Антитела к комплексу фосфатидилсерин/протромбин у пациентов с антифосфолипидным синдромом

Решетняк Т.М., Чельдиева Ф.А., Черкасова М.В., Лила А.М., Насонов Е.Л. Антитела к комплексу фосфатидилсерин/протромбин у пациентов с антифосфолипидным синдромом. Терапевтический архив. 2022;94(5):628–634. DOI: 10.26442/00403660.2022.05.201488

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Reshetnyak TM, Cheldieva FA, Cherkasova MV, Lila AM, Nasonov EL. Antibodies to the phosphatidylserine/prothrombin complex in the diagnosis of antiphospholipid syndrome. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(5):628–634. DOI: 10.26442/00403660.2022.05.201488

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Аннотация

Цель. Определить значение антител к комплексу фосфатидилсерин/протромбин (анти-ФС/ПТ) у пациентов с системной красной волчанкой (СКВ) и антифосфолипидным синдромом (АФС).
Материалы и методы. В исследование включены 190 пациентов: 123 (64,7%) с достоверной СКВ и 55 (29%) – с первичным АФС. Контрольную группы оставили 100 относительно здоровых человек, сопоставимых по возрасту. Всем пациентам исследовались классические антифосфолипидные антитела, а также иммуноглобулин (Ig)G/IgM-анти-ФС/ПТ иммуноферментным анализом.
Результаты. На основании средних значений IgG/IgM-анти-ФС/ПТ группы контроля выделены уровни позитивности – среднее арифметическое (М) + 3 или 5 стандартных отклонений (SD): М+3SD и М+5SD. Уровни IgG-анти-ФС/ПТ выше 73,6 Ед/мл (M+5SD) диагностически более точные, для IgМ-анти-ФС/ПТ – выше 18,0 Ед/мл. IgG-анти-ФС/ПТ выявлены у 84 (44%) из 190 пациентов. Уровни выше диагностических выявлялись у 68 (65%) из 104 пациентов с АФС (55 – с первичным АФС и 59 – с СКВ+АФС). Тромбозы достоверно чаще отмечались у пациентов с IgG-анти-ФС/ПТ по сравнению с пациентами, негативными по IgG-анти-ФС/ПТ. Артериальные, но не венозные тромбозы ассоциировались с позитивностью по IgG-анти-ФС/ПТ.
Заключение. Частота выявления IgG-анти-ФС/ПТ у обследованных пациентов составила 44%, IgМ-анти-ФС/ПТ – 29% и их сочетание – 19% из 190 больных. Медиана уровней IgG-анти-ФС/ПТ достоверно выше у пациентов с АФС по сравнению с пациентами без АФС и контрольной группой. Тромбоз ассоциировался с позитивностью IgG-анти-ФС/ПТ. Артериальные тромбозы значимо чаще регистрировались у пациентов с IgG-анти-ФС/ПТ. Чувствительность IgG-анти-ФС/ПТ для достоверного АФС при уровнях позитивности более 73,6 Ед/мл составила 59%, специфичность – 92%, для IgМ-анти-ФС/ПТ – 35 и 91% соответственно.

Ключевые слова: антифосфолипидный синдром, системная красная волчанка, антитела к комплексу фосфатидилсерин/протромбин, антифосфолипидные антитела

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Aim. To determine the significance of antibodies to the phosphatidylserine/prothrombin complex (aPS/PT) in patients with systemic lupus erythematosus (SLE) antiphospholipid syndrome (APS).
Materials and methods. A total of 190 patients were included in the study: 123 (64.7%) with reliable SLE and 55 (29%) with PAPS. The control group included 100 relatively healthy subjects of comparable age. All patients were tested for classical aPL as well as IgG/IgM-anti-PS/PT by enzyme immunoassay.
Results. Based on the average values of IgG/IgM aPS/PT of the control group, the levels of positivity were allocated mean (M) + 3 or 5 standard deviations (SD): M+3SD and M+5SD. IgG aPS/PT levels above 73.6 U/ml (M+5SD) were more accurate diagnostic, for IgM aPS/PT – above 18.0 U/ml. IgG-aPS/PT were detected in 84 (44%) of 190 patients. Levels above diagnostic levels were detected in 68 (65%) of 104 patients with APS (55 with PAPS and 59 with SLE+APS). Thrombosis was significantly more common in patients with IgG aPS/PT compared with patients negative for IgG aPS/PT. Arterial but not venous thrombosis was associated with IgG aPS/PT positivity.
Conclusion. The frequency of detection of IgG aPS/PT in the examined patients was 44%, IgM aPS/PT – 29% and their combination – 19% of 190 patients. Half of the patients with probable APS had positive IgG aPS/PT and third – IgM aPS/PT. Median IgG aPS/PT were significantly higher in patients with APS compared to patients without APS and the control group. Thrombosis was associated with IgG aPS/PT. Arterial thrombosis was significantly more frequently reported in patients with IgG aPS/PT. The sensitivity of IgG aPS/PT for reliable APS at levels greater than 73.6 units/ml was 59%, specificity – 92%, for IgM aPS/PT – 35% and 91%, respectively.

Keywords: antiphospholipid syndrome, systemic lupus erythematosus, antibodies to phosphatidylserine/prothrombin complex, antiphospholipid antibodies

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Список литературы

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7. Radin M, Cecchi I, Foddai SG, et al. Validation of the Particle-Based Multi-Analyte Technology for Detection of Anti-Phosphatidyl Serine/Prothrombin Antibodies. Biomedicines. 2020;8(12):622. DOI:10.3390/biomedicines8120622
8. Devreese KMJ. How to Interpret Antiphospholipid Laboratory Tests. Curr Rheumatol Rep. 2020;22(8):38. DOI:10.1007/s11926-020-00916-5
9. Antovic A, Norberg EM, Berndtsson M, et al. Effects of direct oral anticoagulants on lupus anticoagulant assays in a real-life setting. Thromb Haemost. 2017;117(9):1700-4. DOI:10.1160/TH17-03-0204
10. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7(10):1737-40. DOI:10.1111/j.1538-7836.2009.03555.x
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12. Hoxha A, Banzato A, Ruffatti A, Pengo V. Detection of lupus anticoagulant in the era of direct oral anticoagulants. Autoimmun Rev. 2017;16(2):173-8. DOI:10.1016/j.autrev.2016.12.010
13. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306. DOI:10.1111/j.1538-7836.2006.01753.x
14. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. DOI:10.1002/art.1780400928

15. Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992;35(6):630-40. DOI:10.1002/art.1780350606

16. Bajaj SP, Rapaport SI, Fierer DS, et al. A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome. Blood. 1983;61(4):684-92.
17. Oosting JD, Derksen RH, Entjes HT, et al. Lupus anticoagulant activity is frequently dependent on the presence of beta 2-glycoprotein I. Thromb Haemost. 1992;67(5):499-502.
18. Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood. 1988;72(2):512-9.
19. Bertolaccini ML, Atsumi T, Koike T, et al. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb Haemost. 2005;93(2):289-97. DOI:10.1160/TH04-06-0382
20. Bardin N, Alessi MC, Dignat-George F, et al. Does the antiprothrombin antibodies measurement provide additional information in patients with thrombosis? Immunobiology. 2007;212(7):557-65. DOI:10.1016/j.imbio.2007.02.001
21. Žigon P, Čučnik S, Ambrožič A, et al. Antibodies to phosphatidylserine/prothrombin complex as an additional diagnostic marker of APS? Lupus. 2012;21(7):790-2. DOI:10.1177/0961203312444173
22. Shi H, Zheng H, Yin YF, et al. Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential diagnostic markers and risk predictors of venous thrombosis and obstetric complications in antiphospholipid syndrome. Clin Chem Lab Med. 2018;56(4):614-24. DOI:10.1515/cclm-2017-0502
23. Ruffatti A, Del Ross T, Ciprian M, et al; Antiphospholipid Syndrome Study Group of Italian Society of Rheumatology. Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study. Ann Rheum Dis. 2011;70(6):1083-6. DOI:10.1136/ard.2010.142042
24. Reynaud Q, Lega JC, Mismetti P, et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev. 2014;13(6):595-608. DOI:10.1016/j.autrev.2013.11.004

25. Sciascia S, Sanna G, Murru V, et al. Anti-prothrombin (aPT) and antiphosphatidylserine/ prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb Haemost. 2014;111(2):354-64. DOI:10.1160/TH13-06-0509
26. Sciascia S, Sanna G, Murru V, et al. GAPSS: The Global Anti-Phospholipid Syndrome Score. Rheumatology (United Kingdom). 2013:52(8):1397-403.

DOI:10.1093/rheumatology/ kes388
27. Otomo K, Atsumi T, Amengual O, et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum. 2012;64(2):504-12. DOI:10.1002/art.33340
28. Sciascia S, Murru V, Sanna G, et al. Clinical Accuracy for Diagnosis of Antiphospholipid Syndrome in Systemic Lupus Erythematosus: Evaluation of 23 Possible Combinations of Antiphospholipid Antibody Specificities. J Thromb Haemost. 2012;10(12):2512-8. DOI:10.1111/jth.12014
29. Fabris M, Giacomello R, Poz A, et al. The Introduction of Anti-Phosphatidylserine/Prothrombin Autoantibodies in the Laboratory Diagnostic Process of Anti-Phospholipid Antibody Syndrome: 6 Months of Observation. Autoimmun Highlights. 2014;5(2):63-7. DOI:10.1007/s13317-014-0061-3
30. Sciascia S, Radin M, Cecchi I, et al. Reliability of Lupus Anticoagulant and Anti-phosphatidylserine/prothrombin Autoantibodies in Antiphospholipid Syndrome: A Multicenter Study. Front Immunol. 2019;10:376. DOI:10.3389/fimmu.2019.00376
31. Atsumi T, Amengual O, Yasuda S, Koike T. Antiprothrombin antibodies-are they worth assaying? Thromb Res. 2004;114(5-6):533-8. DOI:10.1016/j.thromres.2004.08.024; PMID: 15507288

________________________________________________

1. Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018;378(21):2010-21. DOI:10.1056/NEJMra1705454
2. Nasonov EL. Antifosfolipidnyi sindrom. Moscow: Littera, 2008 (in Russian).
3. Reshetnyak TM, Cheldieva FA, Nurbaeva KS, et al. Antiphospholipid syndrome: diagnosis, mechanism of development, therapy issues. Tromboz, gemostaz i reologiya. 2020;4:4-21 (in Russian). DOI:10.25555/THR.2020
4. Schreiber K, Sciascia S, de Groot PG, et al. Antiphospholipid syndrome. Nat Rev Dis Primers. 2018;4:17103. DOI:10.1038/nrdp.2017.103
5. Reshetnyak TM. Antiphospholipid syndrome: diagnosis and clinical manifestations (lecture). Nauchno-prakticheskaya revmatologiya. 2014;52(1):56-71 (in Russian).
6. Cheldieva FA, Reshetnyak TM, Lila AM. Antiphospholipid antibodies and their clinical significance. Tromboz, gemostaz i reologiya. 2021;(2):4-15 (in Russian).
7. Radin M, Cecchi I, Foddai SG, et al. Validation of the Particle-Based Multi-Analyte Technology for Detection of Anti-Phosphatidyl Serine/Prothrombin Antibodies. Biomedicines. 2020;8(12):622. DOI:10.3390/biomedicines8120622
8. Devreese KMJ. How to Interpret Antiphospholipid Laboratory Tests. Curr Rheumatol Rep. 2020;22(8):38. DOI:10.1007/s11926-020-00916-5
9. Antovic A, Norberg EM, Berndtsson M, et al. Effects of direct oral anticoagulants on lupus anticoagulant assays in a real-life setting. Thromb Haemost. 2017;117(9):1700-4. DOI:10.1160/TH17-03-0204
10. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7(10):1737-40. DOI:10.1111/j.1538-7836.2009.03555.x
11. Chaudhary R, Sharma T, Garg J, et al. Direct oral anticoagulants: a review on the current role and scope of reversal agents. J Thromb Thrombolysis. 2020;49(2):271-86. DOI:10.1007/s11239-019-01954-2
12. Hoxha A, Banzato A, Ruffatti A, Pengo V. Detection of lupus anticoagulant in the era of direct oral anticoagulants. Autoimmun Rev. 2017;16(2):173-8. DOI:10.1016/j.autrev.2016.12.010
13. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306. DOI:10.1111/j.1538-7836.2006.01753.x
14. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. DOI:10.1002/art.1780400928
15. Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992;35(6):630-40. DOI:10.1002/art.1780350606
16. Bajaj SP, Rapaport SI, Fierer DS, et al. A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome. Blood. 1983;61(4):684-92.
17. Oosting JD, Derksen RH, Entjes HT, et al. Lupus anticoagulant activity is frequently dependent on the presence of beta 2-glycoprotein I. Thromb Haemost. 1992;67(5):499-502.
18. Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood. 1988;72(2):512-9.
19. Bertolaccini ML, Atsumi T, Koike T, et al. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb Haemost. 2005;93(2):289-97. DOI:10.1160/TH04-06-0382
20. Bardin N, Alessi MC, Dignat-George F, et al. Does the antiprothrombin antibodies measurement provide additional information in patients with thrombosis? Immunobiology. 2007;212(7):557-65. DOI:10.1016/j.imbio.2007.02.001
21. Žigon P, Čučnik S, Ambrožič A, et al. Antibodies to phosphatidylserine/prothrombin complex as an additional diagnostic marker of APS? Lupus. 2012;21(7):790-2. DOI:10.1177/0961203312444173
22. Shi H, Zheng H, Yin YF, et al. Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential diagnostic markers and risk predictors of venous thrombosis and obstetric complications in antiphospholipid syndrome. Clin Chem Lab Med. 2018;56(4):614-24. DOI:10.1515/cclm-2017-0502
23. Ruffatti A, Del Ross T, Ciprian M, et al; Antiphospholipid Syndrome Study Group of Italian Society of Rheumatology. Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study. Ann Rheum Dis. 2011;70(6):1083-6. DOI:10.1136/ard.2010.142042
24. Reynaud Q, Lega JC, Mismetti P, et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev. 2014;13(6):595-608. DOI:10.1016/j.autrev.2013.11.004
25. Sciascia S, Sanna G, Murru V, et al. Anti-prothrombin (aPT) and antiphosphatidylserine/ prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb Haemost. 2014;111(2):354-64. DOI:10.1160/TH13-06-0509
26. Sciascia S, Sanna G, Murru V, et al. GAPSS: The Global Anti-Phospholipid Syndrome Score. Rheumatology (United Kingdom). 2013:52(8):1397-403.
DOI:10.1093/rheumatology/ kes388
27. Otomo K, Atsumi T, Amengual O, et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum. 2012;64(2):504-12. DOI:10.1002/art.33340
28. Sciascia S, Murru V, Sanna G, et al. Clinical Accuracy for Diagnosis of Antiphospholipid Syndrome in Systemic Lupus Erythematosus: Evaluation of 23 Possible Combinations of Antiphospholipid Antibody Specificities. J Thromb Haemost. 2012;10(12):2512-8. DOI:10.1111/jth.12014
29. Fabris M, Giacomello R, Poz A, et al. The Introduction of Anti-Phosphatidylserine/Prothrombin Autoantibodies in the Laboratory Diagnostic Process of Anti-Phospholipid Antibody Syndrome: 6 Months of Observation. Autoimmun Highlights. 2014;5(2):63-7. DOI:10.1007/s13317-014-0061-3
30. Sciascia S, Radin M, Cecchi I, et al. Reliability of Lupus Anticoagulant and Anti-phosphatidylserine/prothrombin Autoantibodies in Antiphospholipid Syndrome: A Multicenter Study. Front Immunol. 2019;10:376. DOI:10.3389/fimmu.2019.00376
31. Atsumi T, Amengual O, Yasuda S, Koike T. Antiprothrombin antibodies-are they worth assaying? Thromb Res. 2004;114(5-6):533-8. DOI:10.1016/j.thromres.2004.08.024; PMID: 15507288

Авторы

Т.М. Решетняк*1,2, Ф.А. Чельдиева1,2, М.В. Черкасова1, А.М. Лила1,2, Е.Л. Насонов1,3

1 ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой», Москва, Россия;
2 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
3 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия

*t_reshetnyak@yahoo.com

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Tatiana M. Reshetnyak*1,2, Fariza A. Cheldieva1,2, Mariya V. Cherkasova1, Aleksander M. Lila1,2, Evgeny L. Nasonov1,3

1 Nasonova Research Institute of Rheumatology, Moscow, Russia;
2 Russian Medical Academy of Continuous Professional Education, Moscow, Russia;

3 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia

*t_reshetnyak@yahoo.com

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