Abstract
Context: Herbal remedies are used to treat a large variety of diseases, including blood-related disorders. However, a number of herbal preparations have been reported to cause variations in clotting time, this is mainly by disruption of the coagulation cascade.
Objective: The compiling of plants investigated for effects on the coagulation cascade.
Methods: Information was withdrawn from Google Scholar and the journal databases Scopus and PubMed.
Results: Sixty-five herbal remedies were identified with antiplatelet, anticoagulant, or coagulating ability. Bioactive compounds included polyphenols, taxanes, coumarins, saponins, fucoidans, and polysaccharides.
Conclusion: Although research has been conducted on the effect of herbal remedies on coagulation, most information relies on in vitro assays. Contradictory evidence is present on bleeding risks with herbal uses, though herb–drug interactions pose a threat. As the safety of many herbals has not been proven, nor their effect on blood parameters determined, the use of herbal preparations before undergoing any surgical procedure should discontinued.
Introduction
Cardiovascular diseases remain a prominent killer today, including myocardial infarctions, strokes, and thromboses that can arise from pathologies associated with coagulation (CitationChistokhodova et al., 2002; CitationRang et al., 2007; CitationBuch et al., 2010; CitationEisenreich & Rauch, 2011). Over activity of the coagulation cascade (hypercoagulation) increases the risk of thromboses formation (CitationMekhfi et al., 2004). This can easily lead to thromboembolisms which block blood flow and lead to ischemia with subsequent damage to the afflicted organs (CitationBruno et al., 2001). Hereditary defects and habits, such as smoking, increase blood coagulability (CitationRang et al., 2007). On the other hand, anticoagulants (such as heparin and warfarin), antiplatelet drugs (aspirin) as well as fibrinolytics (streptokinase) decrease blood coagulation and the risk of thrombus formation (CitationVane & Botting, 2003; CitationRang et al., 2007).
The use of plants as remedies for various ailments has formed the basis of our modern medicinal sciences (CitationHutchings et al., 1996). According the CitationWorld Health Organization (2008) approximately 80% of Asia and Africa’s population use traditional medicine as a form of healthcare for treatment of diseases including blood disorders. Plant extracts can be an alternative to currently used antiplatelet agents, as they constitute a rich source of bioactive chemicals. Compounds such as alkaloids, xanthones, coumarins, anthraquinones, flavonoids, stilbenes, and naphthalenes have been reported to have an effect on platelet aggregation (CitationAburjai, 2000; CitationElliott Middleton et al., 2000; CitationChen et al., 2001; CitationChung et al., 2002). Furthermore, polyphenol-rich diets have been shown to be beneficial in vascular functioning including platelet aggregation in humans (CitationMurphy et al., 2003). In this article, the effects of herbal remedies on blood parameters are reviewed. Literature was obtained through use of Scopus and PubMed databases, as well as Google Scholar using the following search parameters, or combinations thereof: “anticoagulant,” “antiplatelet,” “coagulation,” “plant,” “extract,” “herbal,” and “remedy” and articles published prior to and including 2011.
Herbals and their effect on blood parameters
Various plants are used ethnomedicinally for use in blood-related treatments as blood tonics, to prevent excessive bleeding, to treat hemorrhoids, and as wound dressing to staunch blood flow. The efficacy and safety of herbal preparations are not always clearly defined though, and the use of these may cause increased perioperative bleeding risk due to disrupted coagulation (CitationBeckert et al., 2007). Whether these preparations have direct effects on the coagulation system or cause disruption due to drug interactions is not always known (CitationBeckert et al., 2007). Plants studied for effects on coagulation in vitro and/or in vivo, as well as possible bioactive constituents, are listed in .
Table 1. Herbal remedies affecting coagulation.
Various models exist to screen for activity, though popular experiments include effects on prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) both in vitro and ex vivo, while bleeding time and protection against thromboembolism-induced death are monitored in vivo. Since in vitro activity does not always translate to in vivo activity, continued research in this area is of essence.
Although the majority of plants decrease platelet activation and aggregation, it should be kept in mind that many factors are at play. Microtubule stabilization from taxanes (CitationKim & Yun-Choi, 2010) and increased membrane fluidity from garlic-saponins (CitationSu et al., 1996; CitationLiao & Li, 1997) maintains a disaggregated platelet form. Harmane- and harmine-induced reduction of tyrosine phosphorylation limits calcium mobilization and arachidonic acid liberation, which decreases platelet aggregation (CitationIm et al., 2009). The coagulation cascade is attenuated by various phytochemicals such as polyphenols, sulfated polysaccharides, lapachol, allicin, and thiosulfates through inhibition or decreased activity of tissue factor (Lee et al., 2003, Citation2004), thrombin (CitationMedeiros et al., 2008; CitationZhang et al., 2008), vitamin K-epoxide reductase (CitationPreusch & Smalley, 1990), plasminogen activator, phospholipase, thromboxane A2, lipoxygenase (CitationSrivastava, 1986; CitationBeckert et al., 2007), thiol enzymes (coenzyme A and 3-hydroxy-3-methylglutaryl coenzyme A reductase) (CitationLiao & Li, 1997), and other clotting factors, as well as potentiation of heparin co-factor II (CitationMedeiros et al., 2008; CitationMao et al., 2009), and increased fibrinolysis. Coumarin compounds have the ability to affect coagulation through scavenging of reactive oxygen species, inhibiting cyclic nucleotide phosphodiesterases, inhibiting the activity of vitamin K-dependent γ-carboxylase (activation of coagulation factors) and prostaglandin synthesis (CitationHoult & Paya, 1996; CitationCoppinger et al., 2004). Increased coagulation could be explained through synthesis of protein networks and increased erythrocyte aggregation, such as with Ankaferd Blood Stopper® (CitationGoker et al., 2008), or activation of several clotting factors or platelets due to glycoconjugates (CitationPawlaczyk et al., 2010).
Adverse effects after herbal usage
Four plants have mainly been implicated in spontaneous or perioperative bleeding, which has been attributed to a drug–herb interaction (). Such interactions are especially of importance when used together with warfarin which has a narrow therapeutic window (CitationLee et al., 2004; CitationBeckert et al., 2007; CitationJurgens & Whelan, 2009). St. John’s wort has been found to increase the metabolism of warfarin in humans and animals thereby decreasing its efficacy (CitationRoby et al., 2000). Catechins (found to have antiplatelet activity) as well as vitamin K present in green tea would appear to antagonize the anticoagulant effects of warfarin (CitationTaylor & Wilt, 1999). Intraoperative bleeding has been reported after the consumption of Aloe tablets – due to a possible herb–drug interaction with sevoflurane (CitationSteenkamp & Stewart, 2007).
Table 2. Herbal remedies which have been reported to adversely affect clotting.
Ginkgo biloba L. (Ginkgoaceae) has been found to increase bleeding risks, especially during concomitant use of anticoagulants or antiplatelet drugs (CitationKim et al., 2010). However, an open-label, randomized, crossover study reported that there was no difference in bleeding times or platelet aggregation between ticlopidine (250 mg) and ticlopidine/Ginkgo biloba (250/80 mg) treatment groups (CitationKim et al., 2010).
A clinical study in which Gingko biloba, garlic, Asian ginseng [Panax ginseng C.A. Meyer (Araliaceae)], St. John’s wort, and saw palmetto were given to adult volunteers (5 cycles of 4 weeks, 2 week treatment and 2 week wash-out) indicated that these plants were unable to induce any changes to in vivo platelet function (CitationBeckert et al., 2007).
Increased blood coagulation time has been noted when using warfarin with Peumus boldus Molina (Monimiaceae), Dong quai, and garlic. Whether this is due to additive anticoagulant activity or increased plasma concentration of warfarin has as yet not been established (CitationLambert & Cormier, 2001; CitationBasila & Yuan, 2005).
Discussion
As with all research, it is imperative to use a variety of methods to elucidate the mechanism of action of a compound or extract. Single assays are more likely to lead to false positives or inaccurate data, and the advantages or disadvantages must be weighed to magnify the value of a test. Furthermore, in vivo assays are of great importance, as in vitro studies do not always predict the effect of an herbal or compound once pharmacodynamic and pharmacokinetic profiles come into play.
A review of the literature indicated that many herbals reduce clotting via inhibition of coagulation factors or platelet activity. Furthermore, the majority of experiments to determine activity were carried out in vitro, with limited in vivo analyses. It is of great importance to validate in vitro results in animal studies, as there is always the chance that absorption, metabolism, or excretion may lead to significant changes in the herbals effect on coagulation. Many phytochemicals, such as coumarins, polyphenolis, saponins, and salicylates, were elucidated as potent inhibitors, but the concentrations of these may be of such insignificant levels that they pose no threat. Also, depending on manufacturing and processing procedure concentrations and activity of extracts might differ (CitationChukwumah et al., 2007). Herbals have been found to alter the metabolism of anticoagulants as well as other medication through induction or suppression of certain genes. Induction of CYP2C9 (which is responsible for warfarin metabolism) remains a possible mechanism by which herbals cause a decrease in anticoagulant plasma concentration (CitationHenderson et al., 2002).
CitationSaw et al. (2006) reported that 21% of medical ward patients co-ingested herbs with antiplatelet or anticoagulant therapy. Of the latter, 10.5% were at risk of potential herb–drug interaction. Uncontrolled anticoagulation therapy may result in altered international normalized ratio (INR), spontaneous bleeding and can prove fatal. Whether purported herbals have the ability to cause an increased risk of perioperative bleeding is not yet certain, as conflicting reports are available (CitationBeckert et al., 2007).
Conclusion
Cardiovascular thrombotic disease results in widespread mortality and hospitalization, which can be successfully reduced through the use of anticoagulant medicines. The growing use of herbal remedies represents a serious risk of bleeding and thrombosis for patients taking anticoagulants. A relatively small number of studies have been carried out to determine the effect of herbal remedies on coagulation. There is, however, reports describing the effect of herbals on coagulation and platelet function indicating that herbal preparations show significant disruption of the coagulation cascade. As the safety of many herbals has not been proven, nor their effect on blood parameters determined, the use of herbal preparations before undergoing any surgical procedure should rather be ceased. Patients on anticoagulant therapy should be warned against the concurrent use of herbals, and have their INR checked within a week of starting herbal remedy use.
Declaration of interest
The authors report no declarations of interest.
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