(Applicant's list of Aims) Specific Aim 1. To assess the dynamics of platelet-leukocyte interactions using intravital microscopy in mouse models of thrombosis in the mesenteric and cremasteric circulations.
Specific Aim 2. To assess whether leukocyte deposition on platelets after vascular injury contributes to blood vessel passivation, that is, a return to a state in which platelets are no longer recruited. Deposition of radiolabeled platelets over select 30 min periods for 6 hours after femoral artery injury will be measured in wild-type mice, beta3 integrin -/- mice, P-selectin -/- mice, alphaMbeta -/- mice, and PECAM-1 -/- mice.
Specific Aim 3. To assess the role of platelet-leukocyte interactions in leukocyte transmigration and the development of intimal hyperplasia after vascular injury. Using our murine model, leukocyte transmigration into the blood vessel media during the first 6 hours will be assessed and correlated with the intimal hyperplasia that develops after 4 weeks in wild-type mice and mice deficient in beta3 integrins, P-selectin, alphaMbeta2, and PECAM-1.
Specific Aim 4. To assess ex vivo the effects of platelet-leukocyte interactions during contact of normal whole human blood with a stainless steel stent on: 1) thrombus formation; 2) release into the downstream circulation of tissue factor; thrombin; activated platelets (P- selectin); activated neutrophils (alphaMbeta2); platelet-neutrophil, platelet- monocyte, and platelet-platelet aggregates; platelet microparticles; VEGF; the cytokine 1-309; and """"""""soluble"""""""" CD40 ligand; 3) passivation of platelet deposition on the stent, and 4) stent thrombus morphology. Studies using blocking antibodies to GPIIb/IIIa and/or alphaVbeta3, P-selectin, alphaMbeta2, and PECAM-1 will be conducted to assess the contributions of these receptors.
Specific Aim 5. To assess the presence of platelet- leukocyte interactions in the systemic circulation of patients with risk factors for thrombosis and controls, before and after interventions to modify the risk factors, and correlate these findings with markers of a systemic inflammatory state (see Project 1). Blood will be tested for platelet- neutrophil aggregates, platelet-monocyte aggregates, platelet-platelet aggregates, leukocyte alphaMbeta2 expression, platelet P-selectin expression, and platelet microparticles. These data will be correlated with data obtained on circulating tissue factor, C-reactive protein, tissue factor pathway inhibitory, prothrombin fragment F1.2, and thrombus formation in flow chamber studies.
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