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

评估固定剂量类黄酮异槲皮素对稳定镰状细胞病患者血栓炎症生物标志物影响的研究

• 批准号: 10929196
• 负责人: Arun Shet
• 金额: $ 57.22万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10929196
• 关键词: Adherence; American Society of Hematology; Anticoagulants; Anticoagulation; Attenuated; Biological Markers; Blood; Blood Platelets; Blood Vessels; Cell surface; Clinical; Coagulants; Coagulation Process; Deposition; Development; Disease; Dose; Endothelium; Erythrocytes; Exposure to; Factor Va; Fibrin; Fibrinolytic Agents; Flavonoids; Generations; Hemorrhage; Homeostasis; Human; Hypoxia; Inflammation; Injury; Intake; Isomerase; Leukocytes; Malignant Neoplasms; Manuscripts; Measures; Mus; Oral; P-Selectin; Patients; Placebos; Plasma; Plasma Proteins; Platelet Activation; Production; Protein Disulfide Isomerase; Publishing; Quercetin; Randomized; Rationalization; Recurrence; Reporting; Research; Risk; Safety; Sickle Cell; Sickle Cell Anemia; Sulfhydryl Compounds; Surface; Switzerland; Testing; Therapeutic Intervention; Thrombin; Thrombophilia; Thromboplastin; Thrombosis; Venous; Venous Thrombosis; Warfarin; atherothrombosis; data curation; dietary; double-blind placebo controlled trial; experience; extracellular vesicles; improved; inhibitor; isoquercetin; meetings; mortality; novel; pharmacologic; phase II trial; predictive marker; primary outcome; safety assessment; secondary outcome; thromboinflammation; vascular injury; vaso-occlusive crisis; venous thromboembolism

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 cell surface 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 tested this hypothesis in a randomized double blinded placebo controlled trial in patients with stable SCD. The study completed accrual and all subjects completed the study in July 2022. The study was unblinded, the data curation and analyzed and the first set of research abstracts were published at the Annual Meeting of the American Society of Hematology in December 2022. The manuscript reporting the results in currently under review.

镰状细胞病（SCD）与获得性高凝状态相关，其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，并且患者在长期抗凝治疗时出血风险增加，因此需要安全性更高的新型抗血栓形成药物。 科学证据支持炎症扰乱内皮和白细胞稳态并上调组织因子（TF）和P-选择素表达的观点，这是SCD中血栓炎性病理学的两个主要贡献者。因此，TF促凝血活性增加触发血管内凝血激活，其与静脉淤滞/缺氧结合引起静脉血栓栓塞（VTE）。SCD中的内皮和血小板损伤也可能导致血浆蛋白二硫键异构酶（PDI）水平升高，这可能解释了镰状红细胞（RBC）表面PDI浓度高于正常红细胞（RBC）的原因。PDI是一种在内皮/血小板损伤期间释放的血管硫醇异构酶，通过在人体中产生血小板因子Va来刺激凝血酶的产生，而在小鼠血管损伤后，促进纤维蛋白沉积。由于SCD患者具有增加的血源性组织因子、持续的凝血酶生成并表现出血小板活化的特征，通过恢复TF的翻译后调节控制来抑制血浆PDI可能会减弱相关的高凝状态。这种方法是合理的，通过观察血浆PDI活性升高的SCD小鼠，当暴露于药理学PDI抑制剂时，表现出减少的血管闭塞危象和微血管血栓形成。在患有活动性癌症的患者的II期试验中，类黄酮异槲皮素（IQ）（Querces AG，瑞士）有力地抑制血浆PDI活性并有利地减少可溶性P-选择素，可溶性P-选择素是预测VTE发展的生物标志物。此外，这些患者均未发生暴露于华法林或非维生素K口服抗凝剂时通常观察到的出血风险增加。在SCD患者中降低可溶性P-选择素的好处是减少炎症和细胞表面TF表达。 我们的总体假设是，类黄酮类药物IQ的治疗干预将降低可溶性P-选择素，同时降低TF的促血栓形成作用，而不会伴随出血风险增加。我们在稳定性SCD患者的随机双盲安慰剂对照试验中检验了这一假设。研究完成入组，所有受试者于2022年7月完成研究。该研究已揭盲，数据整理和分析以及第一组研究摘要已于2022年12月的美国血液学会年会上发表。报告结果的手稿目前正在审查中。