The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2102-2112 ◽  
Author(s):  
Marco Cattaneo
Keyword(s):  
Platelet Function ◽  
Cardiovascular Events ◽  
Thrombus Formation ◽  
Adenosine Diphosphate ◽  
New Drugs ◽  
Drug Induced ◽  
P2y12 Inhibitors ◽  
Major Cardiovascular Events ◽  
Platelet Receptor ◽  
Net Clinical Benefit

Abstract P2Y12, the Gi-coupled platelet receptor for adenosine diphosphate (ADP), plays a central role in platelet function. Patients with congenital P2Y12 defects display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥ 10μM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid. The most important drawback of clopidogrel is its inability to inhibit adequately P2Y12-dependent platelet function in approximately one-third of patients who are therefore not protected from major cardiovascular events. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y12 in the majority of patients, proved to be more efficacious than clopdidogrel in preventing major cardiovascular events. Although they increase the incidence of major bleedings, the net clinical benefit is in favor of the new P2Y12 inhibitors.

Bleeding manifestations of congenital and drug-induced defects of the platelet P2Y12 receptor for adenosine diphosphate

2011 ◽  
Vol 105 (S 06) ◽  
pp. S67-S74 ◽  
Author(s):  
Marco Cattaneo
Keyword(s):  
Platelet Function ◽  
Thrombus Formation ◽  
Adenosine Diphosphate ◽  
New Drugs ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Drug Induced ◽  
High Concentrations ◽  
Therapeutic Doses ◽  
Induced Defects

SummaryP2Y12, one of the two platelet receptors for adenosine diphosphate (ADP), plays a central role in platelet function. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥10 μM), is unable to induce full, irreversible platelet aggregation. Patients with congenital P2Y12 defects display a mild-to-moderate bleeding diathesis of variable severity, characterised by mucocutaneous bleeding and excessive post-surgical and post-traumatic blood loss. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid (ASA). Its most important drawback is the inability to inhibit adequately P2Y12-dependent platelet function in about 1/3 of patients, at the recommended therapeutic doses. The incidence of bleeding events is similar in ASA-treated and clopidogrel-treated patients; however, the combination of ASA and clopidogrel causes more bleeding than each drug in monotherapy. Compared to clopidogrel, new drugs inhibiting P2Y12, such as prasugrel and ticagrelor, decrease the risk of cardiovascular events and increase the risk of bleeding complications, because they adequately inhibit P2Y12-dependent platelet function in the vast majority of treated patients.

Platelet receptor interplay regulates collagen-induced thrombus formation in flowing human blood

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1333-1341 ◽  
Author(s):  
Pia R.-M. Siljander ◽  
Imke C. A. Munnix ◽  
Peter A. Smethurst ◽  
Hans Deckmyn ◽  
Theo Lindhout ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Aggregate Size ◽  
Adenosine Diphosphate ◽  
Collagen Type I ◽  
Type I ◽  
Single Chain ◽  
Collagen Receptors ◽  
Platelet Receptor ◽  
Adp Receptors ◽  
Type I Fibers

Abstract The platelet glycoproteins (GPs) Ib, integrin α2β1, and GPVI are considered central to thrombus formation. Recently, their relative importance has been re-evaluated based on data from murine knockout models. To examine their relationship during human thrombus formation on collagen type I fibers at high shear (1000 s–1), we tested a novel antibody against GPVI, an immunoglobulin single-chain variable fragment, 10B12, together with specific antagonists for GPIbα (12G1 Fab2) and α2β1 (6F1 mAb or GFOGER-GPP peptide). GPVI was found to be crucial for aggregate formation, Ca2+ signaling, and phosphatidylserine (PS) exposure, but not for primary adhesion, even with more than 97% receptor blockade. Inhibiting α2β1 revealed its involvement in regulating Ca2+ signaling, PS exposure, and aggregate size. Both GPIbα and α2β1 contributed to primary adhesion, showing overlapping function. The coinhibition of receptors revealed synergism in thrombus formation: the coinhibition of adenosine diphosphate (ADP) receptors with collagen receptors further decreased adhesion and aggregation, and, crucially, the complete eradication of thrombus formation required the coinhibition of GPVI with either GPIbα or α2β1. In summary, human platelet deposition on collagen depends on the concerted interplay of several receptors: GPIb in synergy with α2β1 mediating primary adhesion, reinforced by activation through GPVI, which further regulates the thrombus formation.

scholarly journals The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 1005-1013 ◽  
Author(s):  
Moritz Stolla ◽  
Lucia Stefanini ◽  
R. Claire Roden ◽  
Massiel Chavez ◽  
Jessica Hirsch ◽  
...  
Keyword(s):  
Antiplatelet Therapy ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Adenosine Diphosphate ◽  
Nucleotide Exchange ◽  
Integrin Activation ◽  
P2y12 Inhibitors ◽  
Nucleotide Exchange Factor ◽  
Thrombotic Complications

Abstract Two major pathways contribute to Ras-proximate-1–mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, RasGRP2) mediates the rapid but reversible activation of integrin αIIbβ3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice. Ex vivo, thrombus formation at arterial or venous shear rates was markedly reduced in CalDAG-GEFI−/− blood, even in the presence of exogenous adenosine diphosphate and thromboxane A2. In vivo, thrombosis was virtually abolished in arterioles and arteries of CalDAG-GEFI−/− mice, while small, hemostatically active thrombi formed in venules. Specific deletion of the C1-like domain of CalDAG-GEFI in circulating platelets also led to protection from thrombus formation at arterial flow conditions, while it only marginally increased blood loss in mice. In comparison, thrombi in the micro- and macrovasculature of clopidogrel-treated wild-type mice grew rapidly and frequently embolized but were hemostatically inactive. Together, these data suggest that inhibition of the catalytic or the C1 regulatory domain in CalDAG-GEFI will provide strong protection from athero-thrombotic complications while maintaining a better safety profile than P2Y12 inhibitors like clopidogrel.

scholarly journals Aspirin Resistance and Newer Combatants against It

2014 ◽  
Vol 8 (2) ◽  
pp. 92-95
Author(s):  
Faruk Ahammad ◽  
Md Shamsunnahar
Keyword(s):  
Antiplatelet Agent ◽  
Aspirin Resistance ◽  
Platelet Function Test ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Major Cardiovascular Events ◽  
Coronary Diseases ◽  
Platelet Receptor ◽  
Function Test ◽  
Failure To Protect

Aspirin is the widely used cheap antiplatelet agent globally. Since marketing it was unbeaten for use in coronary diseases and ischemic stroke patients. Unfortunately for the last two decades the term ''Aspirin resistance'' (AR) has been evolved due to it's failure to protect the aspirin users against major cardiovascular events. Although the PlA1/A2 polymorphism in the GPIIIa platelet receptor along with other factors have been identified as responsible for this resistance, the term has not yet been defined. There is no consensus about ideal platelet function test. So it is more appropriate to say "treatment failure" to aspirin therapy rather using the term AR. Although Clopidogrel is being used alone or in combination with aspirin to overcome AR,platelet receptor (p2y12) inhibitors both Prasugrel and Ticagrelor are more potent than Clopidogrel in Acute Coronary Syndrome (ACS). Worldwide Prasugrel and Ticagrelor have been included in different guidelines to use in ACS DOI: http://dx.doi.org/10.3329/fmcj.v8i2.20394 Faridpur Med. Coll. J. 2013;8(2): 92-95

Benefits and Harm of Treatment with P2Y12 Inhibitors beyond 12 Months in Patients with Coronary Artery Disease

2019 ◽  
Vol 46 (04) ◽  
pp. 446-456
Author(s):  
Mads Lamm Larsen ◽  
Erik Lerkevang Grove ◽  
Steen Dalby Kristensen ◽  
Anne-Mette Hvas
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cardiovascular Events ◽  
Meta Analysis ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Major Cardiovascular Events ◽  
Significant Difference ◽  
Artery Disease ◽  
Stable Cad

AbstractThe trade-off between the benefits and harm of long-term (> 12 months) treatment with P2Y12 inhibitors in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI) remains controversial. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. PubMed and Embase were searched without time restrictions to identify randomized controlled trials comparing > 12-month P2Y12 inhibition versus ≤ 12-month treatment in patients with acute coronary syndrome (ACS) or stable CAD undergoing PCI. A qualitative assessment was performed using the assessment tool from the National Heart, Lung, and Blood Institute of the National Institutes of Health. We performed a meta-analysis of the following endpoints: primary outcome (primarily major cardiovascular events), all-cause death, and major bleeding. Eight trials, comprising 40,218 patients, were included. Five studies were rated “good,” two studies “fair,” and one study “poor.” The meta-analysis showed that > 12-month P2Y12 inhibition significantly reduced the primary outcomes compared with ≤ 12-month treatment (hazard ratio [HR]: 0.85; 95% confidence interval (CI): 0.75–0.97; p = 0.01). No significant difference was demonstrated between groups in all-cause death (HR: 1.02; 95% CI: 0.76–1.36; p = 0.91) or major bleedings (HR: 1.26; 95% CI: 0.93–1.70; p = 0.14). I 2 test showed low to moderate heterogeneity among the included studies (21.6–62.3%). This systematic review and meta-analysis therefore demonstrates a reduction in major cardiovascular events during extended P2Y12-inhibitor treatment beyond 12 months compared with ≤ 12 months in patients with ACS or stable CAD undergoing PCI. There was no significant difference in all-cause death or major bleedings.

scholarly journals Cangrelor Induces More Potent Platelet Inhibition without Increasing Bleeding in Resuscitated Patients

2018 ◽  
Vol 7 (11) ◽  
pp. 442 ◽  
Author(s):  
Florian Prüller ◽  
Lukasz Bis ◽  
Oliver Milke ◽  
Friedrich Fruhwald ◽  
Sascha Pätzold ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Platelet Function ◽  
Academic Research ◽  
Area Under The Curve ◽  
Bleeding Risk ◽  
Adenosine Diphosphate ◽  
Light Transmittance ◽  
P2y12 Inhibitors ◽  
Prospective Comparison ◽  
Resuscitated Patients

Dual antiplatelet therapy is the standard of care for patients with myocardial infarction (MI), who have been resuscitated and treated with therapeutic hypothermia (TH). We compare the antiplatelet effect and bleeding risk of intravenous cangrelor to oral P2Y12-inhibitors in patients with MI receiving TH in a prospective comparison of two matched patient cohorts. Twenty-five patients within the CANGRELOR cohort were compared to 17 patients receiving oral P2Y12-inhibitors. CANGRELOR group (NCT03445546) and the ORAL P2Y12 Group (NCT02914795) were registered at clinicaltrials.gov. Platelet function testing was performed using light-transmittance aggregometry and monitored for 4 days. P2Y12-inhibition was stronger in CANGRELOR compared to ORAL P2Y12 (adenosine diphosphate (ADP) (area under the curve (AUC)) 26.0 (5.9–71.6) vs. 160.9 (47.1–193.7)) at day 1. This difference decreased over the following days as more patients were switched from CANGRELOR to oral P2Y12-inhibitor treatment. There was no difference in the effect of aspirin between the two groups. We did not observe significant differences with respect to thrombolysis in myocardial infarction (TIMI) or Bleeding Academic Research Consortium (BARC) classified bleedings, number of blood transfusions or drop in haemoglobin B (Hb) or hematocrit (Hct) over time. Cangrelor treatment is not only feasible and effective in resuscitated patients, but also inhibited platelet function more effectively than orally administered P2Y12-inhibitors without an increased event rate for bleeding.

Clues for Understanding the Structure and Function of a Prototypic Human Integrin: The Platelet Glycoprotein IIb/IIIa Complex

1994 ◽  
Vol 72 (01) ◽  
pp. 001-015 ◽  
Author(s):  
Juan J Calvete
Keyword(s):  
Structure Function ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Primary Role ◽  
Clot Retraction ◽  
Inhibitory Peptide ◽  
Rgd Sequence ◽  
Platelet Receptor ◽  
Adhesive Proteins ◽  
And Function

SummaryThe glycoprotein (GP) IIb/IIIa, a Ca2+-dependent heterodimer, is the major integrin on the platelet plasma membrane. On resting platelets GPIIb/IIIa is maintained in an inactive conformation and serves as a low affinity adhesion receptor for surface-coated fibrinogen, whereas upon platelet activation signals within the cytoplasma alter the receptor function of GPIIb/IIIa (inside-out signalling), which undergoes a measurable conformational change within its exoplasmic domains, and becomes a competent receptor for soluble fibrinogen and some other RGD sequence-containing plasma adhesive proteins. Upon ligand binding, further structural alterations trigger the association of receptor-occupied GPIIb/IIIa complexes with themselves within the plane of the membrane. The simultaneous binding of dimeric fibrinogen molecules to GPIIb/IIIa clusters on adjacent platelets leads to platelet aggregation, which promotes attachment of fibrinogen-GPIIb/IIIa clusters to the cytoskeleton (outside-in signalling). This, in turn, provides the necessary physical link for clot retraction to occur, and generates a cascade of intracellular biochemical reactions which result in the formation of a multiprotein signalling complex at the cytoplasmic domains of GPIIb/IIIa. Glycoprotein IMIIa, also called αIIbβ3 in the integrin nomenclature, plays thus a primary role in both platelet adhesion and thrombus formation at the site of vascular injury. In addition, the human glycoprotein Ilb/IIIa complex is the most thoroughly studied integrin receptor, its molecular biology and major features of its primary structure having been elucidated mainly during the last six years. Furthermore, localization of functionally relevant monoclonal antibody epitopes, determination of the cross-linking sites of inhibitory peptide ligands, proteolytic dissection of the isolated integrin, and analysis of natural and artificial GPIIb/IIIa mutants have recently provided a wealth of information regarding structure-function relationships of human GPIIb/IIIa. The aim of this review is to summarize these many structural and functional data in the perspective of an emerging model. Although most of the interpretations based on structural elements of this initial biochemical model require independent confirmation, they may help us to understand the structure-function relationship of this major platelet receptor, and of other members of the integrin superfamily, as well as to perform further investigations in order to test current hypotheses.

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