The main focus of our laboratory is understanding the disease mechanisms of a common clinical disorder called heparin-induced thrombocytopenia (HIT). HIT is an immune-mediated thrombotic disorder caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Our laboratory is investigating how this immune response is initiated and how it triggers life-threatening clotting complications in some individuals.
Role of complement activation in the HIT immune response
Our laboratory has recently identified complement activation by the classical pathway as an early event in the host’s encounter with heparin. Using in vitro and ex vivo human samples and mouse models, we are investigating: 1) The role of B cell CD21 in delivering antigen to secondary lymphoid organs, 2) Signaling pathways elicited by binding of complement coated antigen to B cell CD21, 3) IgM as a predictor for seroconversion in patients receiving heparin, and 4)Applications of complement inhibitors to prevent anti-PF4/heparin seroconversions.
Complement Activation in HIT Thrombosis
This project is being done in collaboration with Dr. Doug Cines at the University of Pennsylvania and Dr. Lubica Rauova at the Children’s Hospital of Philadelphia. Using confocal microscopy, flow cytometry, cell-based assays, and patient samples, our lab is: 1) Investigating mechanisms by which complement contributes to thrombosis in HIT and 2) Developing novel tools and assays to define complement-dependent pathways that are relevant to disease manifestations in HIT.
Complement and Immune Complex interactions
We are investigating complex interplay of complement and complement receptors with immune complexes. These lab studies are investigating: 1) Role of complement receptors in mediating IC complex interactions with FcgRIIA and 2) Species usage of the classical and alternative pathway in responding to immune complexes.
Biomarkers of Acute Thrombosis
Acute venous thrombosis is diagnosed through serological markers of clotting (D-dimer) and imaging modalities. Current studies are investigating the role of PF4 as an early biomarker of clotting activation through the prospective study of patients presenting to the Emergency Room with signs or symptoms of venous thrombosis and applications of novel fluorescent compounds for the diagnosis of acute thrombus.