance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 453-453 ◽  
Author(s):  
Willem M Lijfering ◽  
Sverre C Christiansen ◽  
Inger-Anne Naess ◽  
Jens Hammerstrøm ◽  
Astrid van Hylckama Vlieg ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Blood Group ◽  
Odds Ratio ◽  
Reference Group ◽  
Control Group ◽  
Odds Ratios ◽  
Apc Resistance ◽  
Increased Risk ◽  
Fv Leiden ◽  
High Bmi

Abstract Abstract 453 Background: The reason why a high BMI predisposes to venous thrombosis is not clarified. People with overweight or obesity tend to be more immobile which may lead to clot formation through stasis. It is also possible that these subjects acquire a prothrombotic state. Factor (F) VIII can be released by adipose tissue through inflammatory cytokines, which consequently might induce APC-resistance. This APC-resistance could be aggravated in case FV Leiden is also present. In addition, presence of high levels of FVIII in non-O blood group subjects could worsen this further. Objective: To determine whether an association exists between BMI and APC-resistance, and whether the combination of both high BMI and APC-resistance increased the risk of venous thrombosis in the Leiden Trombophilia Study (LETS). Whether increasing FVIII levels induced APC-resistance was also studied. In a pooled analysis of LETS and a Norwegian case-cohort study (TROL), we verified if FV Leiden modified the risk of increasing BMI on the occurence of venous thrombosis and whether these risks were further increased by blood group non-O. Methods: Linear regression was used to determine the relation between increasing APC-resistance and BMI, increasing FVIII levels and BMI, increasing APC-resistance and FVIII levels, and between increasing APC-resistance and BMI adjusted for FVIII levels. Cut-off points needed to create tertile categories of APC-resistance were derived from the control-group of the LETS and the TROL population separately. Logistic regression was used to calculate odds ratios and their 95% confidence intervals, adjusted for age and sex. To make the TROL and LETS population more similar for the current analysis, we restricted the analysis in the TROL subjects to those who were younger than 70 and to those who had a DVT only (n=183 cases and n=696 controls). Results: APC-resistance increased linearly with increasing BMI. A same phenomenon was observed for FVIII, i.e. an increase of BMI led to higher FVIII levels. Increased APC-resistance was in its turn associated with an increase of FVIII levels. FVIII explained part of the relation between APC and BMI, as the slope of the regression line of APC-resistance on BMI levels decreased after adjustment for FVIII. To examine the effect of increasing BMI, independent of existing APC-resistance, on the risk of venous thrombosis, we restricted the analysis to subjects from the LETS in whom APC-resistance was not related to other factors such as FV Leiden or oral contraceptive use. In these subjects (n=237 cases and n=369 controls), the risk of venous thrombosis increased 1.4-fold for those with a BMI in the median tertile (odds ratio 1.4; 95% CI, 0.9-2.3) and 2.5-fold for those in the upper tertile (odds ratio 2.5; 95% CI, 1.6-3.9), as compared to subjects in the lowest tertile. Adjustment for APC-resistance or FVIII led to a slight decrease in these relative risk estimates. Non-FV Leiden-carriers with blood group O were only at risk of venous thrombosis when they had a BMI in the upper tertile compared to non-FV Leiden-carriers with blood group O and a BMI in the lowest tertile; (adjusted odds ratio 1.9). This risk was modestly increased when non FV Leiden carriers with non-O blood group were compared with this reference group, with adjusted odds ratios of 1.5, 2.4 and 3.4, respectively, within the BMI tertiles. This risk was strongly increased when FV Leiden carriers with blood group O were compared to the reference group, with adjusted odds ratios of 3.0, 8.3 and 9.7, respectively, within the BMI tertiles. Risk of FV Leiden carriers with non-O blood group showed the highest risk of venous thrombosis compared to the reference group, no longer in a dose-response way, with adjusted odds ratios of 40.6, 23.3 and 25.2, respectively, within the BMI tertiles. Conclusion: The increased risk of venous thrombosis in subjects with high BMI is mediated by FVIII induced APC-resistance. Subjects with FV Leiden and increasing BMI had a higher risk of venous thrombosis compared to non-carriers, and this risks was more than 20 fold increased in carriers of blood group non-O and FV Leiden. Future studies are needed to show if these risks can be downgraded by weight loss. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Increased risk of venous thrombosis by AB alleles of the ABO blood group and Factor V Leiden in a Brazilian population

2009 ◽  
Vol 32 (2) ◽  
pp. 264-267 ◽  
Author(s):  
Magaly B.P.L.V. Lima ◽  
Aldemir Branco de Oliveira-Filho ◽  
Júlia F. Campos ◽  
Fárida C.B.C. Melo ◽  
Washington Batista das Neves ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Blood Group ◽  
Factor V Leiden ◽  
Brazilian Population ◽  
Abo Blood Group ◽  
Factor V ◽  
Increased Risk

Inherited Risk Factors for Venous Thrombosis

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 452-457 ◽  
Author(s):  
Mary Cushman
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Genetic Risk ◽  
Factor V Leiden ◽  
Clinical Applications ◽  
Factor V ◽  
Inherited Disorders ◽  
Thrombosis Risk ◽  
Genetic Medicine ◽  
Inherited Risk

Abstract Venous thrombosis occurs as a consequence of genetic and environmental risk factors. Since the discovery of factor V Leiden, the most common genetic risk factor, there has been intense interest in clarifying the roles of genes and the environment with thrombosis risk. The translation of this risk information to clinical practice is a challenging one in the setting of a rapidly expanding knowledge base that includes application of genetic medicine. There are benefits, but also potential harms, of testing for inherited disorders associated with thrombosis. This paper reviews inherited risk factors for thrombosis and discuss clinical applications of testing.

Resistance to Activated Protein C and Factor V Leiden as Risk Factors for Venous Thrombosis

1995 ◽  
Vol 74 (01) ◽  
pp. 449-453 ◽  
Author(s):  
Rogier M Bertina ◽  
Pieter H Reitsma ◽  
Frits R Rosendaal ◽  
Jan P Vandenbroucke
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V

Polymorphisms in the protein C gene as risk factor for venous thrombosis

2009 ◽  
Vol 101 (01) ◽  
pp. 62-67 ◽  
Author(s):  
Carine Doggen ◽  
Hans Vos ◽  
Pieter Reitsma ◽  
Frits Rosendaal ◽  
Elisabeth Pomp
Keyword(s):  
Oral Contraceptive ◽  
Venous Thrombosis ◽  
Protein C ◽  
Contraceptive Use ◽  
Factor V Leiden ◽  
Factor V ◽  
Thrombotic Risk ◽  
Control Subjects ◽  
Oral Contraceptive Use ◽  
Increased Risk

SummaryProtein C is an important inhibitor of blood coagulation. We investigated the effect of two polymorphisms within the promoter region of the protein C gene (C/T at position 2405 and A/G at position 2418) on risk of venous thrombosis and on plasma protein C levels. In addition the combined effect of the two polymorphisms with factor V Leiden and oral contraceptive use was investigated. Previous studies on these polymorphisms were small and were not able to investigate synergistic effects. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), protein C levels were determined in 2,043 patients with venous thrombosis and 2,857 control subjects, and the two polymorphisms in 4,285 patients and 4,863 control subjects. The CC/GG genotype was associated with the lowest protein C levels. Compared to carriers of the TT/AA genotype – a genotype associated with higher protein C levels – the risk of venous thrombosis in CC/GG carriers was 1.3-fold increased (95% confidence interval 1.09–1.48). The combination of factor V Leiden with the CC/GG genotype led to a 4.7-fold increased risk, compared to non-carriers with the TT/AA genotype. Oral contraceptive use together with the CC/ GG genotype resulted in a 5.2-fold increased risk. In conclusion, the CC/GG genotype is associated with lower levels of protein C and an elevated risk of venous thrombosis compared to the TT/AA genotype. There is no clear synergistic effect of the CC/ GG genotype with factor V Leiden or oral contraceptive use on thrombotic risk.

Factor V Leiden (G1691A) and Prothrombin Gene G20210A Mutations as Potential Risk Factors for Venous Thromboembolism after Total Hip or Total Knee Replacement Surgery

2002 ◽  
Vol 87 (04) ◽  
pp. 580-585 ◽  
Author(s):  
G. Larson ◽  
T. L. Lindahl ◽  
C. Andersson ◽  
L. Frison ◽  
D. Gustafsson ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Composite Endpoint ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
G20210a Mutation ◽  
Symptomatic Pulmonary Embolism ◽  
Increased Risk ◽  
Prothrombin Gene

SummaryPatients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

scholarly journals High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]

Blood ◽  
1995 ◽  
Vol 85 (6) ◽  
pp. 1504-1508 ◽  
Author(s):  
FR Rosendaal ◽  
T Koster ◽  
JP Vandenbroucke ◽  
PH Reitsma
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Absolute Risk ◽  
Thrombotic Event ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Increased Risk ◽  
The Absolute

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.

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

2001 ◽  
Vol 86 (09) ◽  
pp. 800-803 ◽  
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.

Factor V Leiden Is Associated with Premature Myocardial Infarction.

Blood ◽  
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.

Inherited and Acquired Risk Factors for Venous Thromboembolic Disease Among Women Taking Tamoxifen to Prevent Breast Cancer

2003 ◽  
Vol 21 (19) ◽  
pp. 3588-3593 ◽  
Author(s):  
Catherine Duggan ◽  
Kevin Marriott ◽  
Rob Edwards ◽  
Jack Cuzick
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Hormone Replacement ◽  
Factor V Leiden ◽  
Factor V ◽  
Increased Risk ◽  
Venous Thromboembolic ◽  
Prior Surgery ◽  
Cancer Intervention ◽  
Nested Case Control

Purpose: Venous thromboembolism (VTE) is of particular concern in women receiving tamoxifen in a chemopreventive setting. We investigate the association between acquired and inherited risk factors for VTE in the International Breast Cancer Intervention Study (IBIS-I) trial of tamoxifen prophylaxis for women at increased risk of breast cancer. Methods: We used a nested case-control study design to investigate the role of tamoxifen and acquired risk factors in the risk of developing a VTE. Results: Tamoxifen was associated with a significantly increased risk of developing a major VTE (odds ratio [OR], 2.1; 95% CI, 1.1 to 4.1). Women who had surgery, immobilization, or fracture in the previous month had a greatly increased risk of developing a major VTE (OR, 4.7; 95% CI, 2.2 to 10.1). Prothrombin and factor V Leiden mutations were found exclusively among control women: factor V Leiden in eight of 159 control women (5.0%) and the prothrombin mutation in three control women (1.9%). Thirty-five women with a VTE and a blood sample were negative for these mutations. The upper one-sided 97.5% CI for the OR of having either mutation was 1.87. Being overweight, smoking, or taking hormone replacement therapy was not associated with VTE in this study, but the CIs were wide. Conclusion: Tamoxifen and prior surgery, fracture, or immobilization were associated with a significantly increased risk of developing a VTE. Factor V Leiden and prothrombin mutations were not associated with thrombosis in this population.

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