Association Of Complement With Microvascular Endothelial Cell Injury In Thrombotic Microangiopathy In Vivo And In In Vitro Model Systems.

We have previously shown that plasma from patients with idiopathic as well as HIV and thienopyridine-linked TTP induces apoptosis of microvascular endothelial cells (MVEC) in vitro, with specific sparing of large vessel and pulmonary MVEC, consistent with the clinical syndrome. This correlates with in vivo measures of apoptosis in splenic tissue of TTP patients. We found that osteoprotegrin (OPG), an inhibitor of multiple inducers of MVEC apoptosis, could block TTP plasma-mediated MVEC injury. Utilizing OPG affinity-binding columns and MS-TOFI analysis of column eluates, we subsequently identified complement (C) components and C-regulatory factors as potentially involved in TTP plasma-mediated EC injury. Building on the observation that familial TTP syndromes have been linked to genetic deficiencies of the C-regulatory factors Factor H and MCP, and three cases of sporadic HUS in children have been accompanied by autoantibodies to factor H, we hypothesized that the C-system plays an important role in TTP-induced MVEC injury, facilitated by autoantibody-mediated suppression of C-regulatory proteins. To evaluate the role of the complement system we looked at: