Aggregation and Microparticle Production Through Toll-like Receptor 4 Activation in Platelets From Recently Menopausal Women

Bacterial inflection may increase risk for thrombosis and atherosclerosis. Human platelets express toll-like receptor 4 (TLR4) the receptor for gram-negative bacterial lipopolysaccharide (LPS). Experiments were designed to evaluate direct, acute effects of TLR4 activation oil aggregation, secretion, and generation of prothrombogenic microparticles ill vitro oil platelets derived Front healthy women at risk for development of cardiovascular disease because of their hormonal status. Platelet-rich plasma from recently menopausal women Was incubated With ultrapure Escherichia coli LPS in the absence or presence of antibodies that neutralize the human TLR4. Incubating platelets with LIS (100 ng/mL) for 5 minutes decreased aggregation and dense granule adenosine triphosphate secretion induced by thrombin receptor agonist peptide (TRAP) but not by adenosine diphosphate or collagen. The antibody to TLR4 blocked this effect of LPS. TLR4 activation increased phosphorylation of p38 mitogen-activated protein kinase and decreased production of prothrombotic phosphatidylserine and P-selectin-positive microparticles in response to TRAP Therefore, acute, direct activation of TLR4 reduces platelet reactivity to TRAP stimulation in vitro. Increased thrombotic and cardiovascular risk with bacterial infection most likely reflects the sum of TLR4 activation oil other blood and Vascular Cells to release proinflammatory cytokines/chemokines, which indirectly affect platelet reactivity.