Antiphospholipid antibodies and pregnancy loss: a disorder of inflammation

Abstract

The antiphospholipid syndrome (APS) is a leading cause of miscarriage and maternal and fetal morbidity. APS is characterized by thrombosis and pregnancy loss that occur in the presence of antiphospholipid (aPL) antibodies. Using a mouse model of APS induced by passive transfer of human aPL antibodies, we have shown that complement activation plays an essential and causative role in pregnancy loss and fetal growth restriction, and that blocking activation of the complement cascade rescues pregnancies. Conventional treatment for APS patients is sub-anticoagulant doses of heparin throughout pregnancy. Could heparin prevent pregnancy loss by inhibiting complement? In our experimental model of APS, heparin inhibits activation of complement on trophoblasts in vivo and in vitro, and anticoagulation in and of itself is not sufficient to prevent pregnancy complications. These studies underscore the importance of inflammation in fetal injury associated with aPL antibodies and raise the importance of developing and testing targeted complement inhibitory therapy for patients with APS.

Figure 1

Complement cascade. Schematic diagram of the three complement activation pathways and the products they generate. From Hughes Syndrome, 2^nd Edition, Khamashta, MA (Ed.), 2006, page 396, chapter 31, by Girardi, G and Salmon, J, Figure 31.1. With kind permission of Springer Science and Business Media.

Figure 2

Proposed mechanism for the pathogenic effects of aPL antibodies on tissue injury. APL antibodies are preferentially targeted to the placenta where they activate complement via the classical pathway. The complement cascade is initiated leading to generation of C5a and recruitment and activation of neutrophils, monocytes and platelet cells, and release of inflammatory mediators, including reactive oxidants, proteolytic enzymes, cytokines, chemokines and complement factors. Depending on the extent of damage, either death in utero or fetal growth restriction ensues.