RSS-Feed abonnieren
PDF herunterladen
DOI: 10.1160/th15-06-0459
F11 is associated with recurrent VTE in women
A prospective cohort studyFinancial support: The TEHS study was funded by Janssen-Cilag, Novartis, Organon, Schering, Wyeth, AFA, Centre for Gender Medicine and by the authors’ affiliations. The sponsors were not involved in the design and conduct of the study; collection, management, analysis or interpretation of the data, and preparation, review, or approval of the manuscript. Genotyping using the Illumina platform at the Uppsala University SNP genotyping platform was supported by Uppsala University, Uppsala University Hospital and the Swedish Research Council for Infrastructures. Genotyping and the work on this manuscript were supported by the Swedish Heart-Lung Foundation, the Swedish Research Council (8691), the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283, 20130508). J. O. is supported by a joint grant from the Royal Institute of Technology and Stockholm County Council. R.J.S. is supported by the Strategic Research Program in Diabetes at Karolinska Institutet.
Publikationsverlauf
Received:
08. Juni 2015
Accepted after major revision:
29. August 2015
Publikationsdatum:
22. November 2017 (online)
Summary
Genetic associations for the reoccurrence of venous thromboembolism (VTE) are not well described. Our aim was to investigate if common genetic variants, previously found to contribute to the prediction of first time thrombosis in women, were associated with risk of recurrence. The Thromboembolism Hormone Study (TEHS) is a Swedish nationwide case-control study (2002–2009). A cohort of 1,010 women with first time VTE was followed up until a recurrent event, death or November 2011. The genetic variants in F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446 were assessed together with clinical variables. Recurrence rate was calculated as the number of events over the accumulated patient-time. Cumulative recurrence was calculated by Kaplan-Meier curve. Cox proportional-hazard model was used to estimate hazard ratios (HR) and 95 % confidence intervals (95 % CI) between groups. A total of 101 recurrent events occurred during a mean follow-up time of five years. The overall recurrence rate was 20 per 1,000 person-years (95 % CI; 16-24). The recurrence rate was highest in women with unprovoked first event and obesity. Carriers of the risk alleles of F5 rs6025 (HR=1.7 (95 % CI; 1.1–2.6)) and F11 rs2289252 (HR=1.8 (95 % CI; 1.1–3.0)) had significantly higher rates of recurrence compared to non-carriers. The cumulative recurrence was 2.5-fold larger in carriers of both F5 rs6025 and F11 rs2289252 than in non-carriers at five years follow-up. In conclusion, F5 rs6025 and F11 rs2289252 contributed to the risk of recurrent VTE and the combination is of potential clinical relevance for risk prediction.
Supplementary Material to this article is available online at www.thrombosis-online.com.
-
References
- 1 Martinez C, Cohen AT, Bamber L. et al. Epidemiology of first and recurrent venous thromboembolism: A population-based cohort study in patients without active cancer. Thromb Haemost 2014; 112: 255-263.
- 2 Douketis JD, Gu CS, Schulman S. et al. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med 2007; 147: 766-774.
- 3 Zoller B, Ohlsson H, Sundquist J. et al. Family history of venous thromboembolism (VTE) and risk of recurrent hospitalization for VTE: a nationwide family study in Sweden. J Thromb Haemost 2014; 12: 306-312.
- 4 Coppens M, Reijnders JH, Middeldorp S. et al. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost 2008; 06: 1474-1477.
- 5 Eichinger S, Heinze G, Jandeck LM. et al. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010; 121: 1630-1636.
- 6 Rodger MA, Kahn SR, Wells PS. et al. Identifying unprovoked thromboembol-ism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179: 417-426.
- 7 Tosetto A, Iorio A, Marcucci M. et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10: 1019-1025.
- 8 Vlieg A, Flinterman LE, Bare LA. et al. Genetic variations associated with recurrent venous thrombosis. Circulation Cardiovasc Gen 2014; 07: 806-813.
- 9 Bruzelius M, Bottai M, Sabater-Lleal M. et al. Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors. J Thromb Haemost 2015; 13: 219-227.
- 10 Ljungqvist M, Sonnevi K, Bergendal A. et al. Risk factors for recurrent venous thromboembolism in young and middle-aged women. Thromb Res 2014; 133: 762-767.
- 11 Bergendal A, Bremme K, Hedenmalm K. et al. Risk factors for venous throm-boembolism in pre-and postmenopausal women. Thromb Res 2012; 130: 596-601.
- 12 Cause of Death Register [Dödsorsakregistret]. Socialstyrelsen [National Board of Health and Welfare]. http://www.socialstyrelsen.se/register/dodsorsaksregistret
- 13 National Inpatient Register [Patientregistret] Socialstyrelsen [National Board of Health and Welfare]. http://www.socialstyrelsen.se/register/halsodataregister/patientregistret
- 14 Rovite V, Maurins U, Megnis K. et al. Association of F11 polymorphism rs2289252 with deep vein thrombosis and related phenotypes in population of Latvia. Thromb Res 2014; 134: 659-663.
- 15 Li Y, Bezemer ID, Rowland CM. et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost 2009; 07: 1802-1808.
- 16 Doggen CJ, Rosendaal FR, Meijers JC. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: Opposite and synergistic effects of factors XI and XII. Blood 2006; 108: 4045-4051.
- 17 Gailani D, Smith SB. Structural and functional features of factor XI. J Thromb Haemost 2009; 07 (Suppl. 01) 75-78.
- 18 Meijers JC, Tekelenburg WL, Bouma BN. et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342: 696-701.
- 19 Tucker EI, Marzec UM, White TC. et al. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI. Blood 2009; 113: 936-944.
- 20 Yang DT, Flanders MM, Kim H. et al. Elevated factor XI activity levels are associated with an increased odds ratio for cerebrovascular events. Am J Clin Pathol 2006; 126: 411-415.
- 21 Fjellstrom O, Akkaya S, Beisel HG. et al. Creating Novel Activated Factor XI Inhibitors through Fragment Based Lead Generation and Structure Aided Drug Design. PLoS One 2015; 10: e0113705.
- 22 Buller HR, Bethune C, Bhanot S. et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372: 232-240.
- 23 Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet 2010; 376: 2032-2039.
- 24 de Haan HG, Bezemer ID, Doggen CJ. et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012; 120: 656-663.
- 25 van Hylckama Vlieg A, Flinterman LE, Bare LA. et al. Genetic variations associated with recurrent venous thrombosis. Circulation Cardiovasc Gen 2014; 07: 806-813.
- 26 Dentali F, Sironi AP, Ageno W. et al. Non-O blood type is the commonest genetic risk factor for VTE: results from a meta-analysis of the literature. Semin Thromb Hemost 2012; 38: 535-548.
- 27 Heit JA, Cunningham JM, Petterson TM. et al. Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism. J Thromb Haemost 2011; 09: 1133-1142.
- 28 Gandara E, Kovacs MJ, Kahn SR. et al. Non-OO blood type influences the risk of recurrent venous thromboembolism. A cohort study. Thromb Haemost 2013; 110: 1172-1179.
- 29 Roach RE, Lijfering WM, Rosendaal FR. et al. Sex difference in risk of second but not of first venous thrombosis: paradox explained. Circulation 2014; 129: 51-56.
- 30 Ost D, Tepper J, Mihara H. et al. Duration of anticoagulation following venous thromboembolism: a meta-analysis. J Am Med Assoc 2005; 294: 706-715.