Silvia S. Pierangeli

The antiphospholipid syndrome is a disorder of recurrent thrombosis, pregnancy loss and thrombocytopenia associated with the presence of antiphospholipid antibodies and persistently positive anticardiolipin or lupus anticoagulant positive tests. Since its recognition in the 1980s, growing interest in the field, not only with respect to diagnosis and treatment, but also regarding the pathogenesis of antiphospholipid antibodies, has emerged. First, this review addresses the recently updated classification criteria for diagnosis and treatment of the antiphospholipid syndrome. A discussion on the newly described potential beneficial roles of hydroxychloroquine and the statins for the treatment of antiphospholipid syndrome-associated clinical manifestations is included. Importantly, this article analyzes recent data that examine the molecular and intracellular events that antiphospholipid antibodies trigger in target cells, as well as new findings in the identification of the receptors for these antibodies on the membrane of those cells. A separate section discusses novel pathogenic mechanisms of antiphospholipid antibodies, including the activation of complement and their interaction with homologous catalytic domains of several serine proteases of the coagulation system. Understanding the molecular interactions and the intracellular signaling that antiphospholipid antibodies trigger, new therapeutic and targeted strategies to ameliorate clinical manifestations in patients with antiphospholipid syndrome may be established.

Objective: Antiphospholipid antibodies (aPL) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPL‐induced thrombosis, although not completely understood, may involve platelet and endothelial cell activation as well as procoagulant effects of aPL directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPL‐treated mice. In this study, we tested the hypothesis that aPL are responsible for activation of complement, thus generating split products that induce thrombosis.Methods: To study thrombus dynamics and adhesion of leukocytes we used in vivo murine models of thrombosis and microcirculation, in which injections of aPL were used.Results: Mice deficient in complement components C3 and C5 were resistant to the enhanced thrombosis and endothelial cell activation that was induced by aPL. Furthermore, inhibition of C5 activation using anti‐C5 monoclonal antibodies prevented thrombophilia induced by aPL.Conclusion: These data show that complement activation mediates 2 important effectors of aPL, induction of thrombosis and activation of endothelial cells.

Antiphospholipid antibodies (aPLs) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPL-induced thrombosis is incompletely understood, but it is thought to involve platelet and endothelial cell activation as well as pro-coagulant effects of aPL antibody directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPL-antibody treated mice. We hypothesized that aPL antibodies activate complement, generating split products that induce thrombosis. To test this hypothesis, we used an in vivo model of thrombosis in which aPL antibodies induce a significant increase in thrombus size and a mouse model of endothelial cell activation in which aPLs induce significant adhesion of leukocytes (WBCs) to endothelial cells. We found that mice deficient in complement components C3 and C5 were resistant to enhanced thrombosis and endothelial cell activation induced by aPL antibodies. Furthermore, inhibition of C5 activation using anti-C5 mAb prevented thrombophilia induced by aPL antibodies. Our data show that complement activation mediates two important effectors of aPL antibodies: induction of thrombosis and endothelial activation.