TY - JOUR
T1 - Routine clinical anti-platelet agents have limited efficacy in modulating hypershear-mediated platelet activation associated with mechanical circulatory support
AU - Valerio, Lorenzo
AU - Sheriff, Jawaad
AU - Tran, Phat L.
AU - Brengle, William
AU - Redaelli, Alberto
AU - Fiore, Gianfranco B.
AU - Pappalardo, Federico
AU - Bluestein, Danny
AU - Slepian, Marvin J.
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2018/3
Y1 - 2018/3
N2 - Introduction: Continuous flow ventricular assist devices (cfVADs) continue to be limited by thrombotic complications associated with disruptive flow patterns and supraphysiologic shear stresses. Patients are prescribed complex antiplatelet therapies, which do not fully prevent recurrent thromboembolic events. This is partially due to limited data on antiplatelet efficacy under cfVAD-associated shear conditions. Materials and methods: We investigated the efficacy of antiplatelet drugs directly acting on three pathways: (1) cyclooxygenase (aspirin), (2) phosphodiesterase (dipyridamole, pentoxifylline, cilostazol), and (3) glycoprotein IIb-IIIa (eptifibatide). Gel-filtered platelets treated with these drugs were exposed for 10 min to either constant shear stresses (30 dyne/cm2 and 70 dyne/cm2) or dynamic shear stress profiles extracted from simulated platelet trajectories through a cfVAD (Micromed DeBakey). Platelet activation state (PAS) was measured using a modified prothrombinase-based assay, with drug efficacy quantified based on PAS reduction compared to untreated controls. Results and conclusions: Significant PAS reduction was observed for all drugs after exposure to 30 dyne/cm2 constant shear stress, and all drugs but dipyridamole after exposure to the 30th percentile shear stress waveform of the cfVAD. However, only cilostazol was significantly effective after 70 dyne/cm2 constant shear stress exposure, though no significant reduction was observed upon exposure to median shear stress conditions in the cfVAD. These results, coupled with the persistence of reported clinical thrombotic complication, suggest the need for the development of new classes of drugs that are especially designed to mitigate thrombosis in cfVAD patients, while reducing or eliminating the risk of bleeding.
AB - Introduction: Continuous flow ventricular assist devices (cfVADs) continue to be limited by thrombotic complications associated with disruptive flow patterns and supraphysiologic shear stresses. Patients are prescribed complex antiplatelet therapies, which do not fully prevent recurrent thromboembolic events. This is partially due to limited data on antiplatelet efficacy under cfVAD-associated shear conditions. Materials and methods: We investigated the efficacy of antiplatelet drugs directly acting on three pathways: (1) cyclooxygenase (aspirin), (2) phosphodiesterase (dipyridamole, pentoxifylline, cilostazol), and (3) glycoprotein IIb-IIIa (eptifibatide). Gel-filtered platelets treated with these drugs were exposed for 10 min to either constant shear stresses (30 dyne/cm2 and 70 dyne/cm2) or dynamic shear stress profiles extracted from simulated platelet trajectories through a cfVAD (Micromed DeBakey). Platelet activation state (PAS) was measured using a modified prothrombinase-based assay, with drug efficacy quantified based on PAS reduction compared to untreated controls. Results and conclusions: Significant PAS reduction was observed for all drugs after exposure to 30 dyne/cm2 constant shear stress, and all drugs but dipyridamole after exposure to the 30th percentile shear stress waveform of the cfVAD. However, only cilostazol was significantly effective after 70 dyne/cm2 constant shear stress exposure, though no significant reduction was observed upon exposure to median shear stress conditions in the cfVAD. These results, coupled with the persistence of reported clinical thrombotic complication, suggest the need for the development of new classes of drugs that are especially designed to mitigate thrombosis in cfVAD patients, while reducing or eliminating the risk of bleeding.
KW - Aspirin
KW - Glycoprotein IIb-IIIa inhibitors
KW - Mechanical circulatory support
KW - Phosphodiesterase inhibitors
KW - Shear stress
KW - Thrombosis
UR - http://www.scopus.com/inward/record.url?scp=85041544391&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041544391&partnerID=8YFLogxK
U2 - 10.1016/j.thromres.2017.12.001
DO - 10.1016/j.thromres.2017.12.001
M3 - Article
C2 - 29428715
AN - SCOPUS:85041544391
SN - 0049-3848
VL - 163
SP - 162
EP - 171
JO - Thrombosis Research
JF - Thrombosis Research
ER -