Bleeding Complication in a Patient with Concomitant Use of Rivaroxaban and Saffron Supplement: A Case Report

Direct oral anticoagulants (DOACs) carry a lower potential risk of food/herb and drug interactions compared with oral vitamin K antagonists. However, as a new class of medications some of these interactions have not been fully known. Case presentation: A 64-year old male with a medical history of non-valvular atrial brillation presented to the emergency department with a complaint of acute onset epistaxis and bleeding gums following the concomitant use of rivaroxaban and saffron supplement. Rivaroxaban plasma concentration was 54 ng/ml with a post-intake delay of 17 hours. The results of laboratory tests were unremarkable except for platelet function tests. Whole blood multiple electrode aggregometry was performed to assess platelet function. Area under the aggregation curve (AUC) values were 83 and 51 aggregation unit (AU)*min by arachidonic acid and adenosine diphosphate-induced platelet aggregation tests, respectively. As the patient had not taken any antiplatelet medication, platelet dysfunction was greatly attributed to the saffron supplement. The patient was immediately admitted to hospital and received local hemostatic measures and tranexamic acid. Moreover, saffron was discontinued permanently and rivaroxaban was paused for 24 hours. The bleeding stopped a few hours later and the patient was discharged after 2 days in a good general condition. Subsequently, he was followed up at 4, 8, and 12-week intervals. He was in a stable clinical condition with no bleeding complications. The patient was advised to consult with his doctor or pharmacist before taking any supplement or herbal medicine to ensure possible interactions.


Background
Direct oral anticoagulants (DOACs) carry a lower potential risk of food/herb and drug interactions compared with oral vitamin K antagonists. However, as a new class of medications some of these interactions have not been fully known.

Case presentation:
A 64-year old male with a medical history of non-valvular atrial brillation presented to the emergency department with a complaint of acute onset epistaxis and bleeding gums following the concomitant use of rivaroxaban and saffron supplement. Rivaroxaban plasma concentration was 54 ng/ml with a postintake delay of 17 hours. The results of laboratory tests were unremarkable except for platelet function tests. Whole blood multiple electrode aggregometry was performed to assess platelet function. Area under the aggregation curve (AUC) values were 83 and 51 aggregation unit (AU)*min by arachidonic acid and adenosine diphosphate-induced platelet aggregation tests, respectively. As the patient had not taken any antiplatelet medication, platelet dysfunction was greatly attributed to the saffron supplement. The patient was immediately admitted to hospital and received local hemostatic measures and tranexamic acid. Moreover, saffron was discontinued permanently and rivaroxaban was paused for 24 hours. The bleeding stopped a few hours later and the patient was discharged after 2 days in a good general condition. Subsequently, he was followed up at 4, 8, and 12-week intervals. He was in a stable clinical condition with no bleeding complications. The patient was advised to consult with his doctor or pharmacist before taking any supplement or herbal medicine to ensure possible interactions.

Conclusions
It seems that coadministration of DOACs and saffron supplements should be avoided due to the potential drug-herbal interactions and possible risk of subsequent bleeding complications. However, further studies are needed to con rm the ndings and assess the clinical signi cance. have investigated the protective effects of saffron in the treatment and/or prevention of cardiovascular, nervous system, psychologic, metabolic, infertility, menstruation, and cancer disorders. The main therapeutic properties are attributed to the saffron carotenoids including crocins and crocetin [2].
According to our literature review, it is the rst report of saffron-rivaroxaban interaction which led to minor bleeding in a patient. performed to assess platelet function [3]. Area under the aggregation curve (AUC) values were 83 and 51 aggregation unit (AU)*min by arachidonic acid (AA) and adenosine diphosphate (ADP)-induced platelet aggregation tests (ASPI and ADP), respectively. Antiplatelet drugs decrease platelet aggregation level by an AUC value of lower than 300 AU*min [4].

Case Presentation
The patient was immediately admitted to hospital and received local hemostatic measures (including cold compress and mechanical pressure) and tranexamic acid (10 mg/kg as an intravenous bolus followed by oral dose of 1 gram every 12 hours for 48 hours). Moreover, Krocina® was discontinued permanently and rivaroxaban was paused for 24 hours. The bleeding stopped a few hours later and the patient was discharged after 2 days in a good general condition. Rivaroxaban was restarted due to the high thrombotic risk of AF. The patient was advised to consult with his doctor or pharmacist before taking any supplement or herbal medicine to ensure possible interactions. After discharge, the patient was followed up at 4, 8, and 12-week intervals. He was in a stable clinical condition with no bleeding complications.

Discussion
To the best of our knowledge, we report here the rst case of crocin-rivaroxaban interaction that led to epistaxis and bleeding gums in a patient. He had arbitrarily started daily use of crocin since two weeks before the onset of bleeding. To identify the underlying cause of bleeding, the laboratory tests were done.
Interestingly, the results were unremarkable except for platelet function tests. His platelet dysfunction was comparable to aspirin and/or clopidogrel [5,6]. As the patient had not taken any antiplatelet medication, platelet dysfunction was greatly attributed to the crocin.
Possible antiaggregatory effects of saffron were studied on human platelets. Saffron supplementation inhibited platelet aggregation induced by ADP, epinephrine, and collagen in a dose-dependent manner.
Moreover, it may interfere with the regulation of calcium in ux and signaling pathway in activated platelets. Additionally, a same binding site for aspirin and saffron carotenoids in cyclooxygenase I enzyme has been shown in silico studies [7][8][9].
Although saffron is considered a safe natural product with unrecognized drug interactions, but caution should be taken in concomitant use with anticoagulant, antiplatelet, and antihypertensive medications [10].
Rivaroxaban is the major substrate of CYP3A4 enzyme and P-glycoprotein (P-gp) e ux pump. As a result, its concurrent systemic treatment with strong inhibitors or inducers of CYP3A4 and P-gp should be avoided due to the safety and e cacy concerns. Moreover, pharmacodynamic interactions of rivaroxaban with antiplatelet medications, other anticoagulants, and non-steroidal anti-in ammatory drugs (NSAIDs) should be considered. In addition, there are recognized rivaroxaban-herbal interactions via the pharmacokinetic and/or pharmacodynamic pathways that lead to therapeutic failure or toxicities. Garlic, ginger, ginkgo biloba, ginseng, green tea, and horse chestnut supplements have been known with anticoagulation or antiplatelet activities and caution is needed in concomitant use with rivaroxaban [11].
Based on this experience, saffron appears to have a pharmacodynamic interaction with rivaroxaban. However, further studies are needed to clarify the precise mechanism.

Conclusions
It seems that coadministration of DOACs and saffron supplements should be avoided due to the potential drug-herbal interactions and possible risk of subsequent bleeding complications. However, further studies are needed to con rm the ndings and assess the clinical signi cance. Consent for publication: Written informed consent was obtained from the patient for publication of this case report.
Availability of data and material: The datasets obtained and analyzed in the current study are available from the corresponding author on reasonable request.
Competing interests: The authors declare that they have no competing interests.
Funding: The authors did not receive support from any organization for the submitted work.
Authors' contributions: Zinat Heidari and Maryam Daei treated the patient and wrote the manuscript. Hossein Khalili revised and edited the manuscript. All authors read and approved the nal manuscript.