Microfluidic Thrombosis under Multiple Shear Rates and Antiplatelet Therapy Doses
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{"title"=>"Microfluidic thrombosis under multiple shear rates and antiplatelet therapy doses", "type"=>"journal", "authors"=>[{"first_name"=>"Melissa", "last_name"=>"Li", "scopus_author_id"=>"55277940600"}, {"first_name"=>"Nathan A.", "last_name"=>"Hotaling", "scopus_author_id"=>"56081684200"}, {"first_name"=>"David N.", "last_name"=>"Ku", "scopus_author_id"=>"7103238223"}, {"first_name"=>"Craig R.", "last_name"=>"Forest", "scopus_author_id"=>"7004390009"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "pmid"=>"24404131", "doi"=>"10.1371/journal.pone.0082493", "pui"=>"372577208", "issn"=>"19326203", "sgr"=>"84896752543", "scopus"=>"2-s2.0-84896752543"}, "id"=>"1e6cd9d6-e1b0-3095-996f-cf126ad6ef18", "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.", "link"=>"http://www.mendeley.com/research/microfluidic-thrombosis-under-multiple-shear-rates-antiplatelet-therapy-doses", "reader_count"=>69, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>14, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>23, "Other"=>4, "Student > Master"=>13, "Student > Bachelor"=>6, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>14, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>23, "Other"=>4, "Student > Master"=>13, "Student > Bachelor"=>6, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>25, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>1, "Materials Science"=>2, "Medicine and Dentistry"=>10, "Agricultural and Biological Sciences"=>17, "Neuroscience"=>1, "Business, Management and Accounting"=>1, "Physics and Astronomy"=>2, "Chemical Engineering"=>1, "Chemistry"=>4, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>25}, "Materials Science"=>{"Materials Science"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>4}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>17}, "Computer Science"=>{"Computer Science"=>2}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>3}, "Chemical Engineering"=>{"Chemical Engineering"=>1}}, "reader_count_by_country"=>{"Republic of Singapore"=>1, "United States"=>4, "Switzerland"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/4055338"], "description"=>"<p>Microscopy images (A) show aggregation initiation at the entry of the stenosis, where brighter areas of the images correspond to more platelet mass. Time stamps for images in seconds are shown at the bottom of each image, and correspond with the time axis shown below in (B). As platelets aggregate, the flow rate (B) decreases until it reaches occlusion time. The unstable thrombus detaches, indicated by the sudden increase in flow rate.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894016, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.g002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Formation_and_measurement_of_thrombus_in_a_channel_run_within_the_microfluidic_device_measured_using_both_microscopy_and_flow_rate_at_10000_8722_1_initial_shear_rate_/894016", "title"=>"Formation and measurement of thrombus in a channel run within the microfluidic device measured using both microscopy and flow rate at 10000<sup>−1</sup> initial shear rate.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055293"], "description"=>"<div><p>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.</p><p>In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s<sup>−1</sup>) 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.</p><p>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.</p></div>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894025, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Microfluidic_Thrombosis_under_Multiple_Shear_Rates_and_Antiplatelet_Therapy_Doses_/894025", "title"=>"Microfluidic Thrombosis under Multiple Shear Rates and Antiplatelet Therapy Doses", "pos_in_sequence"=>0, "defined_type"=>6, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055509"], "description"=>"<p>Significance of shear and dose for eptifibatide as judged by MANOVA with Tukey's Posttest.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894023, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.t003", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Significance_of_shear_and_dose_for_eptifibatide_as_judged_by_MANOVA_with_Tukey_s_Posttest_/894023", "title"=>"Significance of shear and dose for eptifibatide as judged by MANOVA with Tukey's Posttest.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055458"], "description"=>"<p>Continues variables measured and their relevant statistics.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894024, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.t001", "stats"=>{"downloads"=>2, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Continues_variables_measured_and_their_relevant_statistics_/894024", "title"=>"Continues variables measured and their relevant statistics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055479"], "description"=>"<p>Intra-subject and inter-subject assay variation.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894022, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.t002", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Intra_subject_and_inter_subject_assay_variation_/894022", "title"=>"Intra-subject and inter-subject assay variation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055587"], "description"=>"<p>Parameter estimates for the prediction of antiplatelet therapy delivery by significant variables from the occlusion formation study.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894019, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.t006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Parameter_estimates_for_the_prediction_of_antiplatelet_therapy_delivery_by_significant_variables_from_the_occlusion_formation_study_/894019", "title"=>"Parameter estimates for the prediction of antiplatelet therapy delivery by significant variables from the occlusion formation study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055410"], "description"=>"<p>Plots show results from its Area Under the (Impedance) Curve (AUC) aggregometer metric after the addition of platelet therapies eptifibatide (A) and ASA (B).</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894018, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.g004", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dose_response_measurement_using_a_low_shear_impedance_aggregometer_/894018", "title"=>"Dose-response measurement using a low shear impedance aggregometer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055563"], "description"=>"<p>Hazard ratio estimates for three therapies compared to each other.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894021, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.t005", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hazard_ratio_estimates_for_three_therapies_compared_to_each_other_/894021", "title"=>"Hazard ratio estimates for three therapies compared to each other.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055542"], "description"=>"<p>Significance of shear and dose for ASA as judged by MANOVA with Tukey's Posttest.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894020, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.t004", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Significance_of_shear_and_dose_for_ASA_as_judged_by_MANOVA_with_Tukey_s_Posttest_/894020", "title"=>"Significance of shear and dose for ASA as judged by MANOVA with Tukey's Posttest.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055380"], "description"=>"<p>Occlusion time (<i>t<sub>occlusion</sub></i>) and standard error vs. antiplatelet therapy concentration at a range of initial shear rates for (A) eptifibatide and (B) ASA for N subjects shown. Subjects not shown did not occlude. (C) and (D) represent the inverse of occlusion time and standard error vs. therapy concentration for a range of initial shear rates, corresponding to (A) and (B), respectively. The inverse (1/<i>t<sub>occlusion</sub></i>) includes non-occluded channel runs by assigning them a zero value, thus each point represents pooled data from N = 5 subjects. The likelihood of thrombus detachment, represented as the number of channel runs with thrombus detachment divided by the total number of channel runs is shown vs. therapy concentration for a range of initial shear rates is shown in (E), (F).</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894017, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_antiplatelet_therapy_on_occlusion_time_and_thrombus_detachment_/894017", "title"=>"Effects of antiplatelet therapy on occlusion time and thrombus detachment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-03 14:43:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/4055311"], "description"=>"<p>The complete device is shown in (A) with detailed view of the stenosis region (B). From a single inlet, four branching channels subject the blood flow to a range of shear rates from physiological to pathological conditions. Dimensions of all four stenoses within the device are identical, with varying shear rates imposed by resistive tubing at the outlet ports.</p>", "links"=>[], "tags"=>["antiplatelet therapy doses", "shear rate", "blood impedance aggregometry", "hazards models.Shear rates", "Antiplatelet Therapy Doses", "CBC", "Multiple Shear Rates", "ASA", "thrombosis", "shear occlusion times", "Antiplatelet therapy dosing"], "article_id"=>894015, "categories"=>["Space Science", "Medicine", "Pharmacology", "Biological Sciences not elsewhere classified", "Cancer", "Hematology"], "users"=>["Melissa Li", "Nathan A. Hotaling", "David N. Ku", "Craig R. Forest"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0082493.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_images_of_the_microfluidic_chip_/894015", "title"=>"Schematic images of the microfluidic chip.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-03 14:43:37"}

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