COAGULATION ACTIVATION IN SICKLE CELL DISEASE

由于存在大血管血栓性并发症，以及持续凝血激活的生化证据，镰状细胞病（SeD）通常被称为高凝状态。然而，凝血激活在SCD发病机制中的作用仍不确定。虽然大多数使用抗凝剂的临床研究显示在预防或治疗急性疼痛发作方面没有令人信服的益处，但这些研究大多规模小且控制不佳。此外，由于急性疼痛发作似乎是由于红细胞和其他细胞成分与血管内皮和内皮下基质蛋白相互作用导致毛细血管后小静脉闭塞所致，因此它可能不是评估SeD患者抗凝效果的理想临床终点。

As a result of the presence of macrovascular thrombotic complications, as well as the biochemical evidence of ongoing coagulation activation, sickle cell disease (SeD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. While the majority of clinical studies using anticoagulants have shown no convincing benefit in the prevention or treatment of acute pain episodes, most of these studies were small and poorly controlled. Furthermore, because the acute pain episode appears to result from the occlusion of postcapillary venules by the interaction of red blood cells and other cellular elements with the vascular endothelium and subendothelial matrix proteins, it may not be the ideal clinical endpoint for assessing the effect of anticoagulation in SeD patients. Pulmonary hypertension (PHT), a common complication associated with significant morbidity and mortality, and with histopathologic find ings of in situ thrombosis involving pulmonary vessels, represents a clinical endpoint that is likely due, at least in part, to increased thrombin generation, and may therefore be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. The UNC Comprehensive Sickle Cell Program offers a large and closely followed patient population in whom we will be able to study in detail the contribution of hypercoagulability to the pathophysiology of SCD-associated PHT. Our expertise in the care of patients with SCD, as well as ongoing research interests in hemostasis and thrombosis, makes our center an ideal one to answer this fundamental question. We hypothesize that increased thrombin generation, as well as platelet activation are central to the pathophysiology of SCD and contribute to the occurrence of several SCDrelated complications, including PHI. As a consequence, treatment modalities that down-regulate thrombin generation would be expected to delay the progression of PHT and result in improved survival in patients with SCD. The long-term goals of our proposed work are to: 1) evaluate the safety and efficacy of anticoagulation in SCD-associated PHT; and 2) evaluate the effect of anticoagulation on plasma markers of thrombin generation, platelet activation, as well as endothelial activation in SCD patients with PHI.