Links Between Complement Activation and Thrombosis

The coagulation and complement systems are central mediators of innate immune defense and aide the peri- and intravascular elimination of invading microorganisms in a process termed immuno-thrombosis. Complement and coagulation proteases are engaged in reciprocal amplifications at different levels of these enzymatic cascades. In addition, activated complement factor (C) 3 specifically stimulates platelets through C3a receptor signaling and thereby amplifies thrombus formation. A non-enzymatic function of complement activation emerged as a crucial mechanism that rapidly alters the function of the extrinsic coagulation activator tissue factor (TF) on monocytes. Activation of the classical complement pathway by therapeutic anti-thymocyte globulin preparations rapidly enhances monocyte TF procoagulant activity. On the one hand, complement activation-associated thiol-disulfide exchange supports protein disulfide isomerase-dependent conformational changes in TF. Insertion of the C5b-C7 complex supports these conformational changes in TF by exposing procoagulant phosphatidylserine (PS). Furthermore, these dual roles of complement activation play a central role in venous thrombosis. C3, but not C5-deficient mice are protected from platelet deposition. In contrast, C5 knock-out mice show diminished PS exposure on leukocytes and lack TF-dependent coagulation activation and fibrin deposition at the flow restricted venous vessel wall. Antiphospholipid antibodies (aPL) also cause TF- and complement-dependent thrombosis. Whereas C3-dependent thiol-disulfide exchange is again required for converting TF to a procoagulant form, aPL do not rely on downstream complement components for the exposure of PS and induce pathological thrombosis in C5-deficient mice. Our recent data show that aPL dissociate a cell surface-localized, inhibited complex with monocyte-expressed TF pathway inhibitor (TFPI). In addition to promoting TF procoagulant activation, complement-dependent thiol-disulfide exchange emerged as an additional central mechanism that allows for aPL internalization and endosomal signaling involving integrin- and TF cytoplasmic domain-dependent translocation of the NADPH oxidase to the endosome. A monoclonal antibody that traps TF with low procoagulant activity on the surface prevents TF endosomal trafficking, aPL signaling and aPL-induced pregnancy loss. These complement-dependent effects require assistance by thrombin-PAR1/PAR2 heterodimer signaling initiated by FXa dissociated from the inhibited TF complex. Monocyte TFPI-dysfunctional mice are protected from aPL pathogenic signaling in vitro and from aPL-induced thrombosis, but form thrombi normally in other experimental thrombosis models. These data show that formation of an inhibited TF cell surface complex specifically primes monocytes for thrombosis and pathogenic aPL signaling. Thus, the evolutionary conserved crosstalk of complement and coagulation cascades not only plays crucial roles in thrombosis, but also regulates thrombo-inflammatory signaling in autoimmune disease.