Alice Apostoli1, Valentina Bianchi1, Nina Bono2, Annalisa Dimasi1, Kaitlyn R Ammann3, Yana Roka Moiia3, Andrea Montisci4, Jawaad Sheriff5, Danny Bluestein5, Gianfranco B Fiore1, Federico Pappalardo6, Gabriele Candiani7, Alberto Redaelli1, Marvin J Slepian3, Filippo Consolo8. 1. Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, Italy. 2. Politecnico di Milano Research Unit, National Interuniversity Consortium of Materials Science and Technology, Milano, Italy. 3. Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, USA. 4. Anesthesia and Intensive Care, Sant'Ambrogio Cardiothoracic Center, Milano, Italy. 5. Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York, USA. 6. Advanced Heart Failure and Mechanical Circulatory Support Program, San Raffaele Scientific Institute, Milano, Italy; Università Vita Salute San Raffaele, Milano, Italy. 7. Biocompatibility and Cell Culture Laboratory "BioCell," Department of Chemistry, Materials and Chemical Engineering "Giulio Natta," Politecnico di Milano, Milano, Italy. 8. Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, Italy; Advanced Heart Failure and Mechanical Circulatory Support Program, San Raffaele Scientific Institute, Milano, Italy; Università Vita Salute San Raffaele, Milano, Italy. Electronic address: consolo.filippo@unisr.it.
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/cm2, 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/cm2 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/cm2 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.
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/cm2, 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/cm2 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/cm2 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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