PLATELET-LEUKOCYTE PATHOBIOLOGY IN CARDIOPULMONARY BYPAS

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Cardiopulmonary bypass (CPB) is associated with clinically significant platelet dysfunction resulting in bleeding, and alterations in leukocyte and endothelial cell function resulting in pulmonary edema, immunodeficiency, and occasionally widespread end organ damage. The investigations proposed here are predicted on the hypothesis that these effects are interrelated, specifically by virtue of CPB induced dynamic alterations in the adhesive interactions of platelets (plts), leukocytes (WBC), and endothelial cells (EC). Preliminary data from our laboratory has demonstrated that (1) specific cell-cell adhesion receptors on plts are quantitatively and qualitatively altered in vivo by CPB, in particular the selectin GMP-140, the integrin gpIIb/IIIa, and the von Willebrand's Factor receptor gpIb; (2) specific receptors on neutrophils (PMN), monocytes, and lymphocytes are similarly altered including the LeuCAM integrin CD11b; (3) these changes result in a time-dependent predictable alteration in in vivo platelet-leukocyte binding during CPB and to other functional changes involved in homotypic and heterotypic cell interactions; and (4) endothelial cell derived endothelin increases in the plasma of patients on CBP and may alter GMP-140 expression on EC. Our laboratory has developed new in vivo techniques for the investigation of these phenomenon which because of their exceedingly low blood volume requirements are applicable to patients of all ages. These techniques include the use of flow cytometry for the study of non-adherent cells and newly available microscope based interactive laser cytometry for the investigation of endothelial cell, adherent phagocyte, and platelet biology. The five specific aims of this project are to address the questions: (1) what are the quantitative and qualitative changes in platelet adhesion receptors that occur during CPB?; (2) what are the changes in leukocyte adhesion receptors during CPB?; (3) what alterations occur in vivo in platelet- leukocyte binding during CPB and what are the functional consequences of this interaction?; (4) what are the effects of these platelet-WBC changes on endothelial cells and how do EC alter platelet-WBC interaction?; (5) do the alterations assessed above correlate with clinical outcome post CPB? The long term goal of the project is to use this knowledge to design therapeutic interventions to minimize the adverse consequences of CPB, especially in the young and the elderly.