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Abstract
Despite the interwoven nature of platelet activation and the coagulation system in thrombosis, few studies relate both analysis of protein and cellular parts of coagulation in the same population. In the present study, we use matched ex vivo samples to determine the influences of standard antiplatelet therapies on platelet function and use advanced rheological analyses to assess clot formation. Healthy volunteers were recruited following fully informed consent then treated for 7 days with single antiplatelet therapy of aspirin (75 mg) or prasugrel (10 mg) or with dual antiplatelet therapy (DAPT) using aspirin (75 mg) plus prasugrel (10 mg) or aspirin (75 mg) plus ticagrelor (90 mg). Blood samples were taken at day 0 before treatment and at day 7 following treatment. We found that aspirin plus prasugrel or aspirin plus ticagrelor inhibited platelet responses to multiple agonists and reduced P-selectin expression. Significant platelet inhibition was coupled with a reduction in fractal dimension corresponding to reductions in mean relative mass both for aspirin plus prasugrel (−35 ± 16% change, p = 0.04) and for aspirin plus ticagrelor (−45 ± 14% change, p = 0.04). Aspirin alone had no effect upon measures of clot structure, whereas prasugrel reduced fractal dimension and mean relative mass. These data demonstrate that platelets are important determinants of clot structure as assessed by fractal dimension (df) and that effective platelet inhibition is associated with a weaker, more permeable fibrin network. This indicates a strong association between the therapeutic benefits of antiplatelet therapies and their abilities to reduce thrombus density that may be useful in individual patients to determine the functional relationship between platelet reactivity, eventual clot quality, and clinical outcome. df could represent a novel risk stratification biomarker useful in individualizing antiplatelet therapies.
Acknowledgements
RBK had support from the British Heart Foundation [FS/12/53/29643]. PMF had support from FAPESP (São Paulo Research Foundation; Grant Number 14/04478-5). LAD, SNS, AS and MJL had support from the NISCHR Biomedical Research Unit (BRU) grant (BR01). We thank Ivana Vojnovic for technical assistance.
Declaration of interests
TDW has received consultancy fees from AstraZeneca relating to clinical development of P2Y12 inhibitors in the previous 3 years. PAE received a grant from National Institute of Social Care and Health Research.
Additional information
Notes on contributors
Rebecca B. Knowles
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Matthew J. Lawrence
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Plinio M. Ferreira
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Melissa A. Hayman
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Lindsay A. D’Silva
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Sophie N. Stanford
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Ahmed Sabra
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Arthur T. Tucker
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Karl M. Hawkins
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Phylip R. Williams
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Timothy D. Warner
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.
Phillip A. Evans
Contribution: R. B. Knowles, L. A. D’Silva, M. J. Lawrence, contributed to concept and design, analysed data and critical writing; P. M. Ferreira, M. A. Hayman, S. N. Stanford, A. Sabra, analysed data; K. M. Hawkins, P. R. Williams, A. T. Tucker, contributed to concept and design and interpreted data. T. D. Warner, P. A. Evans, contributed to concept and design, revised intellectual content and final approval of the version to be published.