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24 The role of complement and complement inhibition in APS pregnancy
  1. Jane Salmon
  1. Hospital for Special Surgery and Weill Cornell Medicine, New York, USA


Women with antiphospholipid syndrome (APS) are at increased risk for adverse pregnancy outcomes, including preeclampsia, fetal and neonatal death and fetal growth restriction. Studies in mice implicate inflammation, particularly complement activation, as an essential and causative factor in placental insufficiency, fetal loss and growth restriction.1 Complement activation is initiated by classical, alternative and lectin pathways. The convergence of the three pathways on C3 results in generation of common effectors: anaphylatoxins, opsonins and the membrane attack complex. Mice deficient in alternative and classical pathway complement components (factor B, C4, C3 and C5) and mice treated with inhibitors of complement activation (anti-C5 mAb, anti-factor B mAb, C5a receptor antagonist peptide) are resistant to fetal injury induced by aPL,1 indicating that both pathways contribute to damage. Similarly, pregnancies in hypertensive mice prone to preeclampsia are rescued with inhibitors of complement activation.2 Studies in humans support the role of complement in aPL-associated pregnancy complications and in preeclampsia and growth restriction in non-autoimmune women.3 Complement fragment C4d, a marker of classical pathway activation, is present in placentae from women with systemic lupus erythematosus (SLE) and/or APS and from women with preeclampsia. Mild hypocomplementemia has also been reported in primary APS. The presence of loss of function variants in complement regulatory proteins in patients with preeclampsia with SLE and/or aPL antibodies or without autoimmunity links complement activation to disease pathogenesis.4 Furthermore, in prospective studies of SLE and/or APL-positive patients and in non-autoimmune patients, elevated levels of the complement activation products in blood, particularly factor Bb, were associated with adverse pregnancy outcomes.5 Taken together, these findings suggest a role for complement inhibition for the prevention of APS-triggered placental insufficiency in high risk pregnancies.

Learning Objectives

  • Explain the risk factors for adverse pregnancy outcomes in APS

  • Describe the mediators and mechanism of pregnancy complications in patients in APS

  • Describe potential targets to treat and prevent pregnancy complications in patients with APS


  1. Girardi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest. 2003;112(11):1644–54.

  2. Gelber SE, Brent E, Redecha P, et al. Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency. J Immunol. 2015;195(3):1129–38.

  3. Chighizola CB, Lonati PA, Trespidi L, Meroni PL, Tedesco F. The Complement System in the Pathophysiology of Pregnancy and in Systemic Autoimmune Rheumatic Diseases During Pregnancy. Front Immunol. 2020;11: 2084.

  4. Salmon JE, Heuser C, Triebwasser M, et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011;8(3):e1001013.

  5. Kim MY, Guerra MM, 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.

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