Low Molecular Weight Heparin Reduces sVCAM-1 and Lung Congestion In a Murine Model of Sickle Cell Disease

Abstract 1635

There is evidence for increased levels of procoagulant proteins, thrombin generation and tissue factor activity in individuals with sickle cell disease. Both thrombin and tissue factor also have potent proinflammatory effects that likely further contribute to the vascular dysfunction and organ injury observed in sickle cell disease. In this study, we examine the effect of the LMW heparin, enoxaparin, on markers of vascular injury and inflammation in the Berkeley mouse model of severe sickle cell disease (HbSS mice). HbSS mice or control HbAA mice (that exclusively express normal human HbA) were treated with continuous subcutaneous infusion of enoxaparin (10 mg/kg/day) or saline for 14 days using a surgically implanted Alzet pump (n=12-14 mice per group). Blood was collected at baseline and following 14 days enoxaparin therapy. Anesthetized animals were perfused with PBS at constant physiologic pressure (80 mmg Hg) and lung and liver collected for pathologic analyses. Enoxaparin-treated mice had steady state LMW heparin levels of 0.45 ± 0.17 anti-Xa U/mL compared to <0.1 anti-Xa U/mL in saline treated animals. Enoxaparin reduced d-dimer levels by approximately 35% in both HbSS and HbAA mice compared to saline-treated mice (p=0.03 and p=0.02, respectively), showing a functional reduction in coagulation and fibrinolytic activity. The hemoglobin level did not change and no obvious hemorrhage was noted in enoxaparin-treated mice suggesting no major bleeding complications. sVCAM-1 is a measure of endothelial injury and is increased at baseline in HbSS mice compared to HbAA mice (p<0.001). sVCAM-1 levels were reduced in HbSS mice after 14 days of enoxaparin therapy (1424 ± 83 ng/mL baseline, 1314 ± 85 ng/mL post enoxaparin, p=0.02), but not in saline treated HbSS mice (1462 ± 69 ng/mL baseline, 1392 ± 85 ng/mL post saline, p=0.3). Furthermore, the sVCAM-1 level negatively correlated with the steady state heparin level (r=-0.48, p=0.02) suggesting a modest dose-dependent effect of heparin on sVCAM-1 level. There was no effect of enoxaparin or saline therapy on sVCAM-1 levels in control HbAA mice. Preliminary histological analysis revealed a reduced number of congested pulmonary arteries in enoxaparin-treated HbSS mice compared to saline treated HbSS mice (p=0.01). These data suggest that enoxaparin therapy may improve endothelial injury as measured by sVCAM-1 and pulmonary vascular congestion in a mouse model of severe sickle cell disease. The data also suggest that heparin-based anticoagulant therapy may be a novel therapeutic approach to improve vascular health in individuals who suffer from sickle cell disease.