TY - JOUR
T1 - Aspirin has limited ability to modulate shear-mediated platelet activation associated with elevated shear stress of ventricular assist devices
AU - Valerio, Lorenzo
AU - Tran, Phat L.
AU - Sheriff, Jawaad
AU - Brengle, William
AU - Ghosh, Ram
AU - Chiu, Wei Che
AU - Redaelli, Alberto
AU - Fiore, Gianfranco B.
AU - Pappalardo, Federico
AU - Bluestein, Danny
AU - Slepian, Marvin J.
N1 - Funding Information:
This work was supported by the National Institute of Biomedical Imaging and Bioengineering Quantum Grant Award No. 5U01EB012487-00 and by Fondazione Cariplo grant no. 2241-2011 .
Publisher Copyright:
© 2016 Elsevier Ltd. All rights reserved.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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/cm2 and 70 dynes/cm2); 2) dynamic shear stress, and 3) initial high shear exposure (70 dynes/cm2) 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.
AB - 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/cm2 and 70 dynes/cm2); 2) dynamic shear stress, and 3) initial high shear exposure (70 dynes/cm2) 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.
KW - Aspirin
KW - Mechanical circulatory support
KW - Platelets
KW - Shear
KW - Thrombosis
KW - Ventricular assist devices
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U2 - 10.1016/j.thromres.2016.01.026
DO - 10.1016/j.thromres.2016.01.026
M3 - Article
C2 - 26938158
AN - SCOPUS:84959564103
SN - 0049-3848
VL - 140
SP - 110
EP - 117
JO - Thrombosis Research
JF - Thrombosis Research
ER -