CHANGES IN THE PARAMETERS OF THROMBODYNAMICS AND BLOOD CLOT CONTRACTION IN PATIENTS WITH RHEUMATOID ARTHRITIS

Autoimmune diseases, including rheumatoid arthritis (RA), are risk factors for thrombotic events. Understanding the pathogenetic role of hemostatic changes in RA can assist in developing measures for prevention, prognosis, early diagnosis, and treatment of immune thromboses.
Objective: to investigate the state of platelet and plasma hemostasis in patients with RA, as compared to other laboratory parameters and clinical manifestations of the disease.
Subjects and methods. Hemostasis was investigated using two relatively new laboratory tests: thrombodynamics and kinetics of blood clot contraction (BCC). Examinations were made in 60 patients with RA and in 50 apparently healthy individuals of the control group.
Results and discussion. In patients with RA, the parameters of thrombodynamics and BCC were found to be significantly different from the normal values. According to thrombodynamics, there was an increase in plasma clot growth rate, size, and density, which indicates chronic hypercoagulation. The rate and completeness of BCC were substantially reduced due to platelet dysfunction in patients with RA compared to healthy individuals. The changes in the parameters of thrombodynamics and BCC correlated with the laboratory signs of systemic inflammation and depended on the radiographic stage of the disease.
Conclusion. The results of this investigation confirm that hemostatic disorders are present in RA and indicate the informative value of thrombodynamics and BCC tests as indicators of a pre-thrombotic state, including autoimmune pathology.

1. Mameli A, Barcellona D, Marongiu F. Rheumatoid arthritis and thrombosis. Сlin Exp Rheumatol. 2009;27(5):846-55.

2. Галушко ЕА, Насонов ЕЛ. Распространенность ревматических заболеваний в России. Альманах клинической медицины. 2018;46(1):32-9. doi: 10.18786/2072-0505-2018-46-1-32-39 [Galushko EA, Nasonov EL. Prevalence of rheumatic diseases in Russia. Al'manakh Klinicheskoi Meditsiny = Almanac of Clinical Medicine. 2018;46(1):32-9. doi: 10.18786/2072-0505-2018-46-1-32-39 (In Russ.)].

3. Olumuyiwa-Akeredolu OO, Page MJ, Soma P, Pretorius E. Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Nat Rev Rheumatol. 2019;15(4):237-48. doi: 10.1038/s41584-019-0187-9

4. Stack JR, Madigan A, Helbert L, et al. Soluble glycoprotein VI, a specific marker of platelet activation is increased in the plasma of subjects with seropositive rheumatoid arthritis. PLoS One. 2017;12(11):e0188027. doi: 10.1371/journal.pone.0188027

5. Van den Oever IA, Sattar N, Nurmohamed MT. Thromboembolic and cardiovascular risk in rheumatoid arthritis: role of the haemostatic system. Ann Rheum Dis. 2014;73(6):954-7. doi: 10.1136/annrheumdis-2013-204767

6. Сатыбалдыева МА, Решетняк ТМ, Середавкина НВ и др. Факторы риска венозных тромбозов у больных ревматоидным артритом. Научно-практическая ревматология. 2018;56(6):692-6. doi: 10.14412/1995-4484-2018-692-696 [Satybaldyeva MA, Reshetnyak TM, Seredavkina NV, et al. Risk factors for venous thromboses in patients with rheumatoid arthritis. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2018;56(6):692-6. doi: 10.14412/1995-4484-2018-692-696 (In Russ.)].

7. Сатыбалдыева МА, Решетняк ТМ, Середавкина НВ и др. Факторы риска развития венозных тромбоэмболических осложнений у больных ревматоидным артритом. Научнопрактическая ревматология. 2016;54(4):398-403. doi: 10.14412/1995-4484-2016-398-403 [Satybaldyeva MA, Reshetnyak TM, Seredavkina NV, et al. Risk factors for venous thromboembolic events in patients with rheumatoid arthritis. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(4):398-403. doi: 10.14412/1995-4484-2016-398-403 (In Russ.)].

8. Сатыбалдыева МА. Ревматоидный артрит и венозные тромбоэмболические осложнения. Научно-практическая ревматология. 2016;54(4):456-62. doi: 10.14412/1995-4484-2016-456-462 [Satybaldyeva MA. Rheumatoid arthritis and venous thromboembolic events. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(4):456-62. doi: 10.14412/1995-4484-2016-456-462 (In Russ.)].

9. Чельдиева ФА, Решетняк ТМ. Ревматоидный артрит: некоторые компоненты гемостаза и воспаление. Современная ревматология. 2019;13(3):87-94. doi: 10.14412/1996-7012-2019- 3-87-94 [Cheldieva FA, Reshetnyak TM. Rheumatoid arthritis: some components of hemostasis and inflammation. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2019;13(3):87-94. doi: 10.14412/1996-7012-2019-3-87-94 (In Russ.)].

10. 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;33(3):297-304. doi: 10.1007/s10067-014-2492-7

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

12. Zoller B, Li X, Sundquist J, et al. Autoimmune diseases and venous thromboembolism: a review of the literature. Am J Cardiovasc Dis. 2012;2:171-83.

13. Beinsberger J, Heemskerk JW, Cosemans JM. Chronic arthritis and cardiovascular disease: altered blood parameters give rise to a prothrombotic propensity. Semin Arthritis Rheum. 2014;44(3):345-52. doi: 10.1016/j.semarthrit.2014.06.006

14. Melki I, Tessandier N, Zufferey A, Boilard E. Platelet microvesicles in health and disease. Platelets. 2017;28(3):214-21. doi: 10.1080/09537104.2016.1265924

15. Santos MJ, Carmona-Fernandes D, Canhä o H, et al. Early vascular alterations in SLE and RA patients – a step towards understanding the associated cardiovascular risk. PLoS One. 2012;7(9):e44668. doi: 10.1371/journal.pone.0044668

16. Juhan-Vague I, Pyke SD, Alessi MC, et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation. 1996;94(9):2057-63. doi: 10.1161/01.CIR.94.9.2057

17. Sinauridze EI, Vuimo TA, Tarandovskiy ID, et al. Thrombodynamics, a new global coagulation test: Measurement of heparin efficiency. Talanta. 2018;180:282-91. doi: 10.1016/j.talanta.2017.12.055

18. Balandina AN, Koltsova EM, Teterina TA, et al. An enhanced clot growth rate before in vitro fertilization decreases the probability of pregnancy. PLoS One. 2019;14(5):e0216724. doi: 10.1371/journal.pone.0216724

19. Tutwiler V, Litvinov RI, Lozhkin AP, et al. Kinetics and mechanics of clot contraction are governed by molecular and cellular blood composition. Blood. 2016;127(1):149-59. doi: 10.1182/blood-2015-05-647560

20. Tutwiler V, Peshkova AD, Andrianova IA, et al. Blood clot contraction is impaired in acute ischemic stroke. Arterioscler Thromb Vasc Biol. 2017;37(2):271-9. doi: 10.1161/ATVBAHA.116.308622

21. Le Minh G, Peshkova AD, Andrianova IA, et al. Impaired contraction of blood clots is a novel prothrombotic mechanism in systemic lupus erythematosus. Clin Sci. 2018;232(2):243-54. doi: 10.1042/CS20171510

22. Каратеев ДЕ, Олюнин ЮА, Лучихина ЕЛ. Новые квалификационные критерии ревмтоидного артита ACR/EULAR 2019 шаг вперед к ранней диагностике. Научно-практическая ревматология. 2011;49(1):10-15. doi: 10.14412/1995-4484-2011-861 [Karateev DE, Olyunin YuA, Luchikhina EL. New ACR/EULAR 2010 classification criteria for rheumatoid arthritis: a step forward in its early diagnosis. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2011;49(1):10-5. doi: 10.14412/1995-4484-2011-861 (In Russ.)].

23. Costabile M. Measuring the 50% haemolytic complement (CH50) activity of serum. J Vis Exp. 2010;37:e1923. doi: 10.3791/1923

24. Magnusson M, Gunnarsson M, Berntorp E, et al. Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans. Eur J Pharmacol. 2008;581(3):290-5. doi: 10.1016/j.ejphar.2007.11.054

25. Chung WS, Peng CL, Lin CL, et al. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Ann Rheum Dis. 2014;73(10):1774-80. doi: 10.1136/annrheumdis-2013-203380

26. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107(9):1303-7. doi: 10.1161/01.CIR.0000054612.26458.B2

27. Kim KJ, Baek IW, Park KS, Association between antiphospholipid antibodies and arterial thrombosis in patients with rheumatoid arthritis. Lupus. 2017;26(1):88-94. doi: 10.1177/0961203316658557

28. Tü rk SM, Cansu DÜ, Teke HÜ, et al. Can we predict thrombotic tendency in rheumatoid arthritis? A thromboelastographic analysis (with ROTEM). Clin Rheumatol. 2018;37(9):2341-9. doi: 10.1007/s10067-018-4134-y

29. Gö bel K, Eichler S, Wiendl H, et al. The coagulation factors fibrinogen, thrombin, and factor XII in inflammatory disorders – a systematic review. Front Immunol. 2018;9:1731. doi: 10.3389/fimmu.2018.01731

30. Peshkova AD, Safiullina SI, Evtugina NG, et al. Premorbid hemostasis in women with a history of pregnancy loss. Thromb Haemost. 2019;119(12):1994-2004. doi: 10.1055/s-0039-1696972

31. Peshkova AD, Malyasev DV, Bredikhin RA, et al. Contraction of blood clots is impaired in deep vein thrombosis. BioNanoScience. 2016,6(4):457-9. doi: 10.1007/s12668-016-0251-8

32. Olumuyiwa-Akeredolu OO, Pretorius E. Platelet and red blood cell interactions and their role in rheumatoid arthritis. Rheumatol Int. 2015;35(12):1955-64. doi: 10.1007/s00296-015-3300-7

33. Yazici S, Yazici M, Erer B, et al. The platelet indices in patients with rheumatoid arthritis: mean platelet volume reflects disease activity. Platelets. 2010;21(2):122-5. doi: 10.3109/09537100903474373

34. Gasparyan AY, Stavropoulos-Kalinoglou A, Mikhailidis DP, et al. Platelet function in rheumatoid arthritis: arthritic and cardiovascular implications. Rheumatol Int. 2011;31(2):153-64. doi: 10.1007/s00296-010-1446-x

35. Habets KL, Trouw LA, Levarht EW, et al. Anti-citrullinated protein antibodies contribute to platelet activation in rheumatoid arthritis. Arthritis Res Ther. 2015;17:209. doi: 10.1186/s13075-015-0665-7

36. Heemskerk JW, Kuijpers MJ, Munnix IC, Siljander PR. Platelet collagen receptors and coagulation. A characteristic platelet response as possible target for antithrombotic treatment. Trends Cardiovasc Med. 2005;15(3):86-92. doi: 10.1016/j.tcm.2005.03.003

37. Vasina EM, Cauwenberghs S, Staudt M, et al. Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. Am J Blood Res. 2013;3(2):107-23.

38. Litvinov RI, Nabiullina RM, Zubairova LD, et al. Lytic susceptibility, structure, and mechanical properties of fibrin in systemic lupus erythematosus. Front Immunol. 2019;10:1626. doi: 10.3389/fimmu.2019.01626