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

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.

New and effective treatment of experimentally induced venous thrombosis with anti-inflammatory rPSGL-Ig.

BACKGROUND: P-selectin antagonism decreases thrombosis and inflammation in animal models of venous thrombosis (VT) prophylaxis. This study defines results using a P-selectin receptor antagonist for VT treatment. METHODS: Eight juvenile baboons underwent 6 h of iliofemoral venous stasis to produce an occlusive VT. Two days later, animals were treated for 14 days with rPSGL-Ig, 4 mg/kg (n3), LMWH (n2) or saline (n3) and treatment continued weekly (rPSGL-Ig) or daily (LMWH, saline). The animals were examined and sacrificed 14 days after treatment initiation (n4) or on day 90 (n4). RESULTS: Percent spontaneous vein reopening revealed a significant increase (p <0.05) in the proximal iliac vein in rPSGL-Ig and LMWH animals compared to controls (62%, 70% vs 8%), without differences in inflammation. No anticoagulation, thrombocytopenia, or wound complications were found in rPSGL-Ig animals. At 90 days, recanalization with iliac vein valve competence was found in treated animals. CONCLUSIONS: rPSGL-Ig successfully treated established VT without anticoagulation.

Effect of carotid atherosclerosis screening on risk stratification during primary cardiovascular disease prevention.

We investigated the effect that carotid plaque area (CPA) and intima media thickness (IMT) measurements have on risk stratification in 95 patients with intermediate Framingham scores (6% to 19%). The risk status of each patient was adjusted to be low, intermediate, or high based on the results of carotid ultrasound. After carotid testing, 44% (IMT) and 45% (CPA) of the intermediate-risk patients were stratified as low risk, and 22% (IMT) and 40% (CPA) were stratified as high risk. Using the threshold values derived from our laboratory, 28% (IMT) and 45% (CPA) of patients were stratified as low risk, and 35% (IMT) and 27% (CPA) were identified as high risk. These tests adjust the risk strata of >/=63% of patients deemed as having intermediate risk by Framingham scores.