title: Aspirin has limited ability to modulate shear-mediated platelet activation associated with elevated shear stress of ventricular assist devices.
abstract: Continuous flow ventricular assist devices (cfVADs) while effective in advanced heart failure, remain plagued by thrombosis related to abnormal flows and elevated shear stress. To limit cfVAD thrombosis, patients utilize complex anti-thrombotic regimens built upon a foundation of aspirin (ASA). While much data exists on ASA as a modulator of biochemically-mediated platelet activation, limited data exists as to the efficacy of ASA as a means of limiting shear-mediated platelet activation, particularly under elevated shear stress common within cfVADs. We investigated the ability of ASA (20, 25 and 125 μM) to limit shear-mediated platelet activation under conditions of: 1) constant shear stress (30 dynes/cm(2) and 70 dynes/cm(2)); 2) dynamic shear stress, and 3) initial high shear exposure (70 dynes/cm(2)) followed by low shear exposure - i.e. a platelet sensitization protocol, utilizing a hemodynamic shearing device providing uniform shear stress in vitro. The efficacy of ASA to limit platelet activation mediated via passage through a clinical cfVAD system (DeBakey Micromed) in vitro was also studied. ASA reduced platelet activation only under conditions of low shear stress (38% reduction compared to control, n=10, p<0.004), with minimal protection at higher shear stress and under dynamic conditions (n=10, p>0.5) with no limitation of platelet sensitization. ASA had limited ability (25.6% reduction in platelet activation rate) to modulate shear-mediated platelet activation induced via cfVAD passage. These findings, while performed under "deconstructed" non-clinical conditions by utilizing purified platelets alone in vitro, provide a potential contributory mechanistic explanation for the persistent thrombosis rates experienced clinically in cfVAD patients despite ASA therapy. An opportunity exists to develop enhanced pharmacologic strategies to limit shear-mediated platelet activation at elevated shear levels associated with mechanical circulatory support devices.
authors.affiliation: Department of Electronics, Information, and Bioengineering, Politecnico di Milano, Milan, Italy; Department of Cardiothoracic Anesthesia and Intensive Care, Istituto Scientifico San Raffaele, Milan, Italy. Electronic address: chairman.syns@gmail.com.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Valerio
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Phat L
authors.initials: PL
authors.lastname: Tran
authors.affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Jawaad
authors.initials: J
authors.lastname: Sheriff
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: William
authors.initials: W
authors.lastname: Brengle
authors.affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Ram
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Wei-Che
authors.initials: WC
authors.lastname: Chiu
authors.affiliation: Department of Electronics, Information, and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Redaelli
authors.affiliation: Department of Electronics, Information, and Bioengineering, Politecnico di Milano, Milan, Italy.
authors.forename: Gianfranco B
authors.initials: GB
authors.lastname: Fiore
authors.affiliation: Department of Cardiothoracic Anesthesia and Intensive Care, Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Pappalardo
authors.affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Bluestein
authors.affiliation: Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA; Department of Medicine, Sarver Heart Center, University of Arizona, Tucson, AZ, USA; Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Slepian
mesh_terms: D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D006353:Heart-Assist Devices / Q000009:adverse effects*; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013314:Stress, Mechanical; D013927:Thrombosis / Q000209:etiology* / Q000517:prevention & control*
chemical_list: D010975:Platelet Aggregation Inhibitors; D001241:Aspirin
keywords: Aspirin; Mechanical circulatory support; Platelets; Shear; Thrombosis; Ventricular assist devices