title: Evidence for heterogeneity of the obstetric antiphospholipid syndrome: thrombosis can be critical for antiphospholipid-induced pregnancy loss.
abstract: BACKGROUND
  Antiphospholipid antibodies are associated with thrombosis and repeated pregnancy losses during the antiphospholipid syndrome. Several experimental findings indicate that purified antiphospholipid antibodies are directly responsible for inflammation-induced pregnancy losses, or for disruption of the annexin A5 shield at the trophoblastic interface. We previously showed that passive transfer of CIC15, a monoclonal antiphospholipid antibody binding to cardiolipin and annexin A5 that was isolated from a patient with primary antiphospholipid syndrome, induces fetal resorption in pregnant mice.
  
  
  OBJECTIVE
  To investigate the mechanisms of CIC15-induced pregnancy loss.
  
  
  RESULTS
  We show that CIC15 induces fetal loss through a new mechanism that is probably related to procoagulant activity. The time course is different from those of previously described models, and histologic analysis shows that the placentas are devoid of any sign of inflammation but display some signs of thrombotic events. Despite these differences, the CIC15 and 'inflammatory' models share some similarities: lack of FcγRI/III dependency, and the efficacy of heparin in preventing fetal losses. However, this latter observation is here mostly attributable to anticoagulation rather than complement inhibition, because fondaparinux sodium and hirudin show similar efficiency. In vitro, CIC15 enhances cardiolipin-induced thrombin generation. Finally, using a combination of surface-sensitive methods, we show that, although it binds complexes of cardiolipin-annexin A5, CIC15 is not able to disrupt the two-dimensional ordered arrays of annexin A5.
  
  
  CONCLUSIONS
  This human monoclonal antibody is responsible for pregnancy loss through a new mechanism involving thrombosis. This mechanism adds to the heterogeneity of the obstetric antiphospholipid syndrome.
authors.affiliation: National Referral Center for Systemic Autoimmune Diseases, Clinical Immunology Department, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg and CNRS UPR 9021, Strasbourg, France. vincent.poindron@chru-strasbourg.fr
authors.forename: V
authors.initials: V
authors.lastname: Poindron
authors.forename: R
authors.initials: R
authors.lastname: Berat
authors.forename: A M
authors.initials: AM
authors.lastname: Knapp
authors.forename: F
authors.initials: F
authors.lastname: Toti
authors.forename: F
authors.initials: F
authors.lastname: Zobairi
authors.forename: A S
authors.initials: AS
authors.lastname: Korganow
authors.forename: M P
authors.initials: MP
authors.lastname: Chenard
authors.forename: C
authors.initials: C
authors.lastname: Gounou
authors.forename: J L
authors.initials: JL
authors.lastname: Pasquali
authors.forename: A
authors.initials: A
authors.lastname: Brisson
authors.forename: T
authors.initials: T
authors.lastname: Martin
mesh_terms: D000022:Abortion, Spontaneous; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000150:complications* / Q000503:physiopathology; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000503:physiopathology*
chemical_list: D017152:Antibodies, Antiphospholipid