Blood Journal
Leading the way in experimental and clinical research in hematology

Multiscale prediction of patient-specific platelet function under flow

  1. Matthew H. Flamm1,
  2. Tom Colace1,
  3. Manash S. Chatterjee1,
  4. Huiyan Jing1,
  5. Songtao Zhou1,
  6. Daniel Jaeger1,
  7. Lawrence F. Brass2,
  8. Talid Sinno1, and
  9. Scott L. Diamond1,*
  1. 1 Institute for Medicine and Engineering, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA, United States;
  2. 2 Department of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, United States
  1. * Corresponding author; email: sld{at}seas.upenn.edu

Abstract

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 an individual's platelet phenotype remains a challenge. A platelet signaling phenotype was obtained for 3 healthy donors using Pairwise Agonist Scanning (PAS), where calcium dye-loaded platelets were exposed to pairwise combinations of ADP, U46619, and convulxin to activate P2Y1/P2Y12, TP, and GPVI receptors, respectively, in the presence or absence of the IP receptor agonist, iloprost. A neural network model was trained on each donor's PAS experiment and then was embedded into a multiscale Monte Carlo simulation of donor-specific platelet deposition under flow. The simulations were directly compared to microfluidic experiments of whole blood flowing over collagen at 200 and 1000 s-1 wall shear rate. The simulations predicted the ranked order of drug sensitivity for indomethacin, aspirin, MRS-2179 (P2Y1 inhibitor), and iloprost. Consistent with measurement and simulation, one donor displayed larger clots, while another donor presented indomethacin-resistance (revealing a novel heterozygote TP-V241G mutation). In silico representations of an individual's platelet phenotype allowed prediction of blood function under flow, essential to identifying patient-specific cardiovascular risks, drug responses, and novel genotypes.

  • Submitted October 26, 2011.
  • Accepted April 3, 2012.