Background P-selectin plays a major role in inflammation and thrombosis and its expression is increased in patients with coronary artery disease. P-selectin inhibition is a potential future target for the prevention and treatment of cardiovascular disease. We investigated the effect of a novel P-selectin inhibitor, PSI-697, in an ex-vivo model of thrombus formation in humans.
Methods Ex-vivo thrombus formation was assessed using the Badimon chamber at low (212 s−1) and high (1690 s−1) shear rates with porcine aortic tunica media as the thrombogenic substrate. In a double-blind randomised crossover study, thrombus formation was measured using the Badimon chamber in 12 healthy volunteers. Subjects were randomly assigned to the extracorporeal administration of saline, tirofiban (50 ng/ml; glycoprotein IIb/IIIa receptor inhibitor), and low (2 μmol) and high-dose (20 μmol) PSI-697. Porcine aorta was fixed and stained and total thrombus was measured histologically using computerised planimetry.
Results Consistent with its potent antiplatelet effects, tirofiban reduced thrombus formation under low and high shear conditions by 30% (change in thrombus area 2830 μm2, 95% CI 1175 to 4484 μm2, p = 0.0034) and 57% (change in thrombus area 6462 μm2, 95% CI 4531 to 8393 μm2, p<0.0001), respectively. Compared with saline, low and high-dose PSI-697 reduced thrombus formation under low shear conditions by 14% (change in thrombus area 1393 μm2, 95% CI 33.56 to 2753 μm2, p = 0.04) and 18% (change in thrombus area 2158 μm2, 95% CI 720 to 3595 μm2, p = 0.0094), respectively, and under high shear conditions by 30% (change in thrombus area 3496 μm2, 95% CI 2129 to 4862 μm2, p = 0.0002) and 41% (change in thrombus area 4724 μm2, 95% CI 2448 to 7001 μm2, p = 0.0008), respectively.
Conclusions The novel P-selectin inhibitor, PSI-697, reduces ex-vivo thrombus formation in humans, especially under conditions of high shear stress. These findings suggest that P-selectin inhibition may be a future therapeutic target in atherothrombotic disease in man.
Funding This work was supported by an award from the Translational Medicine Research Collaboration.