Abstract: Diverse clinical and animal studies suggest complicated platelet-leukocyte interactions involved in cardiovascular diseases. Augmented platelet-neutrophil adhesion has been observed in thrombotic and inflammatory conditions. Activated platelets modulate neutrophil functions through released proteins, such as P-selectin and platelet factor 4 (PF4). We investigated platelet-neutrophil adhesion and neutrophil activation induced by platelet activation, with focus on the roles of P-selectin and PF4. In chapter 2, we examined heterotypic interactions between resting neutrophils and either thrombin receptor activating peptide (TRAP) stimulated platelets or P-selectin bearing beads (Ps-beads) under shear from 14-3000/s in cone-plate viscometer and rheometer. Our study reveals an integrin-independent regime for cell adhesion that may be physiologically relevant. While blocking antibodies against either P-selectin or P-selectin glycoprotein ligand-1 (PSGL-1) alone inhibited platelet-neutrophil adhesion by ∼60% at 140/s, these reagents completely blocked adhesion at 3000/s. Anti-Mac-1 alone did not alter platelet-neutrophil adhesion rates, though in synergy with selectin antagonists it abrogated cell binding at all shear rates. Unstimulated neutrophils avidly bound Ps-beads and activated platelets in an integrin-independent manner, suggesting that purely selectin-dependent binding is possible. In support of this, antagonists against P-selectin or PSGL-1 dissociated previously formed platelet-neutrophil and Ps-bead neutrophil aggregates under shear in a variety of experimental systems. In studies where medium viscosity was varied, a subtle shear threshold for P-selectin PSGL-1 binding was also noted at shear rates below 110/s. In chapter 3, neutrophil activation modulated by PF4 was investigated. We show a mechanism of neutrophil activation induced by PF4 immune complexes. Costimulation of PF4 and anti-PF4 mAb, but not either stimulus alone, induced neutrophil activation marked by Mac-1 upregulation and exocytosis of secondary and tertiary granules. Inhibition studies suggested PF4 mAb recognized neutrophil surface bound PF4 and activated neutrophils through Fc portions of mAb. The process is inhibited by anti-CD32 mAb (IV.3) completely. Similar neutrophil activation was observed when recombinant PF4 (rPF4) was used. PF4 dosage studies showed an optimized PF4 concentration. Introduction of PF4 mutation revealed PF4 activation domains: Pronine-Threonine-Alanine 37-39, Arginine49 and Leucine55. N-terminal mutation was not important for neutrophil activation. Upregulated Mac-1 was shown to mediate neutrophil homotypic aggregation under shear condition.