Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a randomized controlled trial

2012 ◽  
Vol 123 (10) ◽  
pp. 591-600 ◽  
Author(s):  
Alexander O. Spiel ◽  
Ulla Derhaschnig ◽  
Michael Schwameis ◽  
Johann Bartko ◽  
Jolanta M. Siller-Matula ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Controlled Trial ◽  
Platelet Inhibition ◽  
Inhibitory Effect ◽  
Double Blind ◽  
Multiple Electrode Aggregometry ◽  
Von Willebrand ◽  
Plug Formation ◽  
Induced Aggregation

P2Y12 receptor antagonists have become a mainstay for the treatment of CVD (cardiovascular diseases). However, they have rarely been evaluated under pathophysiological conditions apart from arterial diseases. We hypothesized interactions between prasugrel and enhanced vWF (von Willebrand Factor) release in a model of systemic inflammation, and compared the pharmacodynamic effects of prasugrel against placebo on agonist-induced platelet aggregation and shear-induced platelet plug formation. A total of 20 healthy male volunteers were enrolled in a double-blind placebo-controlled two-way crossover trial. Each volunteer received either placebo or a 60 mg loading dose of prasugrel 2 h before endotoxin or placebo infusion. Platelet inhibition was measured with MEA (multiple electrode aggregometry), the PFA-100 system and the VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay. Prasugrel blunted various platelet aggregation pathways, including those induced by ADP (−81%), AA (arachidonic acid) (−60%), ristocetin (−75%; P<0.001 for all) and, to a lesser degree, collagen or TRAP (thrombin-receptor-activating peptide). Prasugrel decreased shear-induced platelet plug formation, but vWF release during endotoxaemia partly antagonized the inhibitory effect of prasugrel as measured with the PFA-100 system. Endotoxaemia acutely decreased ristocetin and TRAP-induced platelet aggregation, and enhanced ristocetin-induced aggregation after 24 h. Strong in vivo blockade of P2Y12 inhibits a broad spectrum of platelet aggregation pathways. However, vWF release may reduce prasugrel's effects under high-shear conditions.

Effects of Strong P2Y12 Receptor Inhibition by Prasugrel on Platelet Inhibition During Endotoxemia: A Randomized Controlled Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1245-1245
Author(s):  
Alexander O Spiel ◽  
Ulla Derhaschnig ◽  
Petra Jilma-Stohlawetz ◽  
Bernd Jilma
Keyword(s):  
Platelet Aggregation ◽  
Conflicts Of Interest ◽  
Platelet Reactivity ◽  
Controlled Trial ◽  
Platelet Inhibition ◽  
P2y12 Receptor ◽  
Reactivity Index ◽  
Double Blind ◽  
Plug Formation ◽  
Induced Aggregation

Abstract Abstract 1245 Background: P2Y12 receptor antagonists have become a mainstay for the treatment of cardiovascular diseases. Yet, they have rarely been evaluated under pathophysiological conditions apart from arterial diseases. Objectives: We hypothesized interactions between prasugrel and enhanced von Willebrand Factor (VWF) release in a model of systemic inflammation, and compared the pharmacodynamic effects of prasugrel versus placebo on agonist-induced platelet aggregation and shear-induced platelet plug formation. Subjects/Methods: Twenty healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Each volunteer received either placebo or a 60 mg-loading dose of prasugrel two hours before endotoxin infusion. Platelet inhibition was measured with Multiple Electrode Aggregometry (MEA), the Platelet Function Analyzer-100 (PFA-100) and the Vasodilator Stimulated Phosphoprotein (VASP) phosphorylation assay, respectively. Results: Prasugrel reduced the platelet reactivity index in the VASP assay from 79% to 5–7%, and unequivocally prolonged the closure times of the Innovance cartridge to >300s, but also the CADP-CT to >300s in the majority of subjects. Prasugrel not only blunted platelet aggregation induced by ADP (−81%), but also other pathways including arachidonic acid (−60%), ristocetin (−75%; p<0.001 for all), and to a lesser degree collagen or thrombin receptor activating peptide (TRAP). Prasugrel decreased shear-induced platelet plug formation but VWF release during endotoxemia partly antagonized the inhibitory effect of prasugrel as measured with the PFA-100. Endotoxemia acutely decreased ristocetin and TRAP induced platelet aggregation, and enhanced ristocetin induced aggregation after 24h. Conclusions: These data for the first time demonstrate that strong in vivo blockade of P2Y12 by prasugrel inhibits a broad spectrum of platelet aggregation pathways. However, VWF release may reduce prasugrel's effects under high shear conditions. Disclosures: No relevant conflicts of interest to declare.

Inhibition of Human Platelet Aggregation by the Proteolytic Effect of Streptokinase (SK). Role of the Factor VIII Related Antigen

1975 ◽  
Author(s):  
R. Castillo ◽  
S. Maragall ◽  
J. A. Guisasola ◽  
F. Casals ◽  
C. Ruiz ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Platelet Rich Plasma ◽  
Gel Filtration ◽  
Inhibitory Effect ◽  
Factor Viii Related Antigen ◽  
Human Factor Viii ◽  
Induced Aggregation

Defective ADP-induced platelet aggregation has been observed in patients treated with streptokinase. This same effect appears “in vitro” when adding SK to platelet rich plasma (PRP). Classic hemophilia and normal platelet poor plasmas (PPP) treated with SK inhibit the aggregation of washed platelets; plasmin-treated normal human serum also shows an inhibitory effect on platelet aggregation. However, von Willebrand SK-treated plasmas do not inhibit the aggregation of washed platelets. The same results appear when plasmas are previously treated with a rabbit antibody to human factor VIII.This confirms that the antiaggregating effect is mainly linked to the digested factor VIII related antigen.The inhibition of ADP-induced platelet aggregation has been proved in gel filtration-isolated and washed platelets from SK-treated PRP.Defective ristocetin-induced platelet aggregation has also been observed- This action does not appear in washed platelets from SK-treated PRP in presence of normal PPP, but it does in presence of SK-treated PPP, which suggests that the inhibition of the ristocetin-induced aggregation is due to the lack of factor VIII and not to the factor VIII-related products.Heparin, either “in vivo” or “in vitro”, has corrected the antiaggregating effect of SK.

Prevention of in vivo Platelet Aggregation by Indobufen in Angina Patients during Exercise

1981 ◽  
Vol 9 (2) ◽  
pp. 113-119 ◽  
Author(s):  
E M Pogliani ◽  
R Fantasia ◽  
C Perini ◽  
G Corvi
Keyword(s):  
Platelet Aggregation ◽  
Bicycle Ergometer ◽  
Crossover Design ◽  
Double Blind ◽  
Before And After ◽  
Circulating Platelet Aggregates ◽  
Platelet Aggregates ◽  
Induced Aggregation ◽  
Platelet Functions

Platelet aggregation induced by 3 concentrations of ADP and collagen was assessed in thirty patients with stable angina, before and after exercise with a bicycle ergometer. The patients received a single oral 200 mg dose of indobufen and placebo according to a crossover design in double-blind conditions. Platelet sensitivity to both aggregating agents increased when exercise was carried out after placebo, whereas indobufen markedly inhibited ADP- and collagen-induced aggregation. Circulating platelet aggregates increased in some patients during exercise after placebo but not after indobufen. These results suggest that effort may be an important factor in activation of platelet functions and that the use of drugs blocking the arachidonate pathway and the release reaction may be appropriate in patients with angina.

Lu 23051, A New Potent Inhibitor Of Platelet Aggregation

1981 ◽  
Author(s):  
H D Lehmann ◽  
J Gries ◽  
D Lenke
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Coronary Vessels ◽  
Inhibitory Effect ◽  
Spontaneously Hypertensive ◽  
Dependent Inhibition ◽  
Induced Aggregation

6- [p-(2-(Chiorpropionylamino)phenyl] -4.5-dihydro-5-methyl-3(2H)-pyridazinone, LU 23051, is primarily characterized by its strong inhibition of platelet aggregation under in vitro and in vivo conditions. In vitro there is a concentration-dependent inhibition of ADP and collagen induced aggregation in platelet rich plasma of man, rat and dog. The inhibitory concentration EC 33 % is 0.0010-0.030 mg/1 (man: ADP-0.030, col 1.-0.013 mg/l) depending on species and type of aggregation. When administered orally in ex vivo experiments on rats and dogs the substance is found to have a dose-dependent antiaggregatory effect in the range from 0.1-3.16 mg/kg. The ED 33 % is 0.27-0.63 mg/kg.-In addition after oral administration the substance has a good inhibitory effect in models being based on intravascular platelet aggregation. Thus, a dose of 1 mg/kg inhibits laser-induced aggregation in mesenteric venules of rats. Mortality after i.v. injection of collagen in mice is reduced by 50 % after a dose of 0.02 mg/kg. A dose of 0.039 mg/kg prolongs the bleeding time of rats by 50 %. The aggregation-inhibiting action is of long duration (0.1 mg/kg p.o.∼24 h). The substance does not interfere with clotting.Besides its effect on platelet aggregation LU 23051 acts as vasodilatator as well. Dilatation of coronary vessels by 100 % is seen in isolated guinea-pig hearts at a concentration of 0.1 mg/l. In spontaneously hypertensive rats the substance has an anti hypertensive effect. The ED 20 % is 0.36 mg/kg p.o.The combination of antiaggregatory and vasodilatatory effects opens up interesting aspects with respect to the pharmacotherapeutic use of the new substance

In Vivo Activity of Tieclopidine, a New Drug with Platelet Aggregation Inhibiting, Antisludge and Antithrombotic Properties

1975 ◽  
Author(s):  
J. C. Ferrand ◽  
D. Aubert ◽  
B. Lacaze ◽  
O. Pepin ◽  
J. J. Thebault
Keyword(s):  
Platelet Aggregation ◽  
Blood Stasis ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Clinical Approach ◽  
Synthetic Compounds ◽  
Antithrombotic Activity ◽  
Daily Dose ◽  
Induced Aggregation

Tieclopidine (53–32 C) belongs to a new series of synthetic compounds which have proved to inhibit significantly blood platelet aggregation in animals. Administered orally to rats, it reduces markedly the plate let aggregation induced by ADP and collagen. The activity appears 2 to 6 hours after a single dose and persists for 24 hours.The sludge and blood stasis induced in rats by protamin sulfate injections disappear completely in five minutes after an intravenous administration of Thieclopidine. Animals pretreated orally with this compound failed to show any sludge formation.The antithrombotic activity of Tieclopidine was demonstrated in rats carrying a dental broach implanted in the abdominal aorta. White thrombideveloped locally in the control animals, but were absent or much less severe in pretreated animals.In man the first clinical approach has shown that at a daily dose of 1 g the inhibitory effect of Tieclopidine on ADP induced aggregation requires 24 to 48 hrs to become significant and reaches a plateau after 5 or 6 days of treatment.

The Inhibition of Platelet Aggregation by an Aorta Intima Extract

1974 ◽  
Vol 32 (02/03) ◽  
pp. 417-431 ◽  
Author(s):  
A. du P Heyns ◽  
D. J van den Berg ◽  
G. M Potgieter ◽  
F. P Retief
Keyword(s):  
Platelet Aggregation ◽  
Degradation Products ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Vascular Trauma ◽  
Wear And Tear ◽  
Sequential Addition ◽  
Aggregation Activity

SummaryThe platelet aggregating activity of extracts of different layers of the arterial wall was compared to that of Achilles tendon. Arterial media and tendon extracts, adjusted to equivalent protein content as an index of concentration, aggregated platelets to the same extent but an arterial intima extract did not aggregate platelets. Platelet aggregation induced by collagen could be inhibited by mixing with intima extract, but only to a maximum of about 80%. Pre-mixing adenosine diphosphate (ADP) with intima extracts diminished the platelet aggregation activity of the ADP. Depending on the relationship between ADP and intima extract concentrations aggregating activity could either be completely inhibited or inhibition abolished. Incubation of ADP with intima extract and subsequent separation of degradation products by paper chromatography, demonstrated a time-dependent breakdown of ADP with AMP, adenosine, inosine and hypoxanthine as metabolic products; ADP removal was complete. Collagen, thrombin and adrenaline aggregate platelets mainly by endogenous ADP of the release reaction. Results of experiments comparing inhibition of aggregation caused by premixing aggregating agent with intima extract, before exposure to platelets, and the sequential addition of first the intima extract and then aggregating agent to platelets, suggest that the inhibitory effect of intima extract results from ADP breakdown. It is suggested that this ADP degradation by intima extract may play a protective role in vivo by limiting the size of platelet aggregates forming at the site of minimal “wear and tear” vascular trauma.

Ex Vivo Inhibition of Platelet Aggregation in Patients with Severe Limb Arteriopathy Treated with BAY U3405, a Specific IX A2 Receptor Antagonist

1994 ◽  
Vol 72 (05) ◽  
pp. 659-662 ◽  
Author(s):  
S Bellucci ◽  
W Kedra ◽  
H Groussin ◽  
N Jaillet ◽  
P Molho-Sabatier ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Randomized Study ◽  
In Vivo Studies ◽  
Walking Distance ◽  
Peripheral Blood Flow ◽  
Walking Ability ◽  
Double Blind ◽  
Platelet Factor

SummaryA double-blind, placebo-controlled randomized study with BAY U3405, a specific thromboxane A2 (TX A2) receptor blocker, was performed in patients suffering from severe stade II limb arteriopathy. BAY U3405 or placebo was administered in 16 patients at 20 mg four times a day (from day 1 to day 3). Hemostatic studies were done before therapy, and on day 2 and day 3 under therapy. On day 3, BAY U3405 was shown to induce a highly statistically significant decrease of the velocity and the intensity of the aggregations mediated by arachidonic acid (56 ± 37% for the velocity, 58 ± 26% for the intensity) or by U46619 endoperoxide analogue (36 ± 35% for the velocity, 37 ± 27% for the intensity). Similar results were already observed on day 2. By contrast, such a decrease was not noticed with ADP mediated platelet aggregation. Furthermore, plasma levels of betathrombo-globulin and platelet factor 4 remained unchanged. Peripheral hemodynamic parameters were also studied. The peripheral blood flow was measured using a Doppler ultrasound; the pain free walking distance and the total walking ability distance were determined under standardized conditions on a treadmill. These last two parameters show a trend to improvement which nevertheless was not statistically significant. All together these results encourage further in vivo studies using BAY U3405 or related compounds on a long-term administration.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

Opposite Effect of Lysine on Platelet Aggregation Induced by Arachidonate and by Other Aggregants

1982 ◽  
Vol 48 (01) ◽  
pp. 078-083 ◽  
Author(s):  
C Ts'ao ◽  
S J Hart ◽  
D V Krajewski ◽  
P G Sorensen
Keyword(s):  
Platelet Aggregation ◽  
Secondary Phase ◽  
Aminocaproic Acid ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Primary Phase ◽  
High Doses ◽  
The Many ◽  
Induced Aggregation

SummaryEarlier, we found that ε-aminocaproic acid (EACA) inhibited human platelet aggregation induced by adenosine diphosphate (ADP) and collagen, but not aggregation by arachidonic acid (AA). Since EACA is structurally similar to lysine, yet these two agents exhibit vast difference in their antifibrinolytic activities, we chose to study the effect of lysine on platelet aggregation. We used L-lysine-HCl in these studies because of its high solubility in aqueous solutions while causing no change in pH when added to human plasma. With lysine, we repeatedly found inhibition of ADP-, collagen- and ristocetin-induced aggregation, but potentiation of AA-induced aggregation. Both the inhibitory and potentiation effects were dose-dependent. Low doses of lysine inhibited the secondary phase of aggregation; high doses of it also inhibited the primary phase of aggregation. Potentiation of AA-induced aggregation was accompanied by increased release of serotonin and formation of malondialdehyde. These effects were not confined to human platelets; rat platelets were similarly affected. Platelets, exposed to lysine and then washed and resuspended in an artificial medium not containing lysine, remained hypersensitive to AA, but no longer showed decreased aggregation by collagen. Comparing the effects of lysine with equimolar concentrations of sucrose, EACA, and α-amino-n-butyric acid, we attribute the potent inhibitory effect of lysine to either the excess positive charge or H+ and C1− ions. The -NH2 group on the α-carbon on lysine appears to be the determining factor for the potentiation effect; the effect seems to be exerted on the cyclooxygenase level of AA metabolism. Lysine and other chemicals with platelet-affecting properties similar to lysine may be used as a tool for the study of the many aspects of a platelet aggregation reaction.

Effects of Ticlopidine of Platelet Function in Men with Stable Angina Pectoris

1985 ◽  
Vol 54 (04) ◽  
pp. 808-812 ◽  
Author(s):  
Ulf Berglund ◽  
Henning von Schenck ◽  
Lars Wallentin
Keyword(s):  
Platelet Aggregation ◽  
Angina Pectoris ◽  
Platelet Function ◽  
Plasma Levels ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Controlled Study ◽  
Double Blind ◽  
Platelet Factor

SummaryThe effects of ticlopidine (T) (500 mg daily) on platelet function were investigated in a double-blind placebo-controlled study in 38 middle-aged men with stable incapacitating angina pectoris. The in vitro platelet reactivity to aggregating agents, the platelet sensitivity to prostacyclin and the plasma levels of platelet specific proteins and fibrinogen were determined before and after 4 and 8 weeks of treatment. T exerted a potent inhibitory effect on ADP- and collagen-induced platelet aggregation. The effect of T was proportional to the pretreatment reactivity to ADP and collagen. The inhibitory effect of T on the epinephrine response was less pronounced. The plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen were not influenced by T. The platelet inhibition of prostacyclin was potentiated by T, and it was demonstrated that T and prostacyclin had synergistic inhibitory effects on platelet aggregation.

Sign in / Sign up

Export Citation Format

Share Document