Use of plasmapheresis in treatment of patients with unfavorable anamnestic pregnancy outcomes coupled to antiphospholipid antibodies

Aim: to evaluate efficacy of plasmapheresis combined with low molecular weight heparins (LMWH) and acetylsalicylic acid (ASA).

Materials and Methods. 327 plasmapheresis sessions were performed for 75 patients: 17 (22.6 %) patients during preparation for pregnancy, 11 (19.0 %) pregnant women in the first trimester, 33 (56.9 %) pregnant women in the second trimester, and 34 (58.6 %) pregnant women in the third trimester. Study inclusion criteria were as follows: high titers of antiphospholipid antibodies (APA) as well as included non-inclusion criteria in pregnant women with miscarriages and unfavorable anamnestic pregnancy outcome. 36 (62.1 %) women had pregnancy loss in anamnesis. All patients received low-dose ASA and LMWH therapy; 15 (25.86 %) pregnant women also received courses of intravenous immunoglobulins in the first and second trimesters.
Results. 47 pregnant women had delivery, whereas 10 of women had pregnancy in progress. Term delivery was in 40 (85.1 %) patients, so that 23 (48.9 %) pregnant women had delivery per vias naturales. The average weight of the fetus was 3364.00 ± 393.76 g, height - 52.13 ± 1.82 cm. In 100 % cases, Apgar score was 8 points. 24 (51.1%) pregnant women had delivery via cesarean section. The average blood loss comprised 528.64 ± 166.10 ml. The average fetal weight in group after surgical delivery was 2982.14 ± 582.88 g, average height - 49.14 ± 4.09 cm, the Apgar score - 7.69 ± 0.47 points. Preterm births were observed in 7 (14.9%) cases, all via cesarean section. In 1 case, early fetal death was at gestational age of 8/9 weeks; according to the karyotyping data, a fetal chromosomal abnormality was detected. No severe obstetric complications were observed.
Conclusions. Combining plasmapheresis with low dose LMWH and ASA therapy demonstrated high efficacy in treating obstetric APS manifested as high percentage of favorable pregnancy outcomes and low number of obstetric complications.

1. Cervera R., Piette J.C., Font J. et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):1019-27. https://doi.org/10.1002/art.10187.

2. Miyakis S., Lockshin M.D., 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. https://doi.org/10.1111/j.1538-12.7836.2006.01753.x.

3. 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. https://doi.org/10.1160/TH13-06-0509.

4. Reynaud Q., Lega J.C., 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 metaanalysis. Autoimm Rev. 2014;13(6):595-608. https://doi.org/10.1016/j.autrev.2013.11.004.

5. Hoxha A., Mattia E., Tonello M. et al. Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome. Clin Chem Lab Med. 2017;55(6):890-8. https://doi.org/10.1515/cclm-2016-0638.

6. Becarevic M. The IgG and IgM isotypes of anti-annexin A5 antibodies: relevance for primary antiphospholipid syndrome. J Thromb Thrombolysis. 2016;42(4):552-7. https://doi.org/10.1007/s11239-016-1389-5.

7. Sebire N.J., Fox H., Backos M. et al. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum Reprod. 2002;17(4):1067-71. https://doi.org/10.1093/humrep/17.4.1067.

8. Di Simone N., Marana R., Castellani R. et al. Decreased expression of heparin-binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipid-mediated defective placentation. Arthritis Rheum. 2010;62(5):1504-12. https://doi.org/10.1002/art.27361.

9. Abrahams V.M., Chamley L.W., Salmon J.E. Emerging treatment models in rheumatology: antiphospholipid syndrome and pregnancy: pathogenesis to translation. Arthritis Rheum. 2017;69(9):1710-21. https://doi.org/10.1002/art.40136.

10. D'Ippolito S., Meroni P.L., Koike T. et al. Obstetric antiphospholipid syndrome: a recent classification for an old defined disorder. Autoimmun Rev. 2014;13(9):901-8. https://doi.org/10.1016/j.autrev.2014.05.004.

11. Holers V.M., Girardi G., Mo L. et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med. 2002;195(2):211-20. https://doi.org/10.1084/jem.200116116.

12. Levine A.B., Lockshin M.D. Antiphospholipid syndrome. In: Contraception and pregnancy in patients with rheumatic disease. Eds. L.R. Sammaritano, B.L. Bermas. New York, NY: Springer, 2014. 109-137.

13. Ruffatti A., Favaro M., Calligaro A. et al. Management of pregnant women with antiphospholipid antibodies. Expert Rev Clin Immunol. 2019;15(4):347-58. https://doi.org/10.1080/1744666X.2019.1565995.

14. Rai R., Cohen H., Dave M., Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997;314(7076):253-7. https://doi.org/10.1136/bmj.314.7076.253.

15. Mak A., Cheung M.W., Cheak A.A., Ho R.C. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford). 2010;49(2):281-8. https://doi.org/10.1093/rheumatology/kep373.

16. Bates S.M., Greer I.A., Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-e736S. https://doi.org/10.1378/chest.11-2300.

17. Gris J.C., Bouvier S., Molinari N. et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study. Blood. 2012;119(11):2624-32. https://doi.org/10.1182/blood-2011-09-381913.

18. Thomsen A.J., Greer I.A. Thromboembolic disease in pregnancy and the puerperium: acute management (Green-top guideline no. 37b). Royal College of Obstetricians and Gynaecologists, 2015. 32 p. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37b.pdf. [Accessed: 12.12.2019].

19. Bao S.H., Sheng S.L., Liao H. et al. Use of D-dimer measurement to guide anticoagulant treatment in recurrent pregnancy loss associated with antiphospholipid syndrome. Am J Reprod Immunol. 2017;78(6):e12770. https://doi.org/10.1111/aji.12770.

20. Erkan D., Patel S., Nuzzo M. et al. Management of the controversial aspects of the antiphospholipid syndrome pregnancies: a guide for clinicians and researchers. Rheumatology (Oxford). 2008;47(Suppl 3):iii23-7. https://doi.org/10.1093/rheumatology/ken181.

21. Ruffatti A., Salvan E., Del Ross T. et al. Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity: a European multicentre retrospective study. Thromb Haemost. 2014;112(6):727-35. https://doi.org/10.1160/TH14120001.

22. Bramham K., Thomas M., Nelson-Piercy C. et al. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117(25):6948-51. https://doi.org/10.1182/blood-2011-02-339234.

23. Mekinian A., Lazzaroni M.G., Kuzenko A. et al. The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from a European multicenter retrospective study. Autoimmun Rev. 2015;14(6):498-502. https://doi.org/10.1016/j.autrev.2015.01.012.

24. Sciascia S., Hunt B.J., Talavera-Garcia E. et al. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol. 2016;214(2):273. e1-273.e8. https://doi.org/10.1016/j.ajog.2015.09.078.

25. Bertolaccini M.L., Contento G., Lennen R. et al. Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome. J Autoimmun. 2016;75:30-38. https://doi.org/10.1016/j.jaut.2016.04.008.

26. Mekinian A., Alijotas-Reig J., Carrat F. et al. Refractory obstetrical antiphospholipid syndrome: features, treatment and outcome in a European multicenter retrospective study. Autoimmun Rev. 2017;16(7):730-4. https://doi.org/10.1016/j.autrev.2017.05.006.

27. Saccone G., Berghella V., Maruotti G.M. et al. Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the PREGNANTS study. Am J Obstet Gynecol. 2017;216(5):525.e1-525. e12. https://doi.org/10.1016/j.ajog.2017.01.026.

28. Empson M., Lassere M., Craig J., Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2005;18(2):CD002859. https://doi.org/10.1002/14651858.CD002859.pub2.

29. Tenti S., Cheleschi S., Guidelli G.M. et al. Intravenous immunoglobulins and antiphospholipid syndrome: how, when and why? A review of the literature. Autoimmun Rev. 2016;15(3):226-35. https://doi.org/10.1016/j.autrev.2015.11.009.

30. Branch D.W., Peaceman A.M., Druzin M. et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. 2000;181(1 Pt 1):122-7. https://doi.org/10.1016/s0002-9378(00)70500-x.

31. Nakamura Y., Yoshida K., Itoh S. et al. Immunoadsorption plasmapheresis as a treatment for pregnancy complicated by systemic lupus erythematosus with positive antiphospholipid antibodies. Am J Reprod Immunol. 1999;41(5):307-11. https://doi.org/10.1111/j.1600-0897.1999.tb00443.x.

32. Bortolati M., Marson P., Chiarelli S. et al. Case reports of the use of immunoadsorption or plasma exchange in high-risk pregnancies of women with antiphospholipid syndrome. Ther Apher Dial. 2009;13(2):157-60. https://doi.org/10.1111/j.1744-9987.2009.00671.x.

33. Hauser A.C., Hauser L., Pabinger-Fasching I. et al. The course of anticardiolipin antibody levels under immunoadsorption therapy. Am J Kidney Dis. 2005;46(3):446-54. https://doi.org/10.1053/j.ajkd.2005.05.023.

34. El-Haieg D.O., Zanati M.F., El-Foual F.M. Plasmapheresis and pregnancy outcome in patients with antiphospholipid syndrome. Int J Gynaecol Obstet. 2007;99(3):236-41. https://doi.org/10.1016/j.ijgo.2007.05.045.

35. Ruffatti A., Marson P., Pengo V. et al. Plasma exchange in the management of high risk pregnant patients with primary antiphospholipid syndrome. A report of 9 cases and a review of the literature. Autoimmun Rev. 2007;6(3):196-202. https://doi.org/10.1016/j.autrev.2006.11.002.

36. Rose H.L., Ho W.K. Management of very high risk pregnancy with secondary anti-phospholipid syndrome and triple positivity to the antiphospholipid antibodies. J Thromb Thrombolysis. 2014;38(4):453-6. https://doi.org/10.1007/s11239-014-1080-7.

37. Mayer-Pickel K., Horn S., Lang U., Cervar-Zivkovic M. Response to plasmapheresis measured by angiogenic factors in a woman with antiphospholipid syndrome in pregnancy. Case Rep Obstet Gynecol. 2015;2015:123408. https://doi.org/10.1155/2015/123408.

38. Ruffatti A., Favaro M., Hoxha A. et al. Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study. J Reprod Immunol. 2016;115:14-9. https://doi.org/10.1016/j.jri.2016.03.004.