March 6, 2024

Isoquercetin for Thromboinflammation

Results from a small phase 2 clinical trial
Although quercetin did not lower P-selectin levels, it did improve several thromboinflammatory biomarkers.


Lizarralde-Iragorri MA, Parachalil Gopalan B, 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. 

Study Objective

To evaluate the safety and efficacy of supplemental isoquercetin (IQ) on thromboinflammation in adult patients with steady-state sickle cell disease

Key Takeaway  

Isoquercetin supplementation was safe and well-tolerated and improved several biomarkers of thromboinflammation in patients with sickle cell disease. 


Single-center, randomized, double-blind, placebo-controlled phase 2 trial


This study included 46 patients, aged 29 to 51 years, 56% female, with steady-state sickle cell disease, 75% of whom were receiving hydroxyurea.


The intervention consisted of 1,000 mg isoquercetin (capsules of 250 mg IQ blended with 62 mg vitamin C and 5 mg vitamin B3) given once daily for 28 to 35 days. 

The placebo contained 62 mg vitamin C and 5 mg vitamin B3. Quercis Pharma provided the isoquercetin. 

Study Parameters Assessed

Investigators collected platelet-free plasma at baseline and after 4 weeks. They evaluated changes in plasma-soluble P-selectin using enzyme-linked immunosorbent assay (ELISA). 

Investigators evaluated several additional markers of thromboinflammation, including whole-blood coagulability, platelet aggregation, procoagulant activity, thrombin and fibrin generation, and mononuclear cell tissue factor messenger RNA expression. They determined adherence by evaluating plasma quercetin levels in random blood samples. Investigators also completed safety assessments at baseline, after treatment, and at the end of the study. 

Primary Outcome

The primary outcome measure was the change in plasma-soluble P-selectin values after 4 weeks of isoquercetin supplementation compared to baseline. 

Key Findings

Overall, the mean change in serum P-selectin levels was not significantly different between groups (IQ 0.10±6.53 vs placebo 0.74±4.54; P=0.64).

This study did not meet its primary endpoint of reducing plasma sP-selectin. There was no change from baseline in D-dimers nor in thrombin/antithrombin complexes in either arm.

Investigators deemed IQ to be well-tolerated when given over a brief period (28–35 days) at a dose of 1,000 mg/day and to be safe alongside hydroxyurea. Parameters of whole-blood coagulation, evaluated via thromboelastography (TEG), improved in the IQ group compared to placebo (P=0.03).

In vitro stimulation of platelet aggregation by low-dose collagen decreased in the IQ group compared to placebo (P=0.03). However, there was no change in stimulated platelet aggregation by stronger platelet agonists. The beneficial changes in both whole blood coagulation (TEG) and platelet aggregation persisted after excluding patients receiving anticoagulation. 


No conflicts of interest were noted. 

Practice Implications & Limitations

Over the past 20 years, the incidence of sickle cell disease worldwide has increased by 41.4%, from 5.5 million in 2000 to 7.7 million in 2021. It is the most common inherited blood disorder in the United States.1 The only cure currently available for sickle cell disease is hematopoietic stem cell transplantation; otherwise treatment is focused on prevention and treatment of complications, primarily veno-occlusive events and infection.2 As of December 2023, the Food and Drug Administration has approved 2 promising treatments that permanently correct the aberrant gene involved in SSD using cell-based gene therapy. Long-term studies are ongoing.

A hypercoagulable state is one of the hallmarks of sickle cell disease; it contributes greatly to its morbidity and often necessitates the use of anticoagulants. As many of us know, anticoagulants come with their own slew of side effects, increased risk of bleeding being the most significant. As the authors state in the current study under review, “systemic anticoagulant use is associated with a 21% increased incidence of clinically relevant major bleeding in patients with SCD.”3 Hypercoagulability occurs in several other conditions including cancer, antiphospholipid syndrome, prolonged immobilization, and several inherited disorders such as factor V Leiden and prothrombin gene mutations. 

A hypercoagulable state is one of the hallmarks of sickle cell disease; it contributes greatly to its morbidity and often necessitates the use of anticoagulants.

While this study did not meet its primary endpoint of decreasing P-selectin levels, the results are still noteworthy. A dose of 1,000 mg quercetin had significant effects on several thromboinflammatory biomarkers, including whole-blood coagulation, platelet aggregation, and tissue-factor expression. The changes in tissue-factor gene expression and protein disulfide isomerase activity indicate possible mechanisms for its ability to modulate thromboinflammation. Additionally, quercetin was shown to be safe and well-tolerated alongside hydroxyurea, which aligns with the results of previous phase 1 and 2 clinical trials.4,5 Hydroxyurea is commonly used to treat polycythemia vera, myeloid leukemias, head and neck carcinoma, meningioma, and myelofibrosis, in addition to sickle cell disease.

Ultimately, this study suggests isoquercetin may provide a treatment option for patients with a hypercoagulable state without the increased risk of off-target bleeding events. 

A few limitations in the study include the relatively small study population, short duration of the study, and the fixed (instead of escalating) dose of quercetin. Nonetheless, the study provides a foundation for future research exploring higher doses and longer treatment durations of isoquercetin in patients with sickle cell disease or other conditions involving thromboinflammation.

Categorized Under


  1. GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021 [published correction appears in Lancet Haematol. 2023;10(8):e574]. Lancet Haematol. 2023;10(8):e585-e599.
  2. Jang T, Poplawska M, Cimpeanu E, Mo G, Dutta D, Lim SH. Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events. J Transl Med. 2021;19(1):397.
  3. Lizarralde-Iragorri MA, Parachalil Gopalan B, 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.
  4. Zwicker JI, Schlechter BL, Stopa JD, et al. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight. 2019;4(4):e125851.
  5. Buonerba C, De Placido P, Bruzzese D, et al. Isoquercetin as an adjunct therapy in patients with kidney cancer receiving first-line sunitinib (QUASAR): results of a phase I trial. Front Pharmacol. 2018;9:189.
  6. Jinna S, Khandhar PB. Hydroxyurea Toxicity. In: StatPearls. Treasure Island (FL): StatPearls Publishing; Aug 8, 2023.