Pathway Platelet Aggregation Inhibitor Pathway, Pharmacodynamics

Effects of antiplatelet drugs on platelet aggregation pathway.
Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
thienopyridine aspirin glycoprotein p450 isoforms collagen collagen vwf f2 f2r p2ry12 p2ry1 p2rx1 glycoproteins tbxa2r g-proteins phospholipase adcy3 prostaglandin gnas pla2 tbxas1 ptgs1 fibrinogen receptor fibrinogen fibrinogen receptor
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Platelet activation and coagulation normally do not occur within an intact blood vessel. After vessel wall injury, platelet-plug formation is initiated by the adherence of platelets to subendothelial collagen. In high shear arterial blood, platelets are first slowed down from their blood flow velocity by interacting with the collagen-bound von Willebrand factor (VWF) and subsequently stopped by binding directly to collagen via their glycoprotein receptor complex. The activation of these collagen receptors on platelets following their binding to collagen activates phospholipase C (PLC)-mediated cascades. This results in a mobilization of calcium from the dense tubula system. An increase in intracellular calcium is associated with activation of several kinases necessary for morphological change, the presentation of the procoagulant surface, the secretion of platelet granular content, the activation of glycoproteins, and the activation of Phospholipase A2 (PLA2). Activation of PLA2 releases arachidonic acid (AA), which is a precursor for TBXA2 synthesis. PTGS1 catalyzes the first step in the formation of TBXA2 from AA. This reaction is irreversibly blocked by aspirin, which also leads to the blockage of platelet aggregation

These processes result in the local accumulation of molecules like thrombin, TBXA2, and ADP, which are important for the further recruitment of platelets as well as the amplification of activation signals as described above. The secreted agonists activate their respective G protein coupled receptors: thrombin receptor (F2R), thomboxane A2 receptor (TBXA2R), and ADP receptors (P2RY1 and P2RY12). The P2RY12 receptor couples to Gi, and when activated by ADP, inhibits adenylate cyclase. This interaction counteracts the stimulation of cAMP formation by endothelial-derived prostaglandins, which alleviates the inhibitory effect of cAMP on IP3-mediated calcium release. Thienopyridines, a class of oral antiplatelet agents, permanently inhibit P2RY12 signaling, which is sufficient to block platelet activation.

F2R, TBXA2R and P2RY1 couple to the Gq-PLC-IP3-Ca2+ pathway, inducing shape change and platelet aggregation. In addition, receptor signaling through G12/13 (F2R; TBXA2R) contributes to morphological changes through activation of kinases.

Platelet adhesion, cyotoskeletal reorganization, secretion, and amplification loops are all different steps towards the formation of a platelet-plug. These cascades result in the activation of the Fibrinogen Receptor expressed on platelet cells. This activation develops binding sites for fibrinogen, which are not available in inactive platelets. The binding of fibrinogen results in the linkage of activated platelets through fibrinogen bridges, thereby mediating aggregation. Inhibition of this receptor through Glycoprotein IIb/IIIa inhibitors blocks platelet aggregation induced by any agonist.

Authors: A.R. Shuldiner, Katrin Sangkuhl.
Sangkuhl Katrin, Shuldiner Alan R, Klein Teri E, Altman Russ B . "Platelet aggregation pathway" Pharmacogenetics and genomics (2010).
Therapeutic Categories:
  • Cardiovascular and hematology agents

Entities in the Pathway

Genes (51)

Drugs/Drug Classes (7)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
AA PGG2 PTGS1 18038215, 8145785
AA PGH2 PTGS1 18038215, 8145785
ADCY3 ADCY3 GNAI1, GNAI2, GNAI3, GNAS, GNB3 11997386, 15187029
ATP cyclic AMP ADCY3 15187029
calcium calcium IP3 15914557
clopidogrel Active metabolite CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5 11127873, 12485953, 17361128, 19812348
ITGA2B, ITGB3 ITGA2B, ITGB3 PLCB1, PLCG2 11964287, 12297512, 15914557
GNAI1, GNAI2, GNAI3, GNB3 GNAI1, GNAI2, GNAI3, GNB3 P2RY12 15187029
GNA11, GNA12, GNA13, GNA15, GNAQ, GNB3 GNA11, GNA12, GNA13, GNA15, GNAQ, GNB3 F2R, F2RL3, P2RY1, TBXA2R 15914557, 8290554, 9653141
CD36, GP1BB, GP5, GP6, GP9, ITGA2 CD36, GP1BB, GP5, GP6, GP9, ITGA2 Collagen-VWF (COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, VWF), COL1A1, COL1A2, COL3A1, COL4A1, COL4A2 11487007, 16149014, 6087354
IP3 IP3 PLCB1, PLCG2 15914557
P2RX1 P2RX1 ATP 15914557
PGG2 TBXA2 TBXAS1 18038215, 8145785
PGH2 TBXA2 TBXAS1 18038215, 8145785
phosphatidylcholine AA PLA2G2A, PLA2G4A, PLA2G4B 18038215, 8145785
phosphatidylethanolamine AA PLA2G2A, PLA2G4A, PLA2G4B 18038215, 8145785
PLCB1, PLCG2 PLCB1, PLCG2 CD36, GNA11, GNA12, GNA13, GNA15, GNAQ, GNB3, GP1BB, GP5, GP6, GP9, ITGA2 11487007, 15914557
PLA2G2A, PLA2G4A, PLA2G4B PLA2G2A, PLA2G4A, PLA2G4B Black Box: intracellular calcium release, calcium, PLCB1, PLCG2 16149014, 8253817
PTGS1 PTGS1 aspirin 18038215, 8145785
FGA, FGB, FGG ITGA2B, ITGB3 abciximab, eptifibatide, tirofiban 11406724, 11929319, 6087354
P2RY1 P2RY1 ADP 15914557
P2RY12 P2RY12 Active metabolite, ADP, prasugrel, ticlopidine 11196645, 15199474, 15914557
TBXA2R TBXA2R TBXA2 18038215, 8145785
F2R, F2RL3 F2R, F2RL3 F2 15817447
calcium calcium P2RX1 15914557

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