Role and mechanism of xanthine oxidase in platelet hyperreactivity of hyperuricemia patients

doi:10.3969/j.issn.1674-8115.2025.12.002

Abstract

Abstract:

Objective ·To analyze the correlation between platelet activation indices and xanthine oxidase (XO) activity in patients and the underlying molecular mechanisms. Methods ·Between January 2023 and June 2025, 24 patients with hyperuricemia were recruited from the Department of Rheumatology and the Physical Examination Center of Huashan Hospital, Fudan University. Twenty-four healthy volunteers from the same center during the same period served as the healthy control group. Demographic data (age, gender), comorbidities, and medication history of all subjects were collected, and their fasting venous blood was drawn. Washed platelets were prepared for subsequent assays. The expression levels of P-selectin and platelet activation complex-1 (PAC-1) on the platelet surface were determined by flow cytometry, while platelet XO activity was measured via an absorbance assay. Spearman correlation analysis was performed to evaluate the relationships between uric acid levels, XO activity, and platelet activation markers. The effects of various concentrations of febuxostat on platelet aggregation induced by collagen, adenosine diphosphate (ADP), U46619, and thrombin were assessed. Platelet spreading on fibrinogen was analyzed. Furthermore, thrombin-induced intraplatelet reactive oxygen species (ROS) production was measured. Results ·Compared with the healthy control group, patients in the hyperuricemia group exhibited significantly higher platelet surface expression of P-selectin and PAC-1 (both P<0.05). However, neither marker showed a significant correlation with serum uric acid levels (both P>0.05). Platelet XO activity showed a positive correlation with thrombin-induced P-selectin expression (r=0.453, P=0.001) and PAC-1 expression (r=0.478, P=0.001). Febuxostat at concentrations of 50 μmol/L and 100 μmol/L significantly inhibited collagen, ADP, U46619, and thrombin-induced platelet aggregation and also significantly suppressed the spreading of platelets on fibrinogen. These inhibitory effects were statistically significant (all P<0.05) and intensified with increasing concentrations of febuxostat, demonstrating a concentration-dependent manner. Meanwhile, febuxostat treatment significantly reduced intraplatelet ROS generation in response to thrombin stimulation (P<0.05). Conclusion ·Platelet activation markers are higher in hyperuricemia patients than in the healthy control group. The expression levels of P-selectin and PAC-1 on the platelet surface show a positive correlation with intraplatelet XO activity. XO inhibitors can modulate platelet activation by reducing intracellular ROS production.

Key words: xanthine oxidase, platelet, reactive oxygen species, hyperuricemia

CLC Number:

R543.3

GAO Wen, PAN Jiesong, ZHAO Yikai, LUO Xinping, LI Jian. Role and mechanism of xanthine oxidase in platelet hyperreactivity of hyperuricemia patients[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(12): 1568-1577.

Figures/Tables 9

Tab 1 Baseline characteristics of the hyperuricemia group and the healthy control group

Item	Hyperuricemia group (n=24)	Healthy control group (n=24)	P value
Age/year	62.13±15.92	70.17±7.52	0.079
Gender (male)/n(%)	17 (70.83)	14 (58.33)	0.365
Hypertension/n(%)	3 (12.5)	0 (0)	0.234
Platelet (×10¹²)/L	206.75±57.25	214.92±61.27	0.636
Red blood cell/(g·L^-1)	4.58±0.52	4.46±0.65	0.485
White blood cell (×10⁹)/L	6.81±1.74	7.34±2.08	0.342
Anti-hyperuricemic drugs/n(%)	6 (25.00)	0 (0)	0.022
Febuxostat/n(%)	5 (20.83)	0 (0)	0.050
Alopurinol/n(%)	1 (4.17)	0 (0)	1.000

Fig 1 Expression of P-selectin and PAC-1 on platelet surface in the hyperuricemia patient group and the healthy control group

Fig 2 Correlation of platelet activation indicators P-selectin and PAC-1 with serum uric acid levels and platelet XO activity

Fig 3 Effect of febuxostat on platelet aggregation induced by different agonists

Fig 4 Effect of febuxostat on platelet aggregation induced by different concentrations of thrombin

Fig 5 Effect of allopurinol on platelet aggregation induced by collagen and thrombin

Fig 6 Effect of febuxostat on platelet spreading

Fig 7 Effect of febuxostat on the production of ROS in platelets

Fig 8 Effect of febuxostat combined with H2O2 or NACA on platelet aggregation

TrendMD

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