Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.

CONTEXT Testing for genetic risks for venous thromboembolism (VTE) is common, but the safety and utility of such testing need review. OBJECTIVES To define rates of recurrent VTE among adults with VTE with a factor V Leiden (FVL) or prothrombin G20210A mutation compared with those without such mutations; to define rates of VTE among family members of adults with a FVL or prothrombin G20210A mutation according to presence or absence of a mutation; and to assess whether testing adults with VTE for FVL or prothrombin G20210A improves outcomes. DATA SOURCES We searched MEDLINE, EMBASE, the Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, and PsycInfo through December 2008. STUDY SELECTION Studies were included if they assessed rates of VTE in individuals with a history of VTE who were tested for FVL or prothrombin G20210A or in family members of individuals with these mutations. Studies assessing the harms and benefits associated with testing were also included. DATA EXTRACTION Two investigators abstracted data and assessed study quality. We pooled the odds of VTE associated with the mutations using random-effects models. We assessed the strength of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. RESULTS We reviewed 7777 titles and included 46 articles. Heterozygosity (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.14-2.12) and homozygosity (OR, 2.65; 95% CI, 1.2-6.0) for FVL in probands are predictive of recurrent VTE compared with individuals without FVL. Heterozygosity for FVL predicts VTE in family members (OR, 3.5; 95% CI, 2.5-5.0), as does homozygosity for FVL (OR, 18; 95% CI, 7.8-40) compared with family members of adults without FVL. Heterozygosity for prothrombin G20210A is not predictive of recurrent VTE in probands compared with individuals without prothrombin G20210A (OR, 1.45; 95% CI, 0.96-2.2). Evidence is insufficient regarding the predictive value of prothrombin G20210A homozygosity for recurrent VTE and the risk of VTE in family members of individuals with prothrombin G20210A. High-grade evidence supports that anticoagulation reduces recurrent VTE events in probands with either mutation. Low-grade evidence supports that this risk reduction is similar to that in individuals with a history of VTE and without mutations. CONCLUSIONS Patients with FVL are at increased risk of recurrent VTE compared with patients with VTE without this mutation. However, it is unknown whether testing for FVL or prothrombin G20210A improves outcomes in adults with VTE or in family members of those with a mutation.

[1]  W. Ageno,et al.  Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment. , 2005, Thrombosis research.

[2]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[3]  F. Rosendaal,et al.  Recurrence Rate After a First Venous Thrombosis in Patients With Familial Thrombophilia , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[4]  Paolo Prandoni,et al.  The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. , 2007, Haematologica.

[5]  P. Wells,et al.  Cognitive and Behavioural Effects of Genetic Testing for Thrombophilia , 2008, Journal of Genetic Counseling.

[6]  Frits R Rosendaal,et al.  Thrombophilia, clinical factors, and recurrent venous thrombotic events. , 2005, JAMA.

[7]  J. Miguel,et al.  Risk of recurrent venous thrombosis in patients with G20210A mutation in the prothrombin gene or factor V Leiden mutation , 2006, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[8]  L. Cameron,et al.  Using the common-sense model to predict risk perception and disease-related worry in individuals at increased risk for venous thrombosis. , 2007, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[9]  H. Büller,et al.  Long-term follow-up of patients with suspected deep vein thrombosis of the upper extremity: survival, risk factors and post-thrombotic syndrome. , 2004, European journal of internal medicine.

[10]  A. Mansilha,et al.  Genetic polymorphisms and risk of recurrent deep venous thrombosis in young people: prospective cohort study. , 2005, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[11]  P. Ridker,et al.  Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism☆ , 2003 .

[12]  P. Kyrle,et al.  Impact of the factor II: G20210A variant on the risk of venous thromboembolism in relatives from families with the factor V: R506Q mutation , 2001, European journal of haematology.

[13]  P. Svensson,et al.  Venous thromboembolism in carriers of the Factor V Leiden mutation and in patients without known thrombophilic risk factor; prediction of recurrence and APC-PCI complex concentration and/or soluble thrombomodulin antigen and activity. , 2007, Thrombosis research.

[14]  F R Rosendaal,et al.  Familial thrombophilia and lifetime risk of venous thrombosis , 2004, Journal of thrombosis and haemostasis : JTH.

[15]  M. Prins,et al.  Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutationRisk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis , 2000 .

[16]  H. Büller,et al.  Social aspects of genetic testing for factor V Leiden mutation in healthy individuals and their importance for daily practice. , 2004, Thrombosis research.

[17]  M. Prins,et al.  The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders , 2002, British journal of haematology.

[18]  A. Tosetto,et al.  The A20210 allele in the prothrombin gene enhances the risk of venous thrombosis in carriers of inherited protein S deficiency , 2000, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[19]  E. Minar,et al.  Family history for venous thromboembolism and the risk for recurrence. , 2006, The American journal of medicine.

[20]  G. Moneta.  Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment , 2007 .

[21]  GualtieroPalareti,et al.  Predictive Value of D-Dimer Test for Recurrent Venous Thromboembolism After Anticoagulation Withdrawal in Subjects With a Previous Idiopathic Event and in Carriers of Congenital Thrombophilia , 2003 .

[22]  F R Rosendaal,et al.  Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT) , 2005, Journal of thrombosis and haemostasis : JTH.

[23]  M. Gent,et al.  Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. , 2008, Blood.

[24]  S Duval,et al.  Trim and Fill: A Simple Funnel‐Plot–Based Method of Testing and Adjusting for Publication Bias in Meta‐Analysis , 2000, Biometrics.

[25]  Jesse A Berlin,et al.  Does blinding of readers affect the results of meta-analyses? , 1997, The Lancet.

[26]  J P Vandenbroucke,et al.  Bias in meta-analysis detected by a simple, graphical test , 1998 .

[27]  P. Prandoni,et al.  Incidence of venous thromboembolism in asymptomatic family members who are carriers of factor V Leiden: a prospective cohort study. , 2002, Blood.

[28]  The Procare Group.  Is recurrent venous thromboembolism more frequent in homozygous patients for the factor V Leiden mutation than in heterozygous patients? , 2003, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[29]  R. Bertina,et al.  Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double‐blind, placebo‐controlled trial , 2001, British journal of haematology.

[30]  E. Minar,et al.  The Risk of Early Recurrent Venous Thromboembolism after Oral Anticoagulant Therapy in Patients with the G20210A Transition in the Prothrombin Gene , 1999, Thrombosis and Haemostasis.

[31]  F. Rosendaal,et al.  Factor V Leiden: the venous thrombotic risk in thrombophilic families , 2000, British journal of haematology.

[32]  G. Guyatt,et al.  Grading quality of evidence and strength of recommendations , 2004, BMJ : British Medical Journal.

[33]  S. Chanock,et al.  Prevalence in the United States of Selected Candidate Gene Variants , 2008, American journal of epidemiology.

[34]  D. Trégouët,et al.  Influence of three potential genetic risk factors for thrombosis in 43 families carrying the factor V Arg 506 to Gln mutation , 1999, British journal of haematology.

[35]  B. Wiman,et al.  The Risk of Recurrent Venous Thromboembolism in Carriers and Non-carriers of the G1691A Allele in the Coagulation Factor V Gene and the G20210A Allele in the Prothrombin Gene , 1999, Thrombosis and Haemostasis.

[36]  E. Oger,et al.  Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden , 2006, Thrombosis and Haemostasis.

[37]  T. Baglin,et al.  Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study , 2003, The Lancet.

[38]  J. Vandenbroucke,et al.  High factor VIII levels contribute to the thrombotic risk in families with factor V Leiden , 2001, British journal of haematology.

[39]  M. Prins,et al.  A Prospective Study of Asymptomatic Carriers of the Factor V Leiden Mutation To Determine the Incidence of Venous Thromboembolism , 2001, Annals of Internal Medicine.

[40]  P. Simioni,et al.  Clinical and laboratory expression of associated thrombophilic conditions (homozygous/heterozygous factor V Leiden mutation and heterozygous prothrombin variant 20210A) in an Italian family , 2000, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[41]  M. Margaglione,et al.  The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. , 2000, British journal of haematology.

[42]  M Gent,et al.  A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. , 1999, The New England journal of medicine.

[43]  Paula M. Saukko,et al.  Are genetic tests exceptional? Lessons from a qualitative study on thrombophilia. , 2006, Social science & medicine.

[44]  F. Bernardi,et al.  Predictive Value of D‐Dimer Test for Recurrent Venous Thromboembolism After Anticoagulation Withdrawal in Subjects With a Previous Idiopathic Event and in Carriers of Congenital Thrombophilia , 2003, Circulation.

[45]  M. Prins,et al.  The Incidence of Venous Thromboembolism in Family Members of Patients with Factor V Leiden Mutation and Venous Thrombosis , 1998, Annals of Internal Medicine.

[46]  S. Schulman,et al.  Risk of recurrent venous thromboembolism or bleeding in relation to thrombophilic risk factors in patients receiving ximelagatran or placebo for long‐term secondary prevention of venous thromboembolism , 2006, British journal of haematology.

[47]  M. Trossaërt,et al.  Diagnosis and clinical characteristics of inherited activated protein C resistance. , 1996, Haemostasis.

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

[49]  Bradley Flansbaum,et al.  Clinical factors and recurrent venous thrombotic events. , 2005, JAMA.

[50]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[51]  M. Prins,et al.  Incidence of Venous Thromboembolism in Families with Inherited Thrombophilia , 1999, Thrombosis and Haemostasis.

[52]  Klaus Lechner,et al.  The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. , 2002, Archives of internal medicine.

[53]  P. Ridker,et al.  G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. , 2001, Journal of the American College of Cardiology.

[54]  S. Ellard,et al.  Patients' understanding of genetic susceptibility testing in mainstream medicine: qualitative study on thrombophilia , 2007, BMC Health Services Research.

[55]  E. Minar,et al.  The risk of recurrent venous thromboembolism in men and women. , 2004, The New England journal of medicine.

[56]  P. Ridker,et al.  Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. , 1995, Circulation.