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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 3  |  Issue : 1  |  Page : 12-20

Experimental antithrombotic effect of medicinal plants: A critical review


Department of Dravyaguna Vijnana, Pt. Khushilal Sharma Government Ayurveda College and Institute, Bhopal, Madhya Pradesh, India

Date of Submission22-Feb-2022
Date of Decision23-Apr-2022
Date of Acceptance17-May-2022
Date of Web Publication15-Jun-2022

Correspondence Address:
Nitin Ujjaliya
Department of Dravyaguna Vijnana, Pt. Khushilal Sharma Government Ayurveda College and Institute, Bhopal, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijaim.ijaim_9_22

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  Abstract 


Thrombosis is one of the major causes of morbidity and mortality in a wide range of cardiovascular disorders (CVDs). CVDs are listed among top ten killer diseases. Antithrombotic drugs reduce the incidence of cardiovascular events about 20%–25% in people. Due to the high prevalence of thrombotic disorders, researches are being carried out on novel antithrombotic agents with minimal adverse effects in which herbal drugs are considered as alternative remedy. Medicinal plants have been used for the management of ailments since ancient times. The objective of this study is to do documentations the effect of herbal drugs on antithrombotic therapy. Herbal remedies are used to treat a large variety of thrombotic disorders. However, a number of herbal preparations have been reported to cause variations in clotting time, bleeding time, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, protein C, TXA2, etc. This is mainly by disruption of the coagulation cascade and platelet plug formation. This review can help to design future researches for antithrombotic drugs discovery with more effectiveness and safety. The reported antithrombotic drugs have the potential of improving quality of life while avoiding the side effects of conventional treatment. Data were collected by existing article on antithrombotic studies from various search engines. This review is focused on plants like Syzygium cumini L. Morus alba L., Zingiber officinal Roscoe, Allium cepa L., Nigella sativa L., Punica granatum L., Mentha longifolia L., Allium sativa L., Boswellia serrate Roxb. and Sesamum indicum L.

Keywords: Anticoagulant, antiplatelet, antithrombotic experimental model, fibrinolytic, medicinal plants, traditional herbs


How to cite this article:
Mandloi S, Ujjaliya N, Jain PV. Experimental antithrombotic effect of medicinal plants: A critical review. Indian J Ayurveda lntegr Med 2022;3:12-20

How to cite this URL:
Mandloi S, Ujjaliya N, Jain PV. Experimental antithrombotic effect of medicinal plants: A critical review. Indian J Ayurveda lntegr Med [serial online] 2022 [cited 2022 Dec 3];3:12-20. Available from: http://www.ijaim.in/text.asp?2022/3/1/12/347503




  Introduction Top


Thrombosis is a pathological condition of blood clot formation inside a vein or artery that obstruct the blood flow. If thrombi fragment (emboli) slips from the vessel wall, it can cause obstruction in the vessels which can lead to heart and vascular diseases.[1] Thrombosis can occur in both artery and vein. Arterial thrombosis is the common cause of myocardial infraction, stroke, and limb gangrene, whereas venous thrombosis is a cause of DVT, pulmonary embolism, etc. The factors influencing thrombosis such as change in blood flow and vessel wall dysfunction caused by atheromatous plaque are responsible for arterial thrombosis, while change in blood components may lead to hyper coagulation in venous thrombosis.[2]

Thrombotic disorders such as cardiovascular disorders are the leading causes of death and disabilities in the world. Globally, it is estimated that about 17.3 million people had died from CADs in 2008 and, by 2030, approximately 23.6 million of the world population might die may be affected from CADs. Thrombotic disorders are generated from pathologies associated with hemostasis.[3]

Due to high prevalence rate, there is a need to discover an alternative antithrombotic drug that devoid of adverse effects. This review is focused on various natural and traditional antithrombotic agents. Traditional medicines have not been evaluated scientifically with regard to their safety and efficacy.[4] The herbal drugs require more extensive research up to desired level. This review will help to explore various herbal drugs that could be a better target for the development of novel antithrombotic drugs.[5] One of the major goals of this study is to provide a scientific and appropriate literature review of effective medicinal herbs which were proven antithrombotic activity.


  Current Treatment Strategies and It's Limitations Top


Antithrombotic medication plays a pivotal role as agents for the prevention and treatment of thrombotic disorders such as coronary artery disease, cerebrovascular disease, and peripheral arterial diseases. Antithrombotic is any drug that decreases clots in the body (by dissolving already formed clots or preventing clot formation). This includes the drug classes such as anticoagulants, antiplatelets, and thrombolytics or fibrinolytic.[6] These medications have their own limitations and side effects apart from being expensive.[7]

Combined antiplatelet drug such as aspirin and clopidogrel has been the standard management in most hospitals but aspirin resistance,[8] prolonged use of aspirin may cause stomach and duodenal ulcerations.[9] Clopidogrel, another antiplatelet drug has been documented to be more effective than aspirin but this drug is costly and has a wider profile of adverse effects like neutropenia and thrombocytopenia.[10] Anticoagulant drug like warfarin has been documented to cause dermatomycosis and teratogenic effects.[9] Fibrinolytic drug like tissue plasminogen activator (tPA), streptokinase still has significant shortcoming, including the need for large doses to be maximally effective, limited fibrin specificity, and bleeding tendency.[11] Hence, there is a need for safe and cost-effective antithrombotic agents.


  Herbal Medicines as an Alternative Source Top


Herbs have been considered as an alternative remedy in pharmaceutical industries.[12] According to the WHO estimates, approximately 80% of the world's population use it for their primary healthcare.[13],[14] Due to the pervading of thrombotic disorders, new antithrombotic drugs are necessary for the prevention and treatment of thrombotic disorders devoid of adverse effects. Recently, several studies have been demonstrated the antiplatelet, anticoagulant, fibrinolytic activities of plant extracts or natural products such as-coumarins, xanthones, alkaloids, Flavonoids, anthraquinones, naphthalenes, and stilbenes.[15],[16],[17],[18],[19],[20],[21],[22],[23],[24] Medicinal plants serve as a greater resource for new medication and their potential currently become a topic of interest to the researchers all over the world. The WHO has recommended medicinal plants to be used more effectively in the health care system.[3]


  Pathophysiology Top


Hemostasis is a normal physiological phenomenon in our body's internal defence system that prevents loss of blood on hemorrhage such as conditions, which converts blood into thick jelly like mass at point of injury.[25] This process involves three fundamental components; the vascular wall, the platelets, and the coagulation cascade. These components are essential for hemostasis to achieve two major purposes: To maintain blood in a liquid, clot-free state and to induce a swift and localized blood clot at the site of vesicular injury.[26] The reactions of hemostasis include spontaneous vasoconstriction, platelet plug formation, blood clotting, and fibrinolysis.[27]

Vasoconstriction

The first hemostatic reaction is vasoconstriction. Immediately after injury, the arterioles and small arteries constrict. Vasoconstriction is a localised phenomenon, when the blood vessels are cut, the endothelium is damaged then subendothelial extra cellular matrix or ECM (e.g., - collagen, elastin, fibronectin, laminin, and glycosaminoglycans) are exposed. Platelets adhere to this collagen and get activated. The activated platelets secrete serotonin and other vasoconstrictor substances which cause constriction of the blood vessel.[28]

Platelet plug formation

There are three processes involved in platelet plug formation.

Platelet adhesion

Glycoprotein 1b (Gp1b) receptor on the platelet recognizes the site of endothelial injury and the circulating platelets adhere to exposed sub endothelial matrix (ECM) (primary aggregation). Von Willebrand's factors (vWF) synthesized by the endothelial cell binds to Gp1b receptor and forms a firm adhesion of platelets with ECM.[29] vWF acts as a bridge between a specific glycoprotein present on the surface of platelet and collagen fibrils.[28]

Platelet release reaction

Activated platelets then undergo release reaction by which the platelet granules are released to the exterior. Two main type of platelet granules are released:

  1. Dense bodies, their release liberates adenosine diphosphate (ADP), ionic calcium, serotonin, histamine, and epinephrine. Release of contents of dense bodies is more important since ADP is further an activator of platelets, and calcium is required in the coagulation cascade
  2. Alpha granules, their release produces fibrinogen, fibronectin, platelet factor 4 (anti-heparin), etc. As a sequel to platelet activation n and release reaction, the phospholipid complex-platelet factor 3 get activated which plays important role in the intrinsic pathway of coagulation.[29]


Platelet aggregation

Following release of ADP, a potent platelet aggregating agent, aggregation of additional platelets takes place (sec. Aggregation). This result in the formation of temporary hemostatic plug.[29] Platelet aggregation is accelerated by platelet activating factor.[28] However, stable haemostatic plug is formed by the action of fibrin, thrombin, thromboxaneA2.

Coagulation of blood

The mechanism of coagulation is a multi-step process involving activation of various enzymes which ultimately use its specific substrate and converts it into active enzyme.[25] substances necessary for clotting are called clotting factors. These are 13 in number. Most of the clotting factors are proteins in the form of enzyme. Normally, all the factors are present in the form of inactive proenzyme. These proenzymes must be activated into enzymes to enforce clot formation. It is carried out by a series of proenzyme-enzyme conversion. First one of the series is converted into an active enzyme that activates the second one, which activates the third one; this continues till the final active enzyme thrombin is formed.[28]

Newly formed thrombin then breaks down soluble fibrinogen into insoluble fibrin.[30] These fibrin threads get attached to the loose platelet plug which blocks the ruptured part of vessel and prevent further blood loss.[28] The process is rapid and efficient and requires regulation because, if it is not controlled, excessive clotting can lead to thrombosis.

Stages of blood clotting[28]

  1. Formation of prothrombin activator
  2. Conversion of prothrombin into thrombin
  3. conversion of fibrinogen into fibrin.


Thus, formation of prothrombin activator occurs through two pathways:

  1. Intrinsic pathway
  2. Extrinsic pathway.


Natural fibrinolytic pathway

Lysis of clot inside the blood vessel is called fibrinolysis. It helps to remove the clot from lumen of the blood vessel. This process requires a substance called plasmin or fibrinolysin.[28]

Plasmin is formed from inactivated glycoprotein called plasminogen. It is synthesized in liver and converted into plasmin by tPA, lysosomal enzyme and thrombin. tPA and lysosomal enzyme are released from damage tissue and endothelium. Thrombin is derived from blood. The tPA is always inhibited by tPA inhibitor and factors V, VIII. There is another plasminogen activator called urokinase plasminogen activator (u-PA). It is derived from blood.[28]

Sequence of event involved in the activation of plasminogen[28]

  1. During intravascular clotting, the endothelium of the blood vessel secretes a thrombin binding protein, the thrombomodulin (TM)
  2. TM combines with thrombin and forms a TM-thrombin complex
  3. This complex activates protein “C”
  4. Activated protein “C” inactivates factor V and VIII in the presence of cofactor called protein 'S”
  5. Protein “C” also inactivates the tPA inhibitor. Now the tPA becomes active
  6. Activated tPA and lysosomal enzymes activate plasminogen to form plasmin. Plasminogen is also activated by thrombin and u-PA.



  Materials and Methods Top


The information about medicinal plants that are used in the management of thrombotic disorders was obtained from published papers and texts on ethnobotanical study. A literature search on electronic databases such as Google Scholar, PubMed, and Scopus. We carried out using antiplatelet herbs, anticoagulant plants, anti-thrombotic, fibrinolytic, animal model, in-vivo, in-vitro, traditional herbs as the keywords for search encompasses only in-vivo and in-vitro experimental studies.


  Experimental Models Top


The selection of animal model for the evaluation of antithrombotic effects depends on several factors. The interaction of a given drug with the blood and vascular components and its metabolic transformation are important considerations. The screening of drugs such as antibiotics, antithrombotic require multi parametric endpoint analysis. Animal models are the most useful system in the evaluation of the effects of these drugs. Finally, it should be stressed that the evaluation of pharmacopoeial and in vitro potency of antithrombotic drugs does not necessarily reflect the in vivo safety/efficacy profile.[31]

Experimental studies which are reviewed in present article were performed in different models like Arachidonic acid, ADP, collagen induced platelet aggregation; Arteriovenous shunt model, venous thrombosis model, tail cutting model, tail vein transection model, k carrageenan induced model, ear vein pricking etc.

K-carrageenan induced thrombosis model is popularly used model for testing antithrombotic substances. K-carrageenan was the most potent thrombogen. As the consequence of thrombosis, tail infarction became visible some minutes after i.v. administration, but it was delayed for about 3 h after the i.p. route and for about 6 h after sub plantar injection.[32]

Advantages: (i) simple induction in small laboratory animals, (ii) easy observation and quantification at all times without killing the animals, and (iii) possible external testing of antithrombotic agents by application of substances on the tail.[32]

Arteriovenous shunt thrombosis model is a method for the direct observation of extracorporeal thrombus formation. Very early studies using this model provided evidence that anticoagulant drugs inhibit thrombus development in AV shunts. Today, this models are often used to evaluate the antithrombotic potential of new Compounds in different species including rabbits, rats, pigs, dogs and cats, and nonhuman primates.[31] In ear vein pricking model, tail cutting model and Tail transection model bleeding time (BT) is measured. BT measurement in animals are used to evaluate the haemorrhagic properties of antithrombotic drugs.[31] AA, ADP, Collagen, thrombin are known to induce platelet aggregation. This in vivo method can be used to evaluate the platelet antiaggregatory properties of test compounds.[31]


  Discussion Top


In present review, some of medicinal plants proven with antithrombotic activity are discussed. Some of them possess nutritional value and are routinely used in day-to-day diets. Hence, apart from the medicinal use, the herbs may offer an effective way for prevention of thrombosis in high-risk patients.[45]

It is imperative to use a variety of parameters and methods in research to elucidate the mechanism of action of a compound or extract. Single assays are more likely to lead to false positives or inaccurate data. Furthermore, in vivo assays are of great importance, as in-vitro studies do not always predict the effect of an herbal drug.[46] Experimental studies which are reviewed in present article were performed on various models and different parameters.

Thrombotic disorders can be prevented or treated by interfering thrombosis formation mechanism. The primary goal of Antithrombotic therapy is to inhibit platelet activation (primary haemostasis) and fibrin formation via cascade (secondary haemostasis).

Parameter interpretation

Various parameters such as thrombin time (TT), PT, activated partial thromboplastin time (APTT), BT, Fb levels, TAT complex, protein C, platelet aggregation, platelet count, thrombus weight, D-dimer, C-reactive protein (CRP), Euglobulin clot lysis time (ECLT); level of TXA2, ADP, serotonin, calcium, and clot lysis were used to evaluate the effect of herbal medicines on thrombosis in the experimental study which are reviewed in the present paper.

Prothrombin time (PT) is an effective assay for evaluating the activity of the factors of the extrinsic coagulation pathway, while the APTT is used for evaluating the activity of factors of the intrinsic and common pathways. The PT is a standard test for monitoring coumarin therapy (Vitamin K antagonists), while the APTT is usually used to monitor the effectiveness of heparin treatment.[47]

PT is the time taken by blood to clot after adding tissue thromboplastin to it. Blood is collected and oxalated so that, the calcium is precipitated and prothrombin is not converted into thrombin. Thus, the blood clotting is prevented. Then, a large quantity of tissue thromboplastin with calcium is added to this blood. Calcium nullifies the effect of oxalate. The tissue thromboplastin activates prothrombin and blood clotting occurs. During this procedure, the time taken by blood to clot after adding tissue thromboplastin is determined. PT indicates the total quantity of prothrombin present in blood. It is prolonged when there is deficiency of prothrombin and other Factors I, V, VII, and X.[28]

APTT is the time taken for the blood to clot after adding activator such as phospholipid, along with calcium to it. This test is useful in monitoring the patients taking anticoagulant drugs. It is carried out by observing clotting time (CT) after adding phospholipid, a surface activator and calcium to patient's plasma. Phospholipid serves as platelet substitute. It is prolonged in anticoagulant therapy and inhibition of factors II, V, VIII, IX, X, XI, and XII.[28] Punica granatum showed only APTT prolongation.[37] Zingiber officinale,[36] Boswellia serrate,[42] and Mentha longifolia[38] drugs caused prolongation of PT and APTT. Thus, the prolonged PT and APTT suggests inhibition of clotting factors.

Inhibition of platelet aggregation includes the reduction of TxA2 formation and prostacyclin (PgI2) enhancement. TxA2 is a potent agonist causing the activation of platelets and thrombus formation. TxA2 causes irreversible platelet aggregation, vasoconstriction, and proliferation of smooth muscle cells.[48] PgI2 is synthesized by PgI2-synthase in endothelial cells and has an effect as an aggregation inhibitor and vasodilator. When the formation of the thrombus is inhibited, blood flow is smooth and BT increase.[49] Morus alba,[34] Nigella sativa,[40] Cicer arietinum,[44] Cymbopogon citratus,[12] and B. serrate[42] caused inhibition of platelet aggregation. M. alba also showed TXA2 Inhibition activity in vitro model.

Protein “C” and TAT complexes were presented as biomarker for cardiovascular and thrombotic events.[50] As Syzygium cumini increased the levels of these biomarker which in turn is cause of reducing thrombin activity. This effect is similar to that of known anticoagulant drug, heparin, which might be probable reason for prolonged BT. It is known that heparin potentiates synthesis of anti-thrombin III (AT-III), which ultimately, promotes complex formation with thrombin and deactivates multiple coagulation factors that increase duration of APTT.[51] AT-III and activated form of PC play major role as natural anticoagulants. AT-III retards activated clotting factors i.e., factor Xa and thrombin (Factor IIa). The increase of thrombin inhibition due to incorporation with AT-III can be estimated by TAT complex.[52] Protein C plays its role in reducing thrombin and deactivate the Factor VIIIa and Factor Va.

BT is the time interval from oozing of blood after injury till arrest of bleeding.[28] It was prolonged in P. granatum, Tamarindus indica, Z. officinal, M. longifolia. CT is the time interval from oozing of blood after injury till the formation of clot.[28] It was found prolonged in Allium cepa, M. longifolia, and P. granatum. Antithrombotic drugs are effective in the control of thrombogenesis at various levels. These drugs are also capable of producing haemorrhagic effects that cannot be predicted using CT and BT testing methods. The bleeding effects of a drug may be direct or indirect; hence assessing efficacy/safety ratios could be a useful parameter.[31]

TT is the time taken for blood to clot after adding thrombin to it. It is done to investigate the presence of heparin in plasma or to detect fibrinogen abnormalities. This test involves observation of CT after adding thrombin. It is prolonged in heparin therapy and during dysfibrinogenemia (abnormal function of fibrinogen with normal fibrinogen level).[28] Z. officinal showed TT prolongation.

P. granatum[37] and Allium sativum[41] Showed shortened ECLT in study. ECLT measures the overall fibrinolytic pathway. Shortened ECLT marks an increased fibrinolytic pathway.[37] M. longifolia,[38] Sessamum indicum[43] caused increased clot lysis activity. M. alba,[34] Glycyrrhiza glabra[39] caused reduction in thrombus weight. P. granatum showed reduction in the length of infarct tail length in k carrageenan induced rat tail model.[37]

coagulation parameters namely D–dimer, fibrinogen, high sensitive CRP, tPA were analyzed for assessing thrombolytic therapy. These parameters were slightly increased when thrombus was formed. tPA is the primary initiator of thrombolysis where in it plays an important role in removing the thrombus formed. Our study reveals that the level of tPA is greatly increased on the commencement of thrombolysis by fruit extracts and standards. The visual evidence in addition to the increased tPA levels proves the efficiency of P. granatum in lysing the clot. The fruit extracts might have triggered the production of tPA apart from directly lysing the clot and hence the increase in plasma tPA levels.[37]

Mode of action

In the present review, it was found that all plants S. cumin,[53] M. alba,[54] T. indica,[55] Z. officinal,[56] P. granatum,[57] M. longifolia,[58] G. glabra,[59] N. sativa,[60] A. cepa,[61] Sesamum indicum,[62] C. arietinum,[63] and C. citratus[64] contains phenolic and flavonoids compound. Flavonoid play an important role as antioxidants and have antithrombotic effect by reducing platelet aggregation and thrombin. Specifically, flavonoids act as TxA2 receptor antagonists, reducing TxA2 which then indirectly inhibits COX-1. In addition, flavanoid compounds increase the production of nitric oxide, which is important for the inhibition of platelet aggregation.[65]

There are various mechanisms involved in thrombosis such as inflammation,[66] hyper lipidaemia, atherosclerosis,[67] and oxidative stress [Table 1] and [Table 2].[68]
Table 1: In-vivo studies on herbal drugs for the management of thrombosis

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Table 2: In-vitro studies on herbal drugs for the management of thrombosis

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In cardiovascular disease, abnormal clotting occurs that can result in heart attacks or stroke. Blood vessels injured by smoking, cholesterol, or high blood pressure develop cholesterol-rich build-ups (plaques) that line the blood vessel; these plaques can rupture and cause the platelets to form a clot. Even though no bleeding is occurring, platelets sense the plaque rupture and are confused, thinking that an injury has taken place that will cause bleeding. Instead of sealing the vessel to prevent bleeding as would occur with a cut, a clot forms in an intact blood vessel, causing blockage of blood flow. Without blood, a portion of the heart muscle can die, leading to heart attack.[69] M. alba,[54] T. indica,[55] Z. officinal,[56] P. granatum,[57] G. glabra,[59] N. sativa,[60] A. cepa,[61] C. arietinum,[63] and C. citratus[64] plants possess hypolipidemic/anti-atherosclerotic activities.

Oxidative stress appears to play a key role in the pathogenesis of atherosclerosis agents that prevent the oxidation of low-density lipoprotein have reduced the development and progression of this disease.[70] Majority of plants[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64] listed here are reported for their antioxidant activities. The combination of lipid lowering and antioxidant activities makes a potential anti-atherosclerotic agent and antithrombotic agent.

Systemic inflammation is a potent prothrombotic stimulus. Inflammatory mechanisms upregulate procoagulant factors, downregulate natural anticoagulants and inhibit fibrinolytic activity. In addition to modulating plasma coagulation mechanisms, inflammatory mediators appear to increase platelet reactivity.[71] Tissue factor is normally present in the circulation at very low levels.[72] Inflammatory mediators promote coagulation by elevating tissue factor. Endotoxin, tumour atherosclerosis factor α (TNF-α) and interleukin-1α (IL-1α) induce tissue factor expression, primarily on monocytes/macrophages,[73],[74] and probably play a role in inducing tissue factor in atherosclerotic plaques as well.[75] All of the reactions are involved in coagulation initiation. Inflammation will also elevate fibrinogen synthesis. The essential element of natural anticoagulants pathway is protein C. This pathway appears to be the most negatively influenced by inflammation. TM and the endothelial cell protein C receptor are both downregulated by inflammatory cytokines like TNFα.[76],[77] T. indica,[55] Z. officinal,[56] P. granatum,[57] M. longifolia,[57] G. glabra,[59] N. sativa,[60] A. cepa,[61] C. arietinum,[63] C. citratus[64] plants show anti-inflammatory activity.

Limitations

Herbal drugs were randomly selected for present review. Further systemic review should be done on herbal drugs possessing anti-inflammatory, anti-oxidant, hypolipidemic activity to evaluate their antithrombotic activity.

Future prospect

Physician should be aware of potencial interaction between prescription drugs and herbal medicines. Care should be taken when physician prescribes these herbal drugs to patients already on anticoagulant therapy.[78]


  Conclusion Top


The current study has shown that various herbal medicines have antithrombotic activity in in-vitro and in vivo models evidenced by affecting various parameters. It can be concluded that regular consumption of these herbs in diet can lower the risk of developing cardiovascular events such as myocardial infraction, stroke, etc., by reducing the risk of thrombosis.

Further research should be done on herbs having antioxidant, anti-inflammatory, hypolipidemic properties and containing flavonoids, alkaloids, xanthones, coumarins, anthraquinones, etc., to explore their antithrombotic potential.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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