Complement and thrombosis in HIT

The project will test the hypothesis that complement responses to HIT ultra-large immune complexes (ULICs) are impacted by heparin and involve distinct cellular targets, activation pathways, and effector mechanisms. Specific aims include: 1) Investigating cell injury by soluble HIT ULICs, focusing on the importance of the proximal complement pathway (C1/C3) and Fcγ receptors for binding to neutrophils and monocytes, initiating cell signaling, FcγR clustering, membrane scramblase, and monocyte tissue factor expression. 2) Examining how cell-bound HIT immune complexes (ICs) promote complement-dependent platelet adhesion and direct endothelial injury, specifically through terminal complement pathway mediated platelet adhesion, upregulation of endothelial cell procoagulant activity, sublytic C5aR-mediated membrane injury, release of von Willebrand Factor multimers, and C5aR-dependent tissue factor expression. 3) Developing complement activation as a biomarker for pathogenic HIT antibodies by characterizing the biologic properties of HIT IgG antibodies that do/do not activate complement and form soluble and cell-bound ULICs, developing a complement activation biomarker assay, and examining complement’s role in the therapeutic efficacy of intravenous immunoglobulin.