Association of Factor V Leiden With Subsequent Atherothrombotic Events

Supplemental Digital Content is available in the text. Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92–1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

P. Deloukas | T. Lehtimäki | C. Held | N. Samani | P. Braund | A. Hingorani | V. Cameron | R. Doughty | J. Spertus | E. Hagström | N. Eriksson | D. Grobbee | N. Sattar | W. März | C. Nelson | S. Hazen | M. Sanak | M. Scholz | M. Bots | F. Dudbridge | R. McPherson | J. van Setten | M. Kähönen | Julie A. Johnson | C. Lang | M. Heydarpour | S. Body | C. Palmer | M. Kleber | L. Lyytikäinen | G. Hovingh | L. Wallentin | Riyaz S. Patel | G. Paré | C. Pepine | S. W. van der Laan | G. Delgado | G. Pasterkamp | F. Asselbergs | K. Nikus | S. W. Laan | M. Holmes | R. Cooper-DeHoff | Y. Gong | H. Allayee | B. Mahmoodi | J. Thiery | W. Szczeklik | J. Hartiala | N. Danchin | O. Klungel | F. Visseren | T. Simon | T. Bergmeijer | J. T. ten Berg | S. James | J. Waltenberger | J. Deanfield | K. Direk | R. Burkhardt | A. Teren | F. Asselbergs | A. Stewart | A. Richards | V. Tragante | A. H. Maitland‐van der Zee | D. Levin | S. Cresci | I. Hoefer | L. Howe | A. Kraaijeveld | A. Åkerblom | C. M. Gijsberts | P. Lenzini | A. Schmidt | J. Muehlschlegel | G. Hovingh | I. Mordi | J. Laurikka | P. Kuukasjärvi | A. M. Zee | W. Wilson Tang | A. Pilbrow | S. Kotti | E. Baranova | R. McCubrey | W. Tang | M. Kaczor | Ragnar O. Vilmundarson | Vinicius Tragante | A. Richards | Winfried März | J. V. Setten | R. Patel | M. V. Holmes | J. T. Berg | M. Kähönen | Stanley L Hazen | C. Gijsberts | C. Nelson | M. Kaczor | Michael V. Holmes | Alexandre F. R. Stewart | Chim C. Lang | Vicky A. Cameron | Laurence J. Howe | Graciela E. Delgado | Christopher P. Nelson | R. Doughty | Julie A. Johnson | Colin N. Palmer | A. Richards | Riyaz S Patel | G. Delgado | G. Hovingh

[1]  Yan V. Sun,et al.  Subsequent Event Risk in Individuals With Established Coronary Heart Disease , 2019, Circulation. Genomic and precision medicine.

[2]  M. Dichgans,et al.  Genetic Study of White Matter Integrity in UK Biobank (N=8448) and the Overlap With Stroke, Depression, and Dementia , 2018, Stroke.

[3]  P. Deloukas,et al.  Impact of Selection Bias on Estimation of Subsequent Event Risk , 2017, Circulation. Cardiovascular genetics.

[4]  Deepak L. Bhatt,et al.  Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease , 2017, The New England journal of medicine.

[5]  Deepak L. Bhatt,et al.  Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation , 2017, The New England journal of medicine.

[6]  Ni Chen,et al.  Platelet‐Derived Factor V Is a Critical Mediator of Arterial Thrombosis , 2017, Journal of the American Heart Association.

[7]  Pavel S. Roshanov,et al.  Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery , 2017, JAMA.

[8]  G. Lip,et al.  Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. , 2016, The New England journal of medicine.

[9]  M. Voskuil,et al.  Hematological Parameters Improve Prediction of Mortality and Secondary Adverse Events in Coronary Angiography Patients , 2015, Medicine.

[10]  A. Algra,et al.  Hypercoagulability Is a Stronger Risk Factor for Ischaemic Stroke than for Myocardial Infarction: A Systematic Review , 2015, PloS one.

[11]  S. Body,et al.  Plasma corin decreases after coronary artery bypass graft surgery and is associated with postoperative heart failure: a pilot study. , 2015, Journal of cardiothoracic and vascular anesthesia.

[12]  T. Egberts,et al.  Treatment with rivastigmine or galantamine and risk of urinary incontinence: results from a Dutch database study , 2015, Pharmacoepidemiology and drug safety.

[13]  P. Pais,et al.  Darapladib for preventing ischemic events in stable coronary heart disease. , 2014, The New England journal of medicine.

[14]  Elizabeth A. McClellan,et al.  Circulating cells as predictors of secondary manifestations of cardiovascular disease: design of the CIRCULATING CELLS study , 2013, Clinical Research in Cardiology.

[15]  A. Folsom,et al.  Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls , 2013, European Journal of Epidemiology.

[16]  Markus Scholz,et al.  Rationale and Design of the Leipzig (LIFE) Heart Study: Phenotyping and Cardiovascular Characteristics of Patients with Coronary Artery Disease , 2011, PloS one.

[17]  T. Lehtimäki,et al.  Common variation in the ADAM8 gene affects serum sADAM8 concentrations and the risk of myocardial infarction in two independent cohorts. , 2011, Atherosclerosis.

[18]  Harlan M Krumholz,et al.  Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH): Design and Rationale of a Prospective Multicenter Registry , 2011, Circulation. Cardiovascular quality and outcomes.

[19]  Brian J. Bennett,et al.  Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease , 2011, Nature.

[20]  S. Kathiresan,et al.  The association of factor V Leiden with myocardial infarction is replicated in 1880 patients with premature disease , 2010, Journal of thrombosis and haemostasis : JTH.

[21]  S. Kittner,et al.  Meta-Analysis of Factor V Leiden and Ischemic Stroke in Young Adults: The Importance of Case Ascertainment , 2010, Stroke.

[22]  V. Cameron,et al.  A Common Variant at Chromosome 9P21.3 Is Associated With Age of Onset of Coronary Disease but Not Subsequent Mortality , 2010, Circulation. Cardiovascular genetics.

[23]  V. Deneer,et al.  Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. , 2010, JAMA.

[24]  L. Smeeth,et al.  Causal Relationship of Susceptibility Genes to Ischemic Stroke: Comparison to Ischemic Heart Disease and Biochemical Determinants , 2010, PloS one.

[25]  J. Rosing,et al.  Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms. , 2010, Blood.

[26]  Claes Held,et al.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes. , 2009, The New England journal of medicine.

[27]  M. Makris.  Thrombophilia: grading the risk. , 2009, Blood.

[28]  A. Skene,et al.  Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. , 2009, American heart journal.

[29]  B. Mahmoodi,et al.  Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age: Results From a Large Family Cohort Study , 2008, Circulation.

[30]  N. Danchin,et al.  The French registry of Acute ST elevation or non-ST-elevation Myocardial Infarction (FAST-MI): study design and baseline characteristics. , 2007, Archives des maladies du coeur et des vaisseaux.

[31]  T. Lehtimäki,et al.  The Finnish Cardiovascular Study (FINCAVAS): characterising patients with high risk of cardiovascular morbidity and mortality , 2006, BMC cardiovascular disorders.

[32]  John Danesh,et al.  Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66 155 cases and 91 307 controls , 2006, The Lancet.

[33]  A. Morris,et al.  Association of common variation in the PPARA gene with incident myocardial infarction in individuals with type 2 diabetes: A Go-DARTS study , 2005, Nuclear receptor.

[34]  P. Burton,et al.  A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) Family Heart Study. , 2005, American journal of human genetics.

[35]  C. Frampton,et al.  B-Type Natriuretic Peptides and Ejection Fraction for Prognosis After Myocardial Infarction , 2003, Circulation.

[36]  B. Nordestgaard,et al.  Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses. , 2002, Blood.

[37]  Jixian Wang,et al.  Comparison of cardiovascular risk between patients with type 2 diabetes and those who had had a myocardial infarction: cross sectional and cohort studies , 2002, BMJ : British Medical Journal.

[38]  W. März,et al.  Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. , 2001, Pharmacogenomics.

[39]  S. Yusuf,et al.  The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. , 2000, European heart journal.

[40]  G. Barosi,et al.  Extended Anticoagulation for Prevention of Recurrent Venous Thromboembolism in Carriers of Factor V Leiden , 2000, Thrombosis and Haemostasis.

[41]  Sonia S Anand,et al.  Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. , 1999, JAMA.

[42]  M L Bots,et al.  Common carotid intima-media thickness and arterial stiffness: indicators of cardiovascular risk in high-risk patients. The SMART Study (Second Manifestations of ARTerial disease). , 1999, Circulation.

[43]  L. Kuller,et al.  Factor V Leiden Is not a Risk Factor for Arterial Vascular Disease in the Elderly: Results from the Cardiovascular Health Study , 1998, Thrombosis and Haemostasis.

[44]  P. Ridker,et al.  Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. , 1997, JAMA.

[45]  T. Raghunathan,et al.  Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. , 1997, Blood.

[46]  P. Ridker,et al.  Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. , 1995, The New England journal of medicine.

[47]  Pieter H. Reitsma,et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C , 1994, Nature.