A Study to Evaluate the Effects of fixed dose Flavonoid Isoquercetin on thrombo-inflammatory biomarkers in subjects with stable Sickle Cell Disease

镰状细胞病(SCD)与获得性高凝状态有关，临床表现为静脉血栓栓塞性疾病，并导致死亡。由于复发性静脉血栓形成很常见，患者在长期抗凝治疗中出血的风险增加，因此需要安全性更高的新型抗血栓药物。 科学证据支持炎症扰乱内皮细胞和白细胞的动态平衡，上调组织因子(TF)和P-选择素的表达，这两个因素是SCD血栓炎症病理生物学的主要因素。因此，TF促凝血剂活性的增加触发了血管内凝血的激活，而血管内凝血又与静脉淤滞/缺氧共同引发静脉血栓栓塞症(VTE)。SCD的内皮和血小板损伤也可能是血浆蛋白二硫键异构酶(PDI)水平升高的原因之一，这可能是镰状红细胞表面PDI浓度高于正常红细胞的原因。PDI是一种血管硫醇异构酶，在内皮/血小板损伤时释放，在人类通过产生血小板因子Va刺激凝血酶的产生，在小鼠血管损伤时，促进纤维蛋白沉积。由于SCD患者血中组织因子升高，凝血酶持续生成，并表现出血小板活化的特征，因此，通过恢复对TF的翻译后调控，抑制血浆PDI可能会减轻相关的高凝状态。这种方法是合理的，观察到血浆PDI活性升高的SCD小鼠，当暴露于药物PDI抑制剂时，显示出血管闭塞危象和微血管血栓的减少。在一项针对活动性癌症患者的II期试验中，类黄酮类Isoquercetin(IQ)(Querces AG，瑞士)有力地抑制了血浆PDI活性，并有利地降低了预测VTE发展的生物标记物--可溶性P-选择素。此外，这些患者中没有人经历过任何出血风险的增加，这通常是在接触华法林或非维生素K口服抗凝剂时观察到的。降低SCD患者的可溶性P-选择素的好处是减少炎症和TF的表达。 我们的总体假设是，类黄酮剂IQ的治疗干预会降低可溶性P-选择素，同时减少TF的血栓前作用，而不会增加出血的风险。我们正在对稳定性SCD患者进行随机、双盲、安慰剂对照试验，以验证这一假设。 到目前为止，这项研究已经招募了46名拟议受试者中的23名，所有这些受试者都完成了研究。

Sickle Cell Disease (SCD) is associated with an acquired hypercoagulable state which clinically manifests as venous thromboembolic disease and contributes to mortality. Since recurrent venous thrombosis is common and patients have an increased risk for bleeding when exposed to long term anticoagulation, the need for novel antithrombotic agents with improved safety is critical. Scientific evidence supports the notion that inflammation perturbs endothelial and leukocyte homeostasis and upregulates tissue factor (TF) and P-selectin expression, two major contributors to thrombo-inflammatory pathobiology in SCD. Consequently, increased TF pro coagulant activity triggers activation of intravascular coagulation which combined with venous stasis/hypoxia provokes venous thromboembolism (VTE). Endothelial and platelet injury in SCD also likely contributes to elevated plasma protein disulfide isomerase (PDI) levels possibly explaining higher PDI concentrations on the surface of sickle RBCs compared to normal red blood cells (RBCs). PDI, a vascular thiol isomerase released during endothelial/platelet injury stimulates thrombin production by generating platelet factor Va in humans, and upon vascular injury in mice, facilitates fibrin deposition. Since SCD patients have increased blood borne tissue factor, sustained thrombin generation and demonstrate features of platelet activation, plasma PDI inhibition, by restoring post-translational regulatory control of TF, might attenuate the associated hypercoagulable state. Such an approach is rationalized by observations of elevated plasma PDI activity SCD mice that when exposed to a pharmacologic PDI inhibitor demonstrated reduced vaso-occlusive crisis and microvascular thrombosis. In a phase II trial of patients with active cancer, the flavonoid Isoquercetin (IQ) (Querces AG, Switzerland)) robustly inhibited plasma PDI activity and favorably reduced soluble P-selectin, a biomarker predictive of VTE development. Besides, none of these patients experienced any increased risk of bleeding typically observed with exposure to warfarin or non-vitamin K oral anticoagulants. The salutatory benefits of lowering soluble P-selectin in SCD patients are both reduced inflammation and TF expression. Our overall hypothesis is that therapeutic intervention with the flavonoid agent IQ would lower soluble P-selectin and simultaneously decrease the prothrombotic effects of TF without a concomitantly increased risk for bleeding. We are testing this hypothesis in a randomized double blinded placebo controlled trial in patients with stable SCD. Till date, the study has enrolled 23 of the proposed 46 subjects and all of these subjects have completed the study.