PATHOPHYSIOLOGICAL MECHANISMS OF OBSTETRIC ANTIPHOSPHOLIPID SYNDROME


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

To analyze the data of modern scientific literature on the possible pathophysiological mechanisms responsible for the development of obstetric antiphospholipid syndrome (APS), which are confirmed by the results of in vitro and in vivo experiments and histopathological studies. Material and methods. The review includes the data of foreign and Russian articles published in the past 10 years and found in Pubmed and eLIBRARY on this topic. Results. Since thrombotic events cannot explain all obstetric manifestations of APS, it is suggested that there are other pathophysiological mechanisms associated with the direct effect of antiphospholipid antibodies on the development and function of the placenta and its complement-mediated inflammation. Conclusion. Understanding the pathogenetic mechanisms extends the possibilities of targeted therapy in patients with APS, especially in those resistant to conventional therapy.

Full Text

Restricted Access

About the authors

Irina Vladimirovna MENZHINSKAYA

Email: i_menzinskaya@oparina4.ru
Ph.D., Senior Researcher, Laboratory of Clinical Immunology, Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia. Moscow 117997, Ac. Oparina str. 4, Russia

Lyudmila Viktorovna VANKO

Email: LVanko@oparina4.ru
MD, Professor, Leading Researcher, Laboratory of Clinical Immunology, Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia Moscow 117997, Ac. Oparina str. 4, Russia

References

  1. Pierangeli S.S., de Groot P.G., Dlott J., Favaloro E., Harris E.N., Lakos G. et al. ‘Criteria/ aPL tests: report of a task force and preconference workshop at the 13th International congress on antiphospholipid antibodies, Galveston, TX, USA, April 2010. Lupus. 2011; 20(2): 182-90.
  2. D’Ippolito S., Meroni P.L., Koike T., Veglia M., Scambia G., Di Simone N. Obstetric antiphospholipid syndrome: A recent classification for an old defined disorder. Autoimmun. Rev. 2014; 13(9): 901-8.
  3. Cervera R., Serrano R., Pons-Estel G.J., Ceberio-Hualde L., Shoenfeld Y., de Ramon E. et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicenter prospective study of 1000 patients. Ann. Rheum. Dis. 2015; 74(6): 1011-8.
  4. Бицадзе В.О., Хизроева Д.Х., Макацария Н.А., Егорова Е.С., Баймурадова С.М., Машкова Т.Я. Антифосфолипидные антитела, их патогенетическое и диагностическое значение при акушерской патологии. Акушерство, гинекология и репродукция. 2014; 8(2): 39-60. [Bitsadze V.O., Hizroeva D.H., Makatsariya N.A., Egorova E.S., Baymuradova S.M., Mashkova T.Ya. Antiphospholipid antibodies, their pathogenetic and diagnostic value in obstetric pathology. Akusherstvo, ginekologiya i reproduktsiya. 2014; 8(2): 39-60. (in Russian)]
  5. Менжинская И.В., Кашенцева М.М., Ионанидзе Т.Б., Ванько Л.В., Сухих Г.Т. Спектр антифосфолипидных антител у женщин с привычным невынашиванием беременности и их диагностическое значение. Иммунология. 2016; 37(1): 4-9. [Menzhinskaya I.V., Kashentseva M.M., Ionanidze T.B., Vanko L.V., Suhih G.T. Spectrum of antiphospholipid antibodies in women with habitual miscarriage and their diagnostic significance. Immunologiya. 2016; 37(1): 4-9. (in Russian)]
  6. Зиганшина М.М., Павлович С.В., Бовин Н.В., Сухих Г.Т. Гуморальное отторжение в генезе акушерской патологии. Акушерство и гинекология. 2013; 6: 3-10. [Ziganshina M.M., Pavlovich S.V., Bovin N.V., Sukhikh G.T. Humoral rejection in the genesis of obstetric pathology. Akusherstvo i Ginekologiya/ Obstetrics and Gynecology. 2013; (6): 3-10. (in Russian)]
  7. Pantham P., Abrahams V.M., Chamley L.W. The role of anti-phospholipid antibodies in autoimmune reproductive failure. Reproduction. 2016; 151(5): R79-90.
  8. Gardiner C., Hills J., Machin S.J., Cohen H. Diagnosis of antiphospholipid syndrome in routine clinical practice. Lupus. 2013; 22: 18-25.
  9. Peaceman A.M., Rehnberg K.A. The effect of immunoglobulin G fractions from patients with lupus anticoagulant on placental prostacyclin and thromboxane production. Am. J. Obstet. Gynecol. 1993; 169(6): 1403-6.
  10. Nayar R., Lage J.M. Placental changes in a first trimester missed abortion in maternal systemic lupus erythematosus with antiphospholipid syndrome; a case report and review of the literature. Hum. Pathol. 1996; 27(2): 201-6.
  11. Willis R., Harris E.N., Pierangeli S.S. Pathogenesis of the antiphospholipid syndrome. Semin. Thromb. Hemost. 2012; 38(4): 305-21.
  12. Oku K., Amengual O., Atsumi T. Pathophysiology of thrombosis and pregnancy morbidity in the antiphospholipid syndrome. Eur. J. Clin. Invest. 2012; 42(10): 1126-35.
  13. 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.
  14. Rand J.H., Wu X.X., Guller S., GH J., Guha A., Scher J., Lockwood C.J. Reduction of annexin-V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am. J. Obstet. Gynecol. 1994; 171(6): 1566-72.
  15. Rand J.H., Wu X.X., Guller S., Scher J., Andree H.A., Lockwood C.J. Antiphospholipid immunoglobulin G antibodies reduce annexin-V levels on syncytiotrophoblast apical membranes and in culture media of placental villi. Am. J. Obstet. Gynecol. 1997; 177(4): 918-23.
  16. Wang X., Campos B., Kaetzel M.A., Dedman J.R. Annexin V is critical in the maintenance of murine placental integrity. Am. J. Obstet. Gynecol. 1999; 180(4): 1008-16.
  17. Irman S., Skarabot M., Musevic I., Rozman B., Bozic B. The use of atomic force microscopy to study the pathologic effects of anti-annexin autoantibodies. J. Autoimmun. 2011; 36(2): 98-105.
  18. 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.
  19. 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.
  20. Adler R.R., Ng A.K., Rote N.S. Monoclonal antiphosphatidylserine antibody inhibits intercellular fusion of the choriocarcinoma line, JAR. Biol. Reprod. 1995; 53(4): 905-10.
  21. 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.
  22. Miyakis S., Robertson S.A., Krilis S.A. Beta-2 glycoprotein I and its role in antiphospholipid syndrome-lessons from knockout mice. Clin. Immunol. 2004; 112(2): 136-43.
  23. Kwak J.Y., Beer A.E., Kim S.H., Mantouvalos H.P. Immunopathology of the implantation site utilizing monoclonal antibodies to natural killer cells in women with recurrent pregnancy losses. Am. J. Reprod. Immunol. 1999; 41: 91-8.
  24. Sebire N.J., Fox H., Backos M., Rai R., Paterson C., Regan L. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum. Reprod. 2002; 17(4): 1067-71.
  25. Di Simone N., Castellani R., Raschi E., Borghi M.O., Meroni P.L., Caruso A. Antibeta-2 glycoprotein I antibodies affect Bcl-2 and Bax trophoblast expression without evidence of apoptosis. Ann. N. Y. Acad. Sci. 2006; 1069(1): 364-76.
  26. Chen Q., Viall C., Kang Y., Liu B., Stone P., Chamley L. Anti-phospholipid antibodies increase non-apoptotic trophoblast shedding: a contribution to the pathogenesis of pre-eclampsia in affected women? Placenta. 2009; 30(9): 767-73.
  27. Pantham P., Rosario R., Chen Q., Print C.G., Chamley L.W. Transcriptomic analysis of placenta affected by antiphospholipid antibodies: following the TRAIL of trophoblast death. J. Reprod. Immunol. 2012; 94(2): 151-4.
  28. Viall C.A., Chen Q., Liu B., Hickey A., Snowise S., Salmon J.E. et al. Antiphospholipid antibodies internalised by human syncytiotrophoblast cause aberrant cell death and the release of necrotic trophoblast debris. J. Autoimmun. 2013; 47: 45-57.
  29. Viall C.A., Holloway H., Chen Q., Stone P.R., Chamley L.W. Development of a simple, cost-effective, semi-correlative light and electron microscopy method to allow the immunoelectron localisation of non-uniformly distributed placental proteins Placenta. 2014; 35(3): 223-7.
  30. Mulla M.J., Brosens J.J., Chamley L.W., Giles I., Pericleous C., Rahman A. et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am. J. Reprod. Immunol. 2009; 62(2): 96-111.
  31. Mulla M.J., Salmon J.E., Chamley L.W., Brosens J.J., Boeras C.M., Kavathas P.B., Abrahams V.M. A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1beta production by human first trimester trophoblast. PLoS One. 2013; 8(6): e65237
  32. Marchetti T., Ruffatti A., Wuillemin C., de Moerloose P., Cohen M. Hydroxychloroquine restores trophoblast fusion affected by antiphospholipid antibodies. J. Thromb. Haemost. 2014; 12(6): 910-20.
  33. Di Simone N., Castellani R., Caliandro D., Caruso A. Antiphospholid antibodies regulate the expression of trophoblast cell adhesion molecules. Fertil. Steril. 2002; 77(4): 805-11.
  34. Di Simone N., Marana R., Castellani R., Di Nicuolo F., DAlessio M.C., Raschi E. et al. Decreased expression of heparin-binding epidermal growth factor-like growth factor as a newly identified pathogenic mechanism of antiphospholipidmediated defective placentation. Arthritis Rheum. 2010; 62(5): 1504-12.
  35. Kovacevic T.M., Radojcic L., Tosic N.M., Pavlovic S.T., Vicovac L.M. Monoclonal antibody 26 cross-reactive with beta2-glycoprotein I affects human trophoblast invasion in vitro. Eur. J. Obstet. Gynecol. Reprod. Biol. 2013; 171: 23-9.
  36. Albert C.R., Schlesinger W.J., Viall C.A., Mulla M.J., Brosens J.J., Chamley L.W., Abrahams V.M. Effect of hydroxychloroquine on antiphospholipid antibody-induced changes in first trimester trophoblast function. Am. J. Reprod. Immunol. 2014; 71(2): 154-64.
  37. Burton G.J., Jauniaux E. Oxidative stress. Best Pract. Res. Clin. Obstet. Gynaecol. 2011; 25(3): 287-99.
  38. Verlohren S., Geusens N., Morton J., Verhaegen I., Hering L., Herse F. et al. Inhibition of trophoblast-induced spiral artery remodeling reduces placental perfusion in rat pregnancy. Hypertension. 2010; 56(2): 304-10.
  39. Borghi M.O., Raschi E., Scurati S., Grossi C., Chen P.P., Pierangeli S.S., Meroni PL. Effects of a toll-like receptor antagonist and anti-annexin A2 antibodies on binding and activation of decidual cells by anti-ß2glycoprotein I antibodies. Clin. Exp. Rheumatol. 2007; 2: 35. abstr. 147.
  40. Francis J., Rai R., Sebire N.J., El-Gaddal S., Fernandes M.S., Jindal P. et al. Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome. Mol. Hum. Reprod. 2006; 12(7): 435-42.
  41. Alvarez A.M., Mulla M.J., Chamley L.W., Cadavid A.P., Abrahams V.M. Aspirin-triggered lipoxin prevents antiphospholipid antibody effects on human trophoblast migration and endothelial cell interactions. Arthritis Rheumatol. 2015; 67(2): 488-97.
  42. Ulrich V., Gelber S.E., Vukelic M., Sacharidou A., Herz J., Urbanus R.T. et al. ApoE Receptor 2 mediates trophoblast dysfunction and pregnancy complications induced by antiphospholipid antibodies in mice. Arthritis Rheumatol. 2016; 68(3): 730-9.
  43. Poulton K., Ripoll V.M., Pericleous C., Meroni P.L., Gerosa M., Ioannou Y. et al. Purified IgG from patients with obstetric but not IgG from non-obstetric antiphospholipid syndrome inhibit trophoblast invasion. Am. J. Reprod. Immunol. 2015; 73(5): 390-401.
  44. Mulla M.J., Myrtolli K., Brosens J.J., Chamley L.W., Kwak-Kim J.Y., Paidas M.J. et al. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am. J. Reprod. Immunol. 2010; 63(5): 339-48. Stone S., Pijnenborg R., Vercruysse L., Poston R., Khamashta M.A., Hunt B.J. et al. The placental bed in pregnancies complicated by primary antiphospholipid syndrome. Placenta. 2006; 27(4-5): 457-67. Wu Z.M., Yang H., Li M., Yeh C.C., Schatz F., Lockwood C.J. et al. Pro-inflammatory cytokine-stimulated first trimester decidual cells enhance macrophage-induced apoptosis of extravillous trophoblasts. Placenta. 2012; 33(3): 188-94.
  45. Martinez de la Torre Y., Buracchi C., Borroni E.M., Dupor J., Bonecchi R., Nebuloni M. et al. Protection against inflammation- and autoantibody-caused fetal loss by the chemokine decoy receptor D6. Proc. Natl. Acad. Sci. USA. 2007; 104(7): 2319-24.
  46. Salmon J.E., de Groot P.G. Pathogenic role of antiphospholipid antibodies. Lupus. 2008; 17(5): 405-11. Holers V.M., Girardi G., Mo L., Guthridge J.M., Molina H., Pierangeli S.S. et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J. Exp. Med. 2002; 195(2): 211-20. Girardi G., Berman J., Redecha P., Spruce L., Thurman J.M., Kraus D. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J. Clin. Invest. 2003; 112(11): 1644-54.
  47. Redecha P., Tilley R., Tencati M., Salmon J. E., Kirchhofer D., Mackman N. et al. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury. Blood. 2007; 110(7): 2423-31.
  48. Blank M., Krause I., Wildbaum G., Karin N., Shoenfeld Y. TNF alpha DNA vaccination prevents clinical manifestations of experimental antiphospholipid syndrome. Lupus. 2003; 12(7): 546-9.
  49. Girardi G., Yarilin D., Thurman J.M., Holers V.M., Salmon J.E. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J. Exp. Med. 2006; 203(9): 2165-75.
  50. 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. e5.
  51. Wirstlein P., Jasinski P., Rajewski M., Gozdziewicz T., Skrzypczak J. Complement inhibitory proteins expression in placentas of thrombophilic women. Folia Histochem. Cytobiol. 2012; 50(3): 460-7.
  52. Salmon J.E., Heuser C., Triebwasser M., Liszewski M.K., Kavanagh D., Roumenina L. et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011; 8(3): e1001013.
  53. Espinosa G., Cervera R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat. Rev. Rheumatol. 2015; 11(10): 586-96.
  54. Сидельникова В.М. Подготовка и ведение беременности у женщин с привычным невынашиванием. Методические пособия и клинические протоколы. М.: МЕДпресс-информ; 2010. [Sidelnikova V.M. Preparation and management of pregnancy in women with habitual miscarriage. Methodical aids and clinical protocols. Moscow: MEDpress-inform; 2010. (in Russian)]
  55. Girardi G., Redecha P., Salmon J.E. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat. Med. 2004; 10(11): 1222-6.
  56. Ziakas P.D., Pavlou M., Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet. Gynecol. 2010; 115(6): 1256-62.
  57. Bramham K., Thomas M., Nelson-Piercy C., Munther Khamashta M., Hunt B.J. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011; 117(25): 6948-51.
  58. Dendrinos S., Sakkas E., Makrakis E. Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. Int. J. Gynaecol. Obstet. 2009; 104(3): 223-5.
  59. Di Simone N., D’Ippolito S., Marana R., Di Nicuolo F., Castellani R., Pierangeli S.S. et al. Antiphospholipid antibodies affect human endometrial angiogenesis: protective effect of a synthetic peptide (TIFI) mimicking the phospholipid binding site of ß2 glycoprotein I. Am. J. Reprod. Immunol. 2013; 70(4): 299-308.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies