Correlations of adenosine diphosphate (ADP)-induced platelet aggregation and activation.

<p><b>(A)</b> Scatter plot showing ADP-induced platelet reactivity by light transmission aggregometry (LTA; x-axis) vs. platelet reactivity by the VerifyNow P2Y₁₂ assay (y-axis). Circles represent individual measurements. Cut-off values for high on-treatment residual platelet reactivity are indicated by the dotted lines. PRU, P2Y₁₂ Reaction Units. <b>(B)</b> Scatter plot showing ADP-induced platelet surface P-selectin expression (x-axis) vs. ADP-induced activated glycoprotein (GP) IIb/IIIa (y-axis). Circles represent individual measurements. Cut-off values for high P-selectin and high GPIIb/IIIa are indicated by the dotted lines. <b>(C)</b> Scatter plot showing platelet reactivity by the VerifyNow P2Y₁₂ assay (x-axis) vs. ADP-induced activated glycoprotein (GP) IIb/IIIa (y-axis). Circles represent individual measurements. Cut-off values for high on-treatment residual platelet reactivity and high GPIIb/IIIa are indicated by the dotted lines. PRU, P2Y₁₂ Reaction Units.</p

Correlations of arachidonic acid (AA)-induced platelet aggregation and platelet activation.

<p><b>(A)</b> Scatter plot showing AA-induced platelet reactivity by light transmission aggregometry (LTA; x-axis) vs. platelet reactivity by the VerifyNow aspirin assay (y-axis). Circles represent individual measurements. Cut-off values for high on-treatment residual platelet reactivity are indicated by the dotted lines. ARU, Aspirin Reaction Units. <b>(B)</b> Scatter plot showing AA-induced platelet surface P-selectin expression (x-axis) vs. AA-induced activated glycoprotein (GP) IIb/IIIa (y-axis). Circles represent individual measurements. Cut-off values for high P-selectin and high GPIIb/IIIa are indicated by the dotted lines. <b>(C)</b> Scatter plot showing AA-induced platelet reactivity by light transmission aggregometry (LTA; x-axis) vs. AA-induced activated glycoprotein (GP) IIb/IIIa (y-axis). Circles represent individual measurements. Cut-off values for high on-treatment residual platelet reactivity and high GPIIb/IIIa are indicated by the dotted lines. ARU, Aspirin Reaction Units.</p

Correlations of adenosine diphosphate (ADP)-induced platelet reactivity by light transmission aggregometry (LTA), the VerifyNow P2Y₁₂ assay, and multiple electrode aggregometry (MEA) with ADP-induced P-selectin expression and activated glycoprotein (GP) IIb/IIIa.

<p>Correlations of adenosine diphosphate (ADP)-induced platelet reactivity by light transmission aggregometry (LTA), the VerifyNow P2Y₁₂ assay, and multiple electrode aggregometry (MEA) with ADP-induced P-selectin expression and activated glycoprotein (GP) IIb/IIIa.</p

Clinical, laboratory and procedural characteristics of the overall study population.

<p>Continuous data are shown as median (interquartile range). Dichotomous data are shown as n (%).</p><p>ACE inhibitors, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers.</p><p>Clinical, laboratory and procedural characteristics of the overall study population.</p

Soluble CD40 ligand levels (sCD40L) in patients without and with the primary and secondary endpoints in the subgroup of patients with stent implantation (n = 205).

<p>Continuous data are given as mean ± SEM.</p><p>Soluble CD40 ligand levels (sCD40L) in patients without and with the primary and secondary endpoints in the subgroup of patients with stent implantation (n = 205).</p

Soluble CD40 ligand levels (sCD40L) in patients without and with the primary and secondary endpoints in the overall study population (n = 562).

<p>Continuous data are given as mean ± SEM.</p><p>Soluble CD40 ligand levels (sCD40L) in patients without and with the primary and secondary endpoints in the overall study population (n = 562).</p

<i>In Vivo</i> and protease-activated receptor-1-mediated platelet activation in patients presenting for cardiac catheterization

<p>Pathways of platelet activation that are not targeted by current antithrombotic therapy may be crucial for the development of ischemic events in patients undergoing coronary angiography. We therefore investigated whether <i>in vivo</i> and thrombin receptor activating peptide (TRAP)-stimulated platelet activation and monocyte-platelet aggregate (MPA) levels can serve as independent risk markers for adverse outcomes in aspirin-treated patients presenting for cardiac catheterization. <i>In vivo</i> and TRAP-stimulated platelet surface P-selectin, activated glycoprotein IIb/IIIa (GPIIb/IIIa) and MPA levels were determined in 682 consecutive patients undergoing cardiac catheterization and in 47 healthy controls. Two-year follow-up data were obtained from 562 patients. <i>In vivo</i> platelet surface P-selectin, activated GPIIb/IIIa and MPA levels were significantly higher in patients with angiographically-proven coronary artery disease than in healthy controls (all <i>p</i>≤0.02). Patients with an acute coronary syndrome (ACS; <i>n</i>=125) had significantly higher levels of <i>in vivo</i> MPA than patients without ACS (<i>n</i>=437; <i>p</i>=0.01). In the overall study population (<i>n</i>=562) the surface expression of P-selectin and activated GPIIb/IIIa, and the levels of MPA <i>in vivo</i> and in response to TRAP were similar in patients without and with subsequent ischemic events (all <i>p</i>>0.05). Similar results were obtained when only patients with angiographically-proven coronary artery disease (<i>n</i>=459), stent implantation (<i>n</i>=205) or ACS (<i>n</i>=125) were analyzed. Receiver-operating characteristic curve analyses did not reveal cut-off values for P-selectin, activated GPIIb/IIIa, and MPA levels for the prediction of ischemic events. In conclusion, <i>in vivo</i> and TRAP-stimulated platelet activation and MPA levels did not predict adverse ischemic outcomes in aspirin-treated patients presenting for cardiac catheterization.</p

Soluble CD40 ligand levels (sCD40L) in patients without and with the primary and secondary endpoints in the subgroup of patients with stent implantation (n = 205).

<p>Continuous data are given as mean ± SEM.</p><p>Soluble CD40 ligand levels (sCD40L) in patients without and with the primary and secondary endpoints in the subgroup of patients with stent implantation (n = 205).</p

Patient characteristics of the overall study population, and of patients with aspirin monotherapy (ASA) vs. dual antiplatelet therapy (ASA+Clo).

<p>Continuous data are shown as mean ± SEM. Dichotomous data are shown as %.</p><p>Abbreviations: ACE, angiotensin converting enzyme; BMI, body mass index; CRP, C-reactive protein; MI, myocardial infarction.</p><p>Patient characteristics of the overall study population, and of patients with aspirin monotherapy (ASA) vs. dual antiplatelet therapy (ASA+Clo).</p

Underlying mechanism and specific prevention of hemolysis-induced platelet activation

<p>Thromboembolic complications significantly impair the outcome of hemolytic disorders. We hypothesized that red cell adenosine diphosphate (ADP) release results in significant platelet activation in hemolysis and that this prothrombotic state can be prevented by inhibition of the ADP P2Y₁₂ receptor. In the current study, we therefore sought to investigate the mechanism and inhibition of hemolysis-induced platelet activation. The expression of activated integrin αIIbß3 was determined by flow cytometry, and platelet aggregation was assessed by multiple electrode platelet aggregometry. We demonstrate platelet activation and increased platelet aggregation by adding hemolytic blood (lysates) to whole blood, similarly to that achieved by the platelet agonist ADP. Enhanced platelet activation and reactivity in the presence of hemolytic blood were significantly abolished by apyrase, which catalyzes ADP degradation, and inhibited by blockade of the platelet ADP P2Y₁₂ receptor with cangrelor. Platelets from patients treated with the ADP P2Y₁₂ receptor antagonist clopidogrel showed a reduced response to lysates compared to platelets from healthy controls without antiplatelet treatment. Further, <i>in vitro</i> blood group ABO incompatibility induced hemolysis and led to increased platelet activation. Finally, “spontaneous” platelet aggregation seen in patients with cold agglutinin disease was completely abolished by cangrelor. In conclusion, hemolysis is associated with increased platelet activation and aggregation due to red cell derived ADP, which can be prevented by ADP receptor blockade.</p