Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support

Alice Apostoli, Valentina Bianchi, Nina Bono, Annalisa Dimasi, Kaitlyn R. Ammann, Yana Roka Moiia, Andrea Montisci, Jawaad Sheriff, Danny Bluestein, Gianfranco B. Fiore, Federico Pappalardo, Gabriele Candiani, Alberto Redaelli, Marvin J Slepian, Filippo Consolo

Research output: Contribution to journalArticle

Abstract

BACKGROUND: We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support. METHODS: Intact and shear-activated human platelets were exposed to non-activated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, and 70 dynes/cm 2 , 10 minutes) via a hemodynamic shearing device. ECs were activated via exposure to inflammatory tumor necrosis factor-α (TNF-α 10 and 100 ng/ml, 24 hours), consistent with inflammatory activation recorded in patients on LVAD circulatory support. RESULTS: Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm 2 shear-activated platelets vs intact platelets: +80%, p < 0.001). Importantly, inflammatory activation of ECs amplified platelet prothrombinase activity progressively with increasing shear stress magnitude and TNF-α concentration: thrombin generation of 70 dynes/cm 2 shear-activated platelets was 2.6-fold higher after exposure and adhesion to 100 ng/ml TNF-α‒activated ECs (p < 0.0001). CONCLUSIONS: We demonstrated synergistic effect of SMPA and cytokine-mediated EC inflammatory activation to enhance EC‒platelet adhesion and platelet prothrombotic function. These mechanisms may contribute to intraventricular thrombosis in the setting of mechanical circulatory support.

Original languageEnglish (US)
JournalJournal of Heart and Lung Transplantation
DOIs
StatePublished - Jan 1 2019

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Heart-Assist Devices
Blood Platelets
Endothelial Cells
Cytokines
Platelet Activation
Thrombosis
Thromboplastin
Thrombin
Tumor Necrosis Factor-alpha
Hemodynamics
Equipment and Supplies

Keywords

  • Endothelial cells
  • inflammation
  • platelets
  • shear stress
  • thrombosis
  • ventricular assist device

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support. / Apostoli, Alice; Bianchi, Valentina; Bono, Nina; Dimasi, Annalisa; Ammann, Kaitlyn R.; Moiia, Yana Roka; Montisci, Andrea; Sheriff, Jawaad; Bluestein, Danny; Fiore, Gianfranco B.; Pappalardo, Federico; Candiani, Gabriele; Redaelli, Alberto; Slepian, Marvin J; Consolo, Filippo.

In: Journal of Heart and Lung Transplantation, 01.01.2019.

Research output: Contribution to journalArticle

Apostoli, A, Bianchi, V, Bono, N, Dimasi, A, Ammann, KR, Moiia, YR, Montisci, A, Sheriff, J, Bluestein, D, Fiore, GB, Pappalardo, F, Candiani, G, Redaelli, A, Slepian, MJ & Consolo, F 2019, 'Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support', Journal of Heart and Lung Transplantation. https://doi.org/10.1016/j.healun.2019.02.009
Apostoli, Alice ; Bianchi, Valentina ; Bono, Nina ; Dimasi, Annalisa ; Ammann, Kaitlyn R. ; Moiia, Yana Roka ; Montisci, Andrea ; Sheriff, Jawaad ; Bluestein, Danny ; Fiore, Gianfranco B. ; Pappalardo, Federico ; Candiani, Gabriele ; Redaelli, Alberto ; Slepian, Marvin J ; Consolo, Filippo. / Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support. In: Journal of Heart and Lung Transplantation. 2019.
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abstract = "BACKGROUND: We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support. METHODS: Intact and shear-activated human platelets were exposed to non-activated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, and 70 dynes/cm 2 , 10 minutes) via a hemodynamic shearing device. ECs were activated via exposure to inflammatory tumor necrosis factor-α (TNF-α 10 and 100 ng/ml, 24 hours), consistent with inflammatory activation recorded in patients on LVAD circulatory support. RESULTS: Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm 2 shear-activated platelets vs intact platelets: +80{\%}, p < 0.001). Importantly, inflammatory activation of ECs amplified platelet prothrombinase activity progressively with increasing shear stress magnitude and TNF-α concentration: thrombin generation of 70 dynes/cm 2 shear-activated platelets was 2.6-fold higher after exposure and adhesion to 100 ng/ml TNF-α‒activated ECs (p < 0.0001). CONCLUSIONS: We demonstrated synergistic effect of SMPA and cytokine-mediated EC inflammatory activation to enhance EC‒platelet adhesion and platelet prothrombotic function. These mechanisms may contribute to intraventricular thrombosis in the setting of mechanical circulatory support.",
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author = "Alice Apostoli and Valentina Bianchi and Nina Bono and Annalisa Dimasi and Ammann, {Kaitlyn R.} and Moiia, {Yana Roka} and Andrea Montisci and Jawaad Sheriff and Danny Bluestein and Fiore, {Gianfranco B.} and Federico Pappalardo and Gabriele Candiani and Alberto Redaelli and Slepian, {Marvin J} and Filippo Consolo",
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T1 - Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support

AU - Apostoli, Alice

AU - Bianchi, Valentina

AU - Bono, Nina

AU - Dimasi, Annalisa

AU - Ammann, Kaitlyn R.

AU - Moiia, Yana Roka

AU - Montisci, Andrea

AU - Sheriff, Jawaad

AU - Bluestein, Danny

AU - Fiore, Gianfranco B.

AU - Pappalardo, Federico

AU - Candiani, Gabriele

AU - Redaelli, Alberto

AU - Slepian, Marvin J

AU - Consolo, Filippo

PY - 2019/1/1

Y1 - 2019/1/1

N2 - BACKGROUND: We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support. METHODS: Intact and shear-activated human platelets were exposed to non-activated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, and 70 dynes/cm 2 , 10 minutes) via a hemodynamic shearing device. ECs were activated via exposure to inflammatory tumor necrosis factor-α (TNF-α 10 and 100 ng/ml, 24 hours), consistent with inflammatory activation recorded in patients on LVAD circulatory support. RESULTS: Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm 2 shear-activated platelets vs intact platelets: +80%, p < 0.001). Importantly, inflammatory activation of ECs amplified platelet prothrombinase activity progressively with increasing shear stress magnitude and TNF-α concentration: thrombin generation of 70 dynes/cm 2 shear-activated platelets was 2.6-fold higher after exposure and adhesion to 100 ng/ml TNF-α‒activated ECs (p < 0.0001). CONCLUSIONS: We demonstrated synergistic effect of SMPA and cytokine-mediated EC inflammatory activation to enhance EC‒platelet adhesion and platelet prothrombotic function. These mechanisms may contribute to intraventricular thrombosis in the setting of mechanical circulatory support.

AB - BACKGROUND: We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support. METHODS: Intact and shear-activated human platelets were exposed to non-activated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, and 70 dynes/cm 2 , 10 minutes) via a hemodynamic shearing device. ECs were activated via exposure to inflammatory tumor necrosis factor-α (TNF-α 10 and 100 ng/ml, 24 hours), consistent with inflammatory activation recorded in patients on LVAD circulatory support. RESULTS: Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm 2 shear-activated platelets vs intact platelets: +80%, p < 0.001). Importantly, inflammatory activation of ECs amplified platelet prothrombinase activity progressively with increasing shear stress magnitude and TNF-α concentration: thrombin generation of 70 dynes/cm 2 shear-activated platelets was 2.6-fold higher after exposure and adhesion to 100 ng/ml TNF-α‒activated ECs (p < 0.0001). CONCLUSIONS: We demonstrated synergistic effect of SMPA and cytokine-mediated EC inflammatory activation to enhance EC‒platelet adhesion and platelet prothrombotic function. These mechanisms may contribute to intraventricular thrombosis in the setting of mechanical circulatory support.

KW - Endothelial cells

KW - inflammation

KW - platelets

KW - shear stress

KW - thrombosis

KW - ventricular assist device

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