A phase 1 study of prasugrel in patients with sickle cell disease: Effects on biomarkers of platelet activation and coagulation

TY - JOUR

T1 - A phase 1 study of prasugrel in patients with sickle cell disease

T2 - Effects on biomarkers of platelet activation and coagulation

AU - Jakubowski, Joseph A.

AU - Zhou, Chunmei

AU - Jurcevic, Stipo

AU - Winters, Kenneth J.

AU - Lachno, D. Richard

AU - Frelinger, Andrew L.

AU - Gupta, Neehar

AU - Howard, Jo

AU - Payne, Christopher D.

AU - Mant, Timothy G.

PY - 2014/2

Y1 - 2014/2

N2 - Introduction: Prasugrel, a P2Y(12) adenosine diphosphate (ADP) receptor antagonist effectively inhibits ADP-mediated platelet activation and aggregation, and may be useful in reducing vaso-occlusive crises in sickle cell disease (SCD). In this study, we assess the effect of prasugrel on biomarkers of platelet activation and coagulation in patients with SCD. Materials and Methods: Twelve adult patients with SCD and 13 healthy subjects were examined before and after 12 +/- 2 days of 5.0 or 7.5 mg/day oral prasugrel. Assessed cellular biomarkers included monocyte-and neutrophil-platelet aggregates, activated glycoprotein IIb-IIIa (GPIIbIIIa), P-selectin, CD40 ligand (CD40L), tissue factor (TF) expression on circulating platelets and on monocyte-platelet aggregates, and platelet-erythrocyte aggregates. Soluble biomarkers included CD40L, prothrombin fragment 1.2 (F1.2), thromboxane B-2 (TXB2), P-selectin, and TF. Results: Patients with SCD had increased platelet baseline activation compared to healthy subjects, as measured by percentages ofmonocyte-platelet aggregates, neutrophil-platelet aggregates, and platelets expressing CD40L. Likewise, baseline levels of soluble F1.2 and TXB2 were elevated in patients with SCD compared to healthy subjects. After 12 days of prasugrel, patients with SCD had a significant reduction in platelet-monocyte aggregates that was not observed in healthy subjects. Following prasugrel administration, those with SCDmaintained higher levels of monocyte-platelet aggregates and soluble F1.2, but had lower levels of platelet-erythrocyte aggregates and soluble TF compared to healthy subjects. Conclusions: These results provide evidence for chronic platelet activation in the SCD steady state, activation that was in part attenuated by prasugrel, thereby suggesting that ADP may mediate platelet activation in SCD.

AB - Introduction: Prasugrel, a P2Y(12) adenosine diphosphate (ADP) receptor antagonist effectively inhibits ADP-mediated platelet activation and aggregation, and may be useful in reducing vaso-occlusive crises in sickle cell disease (SCD). In this study, we assess the effect of prasugrel on biomarkers of platelet activation and coagulation in patients with SCD. Materials and Methods: Twelve adult patients with SCD and 13 healthy subjects were examined before and after 12 +/- 2 days of 5.0 or 7.5 mg/day oral prasugrel. Assessed cellular biomarkers included monocyte-and neutrophil-platelet aggregates, activated glycoprotein IIb-IIIa (GPIIbIIIa), P-selectin, CD40 ligand (CD40L), tissue factor (TF) expression on circulating platelets and on monocyte-platelet aggregates, and platelet-erythrocyte aggregates. Soluble biomarkers included CD40L, prothrombin fragment 1.2 (F1.2), thromboxane B-2 (TXB2), P-selectin, and TF. Results: Patients with SCD had increased platelet baseline activation compared to healthy subjects, as measured by percentages ofmonocyte-platelet aggregates, neutrophil-platelet aggregates, and platelets expressing CD40L. Likewise, baseline levels of soluble F1.2 and TXB2 were elevated in patients with SCD compared to healthy subjects. After 12 days of prasugrel, patients with SCD had a significant reduction in platelet-monocyte aggregates that was not observed in healthy subjects. Following prasugrel administration, those with SCDmaintained higher levels of monocyte-platelet aggregates and soluble F1.2, but had lower levels of platelet-erythrocyte aggregates and soluble TF compared to healthy subjects. Conclusions: These results provide evidence for chronic platelet activation in the SCD steady state, activation that was in part attenuated by prasugrel, thereby suggesting that ADP may mediate platelet activation in SCD.

KW - ADP

KW - Biomarkers

KW - P2Y(12) receptor antagonist

KW - Platelets

KW - Prasugrel

KW - Sickle cell disease

KW - ACTIVE METABOLITE

KW - DOUBLE-BLIND

KW - ANEMIA

KW - HYPERCOAGULABILITY

KW - ANTIPLATELET

KW - INFLAMMATION

KW - CLOPIDOGREL

KW - INHIBITION

KW - MONOCYTE

U2 - 10.1016/j.thromres.2013.12.008

DO - 10.1016/j.thromres.2013.12.008

M3 - Article

SN - 0049-3848

VL - 133

SP - 190

EP - 195

JO - Thrombosis Research

JF - Thrombosis Research

IS - 2

ER -