Plasmapheresis for lowering the risks of placenta-associated complications in antiphospholipid syndrome

Aim: to study plasmapheresis (PP) effect on antiphospholipid syndrome (APS) treatment during preconception preparation and pregnancy.

Materials and Methods. A single-center, prospective, randomized, uncontrolled study was conducted. A total of 137 women aged 22 to 32 years diagnosed with APS-related habitual miscarriage were examined. The patients were stratified as follows: main group consisted of 73 patients underwent a PF course (7 procedures at preconception preparation stage); comparison group – 64 patients not underwent efferent therapy. Antiphospholipid antibodies (APA) circulation was determined by solid-phase immunofluorescence. PР was performed using an intermittent technique. The laboratory study included assessing titers of lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL), anti-β2-glycoprotein 1 antibodies (anti-β2-GP1) and anti-annexin V antibodies (anti-ANX). Antibody titers were measured before and after pregravid preparation.

Results. After PР, anti-β2-GР1 titers decreased by 66.6 % (p = 0.00001) in main group. In patients who underwent standard therapy without PР, no significant changes in circulation level of anti-β2-GР1 were noted. LA frequency in main and comparison group decreased by 57.3 % (p = 0.042) and 10.9 % (p = 0.69), respectively.

Conclusion. The frequency of detecting elevated AРA levels in women after a course of efferent therapy decreased significantly, whereas standard therapy showed no such effects. PР as part of complex therapy is more appropriate for achieving maximum effect.

1. Knight J.S., Branch D.W., Ortel T.L. Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management. BMJ. 2023;380:e069717. https://doi.org/10.1136/bmj-2021-069717.

2. Xu J., Chen D., Duan X. et al. The association between antiphospholipid antibodies and late fetal loss: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2019;98(12):1523–33. https://doi.org/10.1111/aogs.13665.

3. Xu J., Chen D., Tian Y. et al. Antiphospholipid antibodies increase the risk of fetal growth restriction: a systematic meta-analysis. Int J Clin Pract. 2022;2022:4308470. https://doi.org/10.1155/2022/4308470.

4. Alijotas-Reig J., Esteve-Valverde E., Anunciación-Llunell A. et al. Pathogenesis, diagnosis and management of obstetric antiphospholipid syndrome: a comprehensive review. J Clin Med. 2022;11(3):675. https://doi.org/10.3390/jcm11030675.

5. Pons-Estel G.J., Andreoli L., Scanzi F. et al. The antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun. 2017;76:10–20. https://doi.org/10.1016/j.jaut.2016.10.004.

6. Pignatelli P., Ettorre E., Menichelli D. et al. Seronegative antiphospholipid syndrome: refining the value of "non-criteria" antibodies for diagnosis and clinical management. Haematologica. 2020;105(3):562–72. https://doi.org/10.3324/haematol.2019.221945.

7. Petri M. Antiphospholipid syndrome. Transl Res. 2020;225:70–81. https://doi.org/10.1016/j.trsl.2020.04.006.

8. Navarro-Carpentieri D., Del Carmen Castillo-Hernandez M., Majluf-Cruz K. et al. Impact of classical risk factors for arterial or venous thrombosis in patients with antiphospholipid syndrome. Clin Appl Thromb Hemost. 2018;24(5):834–40. https://doi.org/10.1177/1076029617727859.

9. Antovic A., Sennström M., Bremme K., Svenungsson E. Obstetric antiphospholipid syndrome. Lupus Sci Med. 2018;5(1):e000197. https://doi.org/10.1136/lupus-2016-000197.

10. Chaturvedi S., Braunstein E.M., Brodsky R.A. Antiphospholipid syndrome: complement activation, complement gene mutations, and therapeutic implications. J Thromb Haemost. 2021;19(3):607–16. https://doi.org/10.1111/jth.15082.

11. Kim M.Y., Guerra M.M., Kaplowitz E. et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies. Ann Rheum Dis. 2018;77(4):549–55. https://doi.org/10.1136/annrheumdis-2017-212224.

12. Cohen D., Buurma A., Goemaere N.N. et al. Classical complement activation as a footprint for murine and human antiphospholipid antibodyinduced fetal loss. J Pathol. 2011;225(4):502–11. https://doi.org/10.1002/path.2893.

13. Shamonki J.M., Salmon J.E., Hyjek E., Baergen R.N. Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies. Am J Obstet Gynecol. 2007;196(2):167.e1–5. https://doi.org/10.1016/j.ajog.2006.10.879.

14. Tedesco F., Borghi M.O., Gerosa M. et al. Pathogenic role of complement in antiphospholipid syndrome and therapeutic implications. Front Immunol. 2018;9:1388. https://doi.org/10.3389/fimmu.2018.01388.

15. Tong M., Johansson C., Xiao F. et al. Antiphospholipid antibodies increase the levels of mitochondrial DNA in placental extracellular vesicles: Alarmin-g for preeclampsia. Sci Rep. 2017;7(1):16556. https://doi.org/10.1038/s41598-017-16448-5.

16. Pantham P., Viall C.A., Chen Q. et al. Antiphospholipid antibodies bind syncytiotrophoblast mitochondria and alter the proteome of extruded syncytial nuclear aggregates. Placenta. 2015;36(12):1463–73. https://doi.org/10.1016/j.placenta.2015.10.006.

17. Cole M.A., Gerber G.F., Chaturvedi S. Complement biomarkers in the antiphospholipid syndrome – approaches to quantification and implications for clinical management. Clin Immunol. 2023;257:109828. https://doi.org/10.1016/j.clim.2023.109828.

18. Mkaddem S.B., Benhamou M., Monteiro R.C. Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools. Front Immunol. 2019;10:811. https://doi.org/10.3389/fimmu.2019.00811.

19. Sevim E., Zisa D., Andrade D et al.; APS ACTION Investigators. Characteristics of patients with antiphospholipid antibody positivity in the APS ACTION International Clinical Database and repository. Arthritis Care Res. 2022;74(2):324–35. https://doi.org/10.1002/acr.24468.

20. Cervera R., Serrano R., Pons-Estel G.J. et al.; Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74(6):1011–8. https://doi.org/10.1136/annrheumdis-2013-204838.

21. Tong M., Viall C.A., Chamley L.W. Antiphospholipid antibodies and the placenta: a systematic review of their in vitro effects and modulation by treatment. Hum Reprod Update. 2015;21(1):97–118. https://doi.org/10.1093/humupd/dmu049.

22. Chamley L.W., Duncalf A.M., Mitchell M.D., Johnson P.M. Action of anticardiolipin and antibodies to beta2-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death. Lancet. 1998;352(9133):1037–8. https://doi.org/10.1016/s0140-6736(05)60080-3.

23. Di Simone N., Meroni P.L., de Papa N. et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I. Arthritis Rheum. 2000;43(1):140–50. https://doi.org/10.1002/1529-0131(200001)43:13.0.CO;2-P.

24. Carroll T.Y., Mulla M.J., Han C.S. et al. Modulation of trophoblast angiogenic factor secretion by antiphospholipid antibodies is not reversed by heparin. Am J Reprod Immunol. 2011;66(4):286–96. https://doi.org/10.1111/j.1600-0897.2011.01007.x.

25. Marchetti T., Ruffatti A., Wuillemin C. et al. Hydroxychloroquine restores trophoblast fusion affected by antiphospholipid antibodies. J Thromb Haemost. 2014;12(6):910–20. https://doi.org/10.1111/jth.12570.

26. Viall C.A., Chamley L.W. Histopathology in the placentae of women with antiphospholipid antibodies: a systematic review of the literature. Autoimmun Rev. 2015;14(5):446–71. https://doi.org/10.1016/j.autrev.2015.01.008.

27. Simopoulou M., Sfakianoudis K., Maziotis E. et al. The impact of autoantibodies on IVF treatment and outcome: a systematic review. Int J Mol Sci. 2019;20(4):892. https://doi.org/10.3390/ijms20040892.

28. Rolnik D.L., Nicolaides K.H., Poon L.C. Prevention of preeclampsia with aspirin. Am J Obstet Gynecol. 2022;226(2S):S1108-S1119. https://doi.org/10.1016/j.ajog.2020.08.045.

29. Sammaritano L.R. Antiphospholipid syndrome. Best Pract Res Clin Rheumatol. 2020;34(1):101463. https://doi.org/10.1016/j.berh.2019.101463.

30. Naru T., Khan R.S., Ali R. Pregnancy outcome in women with antiphospholipid syndrome on low-dose aspirin and heparin: a retrospective study. East Mediterr Health J. 2010;16(3):308–12.

31. Ambati A., Knight J.S., Zuo Y. Antiphospholipid syndrome management: a 2023 update and practical algorithm-based approach. Curr Opin Rheumatol. 2023;35(3):149–60. https://doi.org/10.1097/BOR.0000000000000932.

32. Pengo V., Denas G., Zoppellaro G. et al. Rivaroxaban vs warfarin in highrisk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365– 71. https://doi.org/10.1182/blood-2018-04-848333.

33. Schreiber K., Hunt B.J. Managing antiphospholipid syndrome in pregnancy. Thromb Res. 2019;181 Suppl 1:S41–S46. https://doi.org/10.1016/S0049-3848(19)30366-4.

34. Moreli J.B., Cirino Ruocco A.M., Vernini J.M. et al. Interleukin 10 and tumor necrosis factor-alpha in pregnancy: aspects of interest in clinical obstetrics. ISRN Obstet Gynecol. 2012;2012:230742. https://doi.org/10.5402/2012/230742.

35. Alijotas-Reig J., Esteve-Valverde E., Llurba E., Gris J.M. Treatment of refractory poor aPL-related obstetric outcomes with TNF-alpha blockers: maternal-fetal outcomes in a series of 18 cases. Semin Arthritis Rheum. 2019;49(2):314–8. https://doi.org/10.1016/j.semarthrit.2019.02.006.

36. Altobelli C., Anastasio P., Cerrone A. et al. Therapeutic plasmapheresis: a revision of literature. Kidney Blood Press Res. 2023;48(1):6678. https://doi.org/10.1159/000528556.

37. Kravchenko E.N., Goncharova A.A. Correlation between indicators of hemostasis system activity and antiphospholipid antibodies levels in women with miscarriage. [Korrelyacionnye svyazi mezhdu pokazatelyami aktivnosti svertyvayushchej sistemy krovi i soderzhaniem antifosfolipidnyh antitel u zhenshchin s nevynashivaniem beremennosti]. Ginekologiya. 2019;21(5):53–8. (In Russ.). https://doi.org/10.26442/20795696.2019.5.190668.

38. Kuneshko N.F., Dolgikh V.T., Ershov A.V., Karpitskaya S.A. Plasmapheresis effect on immunological parameters in patients with recurrent miscarriage associated with antiphospholipid syndrome. [Vliyanie plazmafereza na immunologicheskie pokazateli u pacientok s privychnym nevynashivaniem beremennosti na fone antifosfolipidnogo sindroma]. Vestnik SurGU. Medicina. 2022;(3):68–73. (In Russ.). https://doi.org/10.34822/2304-9448-2022-3.

39. 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.

40. 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.

41. Tektonidou M.G., Andreoli L., Limper M. et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78(10):1296–304. https://doi.org/10.1136/annrheumdis-2019-215213.

42. Santacruz J.C., Mantilla M.J., Rueda I. et al. Obstetric antiphospholipid syndrome from the perspective of a rheumatologist. Cureus. 2022;14(1):e21090. https://doi.org/10.7759/cureus.21090.

43. Hasan H., Surjancev I., Arnason J.A. et al. Corticosteroids, plasmapheresis, argatroban, rituximab, and sirolimus provided clinical benefit for catastrophic antiphospholipid syndrome in a patient with a history of heparin-induced thrombocytopenia. Case Rep Rheumatol. 2023;2023:3226278. https://doi.org/10.1155/2023/3226278.

44. Arias E.J., Bruck B., Vellimana A.K. et al. Plasmapheresis for management of antiphospholipid syndrome in the neurosurgical patient. Oper Neurosurg. 2019;16(4):E124–E129. https://doi.org/10.1093/ons/opy135.

45. Eremeeva D.R., Zainulina M.S., Dolgova J.S. et al. Use of plasmapheresis in treatment of patients with unfavorable anamnestic pregnancy outcomes coupled to antiphospholipid antibodies. [Ispol'zovanie plazmafereza v lechenii pacientok s neblagopriyatnymi iskhodami beremennostej v anamneze i nalichiem antifosfolipidnyh antitel.]. Obstetrics, Gynecology and Reproduction. 2021;15(1):22–31. (In Russ.). https://doi.org/10.17749/2313-7347/ob.gyn.rep.2021.105.