title: Multiscale prediction of patient-specific platelet function under flow.
abstract: During thrombotic or hemostatic episodes, platelets bind collagen and release ADP and thromboxane A(2), recruiting additional platelets to a growing deposit that distorts the flow field. Prediction of clotting function under hemodynamic conditions for a patient's platelet phenotype remains a challenge. A platelet signaling phenotype was obtained for 3 healthy donors using pairwise agonist scanning, in which calcium dye-loaded platelets were exposed to pairwise combinations of ADP, U46619, and convulxin to activate the P2Y(1)/P2Y(12), TP, and GPVI receptors, respectively, with and without the prostacyclin receptor agonist iloprost. A neural network model was trained on each donor's pairwise agonist scanning experiment and then embedded into a multiscale Monte Carlo simulation of donor-specific platelet deposition under flow. The simulations were compared directly with microfluidic experiments of whole blood flowing over collagen at 200 and 1000/s wall shear rate. The simulations predicted the ranked order of drug sensitivity for indomethacin, aspirin, MRS-2179 (a P2Y(1) inhibitor), and iloprost. Consistent with measurement and simulation, one donor displayed larger clots and another presented with indomethacin resistance (revealing a novel heterozygote TP-V241G mutation). In silico representations of a subject's platelet phenotype allowed prediction of blood function under flow, essential for identifying patient-specific risks, drug responses, and novel genotypes.
authors.affiliation: Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, Vagelos Research Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Flamm
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Colace
authors.forename: Manash S
authors.initials: MS
authors.lastname: Chatterjee
authors.forename: Huiyan
authors.initials: H
authors.lastname: Jing
authors.forename: Songtao
authors.initials: S
authors.lastname: Zhou
authors.forename: Daniel
authors.initials: D
authors.lastname: Jaeger
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Brass
authors.forename: Talid
authors.initials: T
authors.lastname: Sinno
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003435:Crotalid Venoms / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D037181:Lectins, C-Type; D008297:Male; D046210:Microfluidic Analytical Techniques / Q000379:methods* / Q000592:standards; D008954:Models, Biological; D010972:Platelet Activating Factor / Q000502:physiology; D010979:Platelet Function Tests / Q000379:methods* / Q000592:standards; D011237:Predictive Value of Tests; D017482:Receptors, Thromboxane / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013927:Thrombosis / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D003435:Crotalid Venoms; D037181:Lectins, C-Type; D010972:Platelet Activating Factor; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C028890:convulxin; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002118:Calcium