Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation

Abstract

P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMWH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p < 0.01). LMWH opening evident after balloon deflation slightly deteriorated over time compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMWH and control animals six hours post thrombus induction (p < 0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.

P-Selectin Inhibition Therapeutically Promotes Thrombus Resolution and Prevents Vein Wall Fibrosis Better Than Enoxaparin and an Inhibitor to von Willebrand Factor

“…MCP-1 directs monocytes to areas of inflammation and initiates a pro-fibrotic environment 23, 24 . Anti P-selectin therapy decreased vein wall collagen, fibrosis, and or intra-thrombus fibrin deposition, while conferring either decreased thrombosis or enhanced thrombus resolution 5, 25, 26 In the present study, fibrin deposition and vein wall collagen was significantly decreased in animals treated with the anti- P-selectin aptamer, and these animals had significant vein re-opening and retention of venous valve competency. In addition, the anti-P-selectin aptamer does not impair inflammatory recruitment to the vein wall.…”

“…Animals receiving the anti-P-selectin aptamer, in the prophylactic protocol, were within normal reference ranges for this thrombosis model 4, 5 . Animals receiving anti-VWF aptamer in a prophylactic manner had significantly increased BT values over baseline (2.5 – 4.5 min) of 20 min (day 2), 16 min (day 6), and 7 min (day 14) [Table 1].…”

“…Animals receiving the anti-P-selectin aptamer and controls were within normal reference ranges 4, 5 . Thrombin clotting times in animals treated with enoxaparin showed transient increases of 77% (day 2), 53% (day 6), and a 69% (day 14) above baseline levels.…”

“…Animals receiving the anti-VWF aptamer had significantly inhibited platelet aggregation and elevated bleeding times. In addition, animals receiving anti-VWF showed increased bleeding times for both prophylaxis and treatment protocols 4, 5, 26, 33 .…”

A Thought Experiment in Contemporary Drug Development: Informed Bench‐to‐Bedside Strategies

“…In an inferior vena cava (IVC) stenosis and thrombosis model 12 PSI‐697 did not reduce either thrombus mass or vessel wall monocyte/total inflammatory cell infiltration, but did reduce vein wall stiffness. In a baboon model of iliac vein thrombosis 13 PSI‐697 administered beginning 3 days before occlusion and continued for 6 days, did not prevent thrombosis, but did demonstrate greater than 80% vein lumen opening over time and decreased vein wall inflammation compared to low molecular weight heparin and vehicle control. The capability of PSI‐697 to inhibit the binding of human P‐selectin to PSGL‐1, reduce leukocyte rolling, modestly reduce venous thrombosis and thrombus weight, and reduce intimal thickness following arterial injury was demonstrated in vivo and in rodent models of vascular inflammation and thrombosis.…”