scholarly journals Central role of the P2Y12 receptor in platelet activation

2004 ◽  
Vol 113 (3) ◽  
pp. 340-345 ◽  
Author(s):  
Robert T. Dorsam ◽  
Satya P. Kunapuli
Keyword(s):  
Platelet Activation ◽  
P2y12 Receptor

Clopidogrel response variability and the advent of personalised antiplatelet therapy

2011 ◽  
Vol 106 (08) ◽  
pp. 265-271 ◽  
Author(s):  
Paul A. Gurbe ◽  
Udaya S. Tantry
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Acute Coronary Syndromes ◽  
Ex Vivo ◽  
Platelet Reactivity ◽  
P2y12 Receptor ◽  
Current Evidence ◽  
Ischaemic Event ◽  
Coronary Syndromes

SummaryPlatelet-mediated thrombosis is a dreaded clinical event and is the primary cause of acute coronary syndromes and post-percutaneous intervention (PCI) ischaemic events. There has been a long standing interest in the ex vivo quantification of platelet reactivity to assess the risk of thrombosis. Early studies demonstrated platelet activation and heightened platelet reactivity in acute coronary syndromes and after PCI. However, a demonstration that heightened reactivity actually precipitated the ischaemic event was lacking. Our knowledge of platelet receptor physiology and the advent of novel inhibitors have significantly advanced the field. The P2Y12 receptor has been shown to play a pivotal role in the amplification of platelet activation by multiple agonists and its inhibition has resulted in improved clinical outcomes. The most widely used drug to block P2Y12 receptor, clopidogrel is associated with resistance in selected patients and these patients have been shown to be at increased risk for post-PCI ischaemic event occurrence in multiple studies. Importantly, a threshold of high platelet reactivity has been demonstrated, and beyond this threshold ischaemic events occur precipitously. Based on the current evidence, it is rational to quantify the intensity of the ADP-P2Y12 interaction in the patient at the greatest risk for thrombosis-the PCI patient. However, there is only evidence from small clinical trials demonstrating the clinical efficacy of changing an antiplatelet regimen based on an ex vivo platelet function measurement. Moreover, there are numerous patients with vulnerable coronary anatomy that have not yet experienced plaque rupture; the prognostic role of a measurement of platelet reactivity in the latter group has never been studied. Large-scale trials are ongoing that will investigate the role of personalised antiplatelet therapy in the PCI patient.

Pharmacology and clinical trials of reversibly-binding P2Y12 inhibitors

2011 ◽  
Vol 105 (S 06) ◽  
pp. S75-S81 ◽  
Author(s):  
Robert Storey
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Platelet Activation ◽  
Clinical Trial Data ◽  
Trial Data ◽  
P2y12 Receptor ◽  
Phase 3 ◽  
P2y12 Inhibitors ◽  
Clopidogrel Therapy

SummaryThe important role of the P2Y12 receptor in amplification of platelet activation and associated responses and the limitations associated with clopidogrel therapy have led to the development of novel inhibitors of this receptor. Three reversibly-binding P2Y12 inhibitors are in phase 3 development, ticagrelor, cangrelor and elinogrel. The pharmacology and clinical trial data for each of these inhibitors are discussed and compared with relevant data for the thienopyridines clopidogrel and prasugrel.

scholarly journals Platelets are relevant mediators of renal injury induced by primary endothelial lesions

2015 ◽  
Vol 308 (11) ◽  
pp. F1238-F1246 ◽  
Author(s):  
Claudia Schwarzenberger ◽  
Jan Sradnick ◽  
Kenneth M. Lerea ◽  
Michael S. Goligorsky ◽  
Bernhard Nieswandt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Platelet Activation ◽  
Concanavalin A ◽  
Renal Injury ◽  
Cell Injury ◽  
Endothelial Injury ◽  
P2y12 Receptor ◽  
Receptor Blocker ◽  
Platelet Depletion

Several studies have suggested a prominent (pro)inflammatory and harmful role of platelets in renal disease, and newer work has also demonstrated platelet release of proangiogenic factors. In the present study, we investigated the role of platelets in a mouse model of selective endothelial cell injury using either platelet depletion or the pharmacological P2Y12 receptor blocker clopidogrel as an interventional strategy. The concanavalin A/anti-concanavalin A model was induced in left kidneys of C57bl/6J wild-type mice after initial platelet depletion or platelet-inhibiting therapy using clopidogrel. FACS analysis of glycoprotein IIb/IIIa/P-selectin double-positive platelets and platelet-derived microparticles demonstrated relevant platelet activation after the induction of selective endothelial injury in mice. Enhanced platelet activation persisted for 5 days after disease induction and was accompanied by increased amounts of circulating platelet-derived microparticles as potential mediators of a prolonged procoagulant state. By immunohistochemistry, we detected significantly reduced glomerular injury in platelet-depleted mice compared with control mice. In parallel, we also saw reduced endothelial loss and a consequently reduced repair response as indicated by diminished proliferative activity. The P2Y12 receptor blocker clopidogrel demonstrated efficacy in limiting platelet activation and subsequent endothelial injury in this mouse model of renal microvascular injury. In conclusion, platelets are relevant mediators of renal injury induced by primary endothelial lesions early on, as demonstrated by platelet depletion as well as platelet inhibition via the P2Y12 receptor. While strategies to prevent platelet-endothelial interactions have shown protective effects, the contribution of platelets during renal regeneration remains unknown.

On The Mechanism Of Heparin-Induced Potentiation Of Platelet Aggregation

1981 ◽  
Author(s):  
M Yamamoto ◽  
K Watanabe ◽  
Y Ando ◽  
H Iri ◽  
N Fujiyama ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Coagulation Factors ◽  
Marked Enhancement ◽  
Matrix Bound ◽  
Induced Aggregation ◽  
Aggregation Of Platelets ◽  
Plasma Heparin

It has been suggested that heparin caused potentiation of aggregation induced by ADP or epinephrine. The exact mechanism of heparin-induced platelet activation, however, remained unknown. In this paper, we have investigated the role of anti-thrombin III ( AT ) in heparin-induced platelet activation using purified AT and AT depleted plasma. When ADP or epinephrine was added to citrated PRP one minute after addition of heparin ( 1 u/ml, porcine intestinal mucosal heparin, Sigma Co. USA ), marked enhancement of platelet aggregation was observed, compared with the degree of aggregation in the absence of heparin. However, in platelet suspensions prepared in modified Tyrode’s solution, heparin exhibited no potentiating effect on platelet aggregation induced by epinephrine or ADP. Potentiation of epinephrine- or ADP-induced platelet aggregation by heparin was demonstrated when purified AT was added to platelet suspensions at a concentration of 20 μg/ml. AT depleted plasma, which was prepared by immunosorption using matrix-bound antibodies to AT, retained no AT, while determination of α1-antitrypsinα2- macroglobulin and fibrinogen in AT depleted plasma produced values which corresponded to those of the original plasma when dilution factor was taken into account. The activities of coagulation factors were also comparable to those of the original plasma. Heparin exhibited potentiating effect on ADP- or epinephrine-induced aggregation of platelets in original plasma, but no effect in AT depleted plasma. When purified AT was added back to AT depleted plasma at a concentration of 20 μg/ml, potentiation of platelet aggregation by heparin was clearly demonstrated.Our results suggest that effect of heparin on platelet aggregation is also mediated by anti-thrombin III.

Role of Calcium in Platelet Activation: Novel Insights and Pharmacological Implications

2016 ◽  
Vol 12 (2) ◽  
pp. 131-138 ◽  
Author(s):  
Periklis Davlouros ◽  
Ioanna Xanthopoulou ◽  
Nikolaos Mparampoutis ◽  
Georgios Giannopoulos ◽  
Spyridon Deftereos ◽  
...  
Keyword(s):  
Platelet Activation

Lipopolysaccharide induces platelet activation in HIV patients: the role of different viral load patterns

HIV Medicine ◽  
2021 ◽  
Author(s):  
Cristina Nocella ◽  
Ivano Mezzaroma ◽  
Vittoria Cammisotto ◽  
Valentina Castellani ◽  
Cinzia Milito ◽  
...  
Keyword(s):  
Viral Load ◽  
Platelet Activation ◽  
Hiv Patients

scholarly journals The Role of Endogenously Formed Diacylglycerol in the Propagation and Termination of Platelet Activation

1989 ◽  
Vol 264 (6) ◽  
pp. 3274-3285 ◽  
Author(s):  
D de Chaffoy de Courcelles ◽  
P Roevens ◽  
H Van Belle ◽  
L Kennis ◽  
Y Somers ◽  
...  
Keyword(s):  
Platelet Activation

scholarly journals The (Patho)Biology of SRC Kinase in Platelets and Megakaryocytes

Medicina ◽  
2020 ◽  
Vol 56 (12) ◽  
pp. 633
Author(s):  
Lore De Kock ◽  
Kathleen Freson
Keyword(s):  
Platelet Activation ◽  
Knockout Mice ◽  
Missense Variant ◽  
Surface Receptors ◽  
Src Signaling ◽  
Normal Platelet ◽  
Fibrinogen Binding ◽  
Cellular Environment ◽  
Proplatelet Formation

Proto-oncogene tyrosine-protein kinase SRC (SRC), as other members of the SRC family kinases (SFK), plays an important role in regulating signal transduction by different cell surface receptors after changes in the cellular environment. Here, we reviewed the role of SRC in platelets and megakaryocytes (MK). In platelets, inactive closed SRC is coupled to the β subunit of integrin αIIbβ3 while upon fibrinogen binding during platelet activation, αIIbβ3-mediated outside-in signaling is initiated by activation of SRC. Active open SRC now further stimulates many downstream effectors via tyrosine phosphorylation of enzymes, adaptors, and especially cytoskeletal components. Functional platelet studies using SRC knockout mice or broad spectrum SFK inhibitors pointed out that SRC mediates their spreading on fibrinogen. On the other hand, an activating pathological SRC missense variant E527K in humans that causes bleeding inhibits collagen-induced platelet activation while stimulating platelet spreading. The role of SRC in megakaryopoiesis is much less studied. SRC knockout mice have a normal platelet count though studies with SFK inhibitors point out that SRC could interfere with MK polyploidization and proplatelet formation but these inhibitors are not specific. Patients with the SRC E527K variant have thrombocytopenia due to hyperactive SRC that inhibits proplatelet formation after increased spreading of MK on fibrinogen and enhanced formation of podosomes. Studies in humans have contributed significantly to our understanding of SRC signaling in platelets and MK.

scholarly journals Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization

2010 ◽  
Vol 8 (8) ◽  
pp. 1797-1808 ◽  
Author(s):  
J. M. E. M. COSEMANS ◽  
R. VAN KRUCHTEN ◽  
S. OLIESLAGERS ◽  
L. J. SCHURGERS ◽  
F. K. VERHEYEN ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Tam Receptors
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