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Isoquercetin Lowers Several Thromboinflammatory Biomarkers in SCD But Not Plasma Soluble P-Selectin

February 29, 2024

March 2024

Katie Robinson

Katie Robinson is a medical writer based in New York.

A small phase II study of short-term daily fixed-dose isoquercetin use in adults with steady-state sickle cell disease (SCD) did not meet its primary endpoint of lowering plasma soluble P-selectin (sP-selectin), but exposure to the inexpensive oral flavonoid was associated with a reduction in several thromboinflammatory biomarkers. The study, published in Blood Advances, also confirmed that using isoquercetin was safe for these patients.

“Systemic anticoagulants are used to prevent and treat venous thromboembolism in patients with SCD, but they are associated with bleeding complications,” explained corresponding author Arun S. Shet, MD, PhD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland. “By posing no additional bleeding risk, isoquercetin represents a potential paradigm shift for managing thrombotic vascular complications in SCD.”

Isoquercetin treatment lowered thrombosis biomarkers and prevented clinical thrombosis in a small study of patients with cancer. However, the effect of isoquercetin on thromboinflammation in SCD has not been previously studied. Dr. Shet and colleagues tested its safety and efficacy to modulate thromboinflammatory pathophysiology in SCD.

The randomized, double-blind, placebo-controlled trial included 46 adults (mean age = 40 years; 56% female) with steady-state SCD, defined as having no significant complications or a blood transfusion within two months of the baseline visit. Most participants had the HbSS genotype and received disease-modifying therapy with hydroxyurea (75%; average dose = 18 mg/kg). Between November 19, 2019, and July 7, 2022, the patients were randomized 1:1 to receive 1,000 mg of isoquercetin or placebo for four weeks. The primary outcome was the post-treatment change from baseline in sP-selectin. The researchers also assessed safety as a secondary outcome. One participant in each group was excluded because of screening or follow-up failure.

After 28 to 35 days of treatment, no significant difference was found in the mean change of sP-selectin between groups (isoquercetin = 0.10 ± 6.53 vs. placebo = 0.74 ± 4.54; p=0.64). During the intervention period, 22% of the participants experienced acute vaso-occlusive crises (VOC; five in each group). No significant difference was found in the mean change of sP-selectin between groups after excluding patients who experienced acute VOC (p=0.61).

In patients who received isoquercetin, whole blood coagulation and collagen-induced platelet aggregation were significantly reduced from the baseline (p=0.03 for both). These effects persisted after the exclusion of the two participants in each group who were receiving anticoagulants or the three participants in each group who were receiving aspirin. Inducible mononuclear cell tissue factor gene expression and plasma protein disulfide isomerase reductase were also significantly inhibited in patients who received isoquercetin (p=0.003 and p=0.02, respectively). Isoquercetin treatment did not affect D-dimers or thrombin-antithrombin complexes (p=0.81 and p=0.91, respectively). Isoquercetin was well tolerated. None of the 21 adverse events (AEs) or 14 serious AEs reported were attributable to the drug.

“Daily fixed-dose isoquercetin was safe and modulated thromboinflammatory pathophysiology in patients with SCD with no observed increase in either acute VOC or bleeding,” Dr. Shet said.

Limitations to the study include the small number of participants and the use of fixed instead of escalating dose isoquercetin, which may have hampered the detection of the differences in plasma sP-selectin.

“Although the trial did not meet its endpoint of lowering plasma sP-selectin, it showed that exposure to isoquercetin was associated with a reduction in several thromboinflammatory biomarkers. Therefore, trials of higher-dose isoquercetin for more extended treatment durations may show benefit in attenuating thromboinflammatory pathophysiology in patients with SCD,” Dr. Shet said.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Lizarralde-Iragorri M, Gopalan BP, Merriweather B, et al. Isoquercetin for thromboinflammation in sickle cell disease: a randomized double-blind placebo-controlled trial. Blood Adv. 2024;8(1):172-182

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