The Role of Complement Inhibition in Thrombotic Angiopathies and Antiphospholipid Syndrome

Abstract

Antiphospholipid syndrome (APS) is characterized by thrombosis (arterial, venous, small vessel) and/or pregnancy morbidity occurring in patients with persistently positive antiphospholipid antibodies (aPL). Catastrophic APS is the most severe form of the disease, characterized by multiple organ thromboses occurring in a short period and commonly associated with thrombotic microangiopathy (TMA). Similar to patients with complement regulatory gene mutations developing TMA, increased complement activation on endothelial cells plays a role in hypercoagulability in aPL-positive patients. In mouse models of APS, activation of the complement is required and interaction of complement (C) 5a with its receptor C5aR leads to aPL-induced inflammation, placental insufficiency, and thrombosis. Anti-C5 antibody and C5aR antagonist peptides prevent aPL-mediated pregnancy loss and thrombosis in these experimental models. Clinical studies of anti-C5 monoclonal antibody in aPL-positive patients are limited to a small number of case reports. Ongoing and future clinical studies of complement inhibitors will help determine the role of complement inhibition in the management of aPL-positive patients.

Figure 1. Human complement system. Three pathways are activated by immune complexes and apoptotic cells (classical); by microbes and stressors (lectin); and spontaneously (alternative). The effect of complement: clearance of apoptotic cells, opsonization of pathogens and immune complexes for phagocytosis, release of anaphylatoxins and lysis (shown in italics), and activation of effector cells that express receptors for C5a and/or C3a (neutrophils, monocytes, and platelets) are shown on the left. Complement inhibitors are indicated in red. Soluble inhibitors are factor I (FI), C4b-binding protein (C4BP), factor H (FH), and FH-like protein (FHL-1). Membrane-bound inhibitors include MCP (CD46), DAF (CD55), and CD59. Reprinted from Placenta 2010;31:561-567, Lynch AM, Salmon JE, Dysregulated complement activation as a common pathway of injury in preeclampsia and other pregnancy complications. Copyright (2015) with permission from Elsevier.