# Impacts of a polyphenol mixture on hemostasis in rats under anticoagulant therapy

Dorian Teissandier, Fares Moustafa, Christine Morand, Aurélien Lebreton, Laurent-Emmanuel Monfoulet

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Dorian Teissandier, Fares Moustafa, Christine Morand, Aurélien Lebreton, Laurent-Emmanuel Monfoulet. Impacts of a polyphenol mixture on hemostasis in rats under anticoagulant therapy. Food Bioactives and Health (FBHC), JF Landrier, E Reboul, Jun 2025, Marseille, France. hal-05264353

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Submitted on 17 Sep 2025

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# Impacts of a polyphenol mixture on hemostasis in rats under anticoagulant therapy.

Dorian TEISSANDIER¹,², Fares MOUSTAFA ¹,², Christine MORAND¹, Aurélien LEBRETON¹,³ & Laurent-Emmanuel MONFOULET¹.

¹ Clermont Auvergne, Unité de nutrition humaine, INRAE, F-63000 Clermont-Ferrand

² Emergency department, CHU Clermont-Ferrand

³ Service d'hématologie biologique, Chu Clermont-Ferrand, Clermont Ferrand, France

**Keywords:** Polyphenols, rivaroxaban, bleeding, rats, Thrombin Generation Assay

**Background:** Rivaroxaban is one of the most common anticoagulant treatments used for preventing blood clots in conditions of cardiovascular risk such as atrial fibrillation and deep vein thrombosis. However, one of its drawbacks is an increased risk of bleeding, which can be problematic in clinical settings. Anticoagulant-related adverse events were responsible for 10% of emergency admissions due to adverse drug reactions [1].

Polyphenols are bioactive compounds exclusively found in plant foods and beverages known for their health benefits, mainly on cardiovascular health. Although still poorly documented at clinical level, compounds of the flavonoid class have been reported to exhibit a direct impact on primary haemostasis by inhibiting platelet aggregation, to be anti-coagulant due to an anti-factor IIa and Xa activity [2-3]. Finally, flavonoids can modulate fibrin clot structure [4-5]. However, it is worth to note that main of these results have been obtained *in vitro* in non-physiological conditions regarding the bioavailability and metabolism of flavonoids.

**Objective:** On this base, we hypothesize that anti-coagulant properties of polyphenols may contribute to an increased risk of haemorrhage in patients under anti-coagulant therapy.

**Method:** To demonstrate the contribution of polyphenols on haemostasis in physiological relevant conditions, Sprague-dawley male rats were fed 1/ a standard diet (SD), 2/ a standard diet with rivaroxaban (riva), 3/ a standard diet supplemented with a polyphenol mixture (0,3 % w/w) mimicking the daily polyphenol intake (qualitatively and quantitatively) of a diet rich in fruits and vegetables (PP) or 4/ a standard diet with rivaroxaban and the polyphenol mixture (riva+PP) for 6 weeks. At the end of this intervention, haemostasis was evaluated measuring the tail bleeding time and the volume of blood lost after a standardized cut. Classic clinical parameters of coagulation and haemostasis on plasma, such as thrombin generation and coagulation factor assays, were assessed. Vascular reactivity of aortic rings in response do phenylephrine and acetylcholine was assessed by myography.

**Results:** Dietary intervention did not modify daily intake, weight gain, body composition, systolic and diastolic blood pressure, and heart rate. Anti-Xa activity was detected in rats supplemented with anticoagulant, but not in the other groups. Similarly, Endogenous Thrombin Potential (ETP) and peak thrombin levels, two parameters measured in thrombin generation assay, were significantly lower in rats supplemented with anticoagulant (Riva and Riva+PP) compared to the control and PP groups. Surprisingly, tail bleeding time in anticoagulant rats was not longer than in control rats, and it was significantly lower in the Riva+PP group compared to the PP group. In addition, vascular reactivity measured in aortas
demonstrated that polyphenol supplementation contribute to reverse hyper-reactivity induced by rivaroxaban treatment.

**Conclusion:** This study shed new light on vascular effect of anticoagulant therapy and on the impact of dietary polyphenols on haemostasis, potentially offering a novel approach to mitigating bleeding risks associated with anticoagulant therapy.

**References**

[1] T. van der Hulle et al. "Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis," *J. Thromb. Haemost.* JTH, vol. 12, no. 3, pp. 320-328, 2014, doi: 10.1111/jth.12485.

[2] M. Bijak et al. "Antithrombin effect of polyphenol-rich extracts from black chokeberry and grape seeds," *Phytother. Res.* PTR, vol. 27, no. 1, pp. 71-76, Jan. 2013, doi: 10.1002/ptr.4682.

[3] M. Bijak et al., "Thrombin inhibitory activity of some polyphenolic compounds," *Med. Chem. Res.*, vol. 23, no. 5, pp. 2324-2337, 2014, doi: 10.1007/s00044-013-0829-4.

[4] T. Sinegre et al., "Epicatechin Impact on Primary Hemostasis, Coagulation and Fibrinolysis," *Blood*, vol. 126, no. 23, pp. 4677-4677, Dec. 2015.

[5] T. Sinegre et al., "Impact of epicatechin on fibrin clot structure," *Eur. J. Pharmacol.*, vol. 893, p. 173830, Feb. 2021, doi: 10.1016/j.ejphar.2020.173830.