P-selectin antagonism reduces thrombus formation in humans.
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.


OBJECTIVE
To investigate the effects of the novel small molecule P-selectin antagonist PSI-697 on thrombus formation in humans.


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.
Chelliah
R
R
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. raj.chelliah@ed.ac.uk
Lucking
A J
AJ
Tattersall
L
L
Daga
S
S
Beresford-Cleary
N J
NJ
Cortas
K
K
Fox
K A A
KA
Feuerstein
G Z
GZ
Connolly
T M
TM
Newby
D E
DE
D000293:Adolescent; D000328:Adult; D001769:Blood / Q000187:drug effects; D002478:Cells, Cultured; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D019007:P-Selectin / Q000037:antagonists & inhibitors*; D010477:Perfusion; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D055815:Young Adult
D006912:Hydroxyquinolines; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D000077466:Tirofiban; C514191:2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo(H)quinoline-4-carboxylic acid