Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry

2014 ◽  
Vol 111 (02) ◽  
pp. 266-272 ◽  
Author(s):  
Philipp Diehl ◽  
Katharina Schnabel ◽  
Patrick Weik ◽  
Qian Zhou ◽  
Christoph Bode ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Platelet Aggregation ◽  
Whole Blood ◽  
Antiplatelet Agents ◽  
Platelet Inhibition ◽  
Current Standard ◽  
Antiplatelet Effect ◽  
P2y12 Antagonists ◽  
Significant Difference ◽  
Induced Aggregation

SummaryThe current standard of antiplatelet therapy of patients after myocardial infarction includes the P2Y12 receptor antagonists clopidogrel, prasugrel or ticagrelor. This study aimed to compare the antiplatelet effect of clopidogrel, prasugrel and ticagrelor in patients after myocardial infarction. In a single-centre registry the antiplatelet effect of clopidogrel, prasugrel and ticagrelor was investigated by aggregometry in patients after myocardial infarction. To assess the overall capacity of platelet aggregation whole blood was induced with thrombin receptor activating peptide (TRAP; 32 μM). To specifically quantify the effect of P2Y12 antagonists, whole blood was stimulated with 6.4 μM adenosine diphophosphate (ADP). Relative ADP induced aggregation (r-ADP-agg) was defined as the ADP-TRAP ratio to reflect an individual degree of P2Y12-dependent platelet inhibition. Platelet function of 238 patients was analysed [clopidogrel (n=58), prasugrel (n=65), ticagrelor (n=115)]. The r-ADP-agg was 35 ± 14% for patients receiving clopidogrel, 28 ± 10% for patients receiving prasugrel and 26 ± 11% for patients receiving ticagrelor. The r-ADP-agg was significantly lower in patients treated with prasugrel (p=0.0024) or ticagrelor (p<0.0001) compared to clopidogrel. There was no significant difference between patients receiving prasugrel or ticagrelor (p=0.2559). In conclusion, prasugrel and ticagrelor provide a stronger platelet inhibition compared to clopidogrel in patients after myocardial infarction. No significant difference in platelet inhibition was detected between prasugrel and ticagrelor. (registry for patients after Myocardial Infarction Treated with AntiPlatelet agents; DRKS00003146).

Multiple electrode aggregometry: A new device to measure platelet aggregation in whole blood

2006 ◽  
Vol 96 (12) ◽  
pp. 781-788 ◽  
Author(s):  
Andreas Calatzis ◽  
Sandra Penz ◽  
Hajna Losonczy ◽  
Wolfgang Siess ◽  
Orsolya Tóth
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
New Device ◽  
Platelet Aggregometry ◽  
Spontaneous Platelet Aggregation ◽  
Induced Aggregation ◽  
Blood Platelet Aggregation ◽  
Multiple Electrode

SummarySeveral methods are used to analyse platelet function in whole blood. A new device to measure whole blood platelet aggregation has been developed, called multiple electrode platelet aggregometry (MEA). Our aim was to evaluate MEA in comparison with the single platelet counting (SPC) method for the measurement of platelet aggregation and platelet inhibition by aspirin or apyrase in diluted whole blood. Platelet aggregation induced by different concentrations of ADP, collagen and TRAP-6 and platelet inhibition by apyrase or aspirin were determined in citrateor hirudin-anticoagulated blood by MEA and SPC. MEA indicated that spontaneous platelet aggregation was lower, and stimulated platelet aggregation was higher in hirudin- than citrate-anticoagulated blood. In hirudin-anticoagulated, but not citrate-anticoagulated blood, spontaneous platelet aggregation measured by MEA was inhibited by apyrase. For MEA compared with SPC the dose response-curves of agonist-induced platelet aggregation in citrate- and hirudin-blood showed similar EC50 values for TRAP, and higher EC50 values for ADP (non-significant) and collagen (p<0.05). MEA and the SPC method gave similar results concerning platelet-inhibition by apyrase and aspirin. MEA was more sensitive than SPC to the inhibitory effect of aspirin in collagen-induced aggregation. In conclusion, MEA is an easy, reproducible and sensitive method for measuring spontaneous and stimulated platelet aggregation, and evaluating antiplatelet drugs in diluted whole blood. The use of hirudin as an anticoagulant is preferable to the use of citrate. MEA is a promising technique for experimental and clinical applications.

“Spontaneous” Platelet Aggregation in Whole Blood in Diabetic and Non Diabetic Survivors of Acute Myocardial Infarction

1993 ◽  
Vol 70 (06) ◽  
pp. 0932-0936 ◽  
Author(s):  
Rosaire P Gray ◽  
Timothy J Hendra ◽  
David L H Patterson ◽  
John S Yudkin
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Platelet Count ◽  
Platelet Aggregation ◽  
Whole Blood ◽  
Significant Difference ◽  
Platelet Thrombi ◽  
Spontaneous Aggregation ◽  
Spontaneous Platelet Aggregation ◽  
Normal Controls

SummaryThere is increasing evidence that platelet thrombi play an important role in the pathogenesis of acute myocardial infarction (AMI). We compared “spontaneous” platelet aggregation in whole blood in 17 non-diabetic and 12 diabetic subjects on admission with AML There was no significant difference in the fall in platelet count between the two groups, expressed as platelets remaining (75.2 ± 7.9% vs 77.3 ± 6.9% at 10 min, 66.6 ± 8.9% vs 68.5 ± 6.3% at 20 min, 63.5 ± 8.2% vs 64.9 ± 6.7% at 30 min and 59.4 ± 10.3% vs 61.3 ± 7.6% at 60 min). The rate of “spontaneous” aggregation was increased in subjects with evidence of heart failure on admission compared to those without (59.9 ± 7.9% vs 66.2 ± 6.6% at 30 min [p = 0.05] and 55.4 ± 9.6% vs 63.1 ± 7.7% at 60 min [p = 0.04]). There was no correlation between the fall in platelet count and admission plasma glucose, glycated heaemoglobin or peak aspartate aminotransferase. The subjects studied on admission with AMI had greater rates of “spontaneous” aggregation than 8 subjects studied between 6 and 12 months after acute myocardial infarction (75.9 ± 7.4% vs 85.8 ± 5.4% at 10 min; p = 0.001 and 64.3 ± 7.5% vs 75.0 ± 7.8% at 30 min; p = 0.006) and compared to normal controls (90.7 ± 4.4% at 10 min; p <0.001 and 83.4 ± 6.5 at 30 min; p <0.001). This study provides evidence of increased “spontaneous” platelet aggregation in subjects admitted with acute myocardial infarction but no difference between diabetic and non-diabetic subjects was observed.

Complexes of Nitric Oxide with Nucleophiles as Agents for the Controlled Biological Release of Nitric Oxide: Antiplatelet Effect

1993 ◽  
Vol 70 (04) ◽  
pp. 654-658 ◽  
Author(s):  
Jean G Diodati ◽  
Arshed A Quyyumi ◽  
Nabeen Hussain ◽  
Larry K Keefer
Keyword(s):  
Nitric Oxide ◽  
Aqueous Solution ◽  
Platelet Aggregation ◽  
Sodium Nitroprusside ◽  
Whole Blood ◽  
Platelet Rich Plasma ◽  
Antiplatelet Agents ◽  
Platelet Inhibition ◽  
Impedance Aggregometry

SummaryNitric oxide (NO) inhibits platelet aggregation. Accordingly, we hypothesized that complexes of diethylamine and spermine with NO (DEA/NO and SPER/NO, respectively), two vasodilators previously shown to release NO spontaneously in aqueous solution, may also be useful antiplatelet agents. Platelet aggregation was measured in whole blood or platelet-rich plasma by impedance aggregometry after addition of collagen. In whole blood, the dose response curve for DEA/NO added 1 min before collagen was similar to that for aspirin (60% inhibition at 10-4 M), while SPER/NO and sodium nitroprusside were less potent by an order of magnitude. In platelet-rich plasma, 10-6 M DEA/NO caused 60% inhibition, while SPER/NO and sodium nitroprusside were as active only at 10-5 M; aspirin’s potency was unchanged from that in whole blood. In vivo, DEA/NO and sodium nitroprusside produced significant platelet inhibition 1 min after intravenous injection in the rabbit at 50 nmol/kg. Similar in vivo platelet inhibition was observed with SPER/NO and aspirin, but only at higher dose. The effects of DEA/NO and sodium nitroprusside were transient, lasting less than 30 min after treatment, while the activity of SPER/NO and aspirin was sustained throughout the 30 min experiment. The magnitude and duration of the antiplatelet effects of DEA/NO and SPER/NO correlate with the rates at which they release nitric oxide spontaneously in aqueous solution. Thus, NO/nucleophile complexes merit further exploration both as research tools and as potential antiplatelet agents.

Dipyridamole Inhibits Platelet Aggregation in Whole Blood

1983 ◽  
Vol 50 (04) ◽  
pp. 852-856 ◽  
Author(s):  
P Gresele ◽  
C Zoja ◽  
H Deckmyn ◽  
J Arnout ◽  
J Vermylen ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Significant Negative Correlation ◽  
Significant Inhibition ◽  
Oral Drug ◽  
Human Blood Samples ◽  
Induced Aggregation

SummaryDipyridamole possesses antithrombotic properties in the animal and in man but it does not inhibit platelet aggregation in plasma. We evaluated the effect of dipyridamole ex vivo and in vitro on platelet aggregation induced by collagen and adenosine- 5’-diphosphate (ADP) in human whole blood with an impedance aggregometer. Two hundred mg dipyridamole induced a significant inhibition of both ADP- and collagen-induced aggregation in human blood samples taken 2 hr after oral drug intake. Administration of the drug for four days, 400 mg/day, further increased the antiplatelet effect. A significant negative correlation was found between collagen-induced platelet aggregation in whole blood and dipyridamole levels in plasma (p <0.001). A statistically significant inhibition of both collagen (p <0.0025) and ADP-induced (p <0.005) platelet aggregation was also obtained by incubating whole blood in vitro for 2 min at 37° C with dipyridamole (3.9 μM). No such effects were seen in platelet-rich plasma, even after enrichment with leukocytes. Low-dose adenosine enhanced in vitro inhibition in whole blood.Our results demonstrate that dipyridamole impedes platelet aggregation in whole blood by an interaction with red blood cells, probably involving adenosine.

EFFECTS OF BLOOD CELLS ON PLATELET AGGREGATION BY IMPEDANCE METHOD

1987 ◽  
Author(s):  
L Mannucci ◽  
R Redaelli ◽  
E Tremoll
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Blood Cells ◽  
White Blood Cells ◽  
Normal Subjects ◽  
Impedance Method ◽  
Induced Aggregation ◽  
Vitro Data ◽  
In Vitro Data

To evaluate the effects of blood cells on the response of platelets to aggregating agents using whole blood impedance aggregometer, studies were carried out on whole blood (WB) of normal subjects and of patients with: polycythemia vera (PV), iatrogenic anemia (IA), primary thrombocytosis (PT), idiopathic thrombotic purpura (ITP), myeloid chronic leukemia (MCL), iatrogenic leukopenia (IL). The in vitro effects of red blood cells (RBC) and of white blood cells (WBC) on platelet rich plasma (PRP) aggregation were also evaluated. WB, PRP, WBC and RBC were prepared by conventional methods. Aggregation was performed using the impedance aggregometer (mod. 540, Chrono Log Corp). In normal subjects the concentration of collagen giving 50 % aggregation (AC50 ) found in PRP did not differ from that of WB, indicating that hematocrit values within the normal range did not appreciably affect platelet aggregation. The results obtained in WB of patients are summarized in the table: In vitro data showed that aggregation in prp in wb of normal subjects was related to the number of platelets present in the sample. RBC added to PRP significant reduced aggregation only when the RBC number was greater than 4.101 cells. No effect of WBC on collagen induced aggregation of PRP was observed, whereas significant inhibition was detected after ADP. It is concluded that the aggregation evaluated in WB with impedance method is dependent on the platelet number. Also, in vitro data and studies in WB of patients indicate that aggregation is significantly affected by the presence of cells other than platelets only in conditions of changes of the ratio between platelets and leukocytes and/or red cells.

Enhanced platelet aggregation and activation under conditions of hypothermia

2007 ◽  
Vol 98 (12) ◽  
pp. 1266-1275 ◽  
Author(s):  
Ruben Xavier ◽  
Ann White ◽  
Susan Fox ◽  
Robert Wilcox ◽  
Stan Heptinstall
Keyword(s):  
Cardiac Surgery ◽  
Platelet Aggregation ◽  
Platelet Function ◽  
Whole Blood ◽  
Platelet Rich Plasma ◽  
Baseline Levels ◽  
Spontaneous Aggregation ◽  
High Concentrations ◽  
Induced Aggregation ◽  
P2y12 Antagonist

SummaryThe effects on platelet function of temperatures attained during hypothermia used in cardiac surgery are controversial. Here we have performed studies on platelet aggregation in whole blood and platelet-rich plasma after stimulation with a range of concentrations of ADP, TRAP, U46619 and PAF at both 28°C and 37°C. Spontaneous aggregation was also measured after addition of saline alone. In citrated blood, spontaneous aggregation was markedly enhanced at 28°C compared with 37°C. Aggregation induced by ADP was also enhanced. Similar results were obtained in hirudinised blood. There was no spontaneous aggregation in PRP but ADP-induced aggregation was enhanced at 28°C. The P2Y12 antagonist AR-C69931 inhibited all spontaneous aggregation at 28°C and reduced all ADP-induced aggregation responses to small, reversible responses. Aspirin had no effect. Aggregation was also enhanced at 28°C compared with 37°C with low but not high concentrations of TRAP and U46619. PAF-induced aggregation was maximal at all concentrations when measured at 28°C, but reversal of aggregation was seen at 37°C. Baseline levels of platelet CD62P and CD63 were significantly enhanced at 28°C compared with 37°C. Expression was significantly increased at 28°C after stimulation with ADP, PAF and TRAP but not after stimulation with U46619. Overall, our results demonstrate an enhancement of platelet function at 28°C compared with 37°C, particularly in the presence of ADP.

EFFECT OF Ca2+ and Mg2+ ON PLATELET ACTIVATING FACTOR (PAF) INDUCED AGGREGATION AND SPECIFIC BINDING TO HUMAN PLATELETS

1987 ◽  
Author(s):  
C M Chesney ◽  
D D Pifer
Keyword(s):  
Platelet Aggregation ◽  
Calcium Channel ◽  
Binding Sites ◽  
Competitive Inhibition ◽  
Specific Binding ◽  
Human Platelets ◽  
High Affinity ◽  
Specific Binding Sites ◽  
Significant Difference ◽  
Induced Aggregation

Gel filtered human platelets (GFP) collected in Tyrode's buffer containing 0.5 mM Ca+2, ImM Mg+2, and 0.35% albumin exhibit high affinity binding of 3H-PAF with a Kd of 0.109 α 0.029 nM (mean α SD; n=13) and 267 α 70 sites per platelet. When fibrinogen (1.67 mg/ml final concentration) is added to these GFP preparations biphasic aggregation is observed with PAF (4 nM). Normal aggregation is also observed with other platelet agonists including ADP, epinephrine, collagen, arachidonic acid, A23187 and thrombin. If GFP is prepared without added Ca+2 or Mg+2 in the presence of 3mM EDTA, platelets do not aggregate in response to PAF. However the number of specific binding sites remains unchanged (387 per platelet) with some decrease in affinity of binding (Kd = 0.2l4nM). In the presence of ImM Mg+2 there is no significant difference in binding kinetics over a range of Ca+2 concentrations (0-2mM). On the other hand the calcium channel blocker verapamil (5-10uM) exhibits competitive inhibition of 3H-PAF as analyzed by Lineweaver-Burk plots. Specific binding of 3H-PAF to GFP in the presence of ImM Mg+2 and ImM EGTA shows Kd of 0.l66nM but with increase in specific binding sites to 665. Despite increase in number of sites and no change in binding affinity, GFP under these conditions does not exhibit platelet aggregation with PAF in doses up to 80 nM.From these data it appears that external Ca+2 is not necessary for specific binding of 3H-PAF to its high affinity receptor. However, calcium does appear to be necessary for second wave aggregation with PAF. While Mg+2 appears to enhance 3H-PAF binding to platelets Mg+2 cannot substitute for Ca+2 in PAF induced platelet aggregation. Although verapamil appears to competitively inhibit binding of PAF to GFP it is not clear whether the inhibition is due to competition at or near the actual PAF receptor or at a site involving the calcium channel.

scholarly journals Antithrombotic Effects of Paeoniflorin from Paeonia suffruticosa by Selective Inhibition on Shear Stress-Induced Platelet Aggregation

2019 ◽  
Vol 20 (20) ◽  
pp. 5040 ◽  
Author(s):  
Thien Ngo ◽  
Keunyoung Kim ◽  
Yiying Bian ◽  
Hakjun Noh ◽  
Kyung-Min Lim ◽  
...  
Keyword(s):  
Shear Stress ◽  
Platelet Aggregation ◽  
Ex Vivo ◽  
Antiplatelet Agents ◽  
Human Platelets ◽  
Platelet Glycoprotein ◽  
High Shear ◽  
High Shear Stress ◽  
Paeonia Suffruticosa ◽  
Induced Aggregation

Antiplatelet agents are important in the pharmacotherapeutic regime for many cardiovascular diseases, including thrombotic disorders. However, bleeding, the most serious adverse effect associated with current antiplatelet therapy, has led to many efforts to discover novel anti-platelet drugs without bleeding issues. Of note, shear stress-induced platelet aggregation (SIPA) is a promising target to overcome bleeding since SIPA happens only in pathological conditions. Accordingly, this study was carried out to discover antiplatelet agents selectively targeting SIPA. By screening various herbal extracts, Paeonia suffruticosa and its major bioactive constituent, paeoniflorin, were identified to have significant inhibitory effects against shear-induced aggregation in human platelets. The effects of paeoniflorin on intraplatelet calcium levels, platelet degranulation, and integrin activation in high shear stress conditions were evaluated by a range of in vitro experiments using human platelets. The inhibitory effect of paeoniflorin was determined to be highly selective against SIPA, through modulating von Willebrand Factor (vWF)-platelet glycoprotein Ib (GP Ib) interaction. The effects of paeoniflorin on platelet functions under high shear stress were confirmed in the ex vivo SIPA models in rats, showing the good accordance with the anti-SIPA effects on human platelets. Treatment with paeoniflorin significantly prevented arterial thrombosis in vivo from the dose of 10 mg/kg without prolonging bleeding time or blood clotting time in rats. Collectively, our results demonstrated that paeoniflorin can be a novel anti-platelet agent selectively targeting SIPA with an improved safety profile.

WHOLE BLOOD AGGREGOMETER IN THE ASSESSMENT OF PLATELET HYPER-AGGREGABILITY

1987 ◽  
Author(s):  
R Abbate ◽  
M Boddi ◽  
S Favilla ◽  
G Costanzo ◽  
R Paniccia ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Platelet Rich Plasma ◽  
Vascular Complications ◽  
Thromboembolic Complications ◽  
Significant Difference ◽  
Platelet Number ◽  
Patient Groups ◽  
Clinical Conditions ◽  
Selection Of

The aim of this study has been to investigate the reliability of platelet aggregation in whole blood in some clinical conditions associated to thromboembolic complications.18 healthy subjects, 15 patients affected by ischemic heart disease (IHD) and 15 patients affected by insulin independent diabetes, free of vascular complications, were studied. Collagen induced (2.5 mg/L f.c.) platelet aggregation was evaluated both in whole blood (WB) by using impedance whole blood aggregometer (Chrono-Log) and in platelet rich plasma (PRP) by Born aggregometer. Aggregation was significantly higher in whole blood than in PRP in all the groups investigated (p < 0.01). No significant difference was found in PRP aggregation among the three groups, whereas WB aggregation was significantly higher in the two patient groups (IHD 79.5 + 14.2%, Diabetes 81.3 + 17.6%) than in controls (64.8 ± 14.1%) (p < 0.01 for both comparisons). No relationship was found between WB aggregation and Hct or platelet number in any of the groups studied. A slight relationship was found between megathrombocyte count and WE aggregation values (r=0.31, p < 0.05).Collagen platelet aggregation in WB seems to be provided with higher sensibility than PRP aggregation in detecting hyper-aggregability, probably because it does not imply the selection of platelet populations with loss of larger platelets and of other blood cells.

Mode of action of P2Y12 antagonists as inhibitors of platelet function

2011 ◽  
Vol 105 (01) ◽  
pp. 96-106 ◽  
Author(s):  
Jackie Glenn ◽  
Ann White ◽  
Sue Fox ◽  
Hans van Giezen ◽  
Sven Nylander ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
G Protein ◽  
Platelet Function ◽  
Adenosine Diphosphate ◽  
P2y12 Receptor ◽  
Receptor Antagonists ◽  
Receptor Agonists ◽  
P2y12 Antagonists ◽  
Induced Aggregation ◽  
G Protein Coupled

SummaryP2Y12 receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y12 receptors. However, some P2Y12 receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y12 antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y12 receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A2A agonists, which act at Gs-coupled receptors. All three P2Y12 antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A2 mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y12 antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the Gs-coupled receptor agonists always produced strong inhibition of aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y12 antagonists acting through PAR1, TP, IP, EP4, A2A or EP3 receptors. All three P2Y12 antagonists enhanced VASPphosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A2A agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y12 receptors and not through another G-protein-coupled receptor.

Sign in / Sign up

Export Citation Format

Share Document