Biomedicine & Pharmacotherapy 83 (2016) 1421

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Review

Review on mechanisms and interactions in concomitant use of herbs

and warfarin therapy
Paula Mendona Leite, Maria Auxiliadora Parreiras Martins, Rachel Oliveira Castilho*
Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Antnio Carlos 6627, Belo Horizonte, Minas Gerais,
Brazil

A R T I C L E I N F O A B S T R A C T

Article history:
Received 1 April 2016 The effectiveness of warfarin, an oral anticoagulant originally derived from a plant, is strongly affected by
Received in revised form 2 June 2016 patients characteristics such as the age, presence of comorbidities, and concomitant use of another drug.
Accepted 7 June 2016 Warfarin has the potential to interact with many drugs, medicinal plants, and food, which increases the
risk of adverse events. A critical analysis of scientic literature was conducted to assess the interferences
Keywords: of medicinal plants with blood haemostasis and then with warfarin anticoagulation. We found 58
Anticoagulants different plants that may alter the blood haemostasis and anticoagulation with warfarin. The herbs that
Blood coagulation showed the greatest potential to interact with warfarin include garlic, ginger, ginkgo, St. Johns wort, and
Drug-herb interaction
ginseng, i.e. plants normally consumed as food and also used for therapeutic purposes. The interactions
Medicinal plants
between drugs and herbs are varied because of the complex chemical matrix of plants. Mainly coumarins,
quinones, xanthones, terpenes, lignans, and vitamin K showed signicant inuence on warfarin
treatment. In general, these plants can potentiate the effect of warfarin by stimulating anticoagulation in
multiple ways, and the clinical outcome associated with this interaction is the increase of bleeding risk.
Moreover, potential interactions between herbal products and drugs are a safety concern, especially for
drugs with a narrow therapeutic index or for patients receiving drug treatment for chronic diseases, and
both of these apply to warfarin pharmacotherapy. Therefore, this review article summarises the data on
the inuence of medicinal plants on warfarin treatment and analyses this information in view of the
interaction targets. The relevant plants were categorised according to their target, and their effects are
discussed in order to organise the isolated information and to highlight the need of further discussion and
new studies on the safety of herbal medicines and warfarin.
2016 Elsevier Masson SAS. All rights reserved.

Contents

1. The herbs and the anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1.1. Mechanisms of anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.1. Study search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.2. Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3. Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3. Interactions between warfarin and medicinal plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1. Interactions potentiating the effect of warfarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1.1. Platelet function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1.2. Platelet aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1.3. PAF inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.1.4. Arachidonic acid cascade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.1.5. Pharmacokinetics of warfarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

* Corresponding author at: Faculdade de Farmcia, Universidade Federal de

Minas Gerais, Av. Antnio Carlos 6627, Belo Horizonte, Minas Gerais, Brazil.
E-mail address: rocastilho40@gmail.com (R.O. Castilho).

http://dx.doi.org/10.1016/j.biopha.2016.06.012
0753-3322/ 2016 Elsevier Masson SAS. All rights reserved.
 P.M. Leite et al. / Biomedicine & Pharmacotherapy 83 (2016) 1421 15

3.1.6. Presence of coumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

3.1.7. Fibrinolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.2. Interactions decreasing the effect of warfarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4. Relevance of medicinal plantwarfarin interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

1. The herbs and the anticoagulation effects, such as the age, gender, body weight, liver and kidney
function, genetic factors, adherence, and others. To avoid
Herbs have been used for thousands of years for their complications, the prothrombin time (PT) test is used to calculate
nutritional and medical benets. The knowledge of their use is the international normalised ratio (INR) and to help with the dose
dynamic, passed from generation to generation, and the adjustment in order to avoid supra- and sub-therapeutic anti-
traditions of different regions, cultures, and families all affect coagulation [7,8].
their use. Medicinal plants are important for the treatment and Cardiovascular diseases that increase the likelihood of throm-
prevention of diseases, but they need to be used safely, and the boembolic events usually require a chronic use of warfarin. Along
material needs to be of high quality [1,2]. Medicinal plants are with the general risks associated with the drug warfarin (hepatic
popularly used in the management of a variety of conditions; metabolism, high protein binding, and a narrow therapeutic
however, their prevalence is unreported because of the easy index), patients on warfarin therapy often exhibit comorbidities
availability and the belief that herbs are unnecessary to report in and use multiple other drugs, increasing even more the risk of
medication history. Thus, despite their extensive use, there is a complications associated with the OA [9]. Aging populations and
lack of information concerning the interactions between drugs increased access to health services have increased the number of
and herbs. Therefore, phytochemical and pharmacological studies patients diagnosed with heart disease, and therefore the use of
must be encouraged to assess their therapeutic potential and anticoagulants is increasing. As a result, it is important that
toxicity [3]. For these reasons, the use of medicinal plants by patients have access to anticoagulation clinics where they can be
patients under warfarin pharmacotherapy is a signicant public monitored for dangerous side effects and educated regarding the
health concern. risks of OA use [10].
Herbs are not only used on a small scale in traditional medicine, The highly complex nature of drug interactions dictates that
but they also have unquestionable industrial and commercial cautions should be exercised with narrow therapeutic index drugs,
value. Medicinal plants are also an inexhaustible source of and herbdrug interactions should not be different in this regard.
therapeutic materials such as phytotherapeutics, phytopharma- Many studies describe the inuence of medicinal plants on
ceuticals, semi-synthetic drugs, and synthetic drug prototypes. warfarin treatment. A recent and relevant paper published in this
Compounds extracted from herbs have complex structures and are eld has summarised the clinical ndings regarding herbwarfarin
pharmacologically active in living organisms, thereby aiding interactions for 38 herbs, highlighting the clinical outcomes,
pharmacotherapy. Warfarin, an important anticoagulant used to severity of documented interactions, and quality of clinical
treat thrombosis, was originally derived from dicoumarol, a evidence. The results showed that only four plants (cranberry,
coumarin that is primarily found in plants such as sweet clover soybean, St Johns wort, and danshen) are regarded as highly
or melilot (Melilotus ofcinalis, Fabaceae) [4]. probable to clinically interact with warfarin [11]. In this article, we
In 1939, the ingestion of sweet clover was identied as the review the medicinal plants that could interact with warfarin
cause of fatal haemorrhages in cattle. It was found by Campbell and treatment by affecting the blood haemostasis and warfarin
Link (1944) that dicoumarol, a compound isolated from sweet pharmacokinetics and classify them based on their interaction
clover, was the active haemorrhagic agent. Following this target. We discuss the role of the chemical composition of
discovery, many synthetic anticoagulants were derived from medicinal plants and the potential consequences associated.
coumarin. Of these, the most widely used anticoagulant is
warfarin, which was originally used only as a rodenticide because 1.1. Mechanisms of anticoagulation
of the concerns regarding its toxicity to humans. However, after an
American soldier survived a suicide attempt by using warfarin, its Anticoagulation therapy is used to treat disorders in which
relative safety was conrmed, and this class of oral anticoagulants coagulation processes are overactive, such as acute deep vein
(OAs) has since become the principal treatment of thromboem- thrombosis, embolism, chronic atrial brillation, and recurrent
bolic disorders [5]. thromboembolism [8,12].
Warfarin is the most commonly used OA; however, despite its Control of blood uidity is very complex because blood must
therapeutic usefulness, it can be unsafe because of its narrow maintain its uidity in blood vessels and yet coagulate rapidly in
therapeutic index, its interactions with other drugs and foods, and the event of a lesion. The process of coagulation involves two
because its users often have special clinical conditions. Many pathways, intrinsic and extrinsic, which begin independently and
different formulations of warfarin are commercially available, but then converge to the same point. In general, coagulation begins
the oral preparation is the most convenient because it allows when platelets are activated by collagen that is released as a
outpatient treatment [6]. Warfarin is a racemate, in which the S- result of injury to the endothelium. These platelets activate
enantiomer is ve-fold more active than the R-enantiomer, and it is signalling pathways that then activate more platelets, which then
nearly 100% bioavailable. Warfarin is biotransformed in the liver adhere to the injured endothelium and form an aggregate,
and eliminated in urine and faeces. It interacts with many other temporarily reducing the loss of blood and promoting the local
drugs and also with foods that are rich in vitamin K. Excess activation of plasma coagulation factors [9]. At this stage,
bleeding is the principal side effect that occurs when the warfarin zymogens are activated into active proteases via peptide bond
effect is exacerbated. Numerous factors can interfere with warfarin cleavage (Fig. 1).
16 P.M. Leite et al. / Biomedicine & Pharmacotherapy 83 (2016) 1421

Fig. 1. Simplied scheme showing the mechanisms of coagulation and brinolysis.

Coagulation is regulated via a process known as brinolysis in 2. Methods

order to remove excessive thrombi and restrict brin to only
injured endothelium (Fig. 1) [13]. Together, coagulation, anti-
coagulation, and brinolysis maintain a delicate balance in the
blood [14]. There are other regulatory mechanisms and factors that
prevent coagulation of intact blood vessels, such as prostacyclin
synthesis, thrombomodulin, protein C, tissular factor, and vitamin
K [15]. The complexity of haemostasis reveals a great number of
potential molecular targets of interference with this process.
Vitamin K is most commonly found in green plants, and
consumption of these plants is the principal source of vitamin K in
humans. Vitamin K is an essential cofactor for g-carboxylation of
glutamate residues on coagulation factors II, VII, IX, and X, which
are synthesised by the liver in their biologically inactive form.
Carboxylation of these factors is directly related to the oxidation of
vitamin K to its epoxide form. Formation of g-carboxyglutamate
residues results in a calcium-dependent conformational change
that promotes the binding of cofactors to the phospholipid surface
and results in coagulation. Warfarin has an anticoagulant effect
due to its structural resemblance of vitamin K (Fig. 2) and as a
result, can bind to vitamin K epoxide reductase, the enzyme that
catalyses the transformation of vitamin K epoxide back to vitamin
K [10]. Based on the complexity of the haemostatic mechanism and
warfarin pharmacokinetics, it is possible to infer that there is a
range of potential interference targets for the active constituents
present in medicinal plants.
2.1. Study search
The literature review process was initiated by reviewing
primary (articles in indexed journals) and secondary (books and
review articles) sources. The secondary sources were included
because some of the primary sources were antique, whereas others
provided supercial information. Electronic searches were per-
formed during 20142015 but covered all years of each database.
Multiple databases were used, including PubMed, OneFile, Scopus,
SciVerse, ScienceDirect, Web of Science, MEDLINE, Springer LINK,
Directory of Open Access Journals, BioMed Central, SAGE
Publications, and Wiley Online Library. The keywords used in
different combinations in English and Portuguese; included
warfarin or anticoagulation combined with herbs; plants; or
interaction. In a second phase; systematic note-taking and
appraisal of the scientic literature were performed.
2.2. Selection
The clinical and experimental studies, in vitro and in vivo were
selected. The studies were researched by analysing their titles,
abstracts, and subsequently, full-text articles according to the
following inclusion criterion: interaction of warfarin with medici-
nal herbs. All of the primary sources containing information about

Fig. 2. The structural resemblance between warfarin (A) and vitamin K (B).
 P.M. Leite et al. / Biomedicine & Pharmacotherapy 83 (2016) 1421
the mechanism of interaction between warfarin and a medicinal
herb or clinical evidence of an interaction, such as changes in
coagulometric parameters, were included in the study. The quality
of the articles was evaluated using the following criteria:
description of the methods applied in view of the quality assurance
and quality control (number of groups included, use of controls),
appropriateness of the methods, presentation of the results, data
analysis, and discussion of the results.
2.3. Design
The following data were extracted from the included studies:
the scientic and common name of the medicinal plant,
concomitant use with warfarin, interaction of warfarin with the
medicinal herb, chemical composition of the medicinal herb, and
associated consequences. After the compilation of the literature
data, we critically reviewed the data and analysed the information,
aiming to identify the targets of interaction between warfarin and
medicinal herbs.
3. Interactions between warfarin and medicinal plants
The literature search identied 58 different plant species.
Some articles were found to be supercial, whereas in other cases,
the interactions of clinical importance were described in case
reports, which did not provide the relevant clinical outcome
information nor quantied the clinical impact. Mechanistic
studies were limited, and many of the primary ndings cited
were theoretical mechanistic reports concerning the effects of
herbal products on some aspect of the coagulation system or
metabolic pathways. This information is important to direct the
studies and create the overall picture of the current scientic
progress on this issue. Thus, to possibly provide the most
complete information, we also used secondary references to
conrm some data.
The clinical outcomes that may result from these interactions in
patients on warfarin therapy basically involve two possibilities, the
risk of bleeding due to exacerbation of the anticoagulant effect of
warfarin [6] and the therapeutic ineffectiveness due to reduction of
the effect of this drug because of blood clot stimulation [16]. The
most commonly cited species are shown in Fig. 3 and include garlic
(Allium sativum), ginkgo (Ginkgo biloba), St. Johns wort (Hypericum
perforatum), and ginseng (Panax ginseng). Among these citations,
84% describe the potentiation of warfarin, and 16% relate the
inhibition of warfarin. Thus, the greatest risk that can occur due to
Fig. 3. The number of citations in the literature describing interactions between warfarin and plants. Only species with ve or more citations are shown.
17
inadequate or unsupervised use of herbs by anticoagulated
patients is bleeding, which increases the morbidity, mortality,
and resource use [7,17].
The effectiveness of phytochemical therapeutics depends on
the complex interaction between the mixture of compounds found
in the plant matrix and physiological processes or drugs used
concomitantly [8,18]. When warfarin is used concomitantly with
plant products, the latter can interfere with warfarin pharmacoki-
netics (absorption, distribution, metabolism, and elimination) or
with coagulation processes such as platelet function, coagulation
cascade, and brinolysis (Fig. 4).
3.1. Interactions potentiating the effect of warfarin
Potentiation of the effect of warfarin increases the risk of
bleeding. The majority of the papers do not show a true clinical
interaction but rather the effects of plants or their metabolites on
metabolic processes involved in warfarin treatment. Several
possible targets can be involved in or induce such an effect,
including the platelet function (29 citations), modication of
warfarin pharmacokinetics (12 citations), the presence of coumar-
ins (8 citations), an action on the prostaglandin cycle (3 citations),
brinolytic properties (2 citations), and others. Some plants, such
as garlic and kava, have more than one possible target and are
included in more than one group (Table 1).
3.1.1. Platelet function
Interference with the platelet function is the most frequently
cited mechanism by which herbs can increase the effect of
warfarin. Platelets contribute to haemostasis in two ways, through
adhesive and cohesive functions that lead to the formation of the
clot and through activation of coagulation mechanisms by the
exposure of the phospholipid surface. Therefore, to promote the
correct haemostasis, platelets should retain their ideal character-
istics for secretory functions and protein expression. Platelets are
normally activated in response to chemical mediators, which are
released by injured cells in normal situations. One of these
chemical mediators is platelet-activating factor (PAF), which is a
common target for plant secondary metabolites [7].
3.1.2. Platelet aggregation
Any event that inhibits platelet function, such as inhibition of
platelet adhesion or aggregation, or inhibition of the chemical
mediators that activate platelet function, has the potential to
decrease platelet function and make the blood less susceptible to
18 P.M. Leite et al. / Biomedicine & Pharmacotherapy 83 (2016) 1421

Arctium lappa,
Centipeta (A)
mnima and Absorption and Metabolism and
Fossythia Platelet distibution elimination
suspensa activation Piper methysticum
Salvia miltiorrhiza
ligans and kavain
sesquiterpenes Danshinone IIa
Glicyrhiza glabra
glabridin;
PAF TXA2 Warfarin Mangifera indica
vitamin A
Angelica sinensis, action
Arnica montana,
Ginkgo biloba. Matricaria chamomille
Ginkgolide B;
(B)
and others coumarins inhibition or
Calophyllum sp Garcinia (scopoletin, bergapten, regeneration
and Hypericum cambogia and umbelliferone)
patulum Platelet aggregation flavonoids;
xanthones; Piper and adhesion Tanacethum
fotokadsura partenium
Lignans and parthenolide
kadsurenone
Reduced Oxidated
vitamin K vitamin K
Platelet Release of
thrombus coagulation
formation factors
(C)
Momordica charantia
compounds

Prothrombin Thrombin + -
Thrombomodulin

Fibrinogen Fibrin
Allium sativum and
Allium cepa allicin

Clot
(D)

Fig. 4. Potential targets for interaction between medicinal plants-warfarin. (A) interference with coagulation cascade in platelet activation and aggregation and release of
coagulation factores; (B) warfarin pharmacokinetics; (C) vitamin K activation and absorption; and (D) brin synthesis. Red arrows indicate targets of medicinal plants and its
compounds.

aggregation and coagulation. Among the plants studied (Table 1),
we found many plants that inhibit platelet aggregation although
the specic mechanisms are not always described, as fenugreek
[19].
However, mechanisms were proposed for some plants: arnica
and basil [20] reduces and inhibits ADP-induced platelet aggrega-
tion, respectively, bitter melon inhibits the release of a chemical
mediator that activates platelet function (factor X) [21], golden
bells prevent the binding of platelets to their activator, and
feverfew contains sesquiterpenes that inhibit the secretion of 5-HT
platelets via neutralization of sulphydryl groups on the inside or
outside of the cell [21].
3.1.3. PAF inhibitors
Some plants affect coagulation by inhibiting PAF (Table 1).
Many members of this group contain compounds that have already
been identied, such as lignans and sesquiterpenes from burdock,
xanthones from hidcote [23], avonoids from garcinia [24], and the
widely reported ginkgolide B from ginkgo [25].
3.1.4. Arachidonic acid cascade
The arachidonic acid cascade is a pathway that produces lipid
mediators. With regard to platelets, the most important function of
this pathway is the production of thromboxane A2, which activates
platelets and stimulates platelet aggregation. Therefore, if the
cascade is inhibited, the platelet activation and aggregation
decrease, and for warfarin users, the effect of the drug may
increase as the stimulus for coagulation decreases. Among the
plants studied (Table 1), saw palmetto and kava were reported to
inhibit cyclooxygenase (COX) [12], and hawthorn and kava were
reported to inhibit the thromboxane production [26].
3.1.5. Pharmacokinetics of warfarin
Warfarin is nearly 100% bioavailable, with 99% of it binding to
plasma proteins such as albumin. Warfarin is biotransformed in
the liver and eliminated in urine and faeces [7], and interactions
can occur at any of these steps. Pomegranate, for example, inhibits
cytochrome P450 and then warfarin metabolism [2729], and so
does ginkgo, which produces bilabolide, a liver inducer [30]. We
also identied two plants that affect warfarin pharmacokinetics,
resulting in an increase in the effect of warfarin, horse chestnut
(Aesculus hippocastanum) and danshen (Salvia miltiorrhiza).
The specic mechanism by which horse chestnut affects the
pharmacokinetics of warfarin is unclear, but it has been well
characterised for danshen. Danshen contains a diterpene named
danshinone IIa, which can bind to albumin and displace warfarin.
Because a large amount of warfarin binds to albumin, displacement
can greatly increase the amount of free warfarin capable of
inhibiting vitamin K epoxide reductase and increasing the warfarin
effect [12]. Regarding its metabolism, warfarin exists as a pair of
enantiomers (R and S), which are metabolised differently by
human cytochrome P450 (CYP) enzymes. R-warfarin is metab-
olised primarily by CYP1A2 to 6- and 8-hydroxywarfarin and by
CYP3A4 to 10-hydroxywarfarin. S-warfarin is primarily metab-
olised by CYP2C9 to 7-hydroxywarfarin. A knowledge of substrates,
inhibitors, and inducers of this family of enzymes can aid in the
prediction of clinically signicant interactions [31]. Thus, every
compound (drug or phytochemical) that has the potential to
inhibit this system can decrease the warfarin metabolism and
increase its effect. Compounds that are metabolised by these
enzymes also have the potential to inhibit warfarin metabolism by
a competitive mechanism. Inhibition of CYP2C9 is particularly
dangerous because S-warfarin is more active than R-warfarin [32].
 P.M. Leite et al. / Biomedicine & Pharmacotherapy 83 (2016) 1421 19

Table 1
Plants that potentialize the effect of warfarin.

Scientic name Common Mechanism Referencesa

name
Plants that affect platelet aggregation
Allium cepa L. Onion Antiplatelet properties [1]
Allim sativum L. Garlic Inhibits platelet aggregation [22]
Arctium lappa L. Burdock Contains lignans and sesquiterpenes that inhibit PAF/platelet binding [1]
Arnica montana L. Mountain It reduces the ADP-induced platelet aggregation [2]
arnica
Centipeda minima (L.) A. Contains lignans and sesquiterpenes that inhibit PAF/platelet binding [1]
Braun & Asch.
Forsythia suspensa Vahl Golden bells Contains lignans and sesquiterpenes that inhibit PAF/platelet binding [1]
Garcinia cambogia Desr. Garcinia Contains avonoids that inhibit platelet adhesion, aggregation, and secretion [1]
Leonurus cardiaca L. Motherwort Inhibits platelet aggregation [2]
Mormordica charantia L. Bitter melon Inhibits PAF and the action of factor X on the coagulation cascade [2]
Ocimum basilicum L. Basil Inhibits ADP-induced platelet aggregation and decreases platelet activation by thrombin [1]
Paeonia sp. Peony Antiplatelet properties [2]
Piper methysticum G.Forst. Kava Inhibits platelet aggregation [3]
Tanacetum parthenium Sch. Feverfew Parthenolide inhibits platelet aggregation [2]
Bip.
Trigonella foenum-graecum L. Fenugreek Inhibits platelet aggregation [4]
Vaccinium uliginosum L. Blueberry Inhibits platelet aggregation [3]

Plants with inhibitor effect on PAF

Alpinia galanga Willd. Galanga PAF inhibitor [1]
Boesenbergia pandurata Chinese PAF inhibitor [1]
Schltr. ginger
Calophyllum sp True kamani Inhibitory effect on PAF due to xanthones [1]
Cinnamomum sp PAF inhibitor [1]
Curcuma sp PAF inhibitor [1]
Ginkgo biloba L. Ginkgo PAF receptor antagonist. Ginkgolide B inhibits the binding PAF to its receptors on platelet membranes [23]
Goniothalamus malayanus PAF inhibitor [1]
Hook.f. & Thomson
Hypericum patulum Thunb. Hidcote Inhibitory effect on PAF due to xanthones [1]
Momordica charantia L. Bitter melon PAF inhibitor and also inhibits the action of factor X on the coagulation cascade [2]
Piper aduncum L. PAF inhibitor [1]
Piper futokadsura Siebold Haifenteng Contains PAF receptor antagonists 2,5-diaryltetrahydrofuran-type lignans and kadsurenone [3]
Thuja orientalis L. Thuja PAF receptor antagonist [1]
Zingiber ofcinale Roscoe. Ginger PAF inhibitor [9]

Plants that interact with the arachidonic acid cascade

Crataegus monogyna Jacq. Hawthorn Inhibits biosynthesis of thromboxane A2 [1]
Piper methysticum G.Forst. Kava Contains kavain, which has antithrombotic activities due to inhibition of aggregation, endogenous ATP [3]
release, and formation of prostaglandin E2, thromboxane A2, and COX-2.
Serenoa repens (W.Bartram) Saw Inhibits cyclooxygenase [3]
Small palmetto

Plants that increase warfarin metabolism

Allium sativum L. Garlic Inhibits CYP3A4 [23]
Angelica sinensis (Oliv.) Diels Dong quai Inhibits CYP1A2 and CYP3A4 [7]
Matricaria recutita L. Camomile Inhibits CYP IA2 [4]
Glycyrrhiza glabra L. Liquorice Contains glabridin, an isoavan that inhibits CYP3A4 [3]
Harpagophytum procumbens Devil's claw Inhibits CYP2C9 [3]
DC.
Lycium barbarum L. Inhibits CYP2C9 [4]
Mangifera indica L. Mango Inhibits CYP2C19 due to its high vitamin A content. [2]
Punica granatum L. Pomegranate Inhibits enzymes of P450 cytochrome that metabolise warfarin [3]
Serenoa repens (W.Bartram) Saw Inhibits CYP2C9. [3]
Small palmetto
Trifolium pratense L. Red clover Inhibits CYP2C9 [2]
a
The numbers are the references in the end of the text.

The majority of the plants studied, including devils claw, inhibit
CYP2C9 (Table 1). Some specic compounds with inhibitory effects
have been identied. For example, liquorice contains glabridin,
which can inhibit CYP3A4, and mango contains vitamin A, which
can inhibit CYP2C9. The decrease of CYP activity is more common;
however, the increase of CYP activity is also possible, and it can rise
the warfarin metabolisation and then elimination, decreasing its
effect. Although possible, no plants were found to have this effect.
3.1.6. Presence of coumarins
Coumarin-containing plants are important. Since the discovery
of warfarin, it has been believed that this class of compounds could
have anticoagulant properties owing to their structural similarity
to warfarin and vitamin K (Fig. 4) [33]. This similarity enables
warfarin and, possibly, other coumarins to antagonise vitamin K at
the active site of vitamin K epoxide reductase, preventing the
activation of coagulation factors [7]. There is a signicant
documented risk for potentiation of anticoagulant effects when
coumarins are used concurrently with medications such as
warfarin [34].
Among the plants studied, Angelica sinensis [3538], Arnica
montana [39], Borago ofcinalis [40], Matricaria recutita [41],
Glycyrrhiza glabra [38], Mikania glomerata [42], Peumus boldus
[24,41], and Trifolium pratense [12] are known to contain
20 P.M. Leite et al. / Biomedicine & Pharmacotherapy 83 (2016) 1421
Table 2
Plants that decrease the effect of warfarin by affecting pharmacokinetics.
Scientic name Common name
Aloe vera L. Aloe
Medicago sativa L. Lucerne
Plantago ovata Forssk. Psillium
a
The numbers are the references in the end of the text.
coumarins such as scopoletin, bergapten, and umbelliferone and
therefore have the potential to interfere with coagulation.
3.1.7. Fibrinolysis
As previously discussed, brinolysis maintains haemostasis and
degrades unnecessary thrombi by converting plasminogen into
plasmin (Fig. 1) [13]. Naturally occurring compounds, called
brinolytics, activate plasminogen; however, when used with
warfarin, these compounds could contribute to blood antico-
agulation and increase the risk of bleeding. In our study, we
identied two plants that contained compounds with brinolytic
properties, garlic (Allium sativum) and onion (Allium cepa). Effects
of the Allium species are due to their potent inhibition of
thromboxane production, which occurs as a result of direct,
non-competitive inhibition of the COX enzyme by ajoene, a
metabolite of allicin. This inhibition prevents the binding of brin
to platelet receptors and therefore inhibits the platelet activation
and Ca2+ mobilisation induced by thrombin [43].
3.2. Interactions decreasing the effect of warfarin
We identied two possible groups of plants that can decrease
the effect of warfarin and increase the risk of thrombosis. They
include plants that have high amounts of vitamin K and those that
can affect the warfarin pharmacokinetics (Table 2).
As previously discussed, vitamin K is a co-factor in coagulation;
therefore, plants rich in vitamin K may decrease the INR of patients
who use warfarin and cause blood coagulation. We identied ve
plants with a high vitamin K content, green tea [44] (Camellia
sinensis), juniper (Juniperus sargentii), passion ower (Passiora
edulis), soybean (Glycine max), and vervain (Verbena ofcinalis).
However, three of these plants have also been shown to increase
the effect of warfarin. Thus, catechin and caffeine from green tea
may have antiplatelet effects [45], whereas the compounds in
passion ower [46] and soy extracts may inhibit CYP2C9 and
CYP3A4, and the effect could be a combination of these [47,48].
There are three plants that have been shown to decrease the
effectiveness of warfarin by affecting its pharmacokinetics
(Table 2).
Aloe and psyllium reduce the warfarin absorption. In the case of
aloe, this is due to high anthraquinone content, and these
compounds are known to irritate the bowel and reduce its
absorptive capacity. Mendicago sativa increases the warfarin
clearance owing to its diuretic effect [3].
As discussed, warfarin is metabolised by CYP enzymes, and any
plants that have the potential to upregulate these enzymes can
increase the warfarin metabolism and reduce its effect. These
plants include ginseng [4952] (Panax ginseng), which increases
the metabolism of CYP enzymes by producing metabolites known
as ginsenosides [53], and St. Johns wort (Hypericum perforatum)
[54], which strongly and specically upregulates CYP2C9 and
CYP3A4 [37].
4. Relevance of medicinal plantwarfarin interactions
Warfarin pharmacotherapy can be affected in many ways by the
concomitant use of herbs. Unless some of these interactions are
Mechanism Referencesa
Contains anthraquinone, which decreases warfarin absorption [4]
Reduces effect of warfarin via increasing elimination [3]
Decreases absorption of anticoagulants [1]
well studied and taken into account when using warfarin, they can
cause unpredictable changes in the degree of anticoagulation
experienced by the patient. The included references involved 58
different plants, with garlic, St. Johns wort, ginkgo, and ginseng
being particularly prominent. In general, these plants potentiate
the effect of warfarin and, consequently, the associated risk of
bleeding. Warfarin is affected by a diverse range of targets in blood
haemostasis, including the inhibition of PAF, modication of
warfarin metabolism, brinolysis, inhibition of COX, and other
factors that interfere with coagulation, as well as the presence of
coumarins and other classes of substances or high amounts of
vitamin K.
5. Future perspectives
By exploring the interactions between these plants and
warfarin, we hope to clarify and organise the scattered information
and to initiate a discussion about the safety of herbal medicines
and warfarin. This may encourage new studies on the subject and
emphasise the need to inform health care professionals and
patients about these potential interactions and the risks associated
with misinformation and inattention in this regard.
Conicts of interest
The authors state no conict of interest.
Acknowledgements
This work was supported by grants from Pr-Reitoria de
Pesquisa da Universidade Federal de Minas Gerais (UFMG),
Fundao de Amparo a Pesquisa do Estado de Minas Gerais
(FAPEMIG), Coordenao de Aperfeioamento de Pessoal de Nvel
Superior (CAPES), and Conselho Nacional de Desenvolvimento
Cientco e Tecnolgico (CNPq).
References
[1] M.G.L. Brando, C.F.F. Grael, C.W. Fagg, European naturalists and medicinal
plants in Brazil, in: O. Grillo, G. Venora (Eds.), Biological Diversity and
Sustainable Resources Use, In Tech, Rijeka, 2011, pp. 101120.
[2] K.J. Gohil, J.A. Patel, Herb-drug interactions: a review and study based on
assessment of clinical case reports in literature, Indian J Pharmacol. 39 (2007)
129139.
[3] A.A. Izzo, E. Ernst, Interactions between herbal medicines and prescribed
drugs: a systematic review, Drugs 61 (2001) 21632175.
[4] D.J. Newman, G.M. Cragg, Natural products as sources of new drugs over the 30
years from 1981 to 2010, J. Nat. Prod. 75 (2012) 311335.
[5] G.Y.H. Lip, Recommendations for thromboprophylaxis in the 2012 focused
update of the ESC guidelines on atrial brillation: a commentary, J. Thromb.
Haemost. 11 (2005) 615626.
[6] D. Garcia, E. Libby, M.A. Crowther, The new oral anticoagulants, Blood 115
(2010) 1520.
[7] J.I. Weitz, Blood coagulation NA anticoagulant, brinolytic and antiplatelet
drugs, in: L. Brunton, B. Chabner, B. Knollman (Eds.), Goodman & Gilmans The
Pharmacological Basis of Therapeutics, McGraw-Hill, New York, 2011, pp. 849
876.
[8] J. Sawicka-Powierza, D. Rogowska-Szadkowska, A.M. Oltarzewska, S. Chlabicz,
Factors inuencing activity of oral anticoagulants. Interactions with drugs and
food, Polski Merkuriusz Lekarski 24 (2008) 458462.
[9] A. Nadkarni, M.A. Oldham, M. Howar, I. Berenbaum, Drug-drug interactions
between warfarin and psychotropics: updated review of the literature,
Pharmacotherapy 32 (2012) 932942.
 P.M. Leite et al. / Biomedicine & Pharmacotherapy 83 (2016) 1421
[10] J.J. You, D.E. Singer, P.A. Howard, D.A. Lane, M.H. Eckman, M.C. Fang, E.M. Hylec,
S. Schulman, A.S. Go, M. Hughes, F.A. Spencer, W.J. Manning, J.L. Halperin, G.Y.
Lip, Antithrombotic therapy for atrial brillation: antithrombotic therapy and
prevention of thrombosis 9th ed: American college of chest physicians
evidence-based clinical practice guidelines, Chest 141 (2012) 531575.
[11] B. Ge, Z. Zhang, Z. Zuo, Updates on the clinical evidenced herb-warfarin
interactions, Evid. Based Complement. Altern. Med. 2014 (2014) 118.
[12] M. Das, L. Panter, N. Connor, J. Mills, D. Gupta, The primary care atrial
brillation (PCAF) service: consultant-led anticoagulation assessment clinics
in the primary care setting increase the uptake of anticoagulation therapy in
AF patients at high-risk of stroke, Europace 16 (2014).
[13] H.R. Lijnen, D. Collen, Fibrinolysis and the control of hemostasis, in: S. Majerus,
P. Varmus (Eds.), The Molecular Basis of Blood Diseases, W.B. Saunders Co,
Philadelphia, 2001, pp. 740763.
[14] H.M. Spronk, J.W. Govers-Riemslag, H. ten Cate, The blood coagulation system
as a molecular machine, Bioessays 25 (2003) 12201228.
[15] P. Van Dreden, A. Rouseau, A. Savoure, B. Lenormand, S. Fontaine, M. Vasse,
Plasma thrombomodulin activity, tissue factor activity and high levels of
circulating procoagulant phospholipid as prognostic factors for acute
myocardial infarction, Blood Coagul. Fibrinolysis 20 (2009) 635641.
[16] A. Paoletti, E. Gallo, S. Benemei, M. Vietri, F. Lapi, R. Volpi, F.M. Ippolito, L. Gori,
A. Mugelli, F. Firensuoli, A. Vannacci, Interactions between natural health
products and oral anticoagulants: spontaneous reports in the Italian
surveillance system of natural health products, Evid. Based Complement.
Altern. Med. 2011 (2011) 5.
[17] J.C. Coon, T. Miller, Strategies to reduce bleeding risk in acute coronary
syndromes and percutaneous coronary intervention: new and emerging
pharmacotherapeutic considerations, Pharmacotherapy 34 (2014) 973990.
[18] M.A. Lila, I. Raskin, Health-related interactions of phytochemicals, J. Food Sci.
70 (2005) 2027.
[19] J.P. Lambert, J. Cormier, Potential interaction between warfarin and boldo-
fenugreek, Pharmacotherapy 21 (2001) 509512.
[20] S. Amrani, H. Harna, D. Gadi, H. Mekh, A. Legssyer, M. Aziz, F.M. Nizard, L.
Bosca, Vasorelaxant and anti-platelet aggregation effects of aqueous Ocimum
basilicum extract, J. Ethnopharmacol. 125 (2009) 157162.
[21] I. Jantan, I.A. Ra, J. Jalil, Platelet-activating factor (PAF) receptor-binding
antagonist activity of Malaysian medicinal plants, Phytomedicine 12 (2005)
8892.
[22] A. Pareek, M. Suthar, G.S. Rathore, V. Bansal, Feverfew (Tanacetum parthenium
L.): a systematic review, Pharmacogn. Rev. 5 (2011) 103110.
[23] H. Oku, Y. Ueda, M. Iinuma, K. Ishiguro, Inhibitory effects of xanthones from
guttiferae plants on PAF-induced hypotension in mice, Planta Med. 71 (2005)
9092.
[24] A.S. Koshy, L. Anila, N.R. Vijayalakshmi, Flavonoids from Garcinia cambogia
lower lipid levels in hypercholesterolemic rats, Food Chem. 72 (2001) 289
294.
[25] Z.G. Nie, W.J. Wang, Effect of ginkgolide B on platelet-activating factor induced
activation of rat polymorphonuclear leukocytes, Yao Xue Xue Bao 38 (2003)
98102.
[26] A. Tachjian, V. Maria, A. Jahangir, Use of herbal products and potential
interactions in patients with cardiovascular diseases, J. Am. Coll. Cardiol. 55
(2010) 515525.
[27] M. Andersson, J. Lindh, Possible interaction between pomegranate juice and
warfarin, Lakartidningen 109 (2012) 483.
[28] K.E. Komperda, Potential interaction between pomegranate juice and warfarin,
Pharmacotherapy 29 (2009) 10021006.
[29] S. Jarvis, C. Li, R.G. Bogle, Possible interaction between pomegranate juice and
warfarin, Emerg. Med. J. 27 (2010) 7475.
[30] Y. Taki, K. Yokotani, S. Yamada, K. Shinozuka, Y. Kubota, W. Watanabe, K.
Umegaki, Ginkgo biloba extract attenuates warfarin-mediated anticoagulation
through induction of hepatic cytochrome P450 enzymes by bilobalide in mice,
Phytomedicine 19 (2012) 177182.
[31] E.L. Michalets, Update: clinically signicant cytochrome P-450 drug
interactions, Pharmacotherapy 18 (1998) 84112.
21
[32] L.S. Kaminsky, Z.Y. Zhang, Human P450 metabolism of warfarin, Pharmacol.
Ther. 73 (1997) 6774.
[33] P. Dewick, Medicinal Natural Product a Biosynthetic Approach, third ed.,
Department of Ecology Swedish University of Agricultural Science,
Switzerland, 2009.
[34] R. Segal, L. Pilote, Warfarin interaction with Matricaria chamomilla, Can. Med.
Assoc. J. 174 (2006) 12811282.
[35] R.L. Page, J.D. Lawrence, Potentiation of warfarin by dong quai,
Pharmacotherapy 19 (1999) 870876.
[36] A. Fugh-Berman, Herb-drug interactions, Lancet 355 (2000) 134138.
[37] P.S. Fasinu, P.J. Bouic, B. Rosenkranz, An overview of the evidence and
mechanisms of herb-drug interactions, Front. Pharmacol. 3 (2012) 69.
[38] H.H. Tsai, H.W. Lin, A. Simon Pickard, H.Y. Tsai, G.B. Mahady, Evaluation of
documented drug interactions and contraindications associated with herbs
and dietary supplements: a systematic literature review, Int. J. Clin. Pract. 66
(2012) 10561078.
[39] J. Rywaniak, B. Luzak, A. Podedek, D. Dudzinska, M. Rozalski, C. Watala,
Comparison of cytotoxic and anti-platelet activities of polyphenolic extracts
from Arnica montana owers and Juglans regia husks, Platelets 26 (2015) 168
176.
[40] R. Farhadi, M. Salehi Balashahri, H. Gholami Tileben, M. Sadeghi, Pharmacology
of borage (Borago ofcinalis L.), Int. J. Agron. Plant Prod. 3 (2012) 7377.
[41] A.A. Izzo, Interactions between herbs and conventional drugs: overview of the
clinical data, Med. Princ. Pract. 21 (2012) 404428.
[42] L.C. Santana, M.R. Brito, G.L. Oliveira, A.M. Cito, C.Q. Alves, J.P. David, J.M. David,
R.M. Freitas, Mikania glomerata: phytochemical, pharmacological, and
neurochemical study, Evid. Based Complement. Altern. Med. 2014 (2014) 111.
[43] R. Apitz-Castro, E. Ledezma, J. Escalante, M.K. Jain, The molecular basis of the
antiplatelet action of ajoene: direct interaction with the brinogen receptor,
Biochem. Biophys. Res. Commun. 141 (1986) 145150.
[44] T.O. Cheng, Not only green tea but also green leafy vegetables inhibit warfarin,
Int. J. Cardiol. 125 (2008) 101.
[45] R.J. Moore, K.G. Jackson, A.M. Minihane, Green tea (Camellia sinensis)
catechins and vascular function, Br. J. Nutr. 102 (2009) 17901802.
[46] A.C. Sato, S.A. Andrade, M.V. Brito, A. Miranda, M.U. Sampaio, F.H.A. Maffei, M.L.
Oliva, Effects of compounds from Passiora edulis Sims f. avicarpa juice on
blood coagulation and on proteolytic enzymes, Protein Peptide Lett. 19 (2012)
501508.
[47] A. Argento, E. Tiraferri, M. Marzaloni, Oral anticoagulants and medicinal
plants. An emerging interaction, Ann. Ital. Med. Int. 15 (2000) 139143.
[48] C. Ulbricht, W. Chao, D. Costa, E. Rusie-Semon, W. Weussner, J. Wood, Clinical
evidence of herb-drug interactions: a systematic review by the natural
standard research collaboration, Curr. Drug Metab. 9 (2008) 10631120.
[49] C.S. Yuan, G. Wei, L. Dey, T. Karrison, L. Nahlik, S. Maleckar, K. Kasza, M.A. Lee, J.
Moss, Brief communication: american ginseng reduces warfarin's effect in
healthy patients: a randomized controlled Trial, Ann. Intern. Med. 141 (2004)
2327.
[50] S.H. Lee, Y.M. Ahn, S.Y. Ahn, H.K. Doo, B.C. Lee, Interaction between warfarin
and Panax ginseng in ischemic stroke patients, J. Altern. Complement. Med. 14
(2008) 715721.
[51] M.F. Rosado, Thrombosis of a prosthetic aortic valve disclosing a hazardous
interaction between warfarin and a commercial ginseng product, Cardiology
99 (2003) 111.
[52] G.A. Plotnikoff, D. McKenna, K. Watanabe, M. Blumenthal, G.A. Plotnikoff, D.
McKenna, Ginseng and warfarin interactions, Ann. Intern. Med. 141 (2004)
893894.
[53] C.Y. Malati, S.M. Roberton, J.D. Hunt, C. Chairez, R.M. Alfaro, J.A. Kovacs, S.R.
Penzac, Inuence of Panax ginseng on cytochrome P450 (CYP)3A and P-
glycoprotein (P-gp) activity in healthy participants, J. Clin. Pharmacol. 52
(2012) 932939.
[54] X. Jiang, K.M. Williams, W.S. Liauw, A.J. Ammit, B.D. Roufogali, C.C. Duke, R.O.
Day, A.J. McLachlan, Effect of St Johns wort and ginseng on the
pharmacokinetics and pharmacodynamics of warfarin in healthy subjects, Br.
J. Clin. Pharmacol. 57 (2004) 592599.