Routine clinical anti-platelet agents have limited efficacy in modulating hypershear-mediated platelet activation associated with mechanical circulatory support

Lorenzo Valerio, Jawaad Sheriff, Phat L. Tran, William Brengle, Alberto Redaelli, Gianfranco B. Fiore, Federico Pappalardo, Danny Bluestein, Marvin J Slepian

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)162-171
Number of pages10
JournalThrombosis Research
Volume163
DOIs
StatePublished - Mar 1 2018

Fingerprint

Platelet Activation
Blood Platelets
Pharmaceutical Preparations
Dipyridamole
Pentoxifylline
Platelet Glycoprotein GPIIb-IIIa Complex
Heart-Assist Devices
Platelet Aggregation Inhibitors
Thromboplastin
Cyclooxygenase 2
Aspirin
Thrombosis
Gels
Hemorrhage
cilostazol

Keywords

  • Aspirin
  • Glycoprotein IIb-IIIa inhibitors
  • Mechanical circulatory support
  • Phosphodiesterase inhibitors
  • Shear stress
  • Thrombosis

ASJC Scopus subject areas

  • Hematology

Cite this

Routine clinical anti-platelet agents have limited efficacy in modulating hypershear-mediated platelet activation associated with mechanical circulatory support. / Valerio, Lorenzo; Sheriff, Jawaad; Tran, Phat L.; Brengle, William; Redaelli, Alberto; Fiore, Gianfranco B.; Pappalardo, Federico; Bluestein, Danny; Slepian, Marvin J.

In: Thrombosis Research, Vol. 163, 01.03.2018, p. 162-171.

Research output: Contribution to journalArticle

Valerio, Lorenzo ; Sheriff, Jawaad ; Tran, Phat L. ; Brengle, William ; Redaelli, Alberto ; Fiore, Gianfranco B. ; Pappalardo, Federico ; Bluestein, Danny ; Slepian, Marvin J. / Routine clinical anti-platelet agents have limited efficacy in modulating hypershear-mediated platelet activation associated with mechanical circulatory support. In: Thrombosis Research. 2018 ; Vol. 163. pp. 162-171.
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abstract = "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.",
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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

PY - 2018/3/1

Y1 - 2018/3/1

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

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