Chapter 5 Tissue Factor in Antiphospholipid Antibody-induced Pregnancy Loss: Thrombosis versus Inflammation

Abstract

Abstract Fetal loss in patients with antiphospholipid antibodies (aPL) has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically activation of complement with generation of the anaphylotoxin C5a, is an essential trigger of fetal injury. Thrombosis and inflammation are linked in many clinical conditions. Tissue factor (TF), the major cellular initiator of the coagulation protease cascade, plays important roles in both thrombosis and inflammation. Here we analyze the role of TF in a mouse model of aPL-induced pregnancy loss. Blockade of TF with a monoclonal antibody in wild-type mice and a genetic reduction of TF prevented aPL antibody-induced inflammation and pregnancy loss. In response to aPL antibody-generated C5a, neutrophils express TF, potentiating inflammation in the deciduas and leading to miscarriages. Importantly, we identified TF as an important mediator of C5a-induced oxidative burst in neutrophils in aPL-induced fetal injury. The finding that TF is an important effector in aPL-induced inflammation may allow the development of new therapies to abrogate the inflammatory loop caused by tissue factor and improve pregnancy outcomes in patients with aPL antibodies.