Christine Rinder, MD

Associate Professor, Department of Anesthesiology

Our laboratory has focused on the interactions between circulating hematopoietic cells that have traditionally been viewed as either coagulant or inflammatory, most notably platelet and phagocytes, respectively. Our initial in vitro studies examined these interactions under static conditions and served as the basis for expanding these investigations into the setting of ex vivo extracorporeal circulation and in vivo cardiopulmonary bypass (CPB). These arenas are characterized by profound activation of inflammatory and coagulant pathways that significantly contribute to patient morbidity during in vivo CPB. We first demonstrated hematopoietic cell activation during in vivo CPB, which causes formation of leukocyte-platelet conjugates, and induces clearance of activated, adhesive phagocytes. We next developed an ex vivo model of simulated extracorporeal circulation (SECC) which reproducibly causes platelet and phagocyte activation comparable to and over a similar time course to in vivo CPB. We used this ex vivo model to specifically examine the pathophysiology of these cellular changes as they relate to formation of active complement components, i.e. C3a and C5a, and the terminal membrane attack complex (C5b-9) generation. Using this model, we have shown that early complement anaphylatoxins have a role in monocyte activation during SECC, while late components, C5a and C5b-9, are the primary mediators of neutrophil and platelet activation, respectively. These studies served as the basis of an in vivo phase II trial of C5a and C5b-9 inhibition during CPB, which confirmed the ability of blockade at this complement level to prevent neutrophil and platelet activation. This preliminary study also suggests that this strategy may ameliorate some of the cardiac and neurologic morbidity associated with CPB, and studies to confirm this association are pending. We continue to use our ex vivo model to test alternative strategies for anticoagulation and anti-inflammatory interventions that can give insight into the interplay between coagulation and inflammation during CPB, as well as possibly having in vivo potential.

We have published a number of investigations into poor neurologic outcome post-CPB, including the observation that two markers of platelet activation and adhesive function, increased CD62P expression on platelets and the presence of the PlA2 phenotype of the platelet gpIIIa receptor (beta-3 integrin), correlate with neurocognitive deterioration after surgery. Our future aims are to broaden our research to include the neurocognitive decline that can develop in elderly patients after major surgery, and to identify vascular mediators that may contribute to these changes.