The role of complement in the antiphospholipid syndrome

The anti-phospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis and thrombocytopenia occurring in the presence of antiphospholipid (aPL) antibodies. We hypothesized that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth restriction, and that complement activation by aPL antibodies in other vascular areas causes inflammation and thrombophilia. Here we review studies in a murine model of APS in which human aPL antibodies are passively transferred into pregnant mice. Blockade of complement activation using a C3 convertase inhibitor or genetic deletion of C3 protected mice from pregnancy complications induced by aPL antibodies. These findings demonstrate that complement activation is a central mechanism in aPL antibody-induced pregnancy loss and fetal growth restriction. Although the cause of tissue injury in APS is likely to prove multifactorial, we have shown that complement activation is an absolute requirement for the most serious phenotypic outcomes, pregnancy complications and thrombosis, and, therefore, that this pathway acts upstream of other important effector mechanisms.