Hydroxyurea therapy decreases the in vitro adhesion of sickle erythrocytesto thrombospondin and laminin

The adhesion of sickle erythrocytes to the vascular endothelium and subendo thelial matrix probably contributes to the pathogenesis of vaso-occlusive d isease. The chemotherapeutic agent hydroxyurea (HU) decreases the frequency of vaso-occlusive crises in patients with sickle cell disease. However, th e exact mechanism(s) of HU's effect on vaso-occlusive crises is not fully u nderstood. The goal of this study was to determine the effect of HU therapy on the adhesion of sickle erythrocytes to the subendothelial matrix protei ns thrombospondin (TSP) and laminin under conditions of now in vitro. Eryth rocytes from patients with severe sickle cell disease on HU therapy (n = 14 ) had significantly less adhesion to TSP (687 +/- 92 erythrocytes/mm(2), me an +/-SE) than untreated patients with severe disease (n = 18, 1176 +/- 117 erythrocytes/mm(2), P = 0.003). In addition, there was significantly less adhesion of erythrocytes to immobilized laminin in patients treated with HU (1695 +/- 293 erythrocytes/mm(2)) than in the untreated patients (2590 +/- 296 erythrocytes/mm(2), P = 0.02). Erythrocytes from an additional nine pa tients with severe sickle cell disease were studied both before and after i nitiation of HU therapy. Erythrocytes from these patients became less adhes ive to both TSP (P = 0.001) and laminin (P = 0.01), a change that was susta ined in most patients throughout the duration of the study (2 months to > 1 2 months). This study suggests that RU modulates the adhesive phenotype of sickle erythrocytes, an effect that may be in addition to, or independent o f. other known effects of HU, such as an increase in fetal haemoglobin leve l.