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Published on: July 30, 2014
Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced
Jeffrey I Zwicker1,2, Benjamin L Schlechter2, Jack D Stopa1
1Division of Hemostasis and Thrombosis and.
Background:
Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models, but the clinical effect of targeting extracellular PDI in humans has not been studied.
Methods:
We conducted a multicenter phase II trial of sequential dosing cohorts to evaluate the efficacy of targeting PDI with isoquercetin to reduce hypercoagulability in cancer patients at high risk for thrombosis. Patients received isoquercetin at 500 mg (cohort A, n = 28) or 1000 mg (cohort B, n = 29) daily for 56 days, with laboratory assays performed at baseline and the end of the study, along with bilateral lower extremity compression ultrasound. The primary efficacy endpoint was a reduction in D-dimer, and the primary clinical endpoint included pulmonary embolism or proximal deep vein thrombosis.
Results:
The administration of 1000 mg isoquercetin decreased D-dimer plasma concentrations by a median of -21.9% (P = 0.0002). There were no primary VTE events or major hemorrhages observed in either cohort. Isoquercetin increased PDI inhibitory activity in plasma (37.0% in cohort A, n = 25, P < 0.001; 73.3% in cohort B, n = 22, P < 0.001, respectively). Corroborating the antithrombotic efficacy, we also observed a significant decrease in platelet-dependent thrombin generation (cohort A median decrease -31.1%, P = 0.007; cohort B median decrease -57.2%, P = 0.004) and circulating soluble P selectin at the 1000 mg isoquercetin dose (median decrease -57.9%, P < 0.0001).
Conclusions:
Isoquercetin targets extracellular PDI and improves markers of coagulation in advanced cancer patients.
Trial Registration:
Clinicaltrials.gov NCT02195232.
Funding:
Quercegen Pharmaceuticals; National Heart, Lung, and Blood Institute (NHLBI; U54HL112302, R35HL135775, and T32HL007917); and NHLBI Consortium Linking Oncology and Thrombosis (U01HL143365).
Insights
Isoquercetin effectively targets protein disulfide isomerase (PDI) in cancer patients, reducing hypercoagulability and improving thrombosis markers. This study demonstrates the clinical potential of targeting PDI to manage coagulation risks in high-risk populations.
Area of Science:
- Biochemistry
- Vascular Biology
- Oncology
Background:
- Protein disulfide isomerase (PDI) is crucial for thrombus formation and is secreted by vascular cells.
- Quercetin flavonoids inhibit PDI, showing potential in preclinical models but lacking human clinical data.
- Targeting extracellular PDI offers a novel therapeutic strategy for thrombotic disorders.
Purpose of the Study:
- To evaluate the efficacy of isoquercetin in reducing hypercoagulability in cancer patients at high risk for thrombosis.
- To assess the safety and tolerability of isoquercetin in this patient population.
- To investigate the impact of isoquercetin on key markers of coagulation and thrombosis.
Main Methods:
- A multicenter phase II trial with sequential dosing of isoquercetin (500 mg or 1000 mg daily for 56 days).
- Laboratory assays measured D-dimer, PDI inhibitory activity, platelet-dependent thrombin generation, and soluble P selectin.
- Clinical endpoints included pulmonary embolism and proximal deep vein thrombosis, assessed via bilateral lower extremity compression ultrasound.
Main Results:
- The 1000 mg dose of isoquercetin significantly decreased D-dimer plasma concentrations by -21.9% (P = 0.0002).
- Isoquercetin demonstrated dose-dependent PDI inhibitory activity (73.3% at 1000 mg) and reduced thrombin generation and soluble P selectin.
- No primary venous thromboembolism (VTE) events or major hemorrhages were observed in either cohort.
Conclusions:
- Isoquercetin effectively targets extracellular PDI, improving coagulation markers in advanced cancer patients.
- The study supports isoquercetin as a potential therapeutic agent for managing hypercoagulability in cancer-associated thrombosis.
- Further clinical investigation is warranted to confirm these findings and establish optimal dosing regimens.
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