Multiscale prediction of patient-specific platelet function under flow

• Published in: Blood Vol. 120; no. 1; pp. 190 - 198
• Main Authors: Flamm, Matthew H., Colace, Thomas V., Chatterjee, Manash S., Jing, Huiyan, Zhou, Songtao, Jaeger, Daniel, Brass, Lawrence F., Sinno, Talid, Diamond, Scott L.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 05.07.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Adenosine Diphosphate - pharmacology; Biological and medical sciences; Blood Coagulation - physiology; Blood Platelets - drug effects; Blood Platelets - physiology; Calcium - metabolism; Crotalid Venoms - pharmacology; HEK293 Cells; Hematologic and hematopoietic diseases; Humans; Lectins, C-Type; Male; Medical sciences; Microfluidic Analytical Techniques - methods; Microfluidic Analytical Techniques - standards; Models, Biological; Platelet Activating Factor - physiology; Platelet Function Tests - methods; Platelet Function Tests - standards; Platelets and Thrombopoiesis; Predictive Value of Tests; Receptors, Thromboxane - genetics; Receptors, Thromboxane - metabolism; Reference Values; Signal Transduction - drug effects; Signal Transduction - physiology; Thrombosis - physiopathology; Vasoconstrictor Agents - pharmacology; Human; Hematology; Predictive factor; Platelet function
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2011-10-388140

During thrombotic or hemostatic episodes, platelets bind collagen and release ADP and thromboxane A2, 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 P2Y1/P2Y12, 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 P2Y1 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.