Abstract 215: Inflammation-Induced Thrombogenic Phenotype in the Microvasculature: The Roles of Enhanced Platelet Production and Reactivity

Abstract

It is well recognized that different pathological conditions associated with inflammation are also accompanied by altered platelet function and enhanced thrombus development. Experimental colitis (induced by dextran sodium sulfate, DSS) and angiotensin II (AngII)-induced hypertension (HTN) are two examples of pathologically distinct inflammation models that exhibit enhanced platelet adhesion in venules and accelerated thrombus formation in arterioles. Whether these responses represent alterations in platelet production, life-span, and/or function remains unclear. In this study, we compared the changes in platelet production and reactivity (to thrombin) that occur in murine models of DSS colitis and AngII-induced HTN. Mature (TO-) and immature (TO+) platelets in blood were quantified using thiazole orange (TO) staining with flow-cytometry. The in vivo biotinylation method was used to determine the life-spans of TO+ and TO- platelets. Platelet aggregation velocity was measured using a low-angle light scattering technique. Thrombus formation, induced by light/dye injury, was monitored in cremaster muscle arterioles and platelet adhesion was quantified in the venules. Our findings indicate that both models of inflammation promote platelet adhesion and enhanced thrombus formation in the microvasculature. The enhanced thrombosis normally detected in both DSS-induced colitis and AngII-induced hypertension models was not evident in interleukin-6 (IL-6) deficient mice and in WT mice treated with an IL-6 receptor blocking antibody. DSS colitis was accompanied by an increased appearance of both TO+ and TO- platelets, increased platelet reactivity (aggregation) to thrombin, and no change in platelet turnover. The AngII HTN model exhibits an increase in platelet turnover, an increased number of TO- (but not TO+) platelets, and no change in platelet aggregation, suggesting that an altered endothelial cell phenotype likely makes a larger contribution to the accelerated arteriolar thrombosis in this model. The divergent responses in these two IL-6 dependent models of microvascular thrombosis may reflect the relative importance of platelets and microvascular endothelial cells as molecular targets for IL-6 mediated thrombogenic responses.