title: Microfluidic thrombosis under multiple shear rates and antiplatelet therapy doses.
abstract: The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies. In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s(-1)) and therapy concentrations (0-2.4 µM for eptifibatide, 0-2 mM for acetyl-salicylic acid (ASA), 3.5-40 Units/L for heparin) using a microfluidic device. We also measured complete blood counts (CBC) and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models. Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose). Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Li
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Hotaling
authors.affiliation: George W. Woodruff Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: David N
authors.initials: DN
authors.lastname: Ku
authors.affiliation: George W. Woodruff Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Forest
mesh_terms: D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D006801:Humans; D046210:Microfluidic Analytical Techniques; D044085:Microfluidics / Q000379:methods*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015203:Reproducibility of Results; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy*
chemical_list: D010975:Platelet Aggregation Inhibitors; D001241:Aspirin