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: 10492974
• 负责人: Arun Shet
• 金额: $ 42.72万
• 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/10492974
• 关键词: Adherence; Anticoagulants; Anticoagulation; Attenuated; Biological Markers; Blood; Blood Platelets; Blood Vessels; Clinical; Coagulants; Coagulation Process; Deposition; Development; Disease; Dose; Endothelium; Enrollment; Erythrocytes; Exposure to; Factor Va; Fibrin; Fibrinolytic Agents; Flavonoids; Generations; Hemorrhage; Homeostasis; Human; Hypoxia; Inflammation; Injury; Isomerase; Leukocytes; Malignant Neoplasms; Measures; Mus; Oral; P-Selectin; Patients; Pharmacology; Placebos; Plasma; Plasma Proteins; Platelet Activation; Production; Protein Disulfide Isomerase; Randomized; Recurrence; Risk; Safety; Sickle Cell; Sickle Cell Anemia; Sulfhydryl Compounds; Surface; Switzerland; Testing; Therapeutic Intervention; Thrombin; Thrombophilia; Thromboplastin; Thrombosis; Venous; Venous Thrombosis; Warfarin; atherothrombosis; double-blind placebo controlled trial; experience; extracellular vesicles; improved; inhibitor/antagonist; mortality; novel; phase II trial; predictive marker; primary endpoint; primary outcome; 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 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.

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，并导致死亡率。由于静脉血栓复发是常见的，并且长期抗凝治疗会增加患者出血的风险，因此对安全性更高的新型抗凝药物的需求至关重要。