Invited Editorial Focus

Recurrent venous thromboembolism: a role for ABO blood group? Francesco Dentali1; Massimo Franchini2 1Department

of Clinical and Experimental Medicine University of Insubria, Varese, Italy; 2Department of Transfusion Medicine and Hematology, “C. Poma” Hospital, Mantova, Italy

Venous thromboembolism (VTE), i.e. deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major health concern worldwide as it affects approximately 70-100 persons per 100,000 annually and results in significant morbidity and mortality (1). Important consequences of a venous thromboembolic event include a delayed hospital discharge or need for readmission, complications from short-term or long-term anticoagulation, recurrent thromboembolism, post-thrombotic syndrome and death. The research in this field has been focused mainly on the identification of possible risk factors for VTE and the identification of ‘high risk’ subgroups (2-4). On the other hand, studies evaluating potential risk factors for recurrence are more limited leaving a substantial grade of uncertainty on the optimal duration of treatment in particular in case of unprovoked events (5). In some populations, VTE may even be under-recognised and under-treated (6). Among the various genetic and acquired VTE risk factors identified (7, 8), there is a growing interest towards the ABO blood groups, due to its profound influence on haemostasis exerted mostly through a direct effect on von Willebrand factor (VWF) and, consequently, factor (F)VIII plasma levels (9-11). Indeed, it is well known that VWF levels are approximately 25% higher in individuals who have blood groups other than O (12).

Correspondence to: Francesco Dentali, MD Department of Clinical and Experimental Medicine University of Insubria, Ospedale di Circolo Fondazione Macchi Viale Borri 57, 21100 Varese, Italy Tel.: +39 0332 278594, Fax: +39 0332 278229 E-mail: [email protected] Received: October 1, 2013 Accepted after minor revision: October 2, 2013 Prepublished online: October 17, 2013 doi:10.1160/TH13-09-0780 Thromb Haemost 2013; 110: 1110–1111

© Schattauer 2013

Among the several clinical studies searching for a possible role of ABO blood type on the risk of developing arterial or thrombotic thrombotic adverse events, the most striking evidences regard a significant association between non-O blood type and unprovoked VTE (13), as observed also by a recent systematic review and meta-analysis of the literature including more than ten thousand VTE patients (14). Overall, the great majority of clinical studies agree to consider non-O blood group as one of the most important determinant of unprovoked VTE, being responsible for a moderate (about two-fold) increased risk (14-17). On the other hand, no study has analysed so far the association between ABO blood type and the risk of recurrent VTE following anticoagulant treatment, which represents on the most challenging issues in the management of these patients (18, 19). In the current issue of Thrombosis and Haemostasis, Gandara et al. have conducted a prospective study on the influence of non-O blood type on the risk of recurrent VTE, using the population of the REVERSE study (20, 21). This study, which followed a cohort of 509 patients with unprovoked VTE off oral anticoagulation therapy for a mean of 4.19 years, found a statistically significant difference in the rate of recurrent VTE events according to the different ABO blood types. Indeed, during 1,552 patient years, 101 events occurred in 380 non-OO patients (6.5 events per 100 patient years; 95% confidence interval [CI] 5.3-7.7) compared to 14 events during 560 patient years of follow up in 129 OO patients (2.4 per 100 patient years; 95% CI 1.3-3.7). Of note, this difference persisted also after adjustment for possible confounding factors such as sex, FVIII and post-thrombotic syndrome (adjusted hazard ratio 2.0; 95% CI 1.2-3.8). The results of this study are in keeping with those of another recent study (22), which assessed the role of ABO blood group on the presence of residual vein obstruction (RVO) a post-thrombotic condi-

tion that has been associated with an increased risk of VTE recurrence (23). Among the 268 patients with a first DVT enrolled, 126 (47%) developed RVO and, at a multivariate analysis, non-O blood group was significantly associated with an increased RVO risk (odds ratio [OR] 3.71), along with active malignancy (OR 5.54) and femoral involvement (OR 3.35) (22). In conclusion, we believe this study represents another important step forward in the understanding the complex relationship between ABO blood group and haemostasis. These findings, if further replicated in larger studies, may candidate ABO blood group as one of the main predictors of VTE recurrence to consider when we establish the duration of oral anticoagulant therapy in a single patient. Conflicts of interest

None declared.

This editorial reflects the view of its author(s) and is not representative of the view of the Editorial Board or the Publishers.

References 1. White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23 Suppl 1): I4-8. 2. Kyrle PA, Eichinger S. Clinical scores to predict recurrence risk of venous thromboembolism. Thromb Haemost 2012; 108: 1061-1064. 3. Thaler J, Ay C, Pabinger I. Venous thromboembolism in cancer patients - risk scores and recent randomised controlled trials. Thromb Haemost 2012;108: 1042-1048. 4. Spyropoulos AC, McGinn T, Khorana AA. The use of weighted and scored risk assessment models for venous thromboembolism. Thromb Haemost 2012; 108: 1072-1076. 5. Ageno W, Dentali F, Donadini MP, Squizzato A. Optimal treatment duration of venous thrombosis. J Thromb Haemost 2013; 11 (Suppl 1): 151-160.

Editorial on ▶Gandara et al. Thromb Haemost 2013; 1110: 1172-1179.

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Invited Editorial Focus 6. Angchaisuksiri P. Venous thromboembolism in Asia - an unrecognised and under-treated problem? Thromb Haemost 2011; 106: 585-590. 7. Wattanakit K, Lutsey PL, Bell EJ, et al. Association between cardiovascular disease risk factors and occurrence of venous thromboembolism. A timedependent analysis. Thromb Haemost 2012; 108: 508-515. 8. Bergrem A, Dahm AE, Jacobsen AF, et al. Differential haemostatic risk factors for pregnancy-related deep-vein thrombosis and pulmonary embolism: a population-based case-control study. Thromb Haemost 2012; 108: 1165-1171. 9. Franchini M, Favaloro EJ, Targher G, et al. ABO blood group, hypercoagulability, and cardiovascular and cancer risk. Crit Rev Clin Lab Sci 2012; 49: 137-149. 10. Franchini M, Liumbruno GM. ABO blood group: old dogma, new perspectives. Clin Chem Lab Med 2013; 51: 1545-1553. 11. Moeller A, Weippert-Kretschmer M, Prinz H, et al. Influence of ABO blood groups on primary hemostasis. Transfusion 2001; 41: 56–60. 12. Gill JC, Endres-Brooks J, Bauer PJ, et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695.

13. Wu O, Bayoumi N, Vickers MA, et al. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 62–69. 14. Dentali F, Sironi AP, Ageno W, et al. Non-O blood type is the commonest genetic risk factor for VTE: results from a metaanalysis of the literature. Semin Thromb Hemost 2012; 38: 535–548. 15. Muellner SK, Haut ER, Streiff MB, et al. ABO blood group as a potential risk factor for venous thromboembolism in acutely injured patients. Thromb Haemost 2011; 105: 5-13. 16. Jang MJ, Yhim HY, Lee JO, et al. ABO blood types are associated with risk of idiopathic venous thromboembolism in the Korean population. A report from the Korean Venous Thromboembolism Working Party (KVTEWP). Thromb Haemost 2012; 107: 799-801. 17. Tufano A, Coppola A, Nardo A, et al. Non-O blood group as a risk factor for cerebral vein thrombosis. Thromb Haemost 2013; 110: 197-199. 18. Le Gal G, Kovacs MJ, Carrier M, et al. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost 2010; 104: 498-503.

19. Lecumberri R, Alfonso A, Jiménez D, et al.; and the RIETE investigators. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013; 110: Epub ahead of print. 20. Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179: 417-426. 21. Gandara E, Kovacs MJ, Kahn KR, et al. Non-OO blood type influences the risk of recurrent venous thromboembolism. A cohort study. Thromb Haemost 2013; 110: 1172-1179. 22. Dentali F, Di Minno MND, Turato S, et al. Role of ABO blood group and of thrombophilic abnormalities on the presence of residual vein obstruction after deep-vein thrombosis of the lower limbs. J Thromb Haemost 2013; 11 (Suppl. 2): 392 (abstract). 23. Cosmi B, Legnani C, Pengo V, et al.; PROLONG Investigators (on behalf of FCSA, Italian Federation of Anticoagulation Clinics). The influence of factor V Leiden and G20210A prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs. Thromb Haemost 2013; 109: 510-516.

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© Schattauer 2013

Recurrent venous thromboembolism: a role for ABO blood group?

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