|RESEARCH ON TCM THEORY
|Year : 2015 | Volume
| Issue : 2 | Page : 38-49
Chinese herbal remedies affecting thrombosis and hemostasis: A review
Quan Li1, Jing-Yu Fan1, Jing-Yan Han2
1 Tasly Microcirculation Research Center, Peking University Health Science Center; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of China; Key Laboratory of Stasis and Phlegm of State Administration of Traditional Chinese Medicine of China, Beijing 100191, China
2 Tasly Microcirculation Research Center, Peking University Health Science Center; Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of China; Key Laboratory of Stasis and Phlegm of State Administration of Traditional Chinese Medicine of China, Beijing 100191, China
|Date of Web Publication||21-Sep-2020|
Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191
Source of Support: None, Conflict of Interest: None
Acute coronary syndrome, stroke and other ischemic events continue to be the most common causes of mortality and morbidity in the world, and their incidence is rapidly increasing in the developing nations. These cardiovascular disorders clinically manifest as acute atherothrombotic events. Application of oral antiplatelet drugs is a milestone in the therapy of cardiovascular diseases. However, the limited efficacy of these drugs in the setting of arterial thrombosis, their unfavorable side effects, cost-to-benefit issues and the drug resistance phenomenon substantiate the need for the development of new and more efficacious antithrombotic drugs. In recent years, with the progress in the study of the Chinese medicine pharmacology, many Chinese herbs and formulas, as well as active constituents have been reported to possess not only effects on platelet aggregation and activation but also beneficial roles in vascular functions. Compared with currently used antithrombotic agents, herb remedies exert antithrombotic effects in a multi-pathway and multi-target manner. This paper will cover the progress in research on the ameliorating effects of herbal remedies on thrombosis, with focusing on their protection of vascular endothelial cells and inhibition of platelet activation.
Keywords: Chinese herbs, thrombosis, endothelium, platelet
|How to cite this article:|
Li Q, Fan JY, Han JY. Chinese herbal remedies affecting thrombosis and hemostasis: A review. World J Tradit Chin Med 2015;1:38-49
|How to cite this URL:|
Li Q, Fan JY, Han JY. Chinese herbal remedies affecting thrombosis and hemostasis: A review. World J Tradit Chin Med [serial online] 2015 [cited 2022 Oct 3];1:38-49. Available from: https://www.wjtcm.net/text.asp?2015/1/2/38/295625
| 1. Introduction|| |
Acute coronary syndrome, stroke and other ischemic events remain a challenge for human health worldwide. Although the incidence of these cardiovascular diseases has decreased in industrialized countries, but is increasing in developing nations. These cardiovascular disorders stem from acute atherothrombotic events. Arterial thrombosis is a pathological process in which the hemostatic system is overly active causing development of platelet aggregates that abate normal blood circulation in coronary, cerebral or peripheral arteries. Obstruction of the blood circulation in these vessels may lead to myocardial infarction, ischemic stroke or limb gangrene.
Thrombosis occurs in four well-defined steps: endothelial activation, platelet tethering and rolling, platelet activation and firm adhesion, in which platelet-endothelium interactions play a critical role. Under normal conditions, platelets circulate in a quiescent state, and do not interact with the endothelial cells that cover the vascular wall. The inflammation resulting from mechanical injury, chemical agents or pathological conditions leads to the exposure of the subendothelial extracellular matrix which provokes the adhesion and subsequent activation of platelets, thereby initiating thrombosis. The activated platelets and endothelial cells release a range of prothrombotic substances near the injured area that favor the recruitment of more platelets to form a stable hemostatic plug. This platelet plug is then stabilized via a fibrin network, forming the final product of the coagulation cascade. Importantly, thrombus formation may occur at an unstable surface, and the hemostatic plug may embolize and occlude vessels downstream of its original location.
The widely used antithrombotic drugs at present include anticoagulant drugs (such as heparin and warfarin), anti-platelet drugs (aspirin) and fibrinolysis drugs (streptokinase), which decrease the risk of thrombus formation and are relatively well tolerated by patients. However, the limited efficacy of these drugs in the setting of arterial thrombosis, their adverse side effects, cost-to-benefit issues and the drug resistance phenomenon substantiate the need for the development of new and more efficacious antithrombotic drugs.
The use of plants as remedies for various ailments has formed the basis of our modern medicinal sciences. According to the World 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. In recent years, with the development of the Chinese medicine pharmacology, many Chinese herbs and formulas, as well as active constituents have been reported to have not only effects on platelet aggregation and activation but also beneficial effects on vascular functions. Compared with currently used antithrombotic agents, herbal remedies exert antithrombotic effects via multiple pathways acting at multiple targets. This review will discuss recent advances in the research on the ameliorating effects of herbal remedies on thrombosis, with focus on their role in protection of vascular endothelial cells and inhibiting platelet activation.
| 2. Effect of Herbs on Vascular Endothelial Cells|| |
The endothelium plays a crucial role in maintaining hemostatic balance. Under physiological conditions, endothelial cells prevent thrombosis through inhibition of platelet aggregation and blood coagulation, as well as through the activation of fibrinolysis by tissue plasminogen activator. Endothelial cells can be activated by a diversity of conditions, such as hypertension, hypercholesterolemia, atherosclerosis, hypoxia and chronic heart failure, exogenous or endogenous substances including lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-a), Interleukin (IL)-1 and viral infections,,. Activated endothelial cells express adhesion molecules that promote platelet and leukocyte adhesion to the endothelium, releasing cytokines and procoagulant factors that assist in thrombosis. Obviously, agent that acts at any of the factors may be expected to modulate thrombosis. Increasing Chinese herbs or their active compounds have revealed potential to interfere in thrombosis by acting at endothelial cells via different mechanisms.
2.1 Effect of herbs on adhesion molecules expression in vascular endothelium
Pathological conditions such as inflammation might not compromise the integrity of the vessel, but can damage and activate the vascular endothelial cells. Activated endothelial cells express many adhesion proteins such as von Willebrand factor (vWF), P- and E-selectins, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Endothelial vWF interacts with platelet GPIb, while endothelial P- and E-selectins interacts with platelet P-selectin glycoprotein ligand-1. ICAM-1 can bind fibrinogen, which accumulates on the endothelial cell surface as deposits and mediates αIIbβ3-dependent platelet adhesion. The close attachment to the damaged area activates platelet outside-in intracellular signals that promote thrombus formation. Many Chinese herbs and active compounds have been reported to inhibit stress-induced expression of adhesion molecules on vascular endothelial cells. Curcumin and Morus alba extract, Flos lonicerae extracts and chlorogenic acid were reported to inhibit significantly P-selectin expression induced by inflammation in endothelial cells. Acacetin was reported to inhibit the expression of E-selectin induced by TNF-a in part by regulating the p38 mitogen activated protein kinase (MAPK) signaling pathway and the nuclear transcription factor-kappa B (NF-κB). Evidence showed that caffeic acid, licorice isoliquiritigenin, Pine bark extract enzogenol, plumericin are able to abolish TNF-a-induced expression of VCAM-1, E-selectin and/or ICAM-1 in endothelial cells by inhibiting NF-αB activation. In addition, Dao-Tan decoction, Ginkgo biloba extract, Grape seed proanthocyanidin extracts,, Toona sinensis extract and gallic acid, Panax notoginseng, Platycodon grandiflorum, astragaloside IV, magnolol, paeonol, phloretin, protocatechuic aldehyde, salvianolic acid B were reported to prevent TNF-α induced up-regulation of VCAM-1, ICAM-1, and E-selectin in endothelial cells by blocking MAPK and/or NF-κB pathway.
2.2 Effect of herbs on antithrombotic factors of endothelium
Endothelial cells are hermetically bound together by tight junctions to prevent extracellular matrix exposure. They are also equipped with a negatively charged glycocalyx on their apical surface that repel circulating platelets and display antithrombotic properties. The most important inhibitors of platelet activation generated by endothelial cells are nitric oxide (NO) and prostacyclin (PGI2). NO and PGI2 are constitutively synthesized by non-activated endothelial cells, and their production is elevated by mechanical stimuli such as shear stress and cyclic stretch. These substances inhibit the activation of circulating platelets by stimulation of inhibitory cyclic guanosine monophosphate (cGMP) - and cyclic adenosine monophosphate (cAMP) - dependent pathways inside these cells. Research has found that saponins derived from the roots of Platycodon grandiflorum stimulate eNOS phosphorylation and NO production in human endothelial cells via activation of phosphoinositide 3-kinases (PI3K) /Akt, p38/MAPK, adenosine monophosphate activated protein kinase (AMPK), and calcium/calmodulin-dependent protein kinase II (CaMK II). Active compounds from Chinese herbal medicines such as andrographolide, aristolochic acid, crocetin, cyclovirobuxine D, resveratrol, sesamol, were reported to enhance NO release from endothelial cells or decrease inactivation of NO, exhibiting superior antithrombotic effect. Honokiol is a bioactive compound extracted from Magnolia officinalis. Research shows that it inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin, and its effect on PGI2 generation attributes to up-regulation of prostacyclin synthase expression.
2.3 Effect of herbs on fibrinolysis and anticoagulation of endothelium
Thrombosis and fibrinolysis are kept in balance in physiological condition by thrombotic and fibrinolytic proteins. The proteins involved in this balance include thrombomodulin, plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (t-PA). Thrombomodulin is a membrane-anchored glycoprotein, which functions in anticoagulation by association with thrombin. The resulted complex can effectively activate protein C, catalyzing the proteolytic inactivation of blood coagulation factors Va and VIIIa, which in turn lead to the down-regulation of the blood coagulation cascade. Studies revealed that the anticoagulant effect of the thrombin/thrombomodulin activated protein C is impaired in parallel with the impairment of endothelial functions. The improvement of the anticoagulant mechanism may reduce the risk of cardiovascular events. Endothelial cells constitutively release t-PA to the blood stream, which, by binding to fibrin deposits, activates the transformation of plasminogen into plasmin by proteolytic cleavage. The protease plasmin subsequently catalyzes the degradation of fibrin fibrils and disassembles the fibrin network. PAI-1 is the primary inhibitor of t-PA, which, together with t-PA, constitutes the major mediators for balancing the fibrinolytic system in vivo. Coronary heart disease and deep-vein thrombosis were reported as vascular disorders with increased PAI or decreased t-PA activity. Research shows that salvianolic acid B can increase the fibrinolytic and anticoagulant potential of endothelial cells by up-regulating the expression of t-PA and thrombomodulin and down-regulating the expression of PAI-1. The same effects have been reported for astragaloside IV, baicalin, icariin, oroxylin A and withaferin A. He et al. reported that Xiang-Qi-Tang, a Chinese herbal formula containing Cyperus rotundus, Astragalus membranaceus and Andrographis paniculata with alpha-Cyperone (CYP), astragaloside IV and andrographolide as the major active components, inhibited the expression of inflammatory and coagulant mediators via MAPKs and NF-κB signaling pathways in rat cardiac microvascular endothelial cells.
In addition, membrane-bound tissue factor (TF) expressed on vascular endothelial cells acts as a receptor for activated factor VII (VIIa). The TF/VIIa complex triggers the coagulation cascade and the formation of activated factor X (Xa), ultimately resulting in thrombin formation, which in turn cleaves protease-activated receptors on the platelet surface, boosting platelet activation and clot formation. In this regard, Chinese herbs display beneficial role as well, and a number of Chinese medicine formula, herbs and their active compounds were found to have inhibitory effect on TF expression and activity, such as Xiang-Qi-Tang, Polygonatum odoratum, a-linolenic acid, berberine, Holothurian glycosaminoglycan, guggulsterone, ligus- trazine, oleanolic acid.
| 3. Effect of Herbs on Platelet|| |
Platelets are blood cells specialized in thrombosis and hemostasis in mammals. When vascular wall is injured and extracellular cell matrix (ECM) exposed, platelets will bind to vWF and collagen via GPIb-IX–V and GPVI, respectively, which are responsible for the initial adhesion and activation of platelets. Platelet activation involving GPIb-IX–V or GPVI leads to secretion of platelet agonists, such as ADP, which functions via the G protein-coupled receptors, P2 and P2Y, to reinforce αIIbβ3-dependent platelet aggregation and thrombosis. Essentially the same events occur in the thrombotic diseases such as heart attack and stroke. Identification of the factors involved in platelet activation and clarification of the relevant mechanisms lead to the development of antiplatelet agents that results in a decline of the death rates of heart disease and stroke by about 25%. Commonly used oral antiplatelet drugs include cyclooxygenase inhibitor aspirin, the glycoprotein IIb/IIIa inhibitor ReoPro, and the P2Y12 inhibitor clopidogrel, among others. However, the limited efficiency and adverse side effects of these antiplatelet drugs make it appeal to develop novel strategy to combat thrombotic disease. Increasing evidence suggests Chinese herbs as a potential resource for this purpose. A number of herbs used in traditional Chinese medicine have been reported to inhibit platelet activation with different mechanisms.
3.1. Inhibition of Platelet Aggregation
Platelet aggregation, a process of the clumping together of platelets in the blood, plays a key role in the hemostasia and pathogenesis of atherothrombosis. The presence of platelet agonists on the injured vascular wall or in blood serum induces platelet activation through stimulation of their plasma membrane receptors. Platelet activation comprises reorganization of the cytoskeleton and shape change, activation of Ca2+ - dependent and independent signaling pathways and activation of adhesion proteins exposed on their surface, increasing their adhesion among platelets and between platelet and ECM, leading to the formation of platelet aggregates. The triggers of platelet aggregation may be either a chemical agent such as ADP, collagen, thrombin, arachidonic acid and platelet activating factor (PAF), or shear stress. Platelet aggregation rate is used as a marker for evaluation of antiplatelet efficacy of a regime. Studies show that a wide range of Chinese herb and formulas can reduce the aggregation rate in patients or animal models with thromboembolic diseases. The Chinese medicine formulas that have been reported to exhibit potential of antiplatelet activation include Buyang Huanwu Decoction, Dan Shen Di Wan, Dang-Gui-Shao-Yao-San, , Jia-Wei-Xiao-Yao-San, SiWu decoction, , Xiao-Chai-Hu-Tang, Xue-Fu-Zhu-Yu-Tang, Mailuoning injection, Anemarrhena asphodeloides, Atractylodis Lanceae Rhizoma and Poria, Artemisia princeps Pampanini, Cyperus rotundus, Hippophae Rhamnoides L, Ilex pubescens, Ocimum basilicum L, Panax notoginseng, Persicae Semen, and Carthami Flos, Trigonella foenumgraecum, Umbilicaria esculenta, Usnea longissima and Veratrum patulum L. Of notice, most of these formulas or herbs have long been used as treatment of diseases that are related to disordered platelet function. A number of active components from herbs show activity to inhibit the platelet aggregation as well, such as brazilin, curdione, diosgenin, hydroxysafflor yellow A, marchantinquinone, morusinol, neferine, obovatol, paeoniflorin and senkyunolide I, protocatechuic aldehyde, protocatechuic acid, quercetin and 3′,4′-dihydroxyflavonol, salvianolic acids, , tetramethylpyrazine and salvianolic acid B, timosaponin B-II and Z-ligustilide.
3.2. Inhibition of platelet granule secretion
Prothrombotic and antithrombotic factors stored in a-granule and dense granule of platelet are released in response to activation including P-selectin (CD62p), glycoprotein (GP) IIbIIIa, CD40 ligand (CD40L), platelet factor 4 (PF-4), β-thromboglobulin (β-TG), and Ca2+. Controlling platelet granule secretion is considered an effective strategy to dampen thrombosis and prevent atherosclerosis.
P-selectin is a transmembrane protein that resides within the a-granule membrane of unstimulated platelets. Upon stimulation, P-selectin is phosphorylated and translocated to the plasma membrane, which is generally applied as a gold marker of platelet activation, and used as an indication of effectiveness of a Chinese herb or its active compound in antiplatelet. By evaluation of the membrane expression of P-selectin, the following preparations have been revealed to have antiplatelet activity in vivo and/or in vitro: Quyu Xiaoban capsules, salvianolate, 5-caffeoylquinic acid and caffeic acid, anthocyanins, delphinidin-3-glucoside, resveratrol, salicylic acid, p-coumaric acid, ferulic acid, 4-hydroxyphenylpropionyl glycine, 5-methoxy-salicylic acid, and catechol.
As a member of the tumor necrosis factor-a family, CD40L has been identified as a proinflammatory mediator and risk factor for cardiovascular events on activated platelets. It can bind to and activate platelet αIIbβ3 in thrombosis. It is also able to activate endothelial cells. Soluble CD40L (sCD40L) is generated by shedding of the surface-bound CD40L. High level of sCD40L significantly increases platelet activation and aggregation, while blockade of this pathway with anti-CD40L antibodies can prevent or delay atheroinflammation progression. Researchers have found that Xinfeng capsules, Allium macrostemon Bunge, parthenolide, delphinidin-3-glucoside and guanosine from Solanum lycopersicum can significantly inhibit the expression of CD40L on the membrane of activated platelets or reduce the levels of sCD40L to dampen undesirable platelet activation.
3.2.3 PF-4 and β-TG
PF-4 and β-TG are platelet a-granule proteins, the high plasma levels of which are the specific indicators of platelet activation and secretion and are commonly present in thromboembolic disease and prethrombotic state. PF-4 enhances the metabolism of membrane phospholipid and arachidonic acid to produce thromboxane (TXA2). Also, PF-4 can promote precipitation and polymerization of fibrin monomer thus accelerate platelet aggregation. β-TG has been reported to inhibit PGI2 production by endothelial cells and enhance the aggregation of platelet. Research has found that QiShen YiQi Dropping Pill and naringin can reduce the p-TG or PF-4 concentration obviously to inhibit platelet aggregation.in hyperlipidemic rabbits.
A central event in platelet activation is the increase of its cytoplasmic Ca2+ concentration, which acts as an integrator of all signaling pathways triggered by the different platelet agonist receptors.
Studies have indicated that some Chinese herbs play a role as calcium channel antagonists and thereby inhibit platelet aggregation and activation, including Salvia Miltiorrhiza, Bulnesia sarmienti, Phellinus baumii, Pistacia chinensis, and Viscum Coloratum, and some active constituents of herbs such as 15,16-dihydrotanshinone I, andrographolide, aristolochic acid, cordycepin, curdione, epigallocatechin gallate, ginsenoside-Rp1, hydroxychavicol, marchantinquinone, naringin, resveratrol, salvianolic acid B, sanguinarine, and sesamol.
3.3. Effect on platelet arachidonic acid metabolism
Both TXA2 and PGI2 are the metabolites of arachidonic acid. TXA2 is produced by platelets as a potent vasoconstrictor, while PGI2 is generated in vascular endothelium with a function of vasodilator. TXA2 is synthesized and released by platelet microsome and quickly degrades to the TXB2. TXA2 promotes the release of Ca2+ in density tube system to make dense bodies constrict and release adenosine diphosphate glucose pyrophospheralase (ADP) and 5-hydroxytryptamine (5-HT), which result in platelet aggregation. Whereas, PGI2 inhibits platelet aggregation by virtue of stimulation of platelet adenyl cyclase. A balance between formation and release of PGI2 and TXA2 in circulation is of utmost importance for the control of intra-arterial thrombi formation and plays a role in the pathogenesis of atherosclerosis. Study shows that DanQi pill can down-regulate the TXB2 and up-regulate the PGI2 in diverse way, suggesting its potential as an antithrombotic therapy by improving the balance of TXA2/PGI2. Similar results have been found for the following herb and active components: alditols and monosaccharides extracted from sorghum vinegar, aristolochic acid, brazilin, hesperetin, phloroglucinol, Pistacia chinensis, Salix matsudana.
3.4. Effect on the signal transduction in platelet activation
Platelet activation has long been recognized as critical for the formation of haemostatic plugs and thrombosis. Over the past decade, using gene-knockout studies and multiple receptor antagonists, the details of the process of platelet activation have become much clearer. It is known that platelet activation requires agonist induction. Because most agonists function synergistically in platelet aggregation, the signaling pathway of platelet activation is complicated. For example, many platelet agonists bind more than one receptor (e.g. von Willebrand factor binds both GPIb and αIIbβ3, collagen binds to GPVI and α2β1, thrombin interacts with protease-activated receptors and GPIb, and ADP binds to at least two ADP receptors on platelets). In addition, activated platelets themselves rapidly secrete additional agonists (e.g. TXA2, ADP, serotonin and ATP), which act as positive feedback mediators that amplify the initial signals to ensure the rapid activation and recruitment of platelets into a growing thrombus. In terms of the signaling pathways involved in platelet activation, the possible antiplatelet targets of Chinese herbs involve (i) agonist receptors; (ii) cAMP/cGMP; and (iii) enzymatic cascades.
3.4.1 Receptor antagonists
Upon agonist stimulation, specific membrane receptor of platelet undergoes conformational change to activate the key enzymes, which produce or release the signal molecules leading to platelet adhesion, aggregation, and ultimately thrombosis. Thus, application of receptor antagonists is potentially a strategy to prevent platelet aggregation. To this end, several TXA2 receptor antagonists have been shown feasibility in the treatment of cardiovascular diseases. Recent reports suggest that antagonists of TXA2 receptors may be able to restrict vascular inflammation in atherosclerotic vessels. Studies have found that active constituent of Chinese herb, such as carnosol and piperlongumine, can inhibit rabbit platelet activation by antagonizing TXA2 receptor.
ADP induces integrin activation and platelet aggregation through its receptors P2Y1 and P2Y12. P2Y12 plays a critical role in platelet activation and thrombosis. Research showed that SalB can inhibit human platelet activation by inhibiting phosphodiesterase and antagonizing P2Y12 receptor. Other study indicated that SalB can inhibit rat platelet adhesion to immobilized collagen by interfering with the collagen receptor α2β1, suggesting the beneficial role of SalB in thrombosis is multifaceted.
Platelets also express chemokine receptors such as chemotaxis growth factor receptor – 4 (CXCR4), stromal-derived factor-1/chemokine CXCL 12 (CXCL12), chemokine receptor (CCR)-4, CCR1 and CCR2 on their cell surface, which mediate weak platelet responses. Research shows that tetramethylpyrazine significantly down-regulates the expression of CXCR4 in platelets and inhibits rat platelet aggregation.
3.4.2 Regulation of GPIIb/IIIa
The GPIIb/IIIa complex, a member of integrin family, is a heterodimeric adhesive protein receptor, located on the surface of resting platelets. Platelet activation induces a calcium-dependent conformational change in GPIIb/IIIa exposing a ligand binding site. The binding of fibrinogen to the activated GPIIb/IIIa receptor is required for platelet aggregation. Procaspase activating compound 1 (PAC-1) is a monoclonal IgM specific for the recognition site within GPIIb/IIIa on activated platelets. The detection of PAC-1 is used as a sensitive measurement of platelet activation.
Salvia miltiorrhiza (SM) has been applied for thousands of years in China and some other Asian countries to treat atherothrombotic diseases. Research shows that Salviaolate, an aqueous extract from SM consisting of three ingredients purified from SM, can reduce ADP-induced PAC-1 binding and P-selectin expression on platelets in patients with acute coronary syndrome. Other studies found that spatholobus suberectus, 2, 3, 5, 4′-tetrahydroxystilbene-2-O-β-D-glucoside, a water-soluble component of the rhizome extract from polygonum multiflorum, phloretin, quercetin and 3′,4′-dihydroxyflavonol can diminish agonist-stimulated expression of the activated form of the GPIIb/IIIa complex, which provide experimental evidences that these compounds improve blood flow following arterial injury in part by attenuating platelet granule exocytosis.
3.4.3 Regulation of cAMP/cGMP
cAMP and cGMP play a pivotal role in platelet regulation. cAMP is synthesized by adenylyl cyclase. Platelet activators, such as ADP and thrombin, block adenylyl cyclase function through inhibitory Ga-i proteins, resulting in a drop in cAMP levels during platelet activation. cGMP production in platelets depends on a single enzyme, the soluble NO-sensitive guanylyl cyclase. Endothelial release of NO is linked to cGMP-dependent platelet inhibition. cAMP elevation and/ or cGMP elevation have shown clinical benefit as platelet inhibitors. Recently, a group of Chinese herbs or compounds have been shown to reduce thrombus formation in animal models by modulating cAMP/cGMP metabolism, including QiShen YiQi Dropping Pill, Pistacia chinensis, 8-Prenylnaringenin, cordycepin, curdione, ent-16β,17-dihydroxy-kauran-19-oic acid, hydroxysafflor yellow A, ginsenoside-Rp1, salvianolic acid A, sanguinarine, sesamol, and sulforaphane.
3.4.4 Inhibition of enzymatic cascades
The platelet signaling pathways are still not completely understood, and their exploration presents an important objective for basic cell biology as well as for the development of both new drugs and diagnosis methods in hemostasis disorders. Most of these G-protein-dependent phosphorylation pathways end in the activation of phospholipase C (PLC) β1-3 isoforms, while integrins and immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors mainly activate PLCγ2 isoforms. Another activation pathway involves phospholipase A2 (PLA2) that is induced by G protein coupled receptor (GPCRs). Activated PLA2 generates arachidonate following platelet activation, which is used by cycloxygenase (COX) enzyme as a substrate to generate TXA2 and to activate platelets further. Finally, PI3K-dependent signaling pathways have been reported to play an important role in platelet activation. PI3K can be activated by GPCRs, ITAM-containing receptors and integrins, which results in increased adhesive functions of integrins. In addition, the presence and activation of 3 members of the MAPK family, p38, extracellular stimuli-responsive kinase (ERK), and c-Jun NH2-terminal kinase (JNK) have been demonstrated in platelets.
In recent years, increasing study has been conducted to address the signaling pathway involved in the inhibitory effect of Chinese herb and formulas on platelet activation. For example, salvianolic acid A was reported to attenuate mouse arterial thrombus formation in vivo by inhibiting platelet activation via downregulating PI3K. Tanshinone IIA and ginsenoside Rg1 inhibit rat or human platelet activation via ERK signaling pathway,. The antiplatelet activities of arsenic trioxide, epigallocatechin gallate, hesperetin, Perganum harmala, and sulforaphane have been reported to be mediated by inhibiting PLCγ2 pathway. Bulnesia sarmienti, ginsenoside-Rp1, Phellinus baummii, phloroglucinol and Pistacia chinensis inhibit platelet activation, granule secretion, aggregation, and thrombus formation most likely by inhibition of P38, ERK2 or JNK1 phosphorylation.
Because an herb usually contains numerous active constituents, its antiplatelet and antithrombotic activity is commonly mediated by multiple mechanisms involving multiple pathways. Research shows that Andrographolide possesses a potent antiplatelet activity, the underlying mechanism involves the activation of the eNOS-NO/cyclic GMP pathway, resulting in the inhibition of the PI3K/Akt-p38 MAPK and PLCγ2-PKC cascades, thereby leading to inhibition of human platelet aggregation. Andrographolide may also increase cGMP/PKG activity, followed by inhibition of the p38 MAPK/(•)HO-NF-κB-ERK2 cascade in activated human platelets. Another study shows that antiplatelet activity of sesamol may involve activation of the cAMP-eNOS/NO-cGMP pathway, resulting in inhibition of the PLCγ2-PKC-p38 MAPK-TXA2 cascade, and, finally, inhibition of human platelet aggregation. Sesamol is also reported to activate cAMP-PKA signaling, followed by inhibition of the NF-κB-PLC-PKC cascade, thereby leading to inhibition of [Ca2+] i mobilization and human platelet aggregation. It has been reported that the inhibitory effects of aristolochic acid or resveratrol on human platelet activation possibly involve (i) inhibition of the p38MAPK-cytosolic phospholipase A2 arachidonic acid-TXA2-[Ca2+] i cascade and (ii) activation of NO/cyclic GMP, resulting in inhibition of phospholipase C and/or PKC activation.
Proteomics-based studies have in recent years shed considerable light on platelet activation mechanisms by identication of novel proteins involved in platelet signaling pathways. Studies have examined signal cascades in rat platelet after salvianolic acid B or notoginsengnosides treatment using deferential proteomics of platelet, contributing significantly towards understanding platelet regulation of Chinese herb and discovering potential therapeutic targets.
| 4. Effect of Herbs on Thrombosis In Vivo|| |
Although in vitro experiments proved successful in both identifying new receptors and pathways and developing potent and selective antithrombotic drugs, but cannot mimic the myriad hemodynamic and spatiotemporal cellular and molecular interactions that occur during the generation and propagation of thrombi in vivo. Animal models, with the availability of modern intravital imaging techniques, have opened new ways to identify both individual roles and the interplay of platelet proteins in complex in vivo settings. A large number of experimental models have been established to allow in vivo observation of thrombus formation. Thrombosis can be induced in large arteries or veins or in arterioles or venules of the microcirculation, often by damaging the vessel. The injury can be applied from the “outside” by puncture, through column laser injury, suture ligation, or the external application of ferric chloride. Injury can also come from the “inside” by systemic administration of inflammatory agents, such as LPS; by generating reactive oxygen species with photo-reactive dyes (Rose bengal, Evans blue, or fluorescein isothiocyanate -dextran); or by focused-laser delivered heat to the endothelium. Thrombosis can also be induced in arteriovenous shunts, catheter grafts, or vessels by infusion of platelet agonists,,. Many Chinese herbs and active compounds have been reported to inhibit thrombus formation in different thrombosis models. Spatholobus suberectus, Umbilicaria esculenta, Usnea longissima, cyclovirobuxine D, diosgenin extract from Dioscorea zingiberensis C.H. Wright, and neferine have been reported to attenuate thrombus formation in collagen-epinephrine-induced acute pulmonary thrombus mouse model or inferior vena cava ligation thrombosis rat model. Veratrum patulum L., crocetin, and honokiol were reported to prolong the thrombus occlusion time in electrical current-stimulated carotid thrombosis model in rats. Soshiho-tang[ ], epigallocatechin gallate[ ], baicalin, 3′,4′-dihydroxyflavonol and quercetin, delphinidin-3-glucoside, ginsenoside Rg1, morusinol , obovatol, protocatechuic acid, and withaferin A have been reported to reduce thrombus formation in FeCl3-induced carotid artery or mesenteric arterioles injury in mouse or rat. Hippophae Rhamnoides L, alpha-linolenic acid, gug-gulsterone, and salvianolic acid A can prolong arterial occlusion time in photochemical injury-induced arterial thrombosis model. Andrographolide, hydroxychavicol, resveratrol, sesamol, and sulforaphane exhibited marked antithrombotic effects in ADP-induced acute pulmonary thrombosis or fluorescein sodium-induced platelet thrombi in mesenteric microvessels of mice. Bulnesia sarmienti, Ocimum basilicum L., ent-16beta, 17-dihydroxy-kauran-19-oic acid, ginsenoside-Rp1, and Z-ligustilide, significantly reduced thrombus weight in a rat model of arterio-venous shunt.
Our research proved that Cardiotonic pills and its active ingredients 3,4-dihydroxy-phenyl lactic acid and salvianolic acid B can inhibit the formation of a thrombus in the rat mesentery induced by photochemical reaction. This function is related to their antioxidant potential and/or their protective effect against the expression of adhesion molecules in neutrophil and platelet, .
| 5. Summary|| |
The interplay between platelets and the vascular wall is a key episode during thrombosis and hemostasis, wherein the underlying molecular mechanisms orchestrate a complex cross talk between the two cell types. This crosstalk seeks to synchronize their prothrombotic responses by the exchange of chemical messages or factors that stimulate each other and promote thrombus formation. The antithrombotic mechanisms of the vascular system prevent spontaneous initiation of thrombosis under normal conditions. However, they are also active during thrombosis, and disturbances of normal endothelial function are implicated in the initiation and progression of atherothrombotic disease. Platelets are resting circulating cells that constantly enter in contact with these prothrombotic and antithrombotic factors present in the blood plasma, and integrate their signals. The balance of these signals will determine the prevailing platelet response and therefore, the initiation of thrombus formation. The detailed characterization of the prevailing mechanisms of thrombosis underlying certain vascular diseases will help to design effective antithrombotic therapies.
Recently, rapid progress has been made in the research of antiplatelet and antithrombotic therapy of Chinese herbs and formulas, suggesting Chinese herbs as a promising alternative option for protection and treatment of atherothrombotic diseases. However, there are still some problems in this field. Firstly, most of the experimental researches are conducted using either an in vivo or an in vitro model, while few studies using both. This limitation in experimental design brings about difficulty in explanation of the result as to the efficiency and mechanism. Secondly, many mechanistic studies focused on one or two constituents of a Chinese herb or formula, though it commonly contains several active compounds. It is well known that thrombosis is a complex, multifactor process, which involves blood cells, vascular endothelium, proteins of the ECM and soluble blood plasma factors. Thus, a systematic study on the anti-thrombotic mechanism of a Chinese herb and formula is preferable. Finally, the safety and efficacy of traditional herbs as anti-thrombotic agents need to be tested in large-scale, multi-center, randomized controlled trials.
| Acknowledgements|| |
The authors thank Professor De-An Guo for this valuable discussion.
| References|| |
Franco M, Cooper RS, Bilal U, Fuster V. Challenges and opportunities for cardiovascular disease prevention. Am J Med
2011, 124(2): 95-102, PMID: 21295188, DOI: 10.1016/j.amjmed.2010.08.015.
Berna-Erro A, Redondo PC, Lopez E, Albarran L, Rosado JA. Molecular interplay between platelets and the vascular wall in thrombosis and hemostasis. Curr Vasc Pharmacol
2013, 11(4): 409-430, PMID: 23905637, DOI: CVP-54231.
Cordier W, Steenkamp V. Herbal remedies affecting coagulation: a review. Pharmaceutical biology
2012, 50(4): 443-452, PMID: 22136282, DOI: 10.3109/13880209.2011.611145.
van Hinsbergh VW. Endothelium–role in regulation of coagulation and inflammation. Semin Immunopathol
2012, 34(1): 93-106, PMID: 21845431, PMCID: 3233666, DOI: 10.1007/s00281-011-0285-5.
Otsuka F, Finn AV, Yazdani SK, Nakano M, Kolodgie FD, Virmani R. The importance of the endothelium in atherothrombosis and coronary stenting. Nat Rev Cardiol
2012, 9(8): 439-453, PMID: 22614618, DOI: 10.1038/nrcardio.2012.64.
Wu KK, Thiagarajan P. Role of endothelium in thrombosis and hemostasis. Annu Rev Med
1996, 47: 315-331, PMID: 8712785, DOI: 10.1146/annurev.med.47.1.315.
Pirvulescu MM, Gan AM, Stan D, Simion V, Calin M, Butoi E, Tirgoviste CI, Manduteanu I. Curcumin and a Morus alba extract reduce pro-inflammatory effects of resistin in human endothelial cells. Phytotherapy research: PTR
2011, 25(12): 1737-1742, PMID: 21442673, DOI: 10.1002/ptr.3463.
Liao Y, Dong S, Kiyama R, Cai P, Liu L, Shen H. Flos lonicerae extracts and chlorogenic acid protect human umbilical vein endothelial cells from the toxic damage of perfluorooctane sulphonate. Inflammation
2013, 36(3): 767-779, PMID: 23392856, DOI: 10.1007/s10753-013- 9603-5.
Tanigawa N, Hagiwara M, Tada H, Komatsu T, Sugiura S, Kobayashi K, Kato Y, Ishida N, Nishida K, Ninomiya M, Koketsu M, Matsushita K. Acacetin inhibits expression of E-selectin on endothelial cells through regulation of the MAP kinase signaling pathway and activation of NF-kappaB. Immunopharmacology and immunotoxicology
2013, 35(4): 471-477, PMID: 23855486, DOI: 10.3109/08923973.2013.811596.
Moon MK, Lee YJ, Kim JS, Kang DG, Lee HS. Effect of caffeic acid on tumor necrosis factor-alpha-induced vascular inflammation in human umbilical vein endothelial cells. Biological & pharmaceutical bulletin
2009, 32(8): 1371-1377, PMID: 19652376.
Kwon HM, Choi YJ, Choi JS, Kang SW, Bae JY, Kang IJ, Jun JG, Lee SS, Lim SS, Kang YH. Blockade of cytokine-induced endothelial cell adhesion molecule expression by licorice isoliquiritigenin through NF-kappaB signal disruption. Experimental biology and medicine
2007, 232(2): 235-245, PMID: 17259331.
Kim DS, Kim MS, Kang SW, Sung HY, Kang YH. Pine bark extract enzogenol attenuated tumor necrosis factor-alpha-induced endothelial cell adhesion and monocyte transmigration. Journal of agricultural and food chemistry
2010, 58(11): 7088-7095, PMID: 20465310, DOI: 10.1021/jf1005287.
Fakhrudin N, Waltenberger B, Cabaravdic M, Atanasov AG, Malainer C, Schachner D, Heiss EH, Liu R, Noha SM, Grzywacz AM, Mihaly- Bison J, Awad EM, Schuster D, Breuss JM, Rollinger JM, Bochkov V, Stuppner H, Dirsch VM. Identification of plumericin as a potent new inhibitor of the NF-kappaB pathway with anti-inflammatory activity in vitro and in vivo. British journal of pharmacology
2014, 171(7): 1676-1686, PMID: 24329519, PMCID: 3966748, DOI: 10.1111/bph.12558.
Huang X, Wang F, Chen W, Li Z, Wang N, Chen Y, von Maltzan K. Dao-Tan decoction inhibits tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 expression by blocking JNK and p38 signaling pathways in human umbilical vein endothelial cells. Pharmaceutical biology
2012, 50(9): 1111-1117, PMID: 22762513, DOI: 10.3109/13880209.2012.658476.
Chen JW, Chen YH, Lin FY, Chen YL, Lin SJ. Ginkgo biloba extract inhibits tumor necrosis factor-alpha-induced reactive oxygen species generation, transcription factor activation, and cell adhesion molecule expression in human aortic endothelial cells. Arteriosclerosis, thrombosis, and vascular biology
2003, 23(9): 1559-1566, PMID: 12893683, DOI: 10.1161/01.ATV.0000089012.73180.63.
Zhang Y, Shi H, Wang W, Ke Z, Xu P, Zhong Z, Li X, Wang S. Antithrombotic effect of grape seed proanthocyanidins extract in a rat model of deep vein thrombosis. Journal of vascular surgery
2011, 53(3): 743-753, PMID: 21095090, DOI: 10.1016/j.jvs.2010.09.017.
Ma L, Gao HQ, Li BY, Ma YB, You BA, Zhang FL. Grape seed proanthocyanidin extracts inhibit vascular cell adhesion molecule expression induced by advanced glycation end products through activation of peroxisome proliferators-activated receptor gamma. Journal of cardiovascular pharmacology
2007, 49(5): 293-298, PMID: 17513948, DOI: 10.1097/FJC.0b013e31803c5616.
Yang HL, Chen SC, Lin KY, Wang MT, Chen YC, Huang HC, Cho HJ, Wang L, Kumar KJ, Hseu YC. Antioxidant activities of aqueous leaf extracts of Toona sinensis on free radical-induced endothelial cell damage. Journal of ethnopharmacology
2011, 137(1): 669-680, PMID: 21718778, DOI: 10.1016/j.jep.2011.06.017.
Wan JB, Lee SM, Wang JD, Wang N, He CW, Wang YT, Kang JX. Panax notoginseng reduces atherosclerotic lesions in ApoE-deficient mice and inhibits TNF-alpha-induced endothelial adhesion molecule expression and monocyte adhesion. Journal of agricultural and food chemistry
2009, 57(15): 6692-6697, PMID: 19722574, DOI: 10.1021/jf900529w.
Kim HG, Hien TT, Han EH, Chung YC, Jeong HG. Molecular mechanism of endothelial nitric-oxide synthase activation by Platycodon grandiflorum root-derived saponins. Toxicology letters
2010, 195 (2–3): 106-113, PMID: 20230881, DOI: 10.1016/j.toxlet.2010. 03.006.
Zhang WJ, Hufnagl P, Binder BR, Wojta J. Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-kappaB activation and adhesion molecule expression. Thrombosis and haemostasis
2003, 90 (5): 904-914, PMID: 14597987, DOI: 10.1267/THRO03050904.
Chen YH, Lin SJ, Chen JW, Ku HH, Chen YL. Magnolol attenuates VCAM-1 expression in vitro in TNF-alpha-treated human aortic endothelial cells and in vivo in the aorta of cholesterol-fed rabbits. British journal of pharmacology
2002, 135(1): 37-47, PMID: 11786478, PMCID: 1573120, DOI: 10.1038/sj.bjp.0704458.
Nizamutdinova IT, Oh HM, Min YN, Park SH, Lee MJ, Kim JS, Yean MH, Kang SS, Kim YS, Chang KC, Kim HJ. Paeonol suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking p38, ERK and nuclear factor-kappaB signaling pathways. International immunopharmacology
2007, 7(3): 343-350, PMID: 17276892, DOI: 10.1016/j.intimp.2006.11.004.
Stangl V, Lorenz M, Ludwig A, Grimbo N, Guether C, Sanad W, Ziemer S, Martus P, Baumann G, Stangl K. The flavonoid phloretin suppresses stimulated expression of endothelial adhesion molecules and reduces activation of human platelets. The Journal of nutrition
2005, 135(2): 172-178, PMID: 15671209.
Zhou Z, Liu Y, Miao AD, Wang SQ. Protocatechuic aldehyde suppresses TNF-alpha-induced ICAM-1 and VCAM-1 expression in human umbilical vein endothelial cells. European journal of pharmacology
2005, 513(1-2): 1-8, PMID: 15878704, DOI: 10.1016/j. ejphar.2005.01.059.
Chen YH, Lin SJ, Ku HH, Shiao MS, Lin FY, Chen JW, Chen YL. Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-alpha-treated human aortic endothelial cells. Journal of cellular biochemistry
2001, 82(3): 512-521, PMID: 11500927.
Egbrink MG, Van Gestel MA, Broeders MA, Tangelder GJ, Heemskerk JM, Reneman RS, Slaaf DW. Regulation of microvascular thromboembolism in vivo. Microcirculation
2005, 12(3): 287-300, PMID: 15814437, DOI: 10.1080/10739680590925628.
Smolenski A. Novel roles of cAMP/cGMP-dependent signaling in platelets. Journal of thrombosis and haemostasis: JTH
2012, 10(2): 167-176, PMID: 22136590, DOI: 10.1111/j.1538-7836.2011. 04576.x.
Lu WJ, Lee JJ, Chou DS, Jayakumar T, Fong TH, Hsiao G, Sheu JR. A novel role of andrographolide, an NF-kappa B inhibitor, on inhibition of platelet activation: the pivotal mechanisms of endothelial nitric oxide synthase/cyclic GMP. Journal of molecular medicine
2011, 89 (12): 1261-1273, PMID: 21822619, DOI: 10.1007/s00109-011- 0800-0.
Shen MY, Liu CL, Hsiao G, Liu CY, Lin KH, Chou DS, Sheu JR. Involvement of p38 MAPK phosphorylation and nitrate formation in aristolochic acid-mediated antiplatelet activity. Planta medica
2008, 74(10): 1240-1245, PMID: 18563667, DOI: 10.1055/s-2008- 1074560.
Higashino S, Sasaki Y, Giddings JC, Hyodo K, Fujimoto Sakata S, Matsuda K, Horikawa Y, Yamamoto J. Crocetin, a Carotenoid from Gardenia jasminoides Ellis, Protects against Hypertension and Cerebral Thrombogenesis in Stroke-prone Spontaneously Hypertensive Rats. Phytother Res
2014, 28(9):1315-9. doi: 10.1002/ptr.5130.
Hu D, Liu X, Wang Y, Chen S. Cyclovirobuxine D ameliorates acute myocardial ischemia by K(ATP) channel opening, nitric oxide release and anti-thrombosis. European journal of pharmacology
2007, 569 (1-2): 103-109, PMID: 17555743, DOI: 10.1016/j.ejphar.2007.04. 038.
Shen MY, Hsiao G, Liu CL, Fong TH, Lin KH, Chou DS, Sheu JR. Inhibitory mechanisms of resveratrol in platelet activation: pivotal roles of p38 MAPK and NO/cyclic GMP. British journal of haematology
2007, 139(3): 475-485, PMID: 17868048, DOI: 10.1111/j.1365-2141.2007.06788.x.
Chang CC, Lu WJ, Chiang CW, Jayakumar T, Ong ET, Hsiao G, Fong TH, Chou DS, Sheu JR. Potent antiplatelet activity of sesamol in an in vitro and in vivo model: pivotal roles of cyclic AMP and p38 mitogen-activated protein kinase. The Journal of nutritional biochemistry
2010, 21(12): 1214-1221, PMID: 20015631, DOI: 10.1016/j. jnutbio.2009.10.009.
Hu H, Zhang XX, Wang YY, Chen SZ. Honokiol inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin. Acta pharmacologica Sinica
2005, 26(9): 1063-1068, PMID: 16115372, DOI: 10.1111/j.1745-7254.2005.00164.x.
Zhang X, Chen S, Wang Y. Honokiol up-regulates prostacyclin synthease protein expression and inhibits endothelial cell apoptosis. European journal of pharmacology
2007, 554(1): 1-7, PMID: 17109844, DOI: 10.1016/j.ejphar.2006.09.065.
Shi CS, Huang HC, Wu HL, Kuo CH, Chang BI, Shiao MS, Shi GY. Salvianolic acid B modulates hemostasis properties of human umbilical vein endothelial cells. Thrombosis research
2007, 119(6): 769-775, PMID: 16844201, DOI: 10.1016/j.thromres.2006.06.008.
Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system. Journal of thrombosis and haemostasis: JTH
2009, 7(1): 4-13, PMID: 19017261, DOI: 10.1111/j.1538-7836. 2008.03220.x.
Myohanen H, Vaheri A. Regulation and interactions in the activation of cell-associated plasminogen. Cellular and molecular life sciences: CMLS
2004, 61(22): 2840-2858, PMID: 15558213, DOI: 10.1007/ s00018-004-4230-9.
Shen GX. Vascular cell-derived fibrinolytic regulators and athero-thrombotic vascular disorders (Review). International journal of molecular medicine
1998, 1(2): 399-408, PMID: 9852242.
Zhang WJ, Wojta J, Binder BR. Regulation of the fibrinolytic potential of cultured human umbilical vein endothelial cells: astragaloside IV downregulates plasminogen activator inhibitor-1 and upregulates tissue-type plasminogen activator expression. Journal of vascular research
1997, 34(4): 273-280, PMID: 9256087.
Lee W, Ku SK, Bae JS. Antiplatelet, anticoagulant, and profibrinolytic activities of baicalin. Archives of pharmacal research
2014, PMID: 24849036, DOI: 10.1007/s12272-014-0410-9.
Zhang WP, Bai XJ, Zheng XP, Xie XL, Yuan ZY. Icariin attenuates the enhanced prothrombotic state in atherosclerotic rabbits independently of its lipid-lowering effects. Planta medica
2013, 79(9): 731-736, PMID: 23700112, DOI: 10.1055/s-0032-1328551.
Ku SK, Lee IC, Bae JS. Antithrombotic activities of oroxylin A in vitro and in vivo. Archives of pharmacal research
2014, 37(5): 679-686, PMID: 23963976, DOI: 10.1007/s12272-013-0233-0.
Ku SK, Bae JS. Antiplatelet, anticoagulant, and profibrinolytic activities of withaferin A. Vascular pharmacology
2014, 60(3): 120-126, PMID: 24534482, DOI: 10.1016/j.vph.2014.01.009.
He CL, Yi PF, Fan QJ, Shen HQ, Jiang XL, Qin QQ, Song Z, Zhang C, Wu SC, Wei XB, Li YL, Fu BD. Xiang-Qi-Tang and its active components exhibit anti-inflammatory and anticoagulant properties by inhibiting MAPK and NF-kappaB signaling pathways in LPS-treated rat cardiac microvascular endothelial cells. Immunopharmacology and immunotoxicology
2013, 35(2): 215-224, PMID: 23171279, DOI: 10.3109/08923973.2012.744034.
Holy EW, Forestier M, Richter EK, Akhmedov A, Leiber F, Camici GG, Mocharla P, Luscher TF, Beer JH, Tanner FC. Dietary alpha-linolenic acid inhibits arterial thrombus formation, tissue factor expression, and platelet activation. Arteriosclerosis, thrombosis, and vascular biology
2011, 31(8): 1772-1780, PMID: 21571683, DOI: 10.1161/ ATVBAHA.111.226118.
Zhang H, Chen L, Kou JP, Zhu DN, Qi J, Yu BY. Steroidal sapogenins and glycosides from the fibrous roots of Polygonatum odoratum with inhibitory effect on tissue factor (TF) procoagulant activity. Steroids
2014, 89:1-10. doi: 10.1016/j.steroids.2014.07.002.
Gao MY, Chen L, Yang L, Yu X, Kou JP, Yu BY. Berberine inhibits LPS-induced TF procoagulant activity and expression through NF-kappaB/ p65, Akt and MAPK pathway in THP-1 cells. Pharmacological reports: PR
2014, 66(3): 480-484, PMID: 24905527, DOI: 10.1016/j. pharep.2013.12.004.
Zhao Y, Zhang D, Wang S, Tao L, Wang A, Chen W, Zhu Z, Zheng S, Gao X, Lu Y. Holothurian glycosaminoglycan inhibits metastasis and thrombosis via targeting of nuclear factor-kappaB/tissue factor/Factor Xa pathway in melanoma B16F10 cells. PloS one
2013, 8(2): e56557,PMID: 23437168, PMCID: 3578936, DOI: 10.1371/journal.pone. 0056557.
Gebhard C, Stampfli SF, Gebhard CE, Akhmedov A, Breitenstein A, Camici GG, Holy EW, LuscherTF, Tanner FC. Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis. Basic research in cardiology
2009, 104(3): 285-294, PMID: 18953480, DOI: 10.1007/s00395-008-0757-5.
Chen Z, Huo JR, Yang L, Zhu HY. Effect of ligustrazine on mice model of hepatic veno-occlusive disease induced by Gynura segetum. Journal of gastroenterology and hepatology
2011, 26(6): 1016-1021, PMID: 21251065, DOI: 10.1111/j.1440-1746.2011.06661.x.
Lee W, Yang EJ, Ku SK, Song KS, Bae JS. Anticoagulant activities of oleanolic acid via inhibition of tissue factor expressions. BMB reports
2012, 45(7): 390-395, PMID: 22831973.
Andrews RK, Berndt MC. Platelet physiology and thrombosis. Thrombosis research
2004, 114(5-6): 447-453, PMID: 15507277, DOI: 10.1016/j.thromres.2004.07.020.
Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Bmj
2002, 324(7329): 71-86, PMID: 11786451, PMCID: 64503.
Wang WR, Lin R, Zhang H, Lin QQ, Yang LN, Zhang KF, Ren F. The effects of Buyang Huanwu Decoction on hemorheological disorders and energy metabolism in rats with coronary heart disease. Journal of ethnopharmacology
2011, 137(1): 214-220, PMID: 21605653, DOI: 10.1016/j.jep.2011.05.008.
Zhao L, Gaudry L, Dunkley S, Brighton T, Guo ZX, Ye ZL, Luo RZ, Chesterman CN. Modulation of platelet and leucocyte function by a Chinese herbal formulation as compared with conventional antiplatelet agents. Platelets
2008, 19(1): 24-31, PMID: 18231935, DOI: 10.1080/09537100701286123.
Shen AY, Wang TS, Huang MH, Liao CH, Chen SJ, Lin CC. Antioxidant and antiplatelet effects of dang-gui-shao-yao-san on human blood cells. The American journal of Chinese medicine
2005, 33(5): 747-758, PMID: 16265987, DOI: 10.1142/S0192415X05 003351.
Nasu Y, Iwashita M, Saito M, Fushiya S, Nakahata N. Inhibitory effects of Atractylodis lanceae rhizoma and Poria on collagen- or thromboxane A2-induced aggregation in rabbit platelets. Biological & pharmaceutical bulletin
2009, 32(5): 856-860, PMID: 19420754.
Yasuda T, Takasawa A, Nakazawa T, Ueda J, Ohsawa K. Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu-To, a traditional Chinese medicine, to rats. The Journal of pharmacy and pharmacology
2003, 55(2): 239-244, PMID: 12631416, DOI: 10.1211/002235702531.
Zhu M, Tang Y, Duan JA, Guo J, Guo S, Su S, Shang E, Qian D, Ding A. Roles of paeoniflorin and senkyunolide I in SiWu decoction on antiplatelet and anticoagulation activities. Journal of separation science
2010, 33(21): 3335-3340, PMID: 20878657, DOI: 10.1002/ jssc.201000340.
Lee JJ, Kim T, Cho WK, Ma JY. Antithrombotic and antiplatelet activities of Soshiho-tang extract. BMC complementary and alternative medicine
2013, 13: 137, PMID: 23773779, PMCID: 3686589, DOI: 10.1186/1472-6882-13-137.
Huang Y, Jiang W, Xiao Y, Wang Y, Wang Y. Multiobjective Optimization on Antiplatelet Effects of Three Components Combination by Quantitative Composition-activity Relationship Modeling and Weighted-Sum Method. Chem Biol Drug Des
2014, 84(5):513-21. doi: 10.1111/cbdd.12338.
Yu L, Li Y, Fan H, Duan J, Zhu Q, Li S. Analysis of marker compounds with anti-platelet aggregation effects in Mailuoning injection using platelet binding assay combined with HPLC-DAD-ESI-MS and solid-phase extraction technique. Phytochemicalanalysis: PCA
2011, 22(1): 87-93, PMID: 20799275, DOI: 10.1002/pca.1260.
Kang LP, Zhang J, Cong Y, Li B, Xiong CQ, Zhao Y, Tan DW, Yu HS, Yu ZY, Cong YW, Liu C, Ma BP. Steroidal glycosides from the rhizomes of Anemarrhena asphodeloides and their antiplatelet aggregation activity. Planta medica
2012, 78(6): 611-616, PMID: 22307934, DOI: 10.1055/s-0031-1298223.
Ryu R, Jung UJ, Kim HJ, Lee W, Bae JS, Park YB, Choi MS. Anticoagulant and Antiplatelet Activities of Artemisia princeps Pampanini and Its Bioactive Components. Preventive nutrition and food science
2013, 18(3): 181-187, PMID: 24471130, PMCID: 3892488, DOI: 10.3746/pnf.2013.18.3.181.
Seo EJ, Lee DU, Kwak JH, Lee SM, Kim YS, Jung YS. Antiplatelet effects of Cyperus rotundus and its component (+)-nootkatone. Journal of ethnopharmacology
2011, 135(1): 48-54, PMID: 21354294, DOI: 10.1016/j.jep.2011.02.025.
Cheng J, Kondo K, Suzuki Y, Ikeda Y, Meng X, Umemura K. Inhibitory effects of total flavones of Hippophae Rhamnoides L on thrombosis in mouse femoral artery and in vitro platelet aggregation. Life sciences
2003, 72(20): 2263-2271, PMID: 12628446.
Jiang ZH, Wang JR, Li M, Liu ZQ, Chau KY, Zhao C, Liu L. Hemiterpene glucosides with anti-platelet aggregation activities from Ilex pubescens. Journal of natural products
2005, 68(3): 397-399, PMID: 15787443, DOI: 10.1021/np049735y.
Tohti I, Tursun M, Umar A, Turdi S, Imin H, Moore N. Aqueous extracts of Ocimum basilicum L. (sweet basil) decrease platelet aggregation induced by ADP and thrombin in vitro and rats arterio–venous shunt thrombosis in vivo. Thrombosis research
2006, 118(6): 733-739, PMID: 16469363, DOI: 10.1016/j.thromres.2005.12.011.
Lau AJ, Toh DF, Chua TK, Pang YK, Woo SO, Koh HL. Antiplatelet and anticoagulant effects of Panax notoginseng: comparison of raw and steamed Panax notoginseng with Panax ginseng and Panax quinquefolium. Journal of ethnopharmacology
2009, 125(3): 380-386, PMID: 19665534, DOI: 10.1016/j.jep.2009.07.038.
Yang NY, Liu L, Tao WW, Duan JA, Liu XH, Huang SP. Antithrombotic lipids from Semen Persicae. Natural product research
2011, 25(17): 1650-1656, PMID: 21899477, DOI: 10.1080/14786419.2011. 568942.
Liu L, Duan JA, Tang Y, Guo J, Yang N, Ma H, Shi X. Taoren-Honghua herb pair and its main components promoting blood circulation through influencing on hemorheology, plasma coagulation and platelet aggregation. Journal of ethnopharmacology
2012, 139(2): 381-387, PMID: 22123200, DOI: 10.1016/j.jep.2011.11.016.
Pang X, Cong Y, Yu HS, Kang LP, Feng B, Han BX, Zhao Y, Xiong CQ, Tan DW, Song W, Liu B, Cong YW, Ma BP. Spirostanol saponins derivated from the seeds of Trigonella foenum-graecum by beta-glucosidase hydrolysis and their inhibitory effects on rat platelet aggregation. Planta medica
2012, 78(3): 276-285, PMID: 22127545, DOI: 10.1055/s-0031-1280373.
Kim MS, Lee KA. Antithrombotic activity of methanolic extract of Umbilicaria esculenta. Journal of ethnopharmacology
2006, 105(3): 342-345, PMID: 16384677, DOI: 10.1016/j.jep.2005.11.011.
Lee KA, Kim MS. Antiplatelet and antithrombotic activities of methanol extract of Usnea longissima. Phytotherapy research: PTR
2005, 19(12): 1061-1064, PMID: 16372374, DOI: 10.1002/ptr.1791.
Song Q, Wang S, Zhao W. Total steroidal alkaloids from Veratrum patulum L. Inhibit platelet aggregation, thrombi formation and decrease bleeding time in rats. Journal of ethnopharmacology
2012, 141(1): 183-186, PMID: 22366682, DOI: 10.1016/j. jep.2012.02.017.
Lee GY, Chang TS, Lee KS, Khil LY, Kim D, Chung JH, Kim YC, Lee BH, Moon CH, Moon CK. Antiplatelet activity of BRX-018, (6aS,cis)-malonic acid 3-acetoxy-6a9-bis-(2-methoxycarbonyl-acetoxy)-6,6a,7,11b-tetrahydro-indeno[2,1-c. chromen-10-yl ester methylester. Thrombosis research
2005, 115(4): 309-318, PMID: 15668191, DOI: 10.1016/j.thromres.2004.09.018.
Xia Q, Wang X, Xu DJ, Chen XH, Chen FH. Inhibition of platelet aggregation by curdione from Curcuma wenyujin essential Oil. Thrombosis research
2012, 130(3): 409-414, PMID: 22560337, DOI: 10.1016/j.thromres.2012.04.005.
Gong G, Qin Y, Huang W. Anti-thrombosis effect of diosgenin extract from Dioscorea zingiberensis C.H. Wright in vitro and in vivo. Phytomedicine: international journal of phytotherapy and phytopharmacology
2011, 18(6): 458-463, PMID: 21036572, DOI: 10.1016/j. phymed.2010.08.015.
Wang C, Wang C, Ma C, Huang Q, Sun H, Zhang X, Bai X. Hydroxysafflor yellow A of Carthamus tinctorius attenuates lung injury of aged rats exposed to gasoline engine exhaust by down-regulating platelet activation. Phytomedicine: international journal of phytotherapy and phytopharmacology
2014, 21(3): 199-206, PMID: 24192212, DOI: 10.1016/j.phymed.2013.09.018.
Liao CH, Ko FN, Wu CL, Teng CM. Antiplatelet effect of marchan-tinquinone, isolated from Reboulia hemisphaerica, in rabbit washed platelets. The Journal of pharmacy and pharmacology
2000, 52(3): 353-359, PMID: 10757426.
Lee JJ, Yang H, Yoo YM, Hong SS, Lee D, Lee HJ, Lee HJ, Myung CS, Choi KC, Jeung EB. Morusinol extracted from Morus alba inhibits arterial thrombosis and modulates platelet activation for the treatment of cardiovascular disease. Journal of atherosclerosis and thrombosis
2012, 19(6): 516-522, PMID: 22472211.
Zhou YJ, Xiang JZ, Yuan H, Liu H, Tang Q, Hao HZ, Yin Z, Wang J, Ming ZY. Neferine exerts its antithrombotic effect by inhibiting platelet aggregation and promoting dissociation of platelet aggregates. Thrombosis research
2013, 132(2): 202-210, PMID: 23773522, DOI: 10.1016/j.thromres.2013.05.018.
Park ES, Lim Y, Lee SH, Kwon BM, Yoo HS, Hong JT, Yun YP. Antiplatelet activity of obovatol, a biphenolic component of Magnolia Obovata, in rat arterial thrombosis and rabbit platelet aggregation. Journal of atherosclerosis and thrombosis
2011, 18(8): 659-669, PMID: 21512279.
Moon CY, Ku CR, Cho YH, Lee EJ. Protocatechuic aldehyde inhibits migration and proliferation of vascular smooth muscle cells and intravascular thrombosis. Biochemical and biophysical research communications
2012, 423(1): 116-121, PMID: 22640742, DOI: 10.1016/j.bbrc.2012.05.092.
Kim K, Bae ON, Lim KM, Noh JY, Kang S, Chung KY, Chung JH. Novel antiplatelet activity of protocatechuic acid through the inhibition of high shear stress-induced platelet aggregation. The Journal of pharmacology and experimental therapeutics
2012, 343(3): 704-711, PMID: 22984226, DOI: 10.1124/jpet.112.198242.
Mosawy S, Jackson DE, Woodman OL, Linden MD. Treatment with quercetin and 3′,4′-dihydroxyflavonol inhibits platelet function and reduces thrombus formation in vivo. Journal of thrombosis and thrombolysis
2013, 36(1): 50-57, PMID: 23070586, DOI: 10.1007/ s11239-012-0827-2.
Tang MK, Ren DC, Zhang JT, Du GH. Effect of salvianolic acids from Radix Salviae miltiorrhizae on regional cerebral blood flow and platelet aggregation in rats. Phytomedicine: international journal of phytotherapy and phytopharmacology
2002, 9(5): 405-409, PMID: 12222659, DOI: 10.1078/09447110260571634.
Yao Y, Wu WY, Liu AH, Deng SS, Bi KS, Liu X, Guo DA. Interaction of salvianolic acids and notoginsengnosides in inhibition of ADP-induced platelet aggregation. The American journal of Chinese medicine
2008, 36(2): 313-328, PMID: 18457363, DOI: 10.1142/ S0192415X08005795.
Li M, Zhao C, Wong RN, Goto S, Wang Z, Liao F. Inhibition of shear-induced platelet aggregation in rat by tetramethylpyrazine and salvianolic acid B. Clinical hemorheology and microcirculation
2004, 31(2): 97-103, PMID: 15310944.
Lu WQ, Qiu Y, Li TJ, Tao X, Sun LN, Chen WS. Antiplatelet and antithrombotic activities of timosaponin B-II, an extract of Anemarrhena asphodeloides. Clinical and experimental pharmacology & physiology
2011, 38(7): 430-434, PMID: 21517935, DOI: 10.1111/ j.1440-1681.2011.05530.x.
Zhang L, Du JR, Wang J, Yu DK, Chen YS, He Y, Wang CY. Z-ligustilide extracted from Radix Angelica Sinensis decreased platelet aggregation induced by ADP ex vivo and arterio-venous shunt thrombosis in vivo in rats. Yakugaku zasshi: Journal of the Pharmaceutical Society of Japan
2009, 129(7): 855-859, PMID: 19571521.
Michelson AD, Furman MI. Laboratory markers of platelet activation and their clinical significance. Current opinion in hematology
1999, 6 (5): 342-348, PMID: 10468151.
Liu YF, Yu HM, Zhang C, Yang RX, Yan FF, Liu Y, Zhang Y, Zhao YX. Effects of Quyu Xiaoban capsules on clinical outcomes and platelet activation and aggregation in patients with unstable angina pectoris. Journal of alternative and complementary medicine
2007, 13(5): 571-576, PMID: 17604562, DOI: 10.1089/acm.2007.6226.
Liu L, Li J, Zhang Y, Zhang S, Ye J, Wen Z, Ding J, Kunapuli SP, Luo X, Ding Z. Salvianolic acid B inhibits platelets as a P2Y antagonist and PDE inhibitor: Evidence from clinic to laboratory. Thromb Res
2014, 134(4):866-76. doi: 10.1016/j.thromres.2014.07.019.
Park JB. 5-Caffeoylquinic acid and caffeic acid orally administered suppress P-selectin expression on mouse platelets. The Journal of nutritional biochemistry
2009, 20(10): 800-805, PMID: 18926684, DOI: 10.1016/j.jnutbio.2008.07.009.
Song F, Zhu Y, Shi Z, Tian J, Deng X, Ren J, Andrews MC, Ni H, Ling W, Yang Y. Plant food anthocyanins inhibit platelet granule secretion in hypercholesterolaemia: Involving the signalling pathway of PI3K-Akt. Thromb Haemost
2014, 112(5):981-91. doi: 10.1160/TH13- 12-1002.
Yang Y, Shi Z, Reheman A, Jin JW, Li C, Wang Y, Andrews MC, Chen P, Zhu G, Ling W, Ni H. Plant food delphinidin-3-glucoside significantly inhibits platelet activation and thrombosis: novel protective roles against cardiovascular diseases. PloS one
2012, 7(5): e37323, PMID: 22624015, PMCID: 3356278, DOI: 10.1371/journal. pone.0037323.
Yang YM, Wang XX, Chen JZ, Wang SJ, Hu H, Wang HQ. Resveratrol attenuates adenosine diphosphate-induced platelet activation by reducing protein kinase C activity. The American journal of Chinese medicine
2008, 36(3): 603-613, PMID: 18543392, DOI: 10.1142/S0192415X08006016.
Ostertag LM, O’Kennedy N, Horgan GW, Kroon PA, Duthie GG, de Roos B. In vitro anti-platelet effects of simple plant-derived phenolic compounds are only found at high, non-physiological concentrations. Molecular nutrition & food research
2011, 55(11): 1624-1636, PMID: 21898791, DOI: 10.1002/mnfr.201100135.
Rui-Kai Z, Jian L. Effects of xinfeng capsules on expression of platelet granule membrane protein 140 and platelet cluster of differentiation 40 ligand in peripheral blood of adjuvant arthritis rats. International journal of rheumatology
2012: 139696, PMID: 22611405, PMCID: 3352581, DOI: 10.1155/2012/139696.
Chen H, Ou W, Wang G, Wang N, Zhang L, Yao X. New steroidal glycosides isolated as CDL inhibitors of activated platelets. Molecules
2010, 15(7): 4589-4598, PMID: 20657379, DOI: 10.3390/ molecules15074589.
Sahler J, Bernard JJ, Spinelli SL, Blumberg N, Phipps RP. The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-kappaB inhibition. Thrombosis research
2011, 127(5): 426-434, PMID: 21272923, PMCID: 3081947, DOI: 10.1016/j.thromres.2010.12. 013.
Fuentes E, Alarcon M, Astudillo L, Valenzuela C, Gutierrez M, Palomo I. Protective mechanisms of guanosine from Solanum lycopersicum on agonist-induced platelet activation: role of sCD40L. Molecules
2013, 18(7): 8120-8135, PMID: 23846753, DOI: 10.3390/molecules18078120.
Wang Y, Wang J, Guo L, Gao X. Antiplatelet effects of qishen yiqi dropping pill in platelets aggregation in hyperlipidemic rabbits. Evidence-based complementary and alternative medicine: eCAM
2012, 2012: 205451, PMID: 22969824, PMCID: 3434420, DOI: 10.1155/2012/205451.
Xiao Y, Li LL, Wang YY, Guo JJ, Xu WP, Wang YY, Wang Y. Naringin administration inhibits platelet aggregation and release by reducing blood cholesterol levels and the cytosolic free calcium concentration in hyperlipidemic rabbits. Experimental and therapeutic medicine
2014, 8(3): 968-972, PMID: 25120631, PMCID: 4113534, DOI: 10.3892/etm.2014.1794.
Kamruzzaman SM, Endale M, Oh WJ, Park SC, Kim KS, Hong JH, Kwak YS, Yun BS, Rhee MH. Inhibitory effects of Bulnesia sarmienti aqueous extract on agonist-induced platelet activation and thrombus formation involves mitogen-activated protein kinases. Journal of ethnopharmacology
2010, 130(3): 614-620, PMID: 20558266, DOI: 10.1016/j.jep.2010.05.049.
Kamruzzaman SM, Endale M, Oh WJ, Park SC, Kim TH, Lee IK, Cho JY, Park HJ, Kim SK, Yun BS, Rhee MH. Antiplatelet activity of Phellinus baummii methanol extract is mediated by cyclic AMP elevation and inhibition of collagen-activated integrin-alpha(IIb) beta (3) and MAP kinase. Phytotherapy research: PTR
2011, 25(11): 1596-1603, PMID: 21394810, DOI: 10.1002/ptr.3450.
Park JY, Hong M, Jia Q, Lee YC, Yayeh T, Hyun E, Kwak DM, Cho JY, Rhee MH. Pistacia chinensis Methanolic Extract Attenuated MAPK and Akt Phosphorylations in ADP Stimulated Rat Platelets In Vitro. Evidence-based complementary and alternative medicine: eCAM
2012, 2012: 895729, PMID: 22899962, PMCID: 3413994, DOI: 10.1155/2012/895729.
Chu W, Qiao G, Bai Y, Pan Z, Li G, Piao X, Wu L, Lu Y, Yang B. Flavonoids from Chinese Viscum coloratum produce cytoprotective effects against ischemic myocardial injuries: inhibitory effect of flavonoids on PAF-induced Ca2+ overload. Phytotherapy research: PTR
2008, 22(1): 134-137, PMID: 17724771, DOI: 10.1002/ ptr.2267.
Park JW, Lee SH, Yang MK, Lee JJ, Song MJ, Ryu SY, Chung HJ, Won HS, Lee CS, Kwon SH, Yun YP, Choi WS, Shin HS. 15,16- dihydrotanshinone I, a major component from Salvia miltiorrhiza Bunge (Dansham), inhibits rabbit platelet aggregation by suppressing intracellular calcium mobilization. Archives of pharmacal research
2008, 31(1): 47-53, PMID: 18277607.
Cho HJ, Cho JY, Rhee MH, Park HJ. Cordycepin (3′-deoxyadenosine) inhibits human platelet aggregation in a cyclic AMP- and cyclic GMP-dependent manner. European journal of pharmacology
2007, 558(1-3): 43-51, PMID: 17229422, DOI: 10.1016/j.ejphar.2006.11. 073.
Jin YR, Im JH, Park ES, Cho MR, Han XH, Lee JJ, Lim Y, Kim TJ, Yun YP. Antiplatelet activity of epigallocatechin gallate is mediated by the inhibition of PLCgamma2 phosphorylation, elevation of PGD2 production, and maintaining calcium-ATPase activity. Journal of cardiovascular pharmacology
2008, 51(1): 45-54, PMID: 18209568, DOI: 10.1097/FJC.0b013e31815ab4b6.
Endale M, Lee WM, Kamruzzaman SM, Kim SD, Park JY, Park MH, Park TY, Park HJ, Cho JY, Rhee MH. Ginsenoside-Rp1 inhibits platelet activation and thrombus formation via impaired glycoprotein VI signalling pathway, tyrosine phosphorylation and MAPK activation. British journal of pharmacology
2012, 167(1): 109-127, PMID: 22471932, PMCID: 3448917, DOI: 10.1111/j.1476-5381. 2012.01967.x.
Chang MC, Uang BJ, Tsai CY, Wu HL, Lin BR, Lee CS, Chen YJ, Chang CH, Tsai YL, Kao CJ, Jeng JH. Hydroxychavicol, a novel betel leaf component, inhibits platelet aggregation by suppression of cyclooxygenase, thromboxane production and calcium mobilization. British journal of pharmacology
2007, 152(1): 73-82, PMID: 17641677, PMCID: 1978281, DOI: 10.1038/sj.bjp.0707367.
Ma C, Yao Y, Yue QX, Zhou XW, Yang PY, Wu WY, Guan SH, Jiang BH, Yang M, Liu X, Guo DA. Differential proteomic analysis of platelets suggested possible signal cascades network in platelets treated with salvianolic acid B. PloS one
2011, 6(2): e14692, PMID: 21379382, PMCID: 3040754, DOI: 10.1371/journal.pone.0014692.
Jeng JH, Wu HL, Lin BR, Lan WH, Chang HH, Ho YS, Lee PH, Wang YJ, Wang JS, Chen YJ, Chang MC. Antiplatelet effect of sanguinarine is correlated to calcium mobilization, thromboxane and cAMP production. Atherosclerosis
2007, 191(2): 250-258, PMID: 16797553, DOI: 10.1016/j.atherosclerosis.2006.05.023.
Chang CC, Lu WJ, Ong ET, Chiang CW, Lin SC, Huang SY, Sheu JR. A novel role of sesamol in inhibiting NF-kappaB-mediated signaling in platelet activation. Journal of biomedical science
2011, 18: 93, PMID: 22168157, PMCID: 3258208, DOI: 10.1186/1423-0127-18-93.
Wang Y, Li C, Liu Z, Shi T, Wang Q, Li D, Wu Y, Han J, Guo S, Tang B, Wang W. DanQi Pill protects against heart failure through the arachidonic acid metabolism pathway by attenuating different cyclooxygenases and leukotrienes B4. BMC complementary and alternative medicine
2014, 14: 67, PMID: 24555740, PMCID: 3933388, DOI: 10.1186/1472-6882-14-67.
Li J, Yu G, Fan J. Alditols and monosaccharides from sorghum vinegar can attenuate platelet aggregation by inhibiting cycloox-ygenase-1 and thromboxane-A2 synthase. Journal of ethnopharmacology
2014, 155(1): 285-292, PMID: 24877847, DOI: 10.1016/j. jep.2014.05.018.
Jin YR, Han XH, Zhang YH, Lee JJ, Lim Y, Chung JH, Yun YP. Antiplatelet activity of hesperetin, a bioflavonoid, is mainly mediated by inhibition of PLC-gamma2 phosphorylation and cyclooxygenase-1 activity. Atherosclerosis
2007, 194(1): 144-152, PMID: 17092506, DOI: 10.1016/j.atherosclerosis.2006.10.011.
Chang MC, Chang HH, Chan CP, Chou HY, Chang BE, Yeung SY, Wang TM, Jeng JH. Antiplatelet effect of phloroglucinol is related to inhibition of cyclooxygenase, reactive oxygen species, ERK/p38 signaling and thromboxane A2 production. Toxicology and applied pharmacology
2012, 263(3): 287-295, PMID: 22789837, DOI: 10.1016/j.taap.2012.06.021.
Zheng YN, Zhang J, Han LK, Sekiya K, Kimura Y, Okuda H. Effects of compounds in leaves of Salix matsudana on arachidonic acid metabolism. Yakugaku zasshi: Journal of the Pharmaceutical Society of Japan
2005, 125(12): 1005-1008, PMID: 16327246.
Lee JJ, Jin YR, Lim Y, Hong JT, Kim TJ, Chung JH, Yun YP. Antiplatelet activity of carnosol is mediated by the inhibition of TXA2 receptor and cytosolic calcium mobilization. Vascular pharmacology
2006, 45(3): 148-153, PMID: 16916624, DOI: 10.1016/j. vph.2006.04.003.
Iwashita M, Saito M, Yamaguchi Y, Takagaki R, Nakahata N. Inhibitory effect of ethanol extract of Piper longum L. on rabbit platelet aggregation through antagonizing thromboxane A2 receptor. Biological & pharmaceutical bulletin
2007, 30(7): 1221-1225, PMID: 17603157.
Iwashita M, Oka N, Ohkubo S, Saito M, Nakahata N. Piperlongumine, a constituent of Piper longum L., inhibits rabbit platelet aggregation as a thromboxane A(2) receptor antagonist. European journal of pharmacology
2007, 570(1-3): 38-42, PMID: 17618620, DOI: 10.1016/j.ejphar.2007.05.073.
Wu YP, Zhao XM, Pan SD, Guo de A, Wei R, Han JJ, Kainoh M, Xia ZL, de Groot PG, Lisman T. Salvianolic acid B inhibits platelet adhesion under conditions of flow by a mechanism involving the collagen receptor alpha2beta1. Thrombosis research
2008, 123(2): 298-305, PMID: 18625517, DOI: 10.1016/j.thromres.2008.05.020.
Cai X, Chen Z, Pan X, Xia L, Chen P, Yang Y, Hu H, Zhang J, Li K, Ge J, Yu K, Zhuang J. Inhibition of angiogenesis, fibrosis and thrombosis by tetramethylpyrazine: mechanisms contributing to the SDF-1/ CXCR4 axis. PloS one
2014, 9(2): e88176, PMID: 24505417 PMCID: 3914919 DOI: 10.1371/journal.pone.0088176.
Lee BJ, Jo IY, Bu Y, Park JW, Maeng S, Kang H, Jang W, Hwang DS, Lee W, Min K, Kim JI, Yoo HH, Lew JH. Antiplatelet effects of Spatholobus suberectus via inhibition of the glycoprotein IIb/IIIa receptor. Journal of ethnopharmacology
2011, 134(2): 460-467, PMID: 21211555, DOI: 10.1016/j.jep.2010.12.039.
Xiang K, Liu G, Zhou YJ, Hao HZ, Yin Z, He AD, Da XW, Xiang JZ, Wang JL, Ming ZY. 2,3,5,4′-tetrahydroxystilbene-2-O-beta-D-gluco- side (THSG) attenuates human platelet aggregation, secretion and spreading in vitro. Thrombosis research
2014, 133(2): 211-217, PMID: 24332167, DOI: 10.1016/j.thromres.2013.11.006.
Mosawy S, Jackson DE, Woodman OL, Linden MD. Inhibition of platelet-mediated arterial thrombosis and platelet granule exocytosis by 3′,4′-dihydroxyflavonol and quercetin. Platelets
2013, 24(8): 594-604, PMID: 23249183, DOI: 10.3109/09537104.2012. 749396.
Di Vito C, Bertoni A, Nalin M, Sampietro S, Zanfa M, Sinigaglia F. The phytoestrogen 8-prenylnaringenin inhibits agonist-dependent activation of human platelets. Biochimica et biophysica acta
2012, 1820(11): 1724-1733, PMID: 22766195, DOI: 10.1016/j.bbagen. 2012.06.018.
Wang JP, Xu HX, Wu YX, Ye YJ, Ruan JL, Xiong CM, Cai YL. Ent-16beta,17-dihydroxy-kauran-19-oic acid, a kaurane diterpene acid from Siegesbeckia pubescens, presents antiplatelet and antithrom-botic effects in rats. Phytomedicine: international journal of phytotherapy and phytopharmacology
2011, 18(10): 873-878, PMID: 21377851, DOI: 10.1016/j.phymed.2011.01.024.
Fan HY, Fu FH, Yang MY, Xu H, Zhang AH, Liu K. Antiplatelet and antithrombotic activities of salvianolic acid A. Thrombosis research
2010, 126(1): e17-22, PMID: 20451955, DOI: 10.1016/j. thromres.2010.04.006.
Jayakumar T, Chen WF, Lu WJ, Chou DS, Hsiao G, Hsu CY, Sheu JR, Hsieh CY. A novel antithrombotic effect of sulforaphane via activation of platelet adenylate cyclase: ex vivo and in vivo studies. The Journal of nutritional biochemistry
2013, 24(6): 1086-1095, PMID: 23246160, DOI: 10.1016/j.jnutbio.2012.08.007.
Huang ZS, Zeng CL, Zhu LJ, Jiang L, Li N, Hu H. Salvianolic acid A inhibits platelet activation and arterial thrombosis via inhibition of phosphoinositide 3-kinase. Journal of thrombosis and haemostasis: JTH
2010, 8(6): 1383-1393, PMID: 20345719, DOI: 10.1111/ j.1538-7836.2010.03859.x.
Maione F, De Feo V, Caiazzo E, De Martino L, Cicala C, Mascolo N. Tanshinone IIA, a major component of Salvia milthorriza Bunge, inhibits platelet activation via Erk-2 signaling pathway. J Ethnopharmacol
2014, 155(2):1236-42. doi: 10.1016/j.jep.2014.07.010.
Zhou Q, Jiang L, Xu C, Luo D, Zeng C, Liu P, Yue M, Liu Y, Hu X, Hu H. Ginsenoside Rg1 inhibits platelet activation and arterial thrombosis. Thrombosis research
2014, 133(1): 57-65, PMID: 24196231, DOI: 10.1016/j.thromres.2013.10.032.
Lin KH, Chang YF, Fan CY, Jayakumar T, Lee JJ, Chou DS, Hsiao G, Sheu JR. Arsenic trioxide-mediated antiplatelet activity: pivotal role of the phospholipase C gamma 2-protein kinase C-p38 MAPK cascade. Translational research: the journal of laboratory and clinical medicine
2010, 155(2): 97-108, PMID: 20129490, DOI: 10.1016/j. trsl.2009.08.005.
Im JH, Jin YR, Lee JJ, Yu JY, Han XH, Im SH, Hong JT, Yoo HS, Pyo MY, Yun YP. Antiplatelet activity of beta-carboline alkaloids from Perganum harmala: a possible mechanism through inhibiting PLCgamma2 phosphorylation. Vascular pharmacology
2009, 50(5-6): 147-152, PMID: 19073282, DOI: 10.1016/j.vph.2008.11.008.
Lu WJ, Lin KH, Hsu MJ, Chou DS, Hsiao G, Sheu JR. Suppression of NF-kappaB signaling by andrographolide with a novel mechanism in human platelets: regulatory roles of the p38 MAPK-hydroxyl radical- ERK2 cascade. Biochemical pharmacology
2012, 84(7): 914-924, PMID: 22771630, DOI: 10.1016/j.bcp.2012.06.030.
Yao Y, Wu WY, Guan SH, Jiang BH, Yang M, Chen XH, Bi KS, Liu X, Guo DA. Proteomic analysis of differential protein expression in rat platelets treated with notoginsengnosides. Phytomedicine: international journal of phytotherapy and phytopharmacology
2008, 15 (10): 800-807, PMID: 18706795, DOI: 10.1016/j.phymed.2008. 06.013.
Sachs UJ, Nieswandt B. In vivo thrombus formation in murine models. Circulation research
2007, 100(7): 979-991, PMID: 17431199, DOI: 10.1161/01.RES.0000261936.85776.5f.
Westrick RJ, Winn ME, Eitzman DT. Murine models of vascular thrombosis (Eitzman series). Arteriosclerosis, thrombosis, and vascular biology
2007, 27(10): 2079-2093, PMID: 17600224, DOI: 10.1161/ATVBAHA.107.142810.
Kretz CA, Vaezzadeh N, Gross PL. Tissue factor and thrombosis models. Arteriosclerosis, thrombosis, and vascular biology
2010, 30 (5): 900-908, PMID: 20393156, DOI: 10.1161/ATVBAHA.108. 177477.
Wang F, Liu YY, Liu LY, Guo J, Sun K, Wang CS, Fan JY, Han JY. Inhibition effect of cardiotonic pills on venous thrombosis induced in rat mesentery by photochemical reaction. Clinical hemorheology and microcirculation
2006, 34(1-2): 131-138, PMID: 16543628.
Wang F, Liu YY, Liu LY, Zeng QJ, Wang CS, Sun K, Yang JY, Guo J, Fan JY, Han JY. The attenuation effect of 3,4-dihydroxy-phenyl lactic acid and salvianolic acid B on venular thrombosis induced in rat mesentery by photochemical reaction. Clinical hemorheology and microcirculation
2009, 42(1): 7-18, PMID: 19363236, DOI: 10.32 33/CH-2009-1180.
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