Current update on herbal sources of antithrombotic activity—a comprehensive review

Background Herbs are commonly used to treat cardiovascular diseases in various traditional medicine. On the other hand, herb-drug interactions are most commonly encountered with conventional antiplatelet and anticoagulant drug prescriptions. This review presents a compilation of plants investigated for antiplatelet and anticoagulation recently and enumerates their possible lead compounds responsible for its action for paving further drug discovery and knowledge update. Main body of the abstract Information about the herbs was withdrawn from the PubMed database of the previous 5 years. We also hand-searched the bibliography of relevant articles for the acquisition of additional information. About 72 herbal sources were identified with the effect of antiplatelet activity, antithrombotic activity, and anticoagulant activity. Bioactive compounds and various secondary metabolites responsible for it, such as alkaloids, saponins, flavonoids, coumarins, polyphenols, furan derivatives, iridoid glycosides, sesquiterpenes, aporphine compounds, were reported. Conclusion Newer pharmacological moieties are needed to prevent or reduce the adverse effects of current anti-thrombotic agents and to improve the safety of patients and cost-effectiveness.


Background
Cardiovascular disease (CVD) due to thrombosis comprises coronary artery disease (CAD), stroke, hypertension, peripheral arterial disease (PAD), venousthrombo-embolic disease (VTE) [1]. As per the National Health and Nutrition Examination Survey (NHANES) 2013-2016, the prevalence of Coronary heart disease (CHD) in the USA was estimated as 18.2 million in > 20 years of age with more risk among males than females, whereas the prevalence of ischaemic stroke was 67.6 million and that of hemorrhagic stroke was 15.3 million [2]. CVD and stroke accounted for 14% of the total expenditure in 2014-2015, more than any diagnostic group results in immense health and economic burden in the USA globally. The AHA's 2020 Impact Goals are to improve the cardiovascular health of all Americans by 20% while reducing deaths attributable to CVD and stroke by 20% [1].
Currently, witnessing an unprecedented pandemic, the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS Co-V-2), associated with a significant risk of thromboembolic complications due to hypercoagulability state of blood which is called as Covid-19 associated coagulopathy (CAC) [3]. Though prophylaxis anti-coagulants were administered, the incidence of VTE complications was reported in twothirds of ICU cases [4] and developed life-threatening thrombotic complications followed by Acute respiratory distress syndrome (ARDS) [5]. Venous thromboembolism Page 2 of 12 Subramani and Sathiyarajeswaran The Egyptian Journal of Internal Medicine (2022) 34:26 (VTE), a major cardiovascular complication, was observed in about more than 20% of critically ill COVID-19 cases, particularly among critically ill viral pneumonia patients [4]. Histologically, significant thrombosis in small blood vessels and micro-vasculature of pulmonary and extra-pulmonary organs have been confirmed [6], widespread prevalence of deep vein thrombosis and pulmonary embolism, as well as microthrombi in the small pulmonary vessels in autopsy findings [7]. Several hypotheses on the mechanism of thrombosis in Covid-19 have been proposed and remain unclear.

Antiplatelets and anti-coagulants
Thrombosis can be classified as arterial thrombosis and venous thrombosis although overlaps may be present. In general, pharmacologically two classes of drugs are used to prevent blood clots such as antiplatelets and anticoagulants [8]. Antiplatelets act by inhibition of platelet adhesion and activation and aggregation of thrombosis [9]. Thrombosis refers to the formation of platelet or fibrin aggregation in the lumen of the blood vessels or heart [10]. Anticoagulants prevent blood clot formation by interfering with proteins responsible for blood clotting or clotting factors [8]. Hypercoagulability is the state of increased tendency to the formation of thrombosis also triggering intracellular signalling for inflammation [10]. The use of antithrombotic medications remains the mainstay of treatment in cardiovascular and cerebrovascular disorders. Aspirin and clopidogrel were the commonly administered antiplatelet drugs to reduce recurrent ischaemic events in CAD and ischaemic stroke. Oral anticoagulants are prescribed for primary prevention and secondary prevention of venous thromboembolic disease [11] and as the best option in the prevention of stroke due to cardio-embolism in atrial fibrillation [12].

Adverse drug reaction due to conventional antithrombotic drug regimen
Aspirin is prone to cause gastrointestinal side effects, hypersensitivity, hypo-responsiveness in some, and bleeding episodes [13]. Low-dose aspirin is commonly used as primary and secondary prevention of cardiovascular disease, which is associated with the risk of upper and lower gastro-intestinal tract lesions, particularly in the upper gastro-intestinal tract which may cause asymptomatic lesions to peptic ulcer bleeding and/or even death Li et al. [14]. Until recently, the vitamin K antagonists were the only oral anticoagulant agents available and warfarin remains the most commonly prescribed oral anticoagulation worldwide [15]. Warfarin has significant variability in dose-response across individuals and a narrow therapeutic window and intensive therapeutic monitoring are essential. When combined with low-dose aspirin, NSAIDs, or clopidogrel, warfarin acts cumulatively and the risk of bleeding is significantly increased [16] The risk of major bleeding associated with oral anti-coagulants ranges from 3.26 to 7.2% annually [11]. Both oral anticoagulation and antiplatelet therapies are essential in 20-30% of patients with co-existing atrial fibrillation (AF) and CAD, together posing a major risk of thrombotic complications [17]. Currently, in the management of patients with IHD and AF, include triple therapy TT (an anticoagulant plus 2antiplatelet drugs) and two types of dual therapy, DAPT (2 antiplatelet drugs) or DT (an anticoagulant plus a single antiplatelet drug) [18].

Herbal resources and secondary metabolites
Herbs play an indispensable role in natural product discovery to meet the growing healthcare needs. Researchers screen herbal sources through reverse pharmacology and observational therapeutics to find novel compounds and harness the potential for future drug discovery. According to WHO (World Health Organization), about 80% of the World's population depends on medicinal plants or herbs to fulfill their medicinal needs. Herbal medicines are a maximum part of complementary and alternative medicine and preferred treatment of people for various reasons such as ethnicity of use, family traditions, and past good experiences [19]. In this review, we have covered 72 herbs, their extracts, their secondary metabolites, and their pharmacological activities studied in both in vivo, ex vivo, and in vitro investigations. Acknowledging the growing significance of traditional medicine and usage, the WHO global report on traditional and complementary medicine 2019 states about the steps taken to promote the safety, quality, and effectiveness of traditional medicine by developing the WHO Traditional Medicine Strategy 2014-2023, in line with WHO Traditional Medicine Strategy (2002)(2003)(2004)(2005). Healthcare professionals need to be aware of and monitor possible risks of concomitant medications of herbs with conventional medicine prescriptions if any [20].

Methods
We conducted a PubMed search for the in-vitro and in vivo studies published between 2016 and 2020 till December using multiple combinations of keywords, including the following: "anti-thrombotic activity", "antiplatelet activity", "anti-coagulant", "antiplatelet aggregation", "anti-hyper-viscosemia", "anti-aggregant", "platelet agglutination inhibitor", "platelet aggregation inhibitor", "platelet targeted pharmacologic agents", "antiplatelet adhesion", "medicinal plants", and "herbal sources". We found 296 publications that were reviewed by two authors. The retrieved articles were examined mechanisms had been postulated such as inhibition of ADP-induced platelet aggregation, inhibition of the arachidonic acid pathway, thereby inhibiting biosynthesis of thromboxane A2; plants containing lignans, xanthones, sesquiterpenes, flavonoids affect coagulation by inhibiting platelet-activating factor (PAF), or PAF receptor antagonists, inhibiting the factor X on the coagulation cascade. Plants containing the coumarin class of compounds antagonise vitamin K and

Mechanism of antiplatelet and anticoagulant activity of herbs
Plant-derived compounds such as alkaloids, anthraquinones, coumarins, flavonoids, xanthones, Lignans, saponins, stilbenes, etc. were found to affect platelet aggregation activity Werner Cordier et al. [91]. Inhibition of platelet adhesion or chemical mediators for activation of platelet function is the common potential of herbs for its antiplatelet activity. Various  prevent coagulation. Few naturally occurring compounds contain fibrinolytics which may activate plasminogen and affect coagulation. Phytochemicals that inhibit the CYP3A4, CYP2C9, and CYP1A2 metabolism were potent to affect coagulation Leite et al. [92]. Herbs identified in this review were listed with possible mechanisms of action responsible for their pharmacological activity in Table 2.

Herb-drug interaction types and mechanism
Among older adults, concomitant herbal medicine use along with prescription drugs had been reported as 5.3  Table 3 Common therapeutic indication of herbs

Herbs Main uses of herb Reference
Angelica sinensis (Oliv.) Diels Promoting circulation Lu et al. [97] Andrographis paniculata (Burm.f.) Nees Myocardial ischaemia, fever, respiratory infections Zhang et al. [6] Apium graveolens Linn Hepatic and spleen disorders, brain disorders, sleep disturbances Al-Asmari et al. [98] Allium sativum L. Hypercholesterolaemia Izzo et al. [96] Aesculus hippocastanum L. Anti-inflammatory, venotonic Sparg et al. [29] Carthamus tinctorius L. Chest pain, traumatic injuries Lim et al. [99] Curcuma longa L. Chest pain, amenorrhoea Lim et al. [99] Centella asiatica L. (Urb). Improving memory Satake et al. [46] Ginkgo biloba L. to 88.3% in a systematic review as potential cause of herbal-drug interaction Agbabiaka et al. [93]. Herbdrug interactions (HDI) may be either due to pharmacokinetic or pharmacodynamic interactions which affects the safety and efficacy of the treatment. Pharmacokinetic interactions affect the absorption, distribution, metabolism, and excretion of drugs which in turn results in a change in drug concentration in body fluids Lee et al. [94]. Various mechanism has been postulated for the altered drug concentration such as induction or inhibition of hepatic and intestinal drug-metabolizing enzymes such as cytochrome P450, UDP-glucorynyl transferase, and carrier proteins such as P-glycoprotein was suggested Kahrman et al. [95]. While pharmacodynamic interactions are related to the pharmacological activity of the interacting agents which may be synergistic or additive resulting in toxicities or antagonistic causing treatment failure Izzo [96].

Herbal drug interaction with aspirin, clopidogrel, and warfarin
Few frequently reported herbs, with its commonly used therapeutic indications (Table 3), and drug interactions with conventional anti-thrombotic medicines were enumerated with increased risk of bleeding as per current evidence (Tables 4, 5, and 6) and types of herb-drug interaction of few herbs are summarised (Table 7).

Safety profile
Salvia miltiorrhiza, Angelica sinensis (Oliv.) Diels and Zingiber officinale Roscoe were identified to cause major interactions with anticoagulant or antiplatelet drugs may lead to life-threatening complications or serious adverse events (Tsai et al. [110]).

Conclusions
In this review, extensive search has been done on herbal sources investigated for anti-thrombotic activity recently were highlighted. Adverse haemorrhagic complications Table 4 List of herb-aspirin interaction causing increased risk of bleeding

Funding
No funding.

Availability of data and materials
Data sharing not applicable to this article as no data sets were generated or analyzed during the current study.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.

Competing interests
Authors have no conflict of interest.  Zingiber officinale Roscoe (B) PAF inhibitor Leite et al. [92]