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ENDOTHELIAL MICROPARTICLE BINDING TO LEUKOCYTES AS A DETERMINANT OF LEUKOCYTE ACTIVATION AND NITRIC OXIDE EXPRESSION IN ACUTE VENOUS THROMBOEMBOLISM

University of Miami School of Medicine, Miami, FL

PURPOSE: The pathophysiology of venous thromboembolism (VTE) involves complex cellular interactions resulting from endothelial damage, hypercoagulability and inflammation. Increased levels of endothelial microparticles (EMP) and leukocyte activation have been reported in VTE. EMP have been shown to induce monocyte and neutrophil activation in vitro. Whether this phenomenon determines leukocyte activation in vivo is unknown. The purpose of this study is to determine the correlation between the leukocyte-bound EMP and leukocyte activation in patients with VTE.

METHODS: We studied 25 patients with confirmed VTE. We measured the following markers in venous blood using flow cytometry: (1) Endothelial microparticles (EMP) identified by CD62E (EMP62E) and CD54 (EMP54); (2) EMP62E- and EMP54-monocyte conjugates; (3) EMP62E- and EMP54-neutrophil conjugates; (4) Expression of activation marker CD11b in leukocytes; (5) Leukocyte levels of nitric oxide (NO) after loading leukocytes with the membrane permeable NO-selective fluorescent indicator DAF-DA.

RESULTS: EMP62E-neutrophil conjugates correlated with CD11b expression in leukocytes (r=0.46; p=0.02). In contrast, EMP54-neutrophil conjugates did not significantly correlate with CD11b expression (r=0.25; p=0.22). EMP62E-neutrophil conjugates predicted CD11b expression independently of free EMP62E (r2 increase=0.21; p=0.02). No correlation was found between EMP-neutrophil conjugates and NO levels in neutrophils. In contrast, EMP54-monocyte conjugates significantly correlated with monocyte NO (r=0.56; p=0.003), whereas EMP62-monocyte conjugates did not (r=0.12; p=0.57). EMP54-monocyte conjugates predicted monocyte NO independently of free EMP54 (r2 increase=0.25; p=0.01).

CONCLUSION: The binding of EMP62E to neutrophils correlates with neutrophil activation as measured by CD11b expression. In contrast, the binding of EMP54 to monocytes appears to be a determinant of intracellular NO levels in monocytes. Our findings suggest that different species of EMP exert different transcellular effects and the binding of EMP to leukocytes may represent an important mechanism that links thrombosis and inflammation in VTE.

CLINICAL IMPLICATIONS: The binding of EMP to leukocytes and subsequent leukocyte activation may represent novel therapeutic targets in VTE.

DISCLOSURE: Julio Chirinos, None.