title: Microfluidic whole blood testing of platelet response to pharmacological agents.
abstract: Platelets present a number of intracellular and transmembrane targets subject to pharmacological modulation, either for cardiovascular disease reduction or as an unintended drug response. Microfluidic devices allow human blood to clot on a defined surface under controlled hemodynamic and pharmacological conditions. The potencies of a number of antiplatelet and anticancer drugs have been tested with respect to platelet deposition on collagen under flow. Inhibitors of cyclooxygenase-1 (COX-1) reduce platelet deposition, either when added ex vivo to blood or ingested orally by patients prior to testing. Some individuals display a functional "aspirin-insensitivity" in microfluidic assay. When certain nonsteroidal anti-inflammatory drugs (NSAIDs) are taken orally, they block COX-1 acetylation by aspirin with concomitant reduction of aspirin efficacy against platelets in microfluidic assay. Both P2Y1and P2Y12inhibitors reduce platelet deposition under flow, as do NO donors and iloprost that target the guanylate cyclase and the prostacyclin receptor, respectively. In a microfluidic assay of 37 kinase inhibitors, dasatinib had potent antiplatelet activity, while bosutinib was less potent. Dasatinib and bosutinib have known profiles against numerous kinases, revealing overlapping and nonoverlapping activities relevant to their unique actions against platelets. Also, dasatinib caused a marked and specific inhibition of GPVI signaling induced by convulxin, consistent with a dasatinib-associated bleeding risk. Microfluidic devices facilitate drug library screening, dose-response testing, and drug-drug interaction studies. Kinase inhibitors developed as anticancer agents may present antiplatelet activities that are detectable by microfluidic assay and potentially linked to bleeding risks.
authors.affiliation: a Institute for Medicine and Engineering, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Li
authors.affiliation: b Institute for Translational Medicine and Therapeutics, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Tilo
authors.initials: T
authors.lastname: Grosser
authors.affiliation: a Institute for Medicine and Engineering, University of Pennsylvania , Philadelphia , PA , USA.|b Institute for Translational Medicine and Therapeutics, University of Pennsylvania , Philadelphia , PA , USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D006801:Humans; D056656:Lab-On-A-Chip Devices; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D004364:Pharmaceutical Preparations
chemical_list: D004364:Pharmaceutical Preparations
keywords: adenosine diphosphate; aspirin; cyclooxygenase; thromboxane