Platelet Aggregation (Plug Formation) (Homo sapiens)

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4, 112, 5, 93cytosolTHPO VWF(23-763) thrombin light chain GP1b-IX-Vcomplex:activatedthrombin (factorIIa)TPO:Thrombopoietinreceptorthrombin light chain ADRA2B NAd Collagen type I fibril activated thrombin(factor IIa)NAd ADRA2C ADRA2C ADR GP1BB ADRA2A GpIb-IX-V:Collagentype I fibril:vWFGP1BA GP9 Collagen type I fibril ADRA2A,B,CADRA2B ADRA2A,B,C:ADR,NAdGP9 Ca2+ GP1BB ADR, NAdMPLMPL GP1BA thrombin heavy chain Integrin signalingADR VWF(23-763) Ca2+ THPOGP5 thrombin heavy chain ADRA2A GP5 13, 1613, 161, 6-8, 10...13, 1613, 16


The tethering of platelets to the site of vascular injury is the first step in the formation of a platelet thrombus. Firm adhesion of these tethered platelets, as well as the additional recruitment of others onto their surface leads to the formation of large platelet aggregates. The formation of a thrombus is strictly dependent on the formation of interplatelet bonds. View original pathway at Reactome.


Pathway is converted from Reactome ID: 76009
Reactome version: 75
Reactome Author 
Reactome Author: de Bono, Bernard

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  1. Hehlgans S, Haase M, Cordes N.; ''Signalling via integrins: implications for cell survival and anticancer strategies.''; PubMed Europe PMC Scholia
  2. Weinshank RL, Zgombick JM, Macchi M, Adham N, Lichtblau H, Branchek TA, Hartig PR.; ''Cloning, expression, and pharmacological characterization of a human alpha 2B-adrenergic receptor.''; PubMed Europe PMC Scholia
  3. Dumas JJ, Kumar R, Seehra J, Somers WS, Mosyak L.; ''Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation.''; PubMed Europe PMC Scholia
  4. Varga-Szabo D, Pleines I, Nieswandt B.; ''Cell adhesion mechanisms in platelets.''; PubMed Europe PMC Scholia
  5. Hirasawa A, Horie K, Tanaka T, Takagaki K, Murai M, Yano J, Tsujimoto G.; ''Cloning, functional expression and tissue distribution of human cDNA for the alpha 1C-adrenergic receptor.''; PubMed Europe PMC Scholia
  6. Calderwood DA.; ''Integrin activation.''; PubMed Europe PMC Scholia
  7. Kasirer-Friede A, Kahn ML, Shattil SJ.; ''Platelet integrins and immunoreceptors.''; PubMed Europe PMC Scholia
  8. Shattil SJ, Newman PJ.; ''Integrins: dynamic scaffolds for adhesion and signaling in platelets.''; PubMed Europe PMC Scholia
  9. Kobilka BK, Matsui H, Kobilka TS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ, Regan JW.; ''Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor.''; PubMed Europe PMC Scholia
  10. Harburger DS, Calderwood DA.; ''Integrin signalling at a glance.''; PubMed Europe PMC Scholia
  11. Ruggeri ZM, Mendolicchio GL.; ''Adhesion mechanisms in platelet function.''; PubMed Europe PMC Scholia
  12. Ata R, Antonescu CN.; ''Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer.''; PubMed Europe PMC Scholia
  13. Butkowski RJ, Elion J, Downing MR, Mann KG.; ''Primary structure of human prethrombin 2 and alpha-thrombin.''; PubMed Europe PMC Scholia
  14. Shattil SJ.; ''Signaling through platelet integrin alpha IIb beta 3: inside-out, outside-in, and sideways.''; PubMed Europe PMC Scholia
  15. Parise LV.; ''Integrin alpha(IIb)beta(3) signaling in platelet adhesion and aggregation.''; PubMed Europe PMC Scholia
  16. Degen SJ, Davie EW.; ''Nucleotide sequence of the gene for human prothrombin.''; PubMed Europe PMC Scholia
  17. Watson SP, Auger JM, McCarty OJ, Pearce AC.; ''GPVI and integrin alphaIIb beta3 signaling in platelets.''; PubMed Europe PMC Scholia


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114829view16:33, 25 January 2021ReactomeTeamReactome version 75
113275view11:34, 2 November 2020ReactomeTeamReactome version 74
112487view15:44, 9 October 2020ReactomeTeamReactome version 73
101399view11:28, 1 November 2018ReactomeTeamreactome version 66
100937view21:04, 31 October 2018ReactomeTeamreactome version 65
100474view19:38, 31 October 2018ReactomeTeamreactome version 64
100019view16:22, 31 October 2018ReactomeTeamreactome version 63
99572view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99195view12:43, 31 October 2018ReactomeTeamreactome version 62
94001view13:50, 16 August 2017ReactomeTeamreactome version 61
93611view11:28, 9 August 2017ReactomeTeamreactome version 61
88098view09:30, 26 July 2016RyanmillerOntology Term : 'homeostasis pathway' added !
88097view09:29, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86719view09:24, 11 July 2016ReactomeTeamreactome version 56
83350view10:56, 18 November 2015ReactomeTeamVersion54
76986view08:27, 17 July 2014ReactomeTeamFixed remaining interactions
76691view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76017view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75726view11:19, 10 June 2014ReactomeTeamReactome 48 Update
75076view14:02, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74723view08:48, 30 April 2014ReactomeTeamReactome46
42100view21:57, 4 March 2011MaintBotAutomatic update
39910view05:56, 21 January 2011MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
ADR MetaboliteCHEBI:28918 (ChEBI)
ADR, NAdComplexR-ALL-390627 (Reactome)
ADRA2A ProteinP08913 (Uniprot-TrEMBL)
ADRA2A,B,C:ADR,NAdComplexR-HSA-390700 (Reactome)
ADRA2A,B,CComplexR-HSA-390664 (Reactome)
ADRA2B ProteinP18089 (Uniprot-TrEMBL)
ADRA2C ProteinP18825 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Collagen type I fibril R-HSA-1474201 (Reactome)
GP1BA ProteinP07359 (Uniprot-TrEMBL)
GP1BB ProteinP13224 (Uniprot-TrEMBL)

complex:activated thrombin (factor

ComplexR-HSA-429532 (Reactome)
GP5 ProteinP40197 (Uniprot-TrEMBL)
GP9 ProteinP14770 (Uniprot-TrEMBL)
GpIb-IX-V:Collagen type I fibril:vWFComplexR-HSA-435464 (Reactome)
Integrin signalingPathwayR-HSA-354192 (Reactome) Integrins are a major family of cell surface receptors that modulate cell adhesion, migration, proliferation and survival through interaction with the extracellular matrix (ECM) and the actin cytoskeleton. Integrins are type 1 transmembrane proteins that exist at the cell surface as heterodimers of alpha and beta subunits, of which there are 18 and 8 different isoforms, respectively, in human cells. In addition to their mechanical role in mediating contact between the ECM and the cytoskeleton, integrins also modulate intracellular signaling pathways governing cytoskeletal rearrangements and pro-survival and mitogenic signaling (reviewed in Hehlgans et al, 2007; Harburger and Calderwood, 2009; Ata and Antonescu, 2017).
In this pathway, we describe signaling through integrin alphaIIb beta3 as a representative example.
At the sites of vascular injury bioactive molecules such as thrombin, ADP, collagen, fibrinogen and thrombospondin are generated, secreted or exposed. These stimuli activate platelets, converting the major platelet integrin alphaIIbbeta3 from a resting state to an active conformation, in a process termed integrin priming or 'inside-out signalling'. Integrin activation refers to the change required to enhance ligand-binding activity. The activated alphaIIbbeta3 interacts with the fibrinogen and links platelets together in an aggregate to form a platelet plug. AlphaIIbbeta3 bound to fibrin generates more intracellular signals (outside-in signalling), causing further platelet activation and platelet-plug retraction.
In the resting state the alpha and beta tails are close together. This interaction keeps the membrane proximal regions in a bent conformation that maintains alphaIIbbeta3 in a low affinity state.
Integrin alphaIIbbeta3 is released from its inactive state by interaction with the protein talin. Talin interacts with the beta3 cytoplasmic domain and disrupts the salt bridge between the alpha and beta chains. This separation in the cytoplasmic regions triggers the conformational change in the extracellular domain that increases its affinity to fibrinogen.
Much of talin exists in an inactive cytosolic pool, and the Rap1 interacting adaptor molecule (RIAM) is implicated in talin activation and translocation to beta3 integrin cytoplasmic domain.
MPL ProteinP40238 (Uniprot-TrEMBL)
MPLProteinP40238 (Uniprot-TrEMBL)
NAd MetaboliteCHEBI:18357 (ChEBI)
THPO ProteinP40225 (Uniprot-TrEMBL)
THPOProteinP40225 (Uniprot-TrEMBL)
TPO:Thrombopoietin receptorComplexR-HSA-443940 (Reactome)
VWF(23-763) ProteinP04275 (Uniprot-TrEMBL)
activated thrombin (factor IIa)ComplexR-HSA-156786 (Reactome)
thrombin heavy chain ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADR, NAdR-HSA-390663 (Reactome)
ADRA2A,B,C:ADR,NAdArrowR-HSA-390663 (Reactome)
ADRA2A,B,CR-HSA-390663 (Reactome)

complex:activated thrombin (factor

ArrowR-HSA-429529 (Reactome)
GpIb-IX-V:Collagen type I fibril:vWFR-HSA-429529 (Reactome)
MPLR-HSA-443926 (Reactome)
R-HSA-390663 (Reactome) Alpha-2 adrenoceptors couple with G protein alpha-i subtype which decreases adenylyl cyclase activity, thus reducing cAMP intracellular levels resulting in smooth muscle contraction. There are three alpha-2 subtypes in humans; 2A (Kobilka BK et al, 1987), 2B (Weinshank RL et al, 1990) and 2C (Hirasawa A et al, 1993).
R-HSA-429529 (Reactome) Thrombin binds to the GP1b-IX-V receptor during platelet aggregation. This leads to increased PAR activation, possibly due to favourable orientation of thrombin towards the PAR extracellular domain.
R-HSA-443926 (Reactome) Thrombopoietin (TPO) is a primary regulator of megakaryocytopoiesis. Binding of TPO to its receptor TPOR (c-Mpl) mediates pleiotropic effects on megakaryocyte development leading to significant increase in circulating platelet numbers. TPOR knockout mice show a marked reduction in bone marrow megakaryocytes and blood platelets. Although thrombopoietin (TPO) by itself has little or no effect on platelet aggregation, pretreatment of platelets with TPO augments the aggregation induced by various agonists such as ADP, thrombin, collagen, and adrenaline.
THPOR-HSA-443926 (Reactome)
TPO:Thrombopoietin receptorArrowR-HSA-443926 (Reactome)
activated thrombin (factor IIa)R-HSA-429529 (Reactome)
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