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P‐selectin antagonism reduces thrombus formation in humans
Author(s) -
CHELLIAH R.,
LUCKING A. J.,
TATTERSALL L.,
DAGA S.,
BERESFORDCLEARY N. J.,
CORTAS K.,
FOX K. A. A.,
FEUERSTEIN G. Z.,
CONNOLLY T. M.,
NEWBY D. E.
Publication year - 2009
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03587.x
Subject(s) - antagonism , thrombus , p selectin , medicine , cardiology , pharmacology , platelet , platelet activation , receptor
Summary. Background: Interaction of P‐selectin with its glycoprotein ligand (P‐selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P‐selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis. Aim: To investigate the effects of the novel small molecule P‐selectin antagonist PSI‐697 on thrombus formation in humans. Methods and Results: In a double‐blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low‐dose (2 m ) and high‐dose (20 m ) PSI‐697 and the glycoprotein IIb–IIIa receptor antagonist tirofiban (50 ng mL −1 ) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb–IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low‐shear and high‐shear chambers, respectively. PSI‐697 caused a dose‐dependent, but more modest, reduction in thrombus formation. Low‐dose PSI‐796 (2 m ) reduced total thrombus area by 14% ( P = 0.04) and 30% ( P = 0.0002) in the low‐shear and high‐shear chambers, respectively. At the high dose (20 m ), PSI‐697 reduced total thrombus area by 18% ( P = 0.0094) and 41% ( P = 0.0008) in the low‐shear and high‐shear chambers, respectively. Conclusions: P‐selectin antagonism with PSI‐697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P‐selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.