Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis

Background

Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus and local thrombotic and inflammatory mechanisms. We hypothesized that inhibition of vein wall injury through reduction of thrombotic and inflammatory events with P-selectin inhibition and/or low-molecular-weight heparin (LMWH) occurs independently of thrombus resolution in a rat model of venous thrombosis.

Methods

Male rats underwent inferior vena cava (IVC) stenosis (94.4% ± 0.5% reduction in IVC diameter) to induce thrombosis. Rats were treated from 2 days after thrombosis until they were killed 7 days later. Groups consisted of (1) PSI-697, a P-selectin inhibitor (30 mg/kg; oral gavage daily); (2) LMWH-Lovenox (LOV; enoxaparin) 3 mg/kg subcutaneously daily; (3) PSI-697 (30 mg/kg; oral gavage daily) plus LOV 3 mg/kg subcutaneously daily (PSI + LOV); (4) and untreated controls. Evaluations included thrombus mass, vein wall tensiometry (stiffness [inverse of compliance]), intimal thickness scoring by light microscopy, vein wall inflammatory mediators by enzyme-linked immunosorbent assay, and vein wall inflammatory cells by histologic evaluation.

Results

Thrombus mass was not reduced by any treatment. Animals treated with PSI-697 alone, LOV alone, or PSI + LOV demonstrated significant decreases in vein wall stiffness when compared with controls. The vein wall stiffness of the PSI-697–treated groups was also significantly lower than in the LOV-only group. Animals treated with PSI-697 showed a significantly decreased intimal thickness score when compared with vehicle control IVCs. Vein wall intimal thickening was also significantly decreased in animals treated with PSI-697 vs LOV. The PSI-697 and PSI + LOV groups manifested significant decreases in the immunoregulatory and inflammatory cytokine interleukin 13 as compared with controls and LOV. Vein wall monocyte chemotactic protein 1 levels were also significantly reduced in the PSI-697 and PSI + LOV groups vs control. Only PSI-697 significantly decreased vein wall levels of platelet-derived growth factor ββ. Both the LOV and PSI + LOV groups had significant increases in vein wall monocytes and total inflammatory cells vs controls.

Conclusions

These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition.

Clinical Relevance

Deep venous thrombosis (DVT) remains a serious health care problem in this country, affecting more than 250,000 patients annually. Chronic venous insufficiency, a major complication of DVT, promotes the impairment of venous outflow, loss of vein compliance, and valvular dysfunction. The current standard of care for both treatment and prophylaxis of DVT is low-molecular-weight heparin. However, this therapy confers a bleeding risk and does not protect against postthrombotic syndrome. In previous rat studies, using a recombinant P-selectin receptor antagonist (rPSGL-Ig) 2 days after thrombosis resulted in less vein wall fibrosis without a decrease in thrombus mass. Further studies in the rat model of DVT have shown that P-selectin inhibition also inhibits profibrotic cytokine production and vein wall collagen. This study evaluated the effects of P-selectin inhibition by using a novel oral agent (PSI-697) on the postthrombotic vein wall and compared this with the current standard of care.