These findings reveal previously unrecognized characteristics and complexity of platelets and their regulation of adhesion/aggregation. The identification of platelet subpopulations also has potentially important consequences to human health and disease as impaired platelet NO-signalling has been identified in patients with coronary artery disease.

No abstract

No abstract

Although lacking a nucleus, platelets are increasingly recognized not only for their complexity, but also for their diversity. Some 50 years ago platelet subpopulations were characterized by size and density, and these characteristics were thought to reflect platelet aging. Since, our knowledge of platelet heterogeneity has grown to recognize that differences in platelet biochemistry and function exist. This includes the identification of vanguard and follower platelets, platelets with differing procoagulant ability including “COAT-platelets” which enhance procoagulant protein retention on their surface, and most recently, the identification of platelet subpopulations with a differential ability to generate and respond to nitric oxide. Hence, in this mini-review, we summarize the current knowledge of platelet subpopulation diversity focusing on their physical, biochemical, and functional heterogeneity. In addition, we review how platelet subpopulations may change between health and disease and how differences among platelets may influence response to anti-platelet therapy. Finally, we look forward and discuss some of the future directions and challenges for this growing field of platelet research.

Background: Platelets facilitate hematogenous metastasis in part by promoting cancer cell immunoevasion, although our understanding of platelet function in modulating the adaptive immune system in cancer is limited. A major negative regulator of the adaptive response is the immune checkpoint protein Programmed Death Ligand 1 (PD-L1).Objectives: As platelets secrete factors that may increase PD-L1 expression, we investigated whether they up-regulate cancer cell PD-L1, thus promoting immunoevasion, and whether common anti-platelet drugs inhibit this process.Methods: Platelets were isolated from human volunteers. A549 lung, PD-L1 null A549, and 786-O renal cancer cells were incubated with and without platelets, and cancer cell PD-L1 expression was measured by qPCR and flow cytometry. Additionally, platelet-cancer cell incubations were performed in the presence of common antiplatelet drugs, and with growth factor neutralizing antibodies. Following incubation with platelets, A549 were co-cultured with T-cells and interleukin-2 (IL-2) levels were measured by flow cytometry as a marker of T-cell activation.Results: Platelets increased PD-L1 mRNA and surface protein expression by A549 and 786-0 cells. Combined neutralization of VEGF and PDGF prevented the plateletinduced up-regulation of PD-L1 by A549, as did the anti-platelet drug eptifibatide.A549 incubated with platelets demonstrated a reduced ability to activate human T-cells, an effect reversed by eptifibatide. Conclusions:As platelets promote immunoevasion of the adaptive immune response by increasing cancer cell PD-L1 expression and as anti-platelet drugs prevent this immunoevasive response, the investigation of anti-platelet drugs as adjuvant therapy to immune checkpoint inhibitors may be warranted in the treatment of cancer.