Platelet Dysfunction during Mechanical Circulatory Support: Elevated Shear Stress Promotes Downregulation of αiIbβ3and GPIb via Microparticle Shedding Decreasing Platelet Aggregability

Yana Roka-Moiia, Samuel Miller-Gutierrez, Daniel E. Palomares, Joseph E. Italiano, Jawaad Sheriff, Danny Bluestein, Marvin J. Slepian

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Mechanical circulatory support has emerged as lifesaving therapy for patients with advanced heart failure. However, mechanical circulatory support remains limited by a paradoxical coagulopathy accompanied by both thrombosis and bleeding. While mechanisms of mechanical circulatory support thrombosis are increasingly defined, mechanical circulatory support-related bleeding, as related to shear-mediated alteration of platelet function, remains poorly understood. We tested the hypothesis that platelet exposure to elevated shear stress, while a defined prothrombotic activator of platelets, coordinately induces downregulation of key platelet adhesion receptors GPIb-IX-V, αIIbβ3, and P-selectin, thus decreasing platelet functional responsiveness to physiological stimuli. Approach and Results: Human gel-filtered platelets were exposed to continuous or pulsatile shear stress in vitro. Surface expression of platelet receptors and platelet-derived microparticle generation were quantified by flow cytometry. Shedding of receptor soluble forms were assessed via ELISA, and platelet aggregation was measured by optical aggregometry. We demonstrate that platelet exposure to elevated shear stress led to a downregulation of GPIb and αIIbβ3receptors on platelets with a progressive increase in the generation of platelet-derived microparticles expressing elevated levels of αIIbβ3and GPIb on their surface. No shear-mediated shedding of GPIb and β3subunit soluble fragments was detected. Soluble P-selectin was extensively shed from platelets, while surface expression of P-selectin on platelets was not significantly altered by shear. Shear-mediated downregulation of GPIb and αIIbβ3on platelets was associated with an evident decrease of platelet aggregatory response induced by ADP and TRAP 6 (thrombin receptor activating peptide 6). Conclusions: Our data clearly indicate that accumulation of shear stress, consistent with supraphysiologic conditions characterizing device-supported circulation (1) induces adequate platelet degranulation, yet (2) causes downregulation of primary platelet adhesion receptors via ejection of receptor-enriched platelet-derived microparticles, thus mechanistically limiting platelet activation and the aggregatory response.

Original languageEnglish (US)
Pages (from-to)1319-1336
Number of pages18
JournalArteriosclerosis, Thrombosis, and Vascular Biology
DOIs
StateAccepted/In press - 2021

Keywords

  • adhesion receptor
  • flow cytometry
  • heart failure
  • platelet aggregation
  • thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Platelet Dysfunction during Mechanical Circulatory Support: Elevated Shear Stress Promotes Downregulation of α<sub>iIb</sub>β<sub>3</sub>and GPIb via Microparticle Shedding Decreasing Platelet Aggregability'. Together they form a unique fingerprint.

Cite this