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Biorheology of Platelet Activation in the Bloodstream Distal to Thrombus Formation

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Abstract

Thrombus growth at the site of vascular injury is mediated by the sequential events of platelet recruitment, activation and aggregation concomitant with the initiation of the coagulation cascade, resulting in local thrombin generation and fibrin formation. While the biorheology of a localized thrombus formation has been well studied, it is unclear whether local sites of thrombin generation propagate platelet activation within the bloodstream. In order to study the physical biology of platelet activation downstream of sites of thrombus formation, we developed a platform to measure platelet activation and microaggregate formation in the bloodstream. Our results show that thrombi formed on collagen and tissue factor promote activation and aggregation of platelets in the bloodstream in a convection-dependent manner. Pharmacological inhibition of the coagulation factors (F) X, XI or thrombin dramatically reduced the degree of distal platelet activation and microaggregate formation in the bloodstream without affecting the degree of local platelet deposition and aggregation on a surface of immobilized collagen. Herein we describe the development and an example of the utility of a platform to study platelet activation and microaggregate formation in the bloodstream (convection-limited regime) relative to the local site of thrombus formation.

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Abbreviations

BSA:

Bovine serum albumin

PBS:

Phosphate buffered saline

DIC:

Differential interference contrast

FACS:

Fluorescence activated cell sorting

FX:

Coagulation factor X

FXI:

Coagulation factor XI

Da:

Dahmköhler number

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Acknowledgements

We thank Cristina Puy for insightful comments and Kevin Phillips for technical assistance. This work was supported by grants from the National Institutes of Health (R01HL101972 and R01GM116184) and the Oregon Health and Science University School of Medicine MD/PhD program. O.J.T. McCarty is an American Heart Association Established Investigator (13EIA12630000). A.I. is a Bayer International Fellow and S.M.B. is a Whitaker International Fellow.

Conflict of interest

R. Vetter and C. Gerdes are employees of Bayer Pharma AG. A. Gruber, E.I. Tucker, and Oregon Health & Science University have a significant financial interest in Aronora Inc., a company that may have a commercial interest in the results of this research. This potential conflict of interest has been reviewed and managed by the Oregon Health & Science University Conflict of Interest in Research Committee. J. Zilberman-Rudenko, A. Itakura, J. Maddala, S.M. Baker-Groberg and O.J.T. McCarty declare no competing financial interests.

Ethical Standards

All human subject research was carried out in accordance with institutional guidelines approved by the Oregon Health & Science University Institutional Review Board. No animal studies were carried out by the authors for this article.

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Authors and Affiliations

  1. Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, 3303 SW Bond Ave., Portland, OR, 97239, USA

    Jevgenia Zilberman-Rudenko, Jeevan Maddala, Sandra M. Baker-Groberg, Erik I. Tucker, András Gruber & Owen J. T. McCarty

  2. Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, USA

    Asako Itakura & Owen J. T. McCarty

  3. Drug Discovery, Bayer Pharma AG, Wuppertal, Germany

    Asako Itakura, Ralf Vetter & Christoph Gerdes

  4. Chemical and Biomedical Engineering, West Virginia University, Morgantown, WV, USA

    Jeevan Maddala

  5. Division of Hematology/Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR, USA

    Erik I. Tucker, András Gruber & Owen J. T. McCarty

  6. Aronora Inc., Portland, OR, USA

    András Gruber

Authors
  1. Jevgenia Zilberman-Rudenko
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  2. Asako Itakura
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  3. Jeevan Maddala
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  4. Sandra M. Baker-Groberg
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  5. Ralf Vetter
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  6. Erik I. Tucker
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  7. András Gruber
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  8. Christoph Gerdes
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  9. Owen J. T. McCarty
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Corresponding author

Correspondence to Owen J. T. McCarty.

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Associate Editor Michael R. King oversaw the review of this article.

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Zilberman-Rudenko, J., Itakura, A., Maddala, J. et al. Biorheology of Platelet Activation in the Bloodstream Distal to Thrombus Formation. Cel. Mol. Bioeng. 9, 496–508 (2016). https://doi.org/10.1007/s12195-016-0448-5

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  • DOI: https://doi.org/10.1007/s12195-016-0448-5

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