Risk factors for venous thromboembolic events in patients with rheumatoid arthritis

Objective: to determine the incidence and risk factors of venous thromboembolic events (VTEE) in patients with rheumatoid arthritis (RA).

Subjects and methods. The investigation enrolled 362 patients (302 women and 60 men) with RA fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism criteria. The patients' mean age was 53.7±13.3 years; the disease duration was 12.4±10.9 years. All the patients were treated at the V.A. Nasonova Research Institute of Rheumatology in the period 2014 to 2015. Each patient underwent standard clinical examination of peripheral joints. RA activity was assessed with DAS28. There was a questionnaire survey that included traditional risk factors for VTEE and risk factors that might be due to RA and its therapy.

Results and discussion. 34 (9.9%) patients were found to have VTEE during their hospitalization or in their history. In 32 of them thromboses were located in the veins of the lower extremities, namely 18 and 14 patients had thromboses in the distal and proximal segments, respectively. One patient was recorded to have upper extremity vein thrombosis and another had central retinal vein thrombosis. Lower extremity deep vein thrombosis was complicated by pulmonary thromboembolism in one case. Multivariate analysis has shown that the risk factors of VTEE in RA patients are bed care, heart failure, varicose vein disease, and oral administration of glucocorticoids (GC) and intraarticular GC administration (>5 injections); the weighted coefficients of the risk factors are 1.0, 0.92, 3.13, 0.02, and 0.52, respectively. According to the model obtained (p < 0.0001), the risk of VTEE can be predicted using the following formula: Z = 1.0 × bed care (yes, 1 / no, 0) + 0.92 × heart failure (yes, 1 / no, 0) + 3.13 × varicose vein disease (yes, 1 / no, 0) + 0.02 × oral GC use (yes, 1 / no, 0) + 0.52 × intraarticular GC administration (>5 injections; yes, 1 / none, 0).

Conclusion. The risk of VTEE should be assessed to timely prescribe adequate prophylactic treatment and to prevent thrombotic events in RA. The classification function value Z = 1.65 identifies groups of patients at high and low risk for VTEE. Accordingly, the value Z >1.65 determines the high risk of thrombosis; in this case it has a sensitivity of 64%, a specificity of 82%, and a positive prognostic accuracy of 80%.

1. Heit JA, Silverstein MD, Mohr DN, et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost. 2001;86:452-63. doi: 10.1161/ATVBAHA.108.162545

2. Савельев ВС, Чазов ЕИ, Гусев ИЕ и др. Российские клинические рекомендации по диагностике, лечению и профилактике венозных тромбоэмболических осложнений. Флебология. 2010;4(2):1-37 [Savel’ev VS, Chazov EI, Gusev IE, et al. Russian clinical recommendations for diagnosis, treatment and prevention of venous thromboembolic events. Flebologiya. 2010;4(2):1-37 (In Russ.)].

3. Zö ller B, Li X, Sundquist J, et al. Autoimmune diseases and venous thromboembolism: a review of the literature. Am J Cardiovasc Dis. 2012;2(3):171-83. Epub 2012 Jul 25.

4. Lijfering WM, Rosendaal FR, Cannegieter SC. Risk factors for venous thrombosis – current understanding from an epidemiological point of view. Br J Haematol. 2010 Jun;149(6):824-33. doi: 10.1111/j.1365-2141.2010.08206.x. Epub 2010 Apr 29.

5. Xu J, Lupu F, Esmon CT. Inflammation, innate immunity and blood coagulation. Hamostaseologie. 2010;30(5-6):8-9.

6. Dahlback B. Coagulation and inflammation-close allies in health and disease. Semin Immunopathol. 2012;34:1-3. doi: 10.1007/s00281-011-0298-0. Epub 2011 Nov 5.

7. Hoppe B, Dö rner T. Coagulation and the fibrin network in rheumatic disease: a role beyond haemostasis. Nat Rev Rheumatol. 2012 Dec;8(12):738-46. doi: 10.1038/nrrheum.2012.184. Epub 2012 Nov 13.

8. Harris ED Jr. Rheumatoid arthritis: pathophysiology band implications for therapy. N Engl J Med. 1990;322:1277-89. doi: 10.1056/NEJM199005033221805

9. Насонов ЕЛ, Каратеев ДЕ, Балабанова РМ. Ревматоидный артрит. В кн.: Насонов ЕЛ, Насонова ВА, редакторы. Ревматология. Национальное руководство. Москва: ГЭОТАР-Медиа; 2008. С. 290-331 [Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Nasonov EL, Nasonova VA, editors. Revmatologiya. Natsional'noe rukovodstvo [Rheumatology. National guidelines]. Moscow: GEOTAR-Media; 2008. P. 290-331].

10. Matta F, Singala R, Yaekoub AY, et al. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009 Jan;101(1):134-8. doi: 10.1160/TH08-08-0551

11. Ramagopalan SV, Wotton CJ, Handel AE, et al. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases record-linkage study. BMC Med. 2011;9:1-8. doi: 10.1186/1741-7015-9-1

12. Zoller B, Li X, Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders a nationwide follow-up study from Sweden. Lancet. 2012;379:244-9. doi: 10.1016/S0140- 6736(11)61306-8. Epub 2011 Nov 25.

13. Johannesdottir SA, Schmidt M, Horvath-Puho E, et al. Autoimmune skin and connective tissue diseases and risk of venous thromboembolism a population-based case-control study. J Thromb Haemost. 2012;10:815-21. doi: 10.1111/j.1538- 7836.2012.04666.x

14. Liang KP, Liang KV, Matteson EL, et al. Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations. Arthritis Rheum. 2006;54(2):642-8. doi: 10.1002/art.21628

15. Алекберова ЗС, Герасимова ЕВ, Голоева РГ, Насонов ЕЛ. Тромбозы и ревматические заболевания: частота встречаемости и механизмы развития (обзор и собственные данные). Научно-практическая ревматология. 2012;50(1):65- 71 [Alekberova ZS, Gerasimova EV, Goloeva RG, Nasonov EL. Thrombosis and rheumatic disease: frequency of occurrence and development mechanisms (review and own data). Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2012;50(1):65-71 (In Russ.)]. doi: 10.14412/1995-4484- 2012-507

16. Wei-Sheng Chung, Chiao-Ling Peng, Cheng-Li Lin, et al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Ann Rheum Dis. 2014;73:1774-80. doi: 10.1136/annrheumdis-2013- 203380. Epub 2013 Aug 7.

17. Kim SC, Schneeweiss S, Liu J, et al. The risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2013 Oct;65(10):1600-7. doi: 10.1002/acr.22039

18. Ungprasert P, Srivali N, Spanuchart I, et al. Risk of venous thromboembolism in patients with rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol. 2014 Mar;33(3):297-304. doi: 10.1007/s10067-014-2492-7. Epub 2014 Jan 15.

19. Яблоков ЕГ, Кириенко АИ, Богачев ВЮ. Хроническая венозная недостаточность. Москва; 1999. 126 с. [Yablokov EG, Kirienko AI, Bogachev VYu. Khronicheskaya venoznaya nedostatochnost' [Chronic venous insufficiency]. Moscow; 1999. 126 p.].

20. Hull RD, Raskob GE. Venous thromboembolic disease. Curr Opin Cardiol. 1991;6:750-6. doi: 10.1097/00001573-199110000- 00014

21. Strebel N, Prins M, Agnelli G, Bü ller HR. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med. 2002;162:1451-6. doi: 10.1001/archinte.162.13.1451

22. Perka C. Preoperative versus postoperative initiation of thromboprophylaxis following major orthopedic surgery: safety and efficacy of postoperative administration supported by recent trials of new oral anticoagulants. Thromb J. 2011 Nov 16;9:17. doi: 10.1186/1477-9560-9-17

23. Pottier P, Fouassier M, Hardouin JB, et al. D-dimers, thrombinantithrombin complexes, and risk factors for thromboembolism in hospitalized patient. Clin Appl Thromb Hemost. 2009 Dec;15(6):666-75. doi: 10.1177/1076029608321436. Epub 2008 Sep 15.

24. Gabriel SE. Cardiovascular morbidity and mortality in rheumatoid arthritis. Am J Med. 2008 Oct;121(10 Suppl 1):S9-14. doi: 10.1016/j.amjmed.2008.06.011

25. Myasoedova E, Crowson CS, Nicola PJ, et al. The influence of rheumatoid arthritis disease characteristics on heart failure. J Rheumatol. 2011 Aug;38(8):1601-6. doi: 10.3899/jrheum.100979. Epub 2011 May 15.

26. Alpaslan M, Onrat E, Evcik D. Doppler echocardiographic evaluation of ventricular function in patients with rheumatoid arthritis. Clin Rheumatol. 2003 May;22(2):84-8. doi: 10.1007/s10067-002- 0677-y

27. Di Franco M, Paradiso M, Mammarella A, et al. Diastolic function abnormalities in rheumatoid arthritis. Evaluation by echo Doppler transmitral flow and pulmonary venous flow: relation with duration of disease. Ann Rheum Dis. 2000 Mar;59(3):227-9. doi: 10.1136/ard.59.3.227

28. Brotman DJ, Girod JP, Posch A, et al. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers. Thromb Res. 2006;118(2):247-52. doi: 10.1016/j.thromres.2005.06.006

29. Сатыбалдыев АМ. Глюкокортикоидный синдром Кушинга в практике ревматолога (обзор литературы). Современная ревматология. 2013;7(4):78-84 [Satybaldyev AM. Cushing’s glucocorticoid syndrome in the practice of a rheumatologist (A review of literature). Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2013;7(4):78-84 (In Russ.)]. doi: 10.14412/1996-7012-2013-2443

30. Higgins PD, Skup M, Mulani PM, et al. Increased risk of venous thromboembolic events with corticosteroid vs biologic therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol. 2015 Feb;13(2):316-21. doi: 10.1016/j.cgh.2014.07.017. Epub 2014 Jul 17.

31. Tsai AW, Cushman M, Rosamond WD, et al. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002 May 27;162(10):1182-9. doi: 10.1001/archinte.162.10.1182

32. Lacut K, van der Maaten J, Le Gal G, et al. Antiplatelet drugs and risk of venous thromboembolism: results from the EDITH casecontrol study. Haematologica. 2008 Jul;93(7):1117-8. doi: 10.3324/haematol.12331

33. Biere-Rafi S, Di Nisio M, Gerdes V, et al. Non-steroidal antiinflammatory drugs and risk of pulmonary embolism. Pharmacoepidemiol Drug Saf. 2011 Jun;20(6):635-42. doi: 10.1002/pds.2130

34. Schmidt M, Christiansen CF, Horvath-Puho E, et al. Nonsteroidal anti-inflammatory drug use and risk of venous thromboembolism. J Thromb Haemost. 2011 Jul;9(7):1326-33. doi: 10.1111/j.1538-7836.2011.04354.x