P‐selectin antagonism reduces thrombus formation in humans

Abstract

P-selectin antagonism reduces thrombus formation in humans. J Thromb Haemost 2009; 7: 1915-9. 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.

Selectin inhibitors: a patent review

“…It has also shown efficacy in disease models of atherosclerosis in mouse [45], restenosis in rat [43], and venous thrombosis in rat [46] and baboon [47]. A recent publication also shows ex vivo activity in humans inhibiting thrombus formation [48]. A second generation series, the asubstituted quinoline salicylic acids, was recently filed on by the same group for the treatment of inflammatory vascular disorders [49,50].…”

Intracoronary shear-related up-regulation of platelet P-selectin and platelet-monocyte aggregation despite the use of aspirin and clopidogrel

“…38 Pathways linking shear stress-mediated up-regulation of P-selectin and PM-Agg warrant further investigation as therapeutic targets for coronary atherosclerosis. 19,39 Current antiplatelet agents such as aspirin, thienopyridines, and GPIIb-IIIa inhibitors attenuate agonist-induced platelet activation, [15][16][17] and GPIIb-IIIa inhibitors reduce shear-induced platelet aggregation. 10,18,19 However, shear-induced platelet aggregation was shown to be independent of ADP and thromboxane, 11 and shear stress was shown to overcome aspirin inhibition of platelet aggregation.…”

Cu2+-RGDFRGDS: exploring the mechanism and high efficacy of the nanoparticle in antithrombotic therapy

“…It is well known that two transmembrane receptors, GPIIb/IIIa and P-selectin, are responsible for platelet aggregation and that both membrane and the cytoplasm domains greatly affect the expression of GPIIb/IIIa and P-selectin. 36,37 Thus via the two-step model, the nanoparticles of Cu 2+ -FS successively bind the membrane and cytoplasm domains and downregulate the expression of GPIIb/IIIa and P-selectin.…”