Hillery C A, Du M C, Wang W C, Scott J P
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Br J Haematol. 2000 May;109(2):322-7. doi: 10.1046/j.1365-2141.2000.02040.x.
The adhesion of sickle erythrocytes to the vascular endothelium and subendothelial matrix probably contributes to the pathogenesis of vaso-occlusive disease. The chemotherapeutic agent hydroxyurea (HU) decreases the frequency of vaso-occlusive crises in patients with sickle cell disease. However, the exact mechanism(s) of HU's effect on vaso-occlusive crises is not fully understood. The goal of this study was to determine the effect of HU therapy on the adhesion of sickle erythrocytes to the subendothelial matrix proteins thrombospondin (TSP) and laminin under conditions of flow in vitro. Erythrocytes from patients with severe sickle cell disease on HU therapy (n = 14) had significantly less adhesion to TSP (687 +/- 92 erythrocytes/mm2, mean +/- SE) than untreated patients with severe disease (n = 18, 1176 +/- 117 erythrocytes/mm2, P = 0.003). In addition, there was significantly less adhesion of erythrocytes to immobilized laminin in patients treated with HU (1695 +/- 293 erythrocytes/mm2) than in the untreated patients (2590 +/- 296 erythrocytes/mm2, P = 0.02). Erythrocytes from an additional nine patients with severe sickle cell disease were studied both before and after initiation of HU therapy. Erythrocytes from these patients became less adhesive to both TSP (P = 0.001) and laminin (P = 0.01), a change that was sustained in most patients throughout the duration of the study (2 months to > 12 months). This study suggests that HU modulates the adhesive phenotype of sickle erythrocytes, an effect that may be in addition to, or independent of, other known effects of HU, such as an increase in fetal haemoglobin level.
镰状红细胞与血管内皮及内皮下基质的黏附可能在血管闭塞性疾病的发病机制中起作用。化疗药物羟基脲（HU）可降低镰状细胞病患者血管闭塞性危象的发生频率。然而，HU对血管闭塞性危象的确切作用机制尚未完全明确。本研究的目的是在体外流动条件下，确定HU治疗对镰状红细胞与内皮下基质蛋白血小板反应蛋白（TSP）和层粘连蛋白黏附的影响。接受HU治疗的重度镰状细胞病患者（n = 14）的红细胞与TSP的黏附（687±92个红细胞/mm²，平均值±标准误）明显低于未治疗的重度疾病患者（n = 18，1176±117个红细胞/mm²，P = 0.003）。此外，接受HU治疗的患者红细胞与固定化层粘连蛋白的黏附（1695±293个红细胞/mm²）也明显低于未治疗患者（2590±296个红细胞/mm²，P = 0.02）。另外9例重度镰状细胞病患者在开始HU治疗前后均进行了研究。这些患者的红细胞对TSP（P = 0.001）和层粘连蛋白（P = 0.01）的黏附性均降低，在大多数患者中，这种变化在整个研究期间（2个月至>12个月）持续存在。本研究表明，HU可调节镰状红细胞的黏附表型，这种作用可能是HU其他已知作用之外的，或是独立于这些作用的，如增加胎儿血红蛋白水平。
