Tissue factor in antiphospholipid antibody-induced pregnancy loss: a pro-inflammatory molecule.
Fetal loss in patients with antiphospholipid antibodies (aPL) has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically complement activation with generation of the anaphylotoxin C5a, is an essential mediator of fetal injury. We have analysed the role of tissue factor (TF) in a mouse model of aPL-induced pregnancy loss. TF is the major cellular activator of the coagulation cascade but also has cell signaling activity. Mice that received aPL-IgG showed strong TF staining throughout the decidua and on embryonic debris. This TF staining was not associated with either fibrin staining or thrombi in deciduas. The absence of fibrin deposition and thrombi suggests that TF-dependent activation of coagulation does not mediate aPL-induced pregnancy loss.We found that either blockade of TF with a monoclonal antibody in wild type mice or a genetic reduction of TF prevented aPL-induced inflammation and pregnancy loss indicated a pathogenic role for TF in aPL-induced pregnancy complications. In response to aPL-generated C5a, neutrophils express TF potentiating inflammation in the deciduas and leading to miscarriages. Importantly, we showed that TF in myeloid cells, but not fetal-derived cells (trophoblasts), was associated with fetal injury, suggesting that the site for pathologic TF expression is neutrophils. We found that TF expression in neutrophils contributes to respiratory burst and subsequent trophoblast injury and pregnancy loss induced by aPL. The identification of TF, acting as an important pro-inflammatory mediator in aPL-induced fetal injury, provides a new target for therapy to prevent pregnancy loss in the aPL syndrome.
Girardi
G
G
Department of Medicine, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, USA. GirardiG@HSS.EDU
Mackman
N
N
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000502:physiology*; D000937:Antigen-Antibody Reactions / Q000502:physiology*; D016736:Antiphospholipid Syndrome / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005313:Fetal Death / Q000209:etiology*; D006801:Humans; D051379:Mice; D011247:Pregnancy; D013925:Thromboplastin / Q000502:physiology*
D017152:Antibodies, Antiphospholipid; D013925:Thromboplastin