Mechanism of agonist-induced platelet activation and research progress of anti-platelet drugs

ZHANG Qian; CHEN Cen; YANG Fengqing; XIA Zhining

doi:10.11665/j.issn.1000-5048.20140604

Journal of China Pharmaceutical University > 2014 > 45(6): 632-648. > DOI: 10.11665/j.issn.1000-5048.20140604

ZHANG Qian, CHEN Cen, YANG Fengqing, XIA Zhining. Mechanism of agonist-induced platelet activation and research progress of anti-platelet drugs[J]. Journal of China Pharmaceutical University, 2014, 45(6): 632-648. DOI: 10.11665/j.issn.1000-5048.20140604

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Mechanism of agonist-induced platelet activation and research progress of anti-platelet drugs

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Abstract

Abstract

Thrombin, collagen, platelet activating factor, arachidonic acid, adenosine diphosphate, adrenaline, serotonin and other platelet agonists can stimulate platelet to generate a series of complex signal transduction and then cause platelet physiological responses including deformation, granule release and aggregation etc. Although platelet activation and aggregation at sites of vascular injury is an essential step in coagulation process, excessive platelet accumulation leads to the formation of occlusive thrombi, which are responsible for acute ischemic events. Therefore, anti-platelet therapy is an important approach for the treatment of thrombotic diseases. Currently used anti-platelet drugs, which primarily act through receptors and/or signaling molecules in activation pathways, achieving their effects by inhibiting platelet receptors or blocking signal transmission. In this review, the targets of the above-mentioned platelet agonists and their specific activation mechanisms are introduced; receptor antagonists and other anti-platelet drugs are also summarized.
- platelet activation,
- agonists,
- receptors,
- anti-platelet drugs,
- thrombin,
- collagen,
- platelet activating factor,
- arachidonic acid,
- adenosine diphosphate

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References

[1]	Nurden AT.Platelets,inflammation and tissue regeneration[J].Thromb Haemost,2011,105(1):S13.
[2]	Michelson AD.Antiplatelet therapies for the treatment of cardiovascular disease[J].Nat Rev Drug Discov,2010,9(2):154-169.
[3]	Ferreiro JL,Angiolillo DJ.New directions in antiplatelet therapy[J].Circulation:Cardiovascular Int,2012,5(3):433-445.
[4]	Martin Quinn DF.Platelet Function(Assesement,Pragnosis and Treatment)[M].Beijing:Beijing Science Press,2008:3-6.
[5]	Licari LG,Kovacic JP.Thrombin physiology and pathophysiology[J].J Vet Emerg Crit Car,2009,19(1):11-22.
[6]	Coughlin SR.Protease-activated receptors in hemostasis,thrombosis and vascular biology[J].Thromb Haemost,2005,3(8):1 800-1 814.
[7]	Traynelis SF,Trejo J.Protease-activated receptor signaling:new roles and regulatory mechanisms[J].Curr Opin Hematol,2007,14(3):230-235.
[8]	Michelson AD. Platelets[M]. 3rd ed. British: Academic Press, 2013.
[9]	Covic L,Gresser AL,Kuliopulos A.Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets[J].J Biol Chem,2000,39(18):5 458-5 467.
[10]	Wu CC,Wu SY,Liao CY,et al.The roles and mechanisms of PAR4 and P₂Y₁₂/phosphatidylinositol 3-kinase pathway in maintaining thrombin-induced platelet aggregation[J].Br J Pharmacol,2010,161(3):643-658.
[11]	Gibbins JM.Platelet adhesion signalling and the regulation of thrombus formation[J].J Cell Sci,2004,117(16):3 415-3 425.
[12]	Jung SM,Moroi M.Platelet glycoprotein VI[J].Adv Exp Med Biol,2008,640:53-63.
[13]	Jarvis GE,Best D,Watson SP.Glycoprotein VI/Fc receptor gamma chain-independent tyrosine phosphorylation and activation of murine platelets by collagen[J].J Biol Chem,2004,383(3):581-588.
[14]	Nissinen L, Koivunen J, Kapyla J, et al. Novel α2β1 integrin inhibitors reveal that integrin binding to collagen under shear stress conditions does not require receptor preactivation[J].J Biol Chem,2012,287(53):44 694-44 702.
[15]	Cosemans JM,Iserbyt BF,Deckmyn H,et al.Multiple ways to switch platelet integrins on and off[J].Thromb Haemost,2008,6(8):1 253-1 261.
[16]	Nieswandt B,Watson SP.Platelet-collagen interaction:is GPVI the central receptor[J]?Blood,2003,102(2):449-461.
[17]	Brown SL,Jala VR,Raghuwanshi SK,et al.Activation and regulation of platelet-activating factor receptor:role of Gi and Gq in receptor-mediated chemotactic,cytotoxic and cross-regulatory signals[J].J Immunol,2006,177:3 242-3 249.
[18]	Zimmerman GA,McIntyre TM,Prescott SM,et al.The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis[J].Crit Care Med,2002,30(5):S294-S301.
[19]	Moharam BA,Jantan I,Jalil J.Inhibitory effects of phylligenin and quebrachitol isolated from mitrephora vulpina on platelet activating factor receptor binding and platelet aggregation[J].Molecules,2010,15(11):7 840-7 848.
[20]	McAdam B,Catella-Lawson F,Mardini I,et al.Systemic biosynthesis of prostacyclin by cyclooxygenase(COX)-2:the human pharmacology of a selective inhibitor of COX-2[J].Proc Natl Acad Sci,1999,96(1):272-277.
[21]	Cheng Y,Wang M,Yu Y,et al.Cyclooxygenases,microsomal prostaglandin E synthase-1,and cardiovascular function[J].J Clin Invest,2006,116(5):1 391-1 399.
[22]	Chen C,Yang TL.TXA₂/PGI₂ and cardiovascular disease[J].Prog Mod Biomed(现代科学研究进展),2008,8(11):2 166-2 168.
[23]	Walsh M-T,Foley JF,Kinsella BT.Investigation of the role of the carboxyl-terminal tails of the α and β isoforms of the human thromboxane A₂ receptor(TP)in mediating receptor:effector coupling[J].Biochim Biophys Acta,2000,1 496(2/3):164-182.
[24]	Manganello JM,Djellas Y,Borg C,et al.Cyclic AMP-dependent phosphorylation of thromboxane A₂ receptor-associated Gα13[J].J Biol Chem,1999,274(39):28 003-28 010.
[25]	Mahaut-Smith MP,Ennion SJ,Rolf MG,et al.ADP is not an agonist at P₂X₁ receptors:evidence for separate receptors stimulated by ATP and ADP on human platelets[J].Br J Pharmacol,2000,131(1):108-114.
[26]	Mangin P,Ohlmann P,Eckly A,et al.The P₂Y₁ receptor plays an essential role in the platelet shape change induced by collagen when TXA₂ formation is prevented[J].Thromb Haemost,2004,2(6):969-977.
[27]	Wang TT,Li K,Wei L.Role of vasodilator- stimulated phosphoprotein in the regulation of cytoskeletal[J].Prog Physiol Sci(生理科学进展),2006,37(1):27-30.
[28]	Mahaut-Smith M,Jones S,Evans R.The P₂X₁ receptor and platelet function[J].Purinerg Signal,2011,7(3):341-356.
[29]	Oury C,Toth-Zsamboki E,Vermylen J,et al.P₂X₁-mediated activation of extracellular signal-regulated kinase 2 contributes to platelet secretion and aggregation induced by collagen[J].Blood,2002,100(7):2 499-2 505.
[30]	Moerland M,Kemme M,Dijkmans A,et al.Modulation of vasoactivity and platelet aggregation by selective 5-HT receptor antagonism in humans[J].J Cardiovasc Pharmacol,2011,58(6):575-580.
[31]	Kaumann AJ,Levy FO.5-Hydroxytryptamine receptors in the human cardiovascular system[J].Pharmacol Ther,2006,111(3):674-706.
[32]	Bampalis V,Dwivedi S,Shai E,et al.Effect of 5-HT_2A receptor antagonists on human platelet activation in blood exposed to physiologic stimuli and atherosclerotic plaque[J].Thromb Haemost,2011,9(10):2 112-2 115.
[33]	Hikasa Y,Masuda K,Asakura Y,et al.Identification and characterization of platelet α2-adrenoceptors and imidazoline receptors in rats,rabbits,cats,dogs,cattle,and horses[J].Eur J Pharmacol,2013,720(1):363-375.
[34]	Hollopeter G,Jantzen H-M,Vincent D,et al.Identification of the platelet ADP receptor targeted by antithrombotic drugs[J].Nature,2001,409(6 817):202-207.
[35]	Bhatt DL,Stone GW,Mahaffey KW,et al.Effect of platelet inhibition with cangrelor during PCI on ischemic events[J].New Engl J Med,2013,368(14):1 303-1 313.
[36]	Lindholm D,Varenhorst C,Cannon CP,et al.Ticagrelor vs.clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization:results from the PLATO trial[J].Eur Heart J,2014,35(31):2 083-2 093.
[37]	Wang Y,Vincelette Y,Cunha V,et al.A novel P₂Y₁₂ adenosine diphosphate receptor antagonist that inhibits platelet aggregation and thrombus formation in rat and dog models[J].Thromb Haemost,2007,97(5):847-855.
[38]	Jacobson KA,Boeynaems JM.P₂Y nucleotide receptors:promise of therapeutic applications[J].Drug Discov Today,2010,15(13/14):570-578.
[39]	Johnson FL,Boyer JL,Leese PT,et al.Rapid and reversible modulation of platelet function in man by a novel P₂Y₁₂ ADP-receptor antagonist,INS50589[J].Platelets,2007,18(5):346-356.
[40]	Camaioni E, Boyer JL, Mohanram A, et al. Deoxyadenosine bisphosphate derivatives as potent antagonists at P₂Y₁ receptors[J].J Med Chem,1998,41(2):183-190.
[41]	Mahaut-Smith MP,Tolhurst G,Evans RJ.Emerging roles for P₂X₁ receptors in platelet activation[J].Platelets,2004,15(3):131-144.
[42]	Horner S,Menke K,Hildebrandt C,et al.The novel suramin analogue NF864 selectively blocks P₂X₁ receptors in human platelets with potency in the low nanomolar range[J].Naunyn Schmiedebergs Arch Pharmacol,2005,372(1):1-13.
[43]	Hass WK,Easton JD,Adams Jr,et al.A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients[J].New Engl J Med,1989,321(8):501-507.
[44]	Savi P,Pereillo J,Uzabiaga M,et al.Identification and biological activity of the active metabolite of clopidogrel[J].Thromb Haemost,2000,84(5):891-896.
[45]	Farid NA,Smith RL,Gillespie TA,et al.The disposition of prasugrel,a novel thienopyridine,in humans[J].Drug Metab Dispos,2007,35(7):1 096-1 104.
[46]	Fugate SE,Cudd LA.Cangrelor for treatment of coronary thrombosis[J].Ann Pharmacother,2006,40(5):925-930.
[47]	Husted S,Van Giezen J.Ticagrelor:the first reversibly binding oral P₂Y₁₂ receptor antagonist[J].Cardiovasc Ther,2009,27(4):259-274.
[48]	Humphries R,Tomlinson W,Ingall A,et al.FPL 66096:a novel,highly potent and selective antagonist at human platelet P₂T-purinoceptors[J].Brit J Pharmacol,1994,113(3):1 057-1 063.
[49]	Müller K,Geisler T,Gawaz M.Elinogrel,an orally and intravenously available ADP-receptor antagonist.How does elinogrel affect a personalized antiplatelet therapy[J]?Hamostaseologie,2011,32(3):191-194.
[50]	Scarborough RM,Laibelman AM,Clizbe LA,et al.Novel tricyclic benzothiazolo[2,3-c] thiadiazine antagonists of the platelet ADP receptor(P₂Y₁₂)[J].Bioorg Med Chem Lett,2001,11(14):1 805-1 808.
[51]	Houston D,Ohno M,Nicholas RA,et al.[32P] 2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate([32P] MRS2500),a novel radioligand for quantification of native P₂Y₁ receptors[J].Brit J Pharmacol,2006,147(5):459-467.
[52]	Kim HS,Ohno M,Xu B,et al.2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0] hexane ring system locked in a northern conformation:enhanced potency as P₂Y₁ receptor antagonists[J].J Med Chem,2003,46(23):4 974-4 987.
[53]	Costanzi S,Tikhonova IG,Ohno M,et al.P₂Y₁ antagonists:combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoring[J].J Med Chem,2007,50(14):3 229-3 241.
[54]	Boyer JL,Romero-Avila T,Schachter JB,et al.Identification of competitive antagonists of the P₂Y₁ receptor[J].Mol Pharmacol,1996,50(5):1 323-1 329.
[55]	Hülsmann M,Nickel P,Kassack M,et al.NF449,a novel picomolar potency antagonist at human P₂X₁ receptors[J].Eur J Pharmacol,2003,470(1/2):1-7.
[56]	Wallace E,Smyth S.Targeting platelet thrombin receptor signaling to prevent thrombosis[J].Pharmaceuticals,2013,6(8):915-928.
[57]	Cornelissen I,Palmer D,David T,et al.Roles and interactions among protease-activated receptors and P₂Y₁₂ in hemostasis and thrombosis[J].Proc Natl Acad Sci,2010,107(43):18 605-18 610.
[58]	Zhang C,Srinivasan Y,Arlow DH,et al.High-resolution crystal structure of human protease-activated receptor 1[J].Nature,2012,492(7 429):387-392.
[59]	Angiolillo DJ,Capodanno D,Goto S.Platelet thrombin receptor antagonism and atherothrombosis[J].Eur Heart J,2010,31(1):17-28.
[60]	Goto S,Ogawa H,Takeuchi M,et al.Double-blind,placebo-controlled phase II studies of the protease-activated receptor 1 antagonist E5555(atopaxar)in Japanese patients with acute coronary syndrome or high-risk coronary artery disease[J].Eur Heart J,2010,31(21):2 601-2 613.
[61]	Schulman S,Wåhlander K,Lundström T,et al.Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran[J].New Engl J Med,2003,349(18):1 713-1 721.
[62]	Xiao ZM,Xiong FW.Worldwide recall anticoagulant ximelagatran(Exanta)[J].China Pharm(中国药师),2006,9(9):851-851.
[63]	Connolly SJ,Ezekowitz MD,Yusuf S,et al.Dabigatran versus warfarin in patients with atrial fibrillation[J].New Engl J Med,2009,361(12):1 139-1 151.
[64]	Björk I,Lindahl U.Mechanism of the anticoagulant action of heparin[J].Mol Cell Biochem,1982,48(3):161-182.
[65]	Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide(BAY 59-7939):an oral,direct factor Xa inhibitor[J].J Med Chem,2005,48(19):5 900-5 908.
[66]	Matsushima N,Lee F,Sato T,et al.Bioavailability and safety of the factor Xa inhibitor edoxaban and the effects of quinidine in healthy subjects[J].Clin Pharm Drug Dev,2013,2(4):366.
[67]	Alexander JH, Becker RC, Bhatt DL, et al. Apixaban, an oral,direct,selective factor Xa inhibitor,in combination with antiplatelet therapy after acute coronary syndrome:results of the apixaban for prevention of acute ischemic and safety events(APPRAISE)trial[J].Circulation,2009,119(22):2 877-2 885.
[68]	Tricoci P,Huang Z,Held C,et al.Thrombin-receptor antagonist vorapaxar in acute coronary syndromes[J].New Engl J Med,2012,366(1):20-33.
[69]	Rollini F,Tello-Montoliu A,Angiolill DJ.Atopaxar:a review of its mechanism of action and role in patients with coronary artery disease[J].Future Cardiol,2012,8(4):503-511.
[70]	Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel,reversible,oral direct thrombin inhibitor:interpretation of coagulation assays and reversal of anticoagulant activity[J].Thromb Haemost,2010,103(6):1 116.
[71]	Chuang YJ,Swanson R,Raja SM,et al.Heparin enhances the specificity of antithrombin for thrombin and factor Xa independent of the reactive center loop sequence.Evidence for an exosite determinant of factor Xa specificity in heparin-activated antithrombin[J].J Biol Chem,2001,276(18):14 961-14 971.
[72]	Bassand JP.The place of fondaparinux in the ESC and ACC/AHA guidelines for anticoagulation in patients with non-ST elevation acute coronary 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氀愀洀洀??氀氀攀爀最礀??爀甀最?吀愀爀最攀琀猀??椀???　　???戀????戀????????????戀爀??嬀???崀???椀爀猀琀攀渀????圀愀琀稀?????爀攀琀猀挀栀洀愀爀?????椀?攀琀?愀氀???椀???昀昀椀挀愀挀礀?漀昀?琀栀攀?瀀愀渀?猀攀氀攀挀琀椀渀?愀渀琀愀最漀渀椀猀琀??椀洀漀猀椀愀洀漀猀攀?漀渀?漀稀漀渀攀?椀渀搀甀挀攀搀?愀椀爀眀愀礀?椀渀昀氀愀洀洀愀琀椀漀渀?椀渀?栀攀愀氀琀栀礀?猀甀戀樀攀挀琀猀?愀?搀漀甀戀氀攀?戀氀椀渀搀?爀愀渀搀漀洀椀稀攀搀?瀀氀愀挀攀戀漀?挀漀渀琀爀漀氀氀攀搀?挀爀漀猀猀?漀瘀攀爀?挀氀椀渀椀挀愀氀?琀爀椀愀氀嬀?崀??椀?倀甀氀洀?倀栀愀爀洀愀挀漀氀?吀栀攀爀??椀???　????戀?????戀??????????????戀爀??嬀???崀??匀琀爀愀甀戀???圀攀渀搀攀氀??倀??椀攀琀稀????椀?攀琀?愀氀???椀?匀攀氀攀挀琀椀瘀攀?椀渀栀椀戀椀琀椀漀渀?漀昀?琀栀攀?瀀氀愀琀攀氀攀琀?瀀栀漀猀瀀栀漀椀渀漀猀椀琀椀搀攀???欀椀渀愀猀攀?愀猀?瀀爀漀洀椀猀椀渀最?渀攀眀?猀琀爀愀琀攀最礀?昀漀爀?瀀氀愀琀攀氀攀琀?瀀爀漀琀攀挀琀椀漀渀?搀甀爀椀渀最?攀砀琀爀愀挀漀爀瀀漀爀攀愀氀?挀椀爀挀甀氀愀琀椀漀渀嬀?崀??椀?吀栀爀漀洀戀??愀攀洀漀猀琀??椀???　　???戀?????戀??????　???????戀爀??嬀???崀???猀甀????圀甀?圀???甀愀渀最?吀????猀渀愀欀攀?瘀攀渀漀洀?洀攀琀愀氀氀漀瀀爀漀琀攀椀渀愀猀攀?欀椀猀琀漀洀椀渀?挀氀攀愀瘀攀猀?瀀氀愀琀攀氀攀琀?最氀礀挀漀瀀爀漀琀攀椀渀?嘀??愀渀搀?椀洀瀀愀椀爀猀?瀀氀愀琀攀氀攀琀?昀甀渀挀琀椀漀渀猀嬀?崀??椀?吀栀爀漀洀戀??愀攀洀漀猀琀??椀???　　???戀????戀????????????戀爀??嬀??　崀??唀渀最攀????????????戀爀??嬀??　崀???搀愀洀猀??圀?刀愀洀椀爀攀稀???匀栀椀?夀??椀?攀琀?愀氀??椀???倀????????攀琀栀漀砀礀??椀?一??椀????????洀攀琀栀礀氀???椀????椀??瀀礀爀愀稀漀氀???礀氀???????洀漀爀瀀栀漀氀椀渀漀攀琀栀漀砀礀?瀀栀攀渀礀氀?戀攀渀稀愀洀椀搀攀?愀?渀漀瘀攀氀???栀礀搀爀漀砀礀琀爀礀瀀琀愀洀椀渀攀????爀攀挀攀瀀琀漀爀?愀渀琀愀最漀渀椀猀琀?瀀栀愀爀洀愀挀漀氀漀最椀挀愀氀?瀀爀漀昀椀氀攀?瀀栀愀爀洀愀挀漀欀椀渀攀琀椀挀猀?瀀氀愀琀攀氀攀琀?愀挀琀椀瘀椀琀礀?愀渀搀?瘀愀猀挀甀氀愀爀?戀椀漀氀漀最礀嬀?崀??椀???倀栀愀爀洀愀挀漀氀??砀瀀?吀栀攀爀??椀???　　???戀??????戀?????????　???戀爀??嬀???崀??匀琀愀爀渀攀猀????倀愀琀攀氀????匀琀漀甀昀昀攀爀????伀瀀琀椀洀愀氀?甀猀攀?漀昀?瀀氀愀琀攀氀攀琀?最氀礀挀漀瀀爀漀琀攀椀渀??氀戀????愀?爀攀挀攀瀀琀漀爀?愀渀琀愀最漀渀椀猀琀猀?椀渀?瀀愀琀椀攀渀琀猀?甀渀搀攀爀最漀椀渀最?瀀攀爀挀甀琀愀渀攀漀甀猀?挀漀爀漀渀愀爀礀?椀渀琀攀爀瘀攀渀琀椀漀渀猀嬀?崀??椀??爀甀最猀??椀???　????戀?????戀????????　　????　?　??戀爀??嬀???崀??嘀攀爀最愀爀愀??椀洀攀渀攀稀???吀爀椀挀漀挀椀?倀?匀愀昀攀琀礀?愀渀搀?攀昀昀椀挀愀挀礀?漀昀?愀戀挀椀砀椀洀愀戀?愀猀?愀渀?愀搀樀甀渀挀琀?琀漀?瀀攀爀挀甀琀愀渀攀漀甀猀?挀漀爀漀渀愀爀礀?椀渀琀攀爀瘀攀渀琀椀漀渀嬀?崀??椀?嘀愀猀挀??攀愀氀琀栀?刀椀猀欀??愀渀愀最??椀???　?　??戀????戀?????????戀爀??嬀???崀???愀爀爀椀渀最琀漀渀?刀???氀攀椀洀愀渀?一匀??漀琀琀欀攀??愀爀挀栀愀渀琀????椀?攀琀?愀氀??椀???洀洀攀搀椀愀琀攀?愀渀搀?爀攀瘀攀爀猀椀戀氀攀?瀀氀愀琀攀氀攀琀?椀渀栀椀戀椀琀椀漀渀?愀昀琀攀爀?椀渀琀爀愀瘀攀渀漀甀猀?愀搀洀椀渀椀猀琀爀愀琀椀漀渀?漀昀?愀?瀀攀瀀琀椀搀攀?最氀礀挀漀瀀爀漀琀攀椀渀???戀????愀?椀渀栀椀戀椀琀漀爀?搀甀爀椀渀最?瀀攀爀挀甀琀愀渀攀漀甀猀?挀漀爀漀渀愀爀礀?椀渀琀攀爀瘀攀渀琀椀漀渀嬀?崀??椀??洀????愀爀搀椀漀氀??椀????????戀?????戀???????????????????戀爀??嬀???崀??刀愀猀洀甀猀猀攀渀?匀??甀猀琀攀搀?匀??吀椀爀漀昀椀戀愀渀??最最爀愀猀琀愀琀????渀漀渀?瀀攀瀀琀椀搀攀?最氀礀挀漀瀀爀漀琀攀椀渀???戀????愀?爀攀挀攀瀀琀漀爀?椀渀栀椀戀椀琀漀爀嬀?崀??椀?唀最攀猀欀爀??愀攀最攀爀??椀???　　???戀??????戀??????????????戀爀??嬀???崀??匀漀渀最?夀??瘀愀氀甀愀琀椀漀渀?漀渀?琀栀攀?猀愀昀攀琀礀?愀渀搀?攀昀昀椀挀愀挀礀?漀昀?琀椀爀漀昀椀戀愀渀?椀渀?琀栀攀?琀爀攀愀琀洀攀渀琀?漀昀?愀挀甀琀攀?挀漀爀漀渀愀爀礀?猀礀渀搀爀漀洀攀嬀?崀??椀????甀愀稀栀漀渀最?唀渀椀瘀?匀挀椀?吀攀挀栀渀漀氀漀最??攀搀?匀挀椀???椀??一??聹?晙晛???晓????　　???戀?????戀??????????????戀爀??嬀???崀???漀漀氀攀礀????漀愀?????愀洀椀昀椀戀愀渀嬀?崀??椀??爀甀最猀??椀????????戀?????戀??????????????戀爀??嬀???崀???漀爀搀愀渀?刀??一愀欀愀搀愀??吀?圀攀椀猀洀愀渀?????椀??椀漀瀀栀愀爀洀愀挀攀甀琀椀挀愀氀猀?愀渀??渀搀甀猀琀爀椀愀氀?倀攀爀猀瀀攀挀琀椀瘀攀??椀?嬀?崀??攀爀氀椀渀?匀瀀爀椀渀最攀爀?????????????戀爀??嬀???崀???渀瘀攀猀琀椀最愀琀漀爀猀?倀吀??渀栀椀戀椀琀椀漀渀?漀昀?瀀氀愀琀愀氀攀琀?最氀礀挀漀瀀爀漀琀攀椀渀???戀????愀?眀椀琀栀?攀瀀椀琀椀戀愀琀椀搀攀?椀渀?瀀愀琀椀攀渀琀猀?眀椀琀栀?愀挀甀琀攀?挀漀爀漀渀愀爀礀?猀礀渀搀爀漀洀攀猀嬀?崀??椀?一??渀最氀????攀搀??椀????????戀??????戀??????????????戀爀??嬀???崀???攀渀搀攀爀??吀??攀愀瘀漀?????礀挀氀椀挀?渀甀挀氀攀漀琀椀搀攀?瀀栀漀猀瀀栀漀搀椀攀猀琀攀爀愀猀攀猀?洀漀氀攀挀甀氀愀爀?爀攀最甀氀愀琀椀漀渀?琀漀?挀氀椀渀椀挀愀氀?甀猀攀嬀?崀??椀?倀栀愀爀洀愀挀漀氀?刀攀瘀??椀???　　???戀?????戀???????????　??戀爀??嬀??　崀???愀渀爀椀焀甀攀?刀嘀??愀渀爀椀焀甀攀?嘀?倀氀愀琀攀氀攀琀?爀攀猀椀猀琀愀渀挀攀?琀漀?瀀爀漀猀琀愀挀礀挀氀椀渀??渀栀愀渀挀攀洀攀渀琀?漀昀?琀栀攀?愀渀琀椀愀最最爀攀最愀琀漀爀礀?攀昀昀攀挀琀?漀昀?瀀爀漀猀琀愀挀礀挀氀椀渀?戀礀?瀀攀渀琀漀砀椀昀礀氀氀椀渀攀嬀?崀??椀??渀最椀漀氀漀最礀??椀????????戀?????戀??????　???　???戀爀??嬀???崀???攀??愀??爀甀稀??倀?刀漀洀攀爀漀????匀愀渀挀栀攀稀?倀??椀?攀琀?愀氀??椀???渀琀椀瀀氀愀琀攀氀攀琀?攀昀昀攀挀琀?漀昀?瀀攀渀琀漀砀椀昀礀氀氀椀渀攀?椀渀?栀甀洀愀渀?眀栀漀氀攀?戀氀漀漀搀嬀?崀??椀??攀渀?倀栀愀爀洀愀挀漀氀?嘀愀猀挀??椀????????戀?????戀??????　???　???戀爀??嬀???崀???椀挀欀椀渀猀漀渀?一吀??愀渀最?????愀猀氀愀洀?刀???挀琀椀瘀愀琀椀漀渀?漀昀?挀??倀?猀琀椀洀甀氀愀琀攀搀?瀀栀漀猀瀀栀漀搀椀攀猀琀攀爀愀猀攀?戀礀?渀椀琀爀漀瀀爀甀猀猀椀搀攀?氀椀洀椀琀猀?挀??倀?愀挀挀甀洀

[1]	YU Juping, LIU Wei, YE Meng, TANG Dongyang, GAO Xiangdong. Effect of homologous overexpression of nucleoside diphosphate kinase on the yield and molecular weight of hyaluronic acid[J]. Journal of China Pharmaceutical University, 2022, 53(2): 232-238. DOI: 10.11665/j.issn.1000-5048.20220214
[2]	Determination of Adenosine in Fali Capsules by RP-HPLC[J]. Journal of China Pharmaceutical University, 2003, (6): 103-104.
[3]	Effect of Magnolol on the Arachidonic Acid Metabolizing Enzymes in Rat Neutrophils in vitro[J]. Journal of China Pharmaceutical University, 2003, (2): 55-58.
[4]	Effect of Adenosine on NO Content and NOS Activity in Hypertrophic Left Ventricule Induced by L-Thyroxine in Rats[J]. Journal of China Pharmaceutical University, 2002, (4): 73-76.
[6]	Wang Dinggang, wu Wutong, Zhang Hongxing, Wang Min, Qi Yanming, Du Zhenning. Studies on Kinetics of Immobilized Yeast Cells for Preparation of Fructose-1,6-Diphosphate[J]. Journal of China Pharmaceutical University, 1994, (5).
[9]	Screening Strains Producing FDP and Selecting Optimal Incubation Conditions[J]. Journal of China Pharmaceutical University, 1992, (3): 169-172.
[10]	INFLUENCE OF ANTIAGGREGATIVES ON CHEMILUMINESCENCE OF PLATELET INDUCED BY ARACHIDONIC ACID[J]. Journal of China Pharmaceutical University, 1987, (4): 264-267.

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Mechanism of agonist-induced platelet activation and research progress of anti-platelet drugs

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