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

National Heart, Lung, And Blood Institute

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Abstract

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.