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Influence of Hematocrit Level and Integrin αIIbβIII Function on vWF-Mediated Platelet Adhesion and Shear-Induced Platelet Aggregation in a Sudden Expansion

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Abstract

Purpose

Shear-mediated thrombosis is a clinically relevant phenomenon that underlies excessive arterial thrombosis and device-induced thrombosis. Red blood cells are known to mechanically contribute to physiological hemostasis through margination of platelets and vWF, facilitating the unfurling of vWF multimers, and increasing the fraction of thrombus-contacting platelets. Shear also plays a role in this phenomenon, increasing both the degree of margination and the near-wall forces experienced by vWF and platelets leading to unfurling and activation. Despite this, the contribution of red blood cells in shear-induced platelet aggregation has not been fully investigated—specifically the effect of elevated hematocrit has not yet been demonstrated.

Methods

Here, a microfluidic model of a sudden expansion is presented as a platform for investigating platelet adhesion at hematocrits ranging from 0 to 60% and shear rates ranging from 1000 to 10,000 s−1. The sudden expansion geometry models nonphysiological flow separation characteristic to mechanical circulatory support devices, and the validatory framework of the FDA benchmark nozzle. PDMS microchannels were fabricated and coated with human collagen. Platelets were fluorescently tagged, and blood was reconstituted at variable hematocrit prior to perfusion experiments. Integrin function of selected blood samples was inhibited by a blocking antibody, and platelet adhesion and aggregation over the course of perfusion was monitored.

Results

Increasing shear rates at physiological and elevated hematocrit levels facilitate robust platelet adhesion and formation of large aggregates. Shear-induced platelet aggregation is demonstrated to be dependent on both αIIbβIII function and the presence of red blood cells. Inhibition of αIIbβIII results in an 86.4% reduction in overall platelet adhesion and an 85.7% reduction in thrombus size at 20-60% hematocrit. Hematocrit levels of 20% are inadequate for effective platelet margination and subsequent vWF tethering, resulting in notable decreases in platelet adhesion at 5000 and 10,000 s-1 compared to 40% and 60%. Inhibition of αIIbβIII triggered dramatic reductions in overall thrombus coverage and large aggregate formation. Stability of platelets tethered by vWF are demonstrated to be αIIbβIII-dependent, as adhesion of single platelets treated with A2A9, an anti-αIIbβIII blocking antibody, is transient and did not lead to sustained thrombus formation.

Conclusions

This study highlights driving factors in vWF-mediated platelet adhesion that are relevant to clinical suppression of shear-induced thrombosis and in vitro assays of platelet adhesion. Primarily, increasing hematocrit promotes platelet margination, permitting shear-induced platelet aggregation through αIIbβIII-mediated adhesion at supraphysiological shear rates.

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Data availability

Data will be made available by the corresponding author (K.B. Manning) upon reasonable request.

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Acknowledgments

This work is supported, in part, by NIH HL136369.The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR002014. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We would like to thank Jessica C. Cardenas (University of Texas Health Science Center at Houston) for generously reading this manuscript.

Funding

This work is supported, in part, by NIH HL136369. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR002014.

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Authors and Affiliations

  1. Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, USA

    Connor T. Watson, Shane C. Ward & Keefe B. Manning

  2. Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, Italy

    Stefano A. Rizzo & Alberto Redaelli

  3. Department of Surgery, Penn State Hershey Medical Center, Hershey, PA, USA

    Keefe B. Manning

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Contributions

K.B.M. and A.R. conceived and designed study; C.T.W., S.C.W., and S.A.R. performed experimental studies; C.T.W. analyzed data, interpreted experimental results, generated figures, and drafted manuscript; C.T.W., K.B.M. and A.R. edited and revised manuscript; K.B.M applied for and obtained funding; C.T.W., S.C.W., S.A.R., A.R., and K.B.M. approved final manuscript.

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Correspondence to Keefe B. Manning.

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Competing interest

K.B.M. has a financial interest in Cranial Devices, Inc, a company which could potentially benefit from the results of this research. The interest has been reviewed and is being managed by the University in accordance with its individual Conflict of Interest policy, for the purpose of maintaining the objectivity of research at The Pennsylvania State University. All other authors declare no conflicts.

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Informed consent was obtained from all human subjects in a Pennsylvania State University IRB approved protocol.

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Watson, C.T., Ward, S.C., Rizzo, S.A. et al. Influence of Hematocrit Level and Integrin αIIbβIII Function on vWF-Mediated Platelet Adhesion and Shear-Induced Platelet Aggregation in a Sudden Expansion. Cel. Mol. Bioeng. 17, 49–65 (2024). https://doi.org/10.1007/s12195-024-00796-0

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