Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?

2004 ◽  
Vol 92 (07) ◽  
pp. 89-96 ◽  
Author(s):  
David Payne ◽  
Chris Jones ◽  
Paul Hayes ◽  
Sally Webster ◽  
A. Naylor ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Platelet Inhibition ◽  
Aspirin Resistance ◽  
Arachidonic Acid Metabolism ◽  
Significant Rise ◽  
Control Group

SummaryThe majority of patients who suffer peri-operative thromboembolic complication while undergoing vascular procedures do so despite taking aspirin. This study examined the antiplatelet effect of aspirin during surgery in patients undergoing carotid endarterectomy (CEA). Fifty patients undergoing CEA were standardised to 150 mg aspirin daily for ≥2 weeks. Platelet aggregation in response to arachidonic acid (AA) was measured in platelet rich plasma prepared from blood taken prior to, during, and at the end of surgery. Spontaneous platelet aggregation was also studied, as was the role of physiological agonists (ADP, collagen, thrombin, and epinephrine) in mediating the in vivo and in vitro responses to AA. Eighteen patients undergoing leg angioplasty, also on 150 mg aspirin, without general anaesthesia, served as a control group. In the CEA patients aggregation induced by AA (5 mM) increased significantly from 7.6 ± 5.5% pre-surgery to 50.8 ± 29.5% at the end of surgery (p <0.0001). Aggregation to AA was even greater in samples taken mid-surgery from a sub-set of patients (73.8 ± 7.2%; p = 0.0001), but fell to 45.9 ± 7.4% by the end of surgery. The increased aggregation in response to AA was not due to intra-operative release of physiological platelet agonists since addition of agents that block/neutralise the effects of ADP (apyrase; 4 µg/ml), thrombin (hirudin; 10 units/ml), or epinephrine (yohimbine; 10 µM/l) to the samples taken at the end of surgery did not block the increased aggregation.The patients undergoing angioplasty also showed a significant rise in the response to AA (5 mM), from 5.6 ± 5.5% pre-angioplasty to 32.4 ± 24.9% at the end of the procedure (p <0.0001), which fell significantly to 11.0 ± 8.1% 4 hours later. The antiplatelet activity of aspirin, mediated by blockade of platelet arachidonic acid metabolism, diminished significantly during surgery, but was partially restored by the end of the procedure without additional aspirin treatment.This rapidly inducible and transient effect may explain why some patients undergoing cardiovascular surgery remain at risk of peri-operative stroke and myocardial infarction.

INCREASED RESPONSE TO ARACHIDONIC ACID AND U-46619 AND RESISTANCE TO INHIBITORY PR0STAGLANDING IN PATIENTS WITH CHRONIC MYELOPROLIFE RATIVE DISORDERS

1987 ◽  
Author(s):  
S Cortelazzo ◽  
D Castagna ◽  
M Galli ◽  
T Barbui ◽  
G de Gaetano
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Functional Response ◽  
Platelet Rich Plasma ◽  
Myeloproliferative Disorders ◽  
Normal Subjects ◽  
Control Group ◽  
Arachidonate Metabolism ◽  
Pharmacologic Inhibition

The potency of prostaglandins (PGs) D2, I2 and as inhibitors of platelet aggregation induced by threshold aggregating concentration (TAC) of arachidonic acid (AA) and U-46619 was determined in platelet rich plasma from 20 normal subjects and 20 patients with thrombocytosis (≥500×l09 platelets/L) secondary to myeloproliferative disorders. Patients had a significantly increased response to both AA and U-46619 (p< 0.02) than the control group (i.e. TAC for AA, mean+SD, was 0.41±0.10 mM vs 0.48±0.12 mM ; TAC for U-46619 was 220±155 nM vs 375±102 nM). In contrast, platelet sensitivity to all three inhibitoty PGs was significantly lower in patients than in normal subjects. Indeed the threshold inhibiting concentrations (nM) of PGs against AA were the following: PGD2 20.33±4.16 vs 7.00±2.62 (p< 0.001), PGI2 0.76±0.46 vs 0.34±0.22 (p< 0.01) and PGE1 11.83±3.97 vs 6.50±2.22 (p<0.001). The corresponding inhibitory concentrations (nM) against U-46619 were the following: PGD2 4.67±4.24 vs 0.76±0.30 (p< 0.02), PGI2 1.15±0.96 vs 0.03±0.01 (p< 0.0001) and PGE1 21.12±15.27 vs 0.68± 0.30 (p< 0.0001). Selective pharmacologic inhibition of TxA2 sinthase by 40 μM dazoxiben resulted in 6 out of 11 “responders” in patients and 7 out of 10 in normal subjects, a difference not statistically significant. Serum TxB2 was slightly, but not significantly lower in patients than in controls (360±143 ng vs 390±155 ng/3×109 platelets/mL). It is suggested that in patients with myeloproliferative disorders platelet arachidonate metabolism is normal, but the functional response to aggregating and antiag-gregating prostanoids is altered towards a potential hyperaggrega bility. The relevanbe of this “in vitro” finding to thrombotic or haemorragic complications in these patients remains to be establi shed.

Effect of SR121566A, a Potent GP IIb-IIIa Antagonist on Platelet-mediated Thrombin Generation In Vitro and In Vivo

1998 ◽  
Vol 79 (02) ◽  
pp. 383-388 ◽  
Author(s):  
J. P. Herault ◽  
V. Peyrou ◽  
P. Savi ◽  
A. Bernat ◽  
J. M. Herbert
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Venous Thrombosis ◽  
Thrombin Generation ◽  
Platelet Rich Plasma ◽  
Venous Stasis ◽  
Lag Phase ◽  
Dependent Manner

SummaryThe effect of SR121566A, a new non-peptide GP IIb-IIIa antagonist was studied in vitro with regard to thrombin generation in platelet rich plasma and in vivo on stasis-induced venous thrombosis in the rabbit. SR121566A inhibited ADP-, arachidonic acid- and collagen-induced human platelet aggregation with IC50 values of 46 ± 7.5, 56 ± 6 and 42 ± 3 nM, respectively. In the same experimental conditions, SR121566A strongly inhibited thrombin generation triggered by low concentrations of tissue factor. SR121566A reduced in a dose-dependent manner both the area under the curve and the thrombin peak concentration but did not affect the lag phase (defined as the time until 10 nM thrombin was generated). Aspirin (100 µg/ml) did not affect thrombin generation.One hour after intravenous administration to rabbits, SR121566A exhibited a potent ex vivo inhibitory effect against ADP-, arachidonic acid- and collagen-induced platelet aggregation. The ID50 were 0.6 ± 0.25, 0.7 ± 0.08 and 0.13 ± 0.08 mg/kg, respectively. The ability of aspirin and SR121566A to affect venous stasis was determined in a stasis-induced venous thrombosis model in rabbits under high and low thrombogenic challenges. While aspirin was ineffective in both conditions, SR121566A significantly inhibited thrombus formation under low thrombogenic challenge demonstrating for the first time that a potent non-peptide platelet GP IIb-IIIa antagonist inhibits thrombin generation in vivo and exhibits a strong antithrombotic effect with regard to stasis-induced venous thrombosis. These results therefore confirm the existence of a close relationship between platelet activation and thrombin generation leading to blood coagulation but also emphasise the key role of platelets in the development of venous thrombosis, most likely through activation of the GP IIb-IIIa complex.

ADDITIVE EFFECT OF DILTIAZEM (DIL) ON THE INHIBITION OF PLATELET AGGREGATION PRODUCED BY ASPIRIN (ASA).

1987 ◽  
Author(s):  
R Altman ◽  
A Scazziota ◽  
S Windor ◽  
C A Dujovne
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Low Dose ◽  
Platelet Rich Plasma ◽  
Platelet Activating Factor ◽  
Significant Inhibition ◽  
Suppressive Therapy ◽  
Synergistic Activity

Platelet activation in vivo occurs by the action of several stimuli. It is generally agreed that actives products of arachidonic acid derived via the cyclooxy-genase pathway can stimulate platelet aggregation. ASA decrease thromboxane A2 generation and thereby inhibit platelet aggregation produced by AA and, partially, by others agonists. Nevertheless, the antiaggregating effect of ASA can be overcome by the conjointly activity of arachidonic acid(AA) and platelet activating factor (PAF). The inhibition of this cooperative aggregating effect can be important in platelet function suppressive therapy. The effect of DIL was tested in this sys tern. DIL was added in vitro to platelet rich plasma oS talned from volunteers before and after ASA(100mg/dayT intake for 7 days. DIL (2ug/ml) inhibited 50% platelet aggregation induced by AA (0.75mM) in non aspiri-nated volunteers. At even lower concentrations of DIL (0.4-lug/ml) an inhibition of aggregation induced by 300nM of PAF was also observed. After ASA, no aggregation by AA, only a first wave followed by disaggregation when PAF (30nM) was used and a full response when this pair of agonists were added together was obtained. DIL (0.lug/ml) added in vitro, produced significant inhibition of the synergism.The effect in vivo of DIL plus low dose of ASA was also explored. In vivo administration of therapeutic dose of DIL (60mg T.I.D.) and low dose of ASA (75-100 mg/day), prevented the synergistic activity of AA plus PAF on platelet aggregation. In conclusion, DIL may enhance the effectiveness of low dose of ASA in the prevention of arterial thromboembolism.

Enhancement of ADP-induced Platelet Aggregation by Adrenaline in Vivo and Its Prevention

1973 ◽  
Vol 29 (02) ◽  
pp. 490-498 ◽  
Author(s):  
Hiroh Yamazaki ◽  
Itsuro Kobayashi ◽  
Tadahiro Sano ◽  
Takio Shimamoto
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
The Other ◽  
Endothelial Surface ◽  
Important Interaction ◽  
Blood Coagulability ◽  
The Difference

SummaryThe authors previously reported a transient decrease in adhesive platelet count and an enhancement of blood coagulability after administration of a small amount of adrenaline (0.1-1 µg per Kg, i. v.) in man and rabbit. In such circumstances, the sensitivity of platelets to aggregation induced by ADP was studied by an optical density method. Five minutes after i. v. injection of 1 µg per Kg of adrenaline in 10 rabbits, intensity of platelet aggregation increased to 115.1 ± 4.9% (mean ± S. E.) by 10∼5 molar, 121.8 ± 7.8% by 3 × 10-6 molar and 129.4 ± 12.8% of the value before the injection by 10”6 molar ADP. The difference was statistically significant (P<0.01-0.05). The above change was not observed in each group of rabbits injected with saline, 1 µg per Kg of 1-noradrenaline or 0.1 and 10 µg per Kg of adrenaline. Also, it was prevented by oral administration of 10 mg per Kg of phenoxybenzamine or propranolol or aspirin or pyridinolcarbamate 3 hours before the challenge. On the other hand, the enhancement of ADP-induced platelet aggregation was not observed in vitro, when 10-5 or 3 × 10-6 molar and 129.4 ± 12.8% of the value before 10∼6 molar ADP was added to citrated platelet rich plasma (CPRP) of rabbit after incubation at 37°C for 30 second with 0.01, 0.1, 1, 10 or 100 µg per ml of adrenaline or noradrenaline. These results suggest an important interaction between endothelial surface and platelets in connection with the enhancement of ADP-induced platelet aggregation by adrenaline in vivo.

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.

Testosterone Potentiation of Ionophore and ADP Induced Platelet Aggregation : Relationship to Arachidonic Acid Metabolism

1981 ◽  
Vol 46 (02) ◽  
pp. 538-542 ◽  
Author(s):  
R Pilo ◽  
D Aharony ◽  
A Raz
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Unsaturated Fatty Acids ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Arachidonic Acid Metabolism ◽  
Ionophore A23187 ◽  
Low Concentrations ◽  
Induced Aggregation

SummaryThe role of arachidonic acid oxygenated products in human platelet aggregation induced by the ionophore A23187 was investigated. The ionophore produced an increased release of both saturated and unsaturated fatty acids and a concomitant increased formation of TxA2 and other arachidonate products. TxA2 (and possibly other cyclo oxygenase products) appears to have a significant role in ionophore-induced aggregation only when low concentrations (<1 μM) of the ionophore are employed.Testosterone added to rat or human platelet-rich plasma (PRP) was shown previously to potentiate platelet aggregation induced by ADP, adrenaline, collagen and arachidonic acid (1, 2). We show that testosterone also potentiates ionophore induced aggregation in washed platelets and in PRP. This potentiation was dose and time dependent and resulted from increased lipolysis and concomitant generation of TxA2 and other prostaglandin products. The testosterone potentiating effect was abolished by preincubation of the platelets with indomethacin.

Decreased Platelet Vitamin C in Diabetes Mellitus; Possible Role in Peraggregatoon

1979 ◽  
Author(s):  
K.E. Sarji ◽  
J. Gonzalez ◽  
H. Hempling ◽  
J.A. Colwell
Keyword(s):  
Ascorbic Acid ◽  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Vitamin C ◽  
Platelet Rich Plasma ◽  
Solution Ph ◽  
Dose Dependent Fashion ◽  
Insulin Dependent Diabetic ◽  
Induced Aggregation

To determine whether Vitamin C might relate to the increased platelet sensitivity in the diabetic, we have measured levels of platelet Vitamin C and studied the effects of Vitamin C on platelet aggregation. Ascorbic acid levels in washed platelets from diabetics were significantly lower than from normals (4s.2±3 μg/1010 platelets vs. 2s.s±2 μg/1010 platelets, p<.001). The effects of ascorbic acid on platelet aggregation in vitro were studied by adding ascorbic acid in buffered solution (pH 7.35) prior to-aggregating agents. Ascorbic acid in platelet-rich plasma consistently inhibited platelet aggregation with threshold concentrations of ADP, epinephrine, and collagen. With washed platelets, ascorbic acid inhibited arachidonic, acid-induced aggregation. When platelets were incubated at 37°C for 10 minutes with varying concentrations of ascorbic acid, rewashed, and aggregation with arachidonic acid tested, aggregation was inhibited in a linear dose-dependent fashion. Oral ingestion of ascorbic acid (2 gm/day) for seven days by normal non-smoking males produced a marked inhibition of aggregation. In a similar study, platelets from an insulin-dependent diabetic showed no change in aggregation. These results suggest that platelet levels of ascorbic acid may relate to the hyperaggregat ion of platelets from diabetics.

Effects of Ethanol on Pathways of Platelet Aggregation In Vitro

1988 ◽  
Vol 59 (03) ◽  
pp. 383-387 ◽  
Author(s):  
Margaret L Rand ◽  
Marian A Packham ◽  
Raelene L Kinlough-Rathbone ◽  
J Fraser Mustard
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Secondary Phase ◽  
Primary Phase ◽  
Rabbit Platelet ◽  
Membrane Phospholipids ◽  
Rabbit Platelets ◽  
Induced Aggregation

SummaryEthanol, at physiologically tolerable concentrations, did not affect the primary phase of ADP-induced aggregation of human or rabbit platelets, which is not associated with the secretion of granule contents. Potentiation by epinephrine of the primary phase of ADP-induced aggregation of rabbit platelets was also not inhibited by ethanol. However, ethanol did inhibit the secondary phase of ADP-induced aggregation which occurs with human platelets in citrated platelet-rich plasma and is dependent on the formation of thromboxane A2. Inhibition by ethanol of thromboxane production by stimulated platelets is likely due to inhibition of the mobilization of arachidonic acid from membrane phospholipids, as ethanol had little or no effect on aggregation and secretion induced by arachidonic acid or the thromboxane mimetic U46619. Rabbit platelet aggregation and secretion in response to low concentrations of collagen, thrombin, or PAF were inhibited by ethanol. Inhibition of the effects of thrombin and PAF was also observed with aspirin-treated platelets. Thus, in addition to inhibiting the mobilization of arachidonate for thromboxane formation that occurs with most agonists, ethanol can also inhibit aggregation and secretion through other effects on platelet responses.

scholarly journals Are Platelet Aggregation Tests the Best Way to Assess New Drugs for Arterial Disease

2018 ◽  
Vol 1 (1) ◽  
pp. 01-03
Author(s):  
Mark I. M. Noble
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Platelet Rich Plasma ◽  
New Drugs ◽  
In Vitro Test ◽  
In Vivo Efficacy ◽  
Experimental Animals ◽  
Stenosed Artery

Over many years, laboratory testing of platelet aggregability have been carried out in attempts to develop drugs that would prevent thrombosis in arteries. The problems encountered included the question of methodology. Blood samples have to be anticoagulated in order to study the platelets. Anti-coagulation with citrate and tests on derived platelet rich plasma did not correlate at all well with thrombus growth in the stenosed coronary arteries of experimental animals and citrate removes the calcium ions which are vital for platelet function. Anticoagulation with heparin also interfered with platelet function, so that now, hirudins are the preferred anticoagulant. However it was observed that if, instead of stimulating platelet aggregation with adrenaline or ADP, serotonin was applied to the preparation, very little aggregation took place in spite of serotonin 5HT2A antagonists being the most potent inhibitors of thrombus growth in experimental animals. Another indicator that primary platelet agggregation is not a predictor of in vivo efficacy was the finding that 5HT2A antagonism inhibited aggregate growth. In a stenosed artery the platelets are activated by increased shear stress and blood turbulence with release of platelet serotonin causing positive feedback activation of more platelets. At present, there does not seem to be a bench in vitro test that accurately predicts in vivo efficacy in stenosed artery occlusive thrombosis.

Arginine vasopressin release from human platelets after irreversible aggregation

1990 ◽  
Vol 78 (1) ◽  
pp. 113-116 ◽  
Author(s):  
Giovanni Anfossi ◽  
Elena Mularoni ◽  
Mariella Trovati ◽  
Paola Massucco ◽  
Luigi Mattiello ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Arginine Vasopressin ◽  
Platelet Rich Plasma ◽  
Human Platelets ◽  
Vasopressin Release ◽  
Irreversible Aggregation ◽  
Local Release

1. The release of arginine vasopressin from human platelets was investigated in platelet-rich plasma after irreversible aggregation induced by adenosine 5′-pyrophosphate, collagen, sodium arachidonate, thrombin and adrenaline in vitro. 2. Arginine vasopressin levels were significantly higher in the supernatant from stimulated platelet-rich plasma than from unstimulated samples, reaching 3.5 × 10−12 (range 1.6–12.5 × 10−12) mol/l in the absence of an aggregating agent, 8.8 × 10−12 (range 4.2–17.5 × 10−12) mol/l after adenosine 5′-pyrophosphate, 13.7 × 10−12 (2.2–63.2 × 10−12) mol/l after collagen, 7.8 × 10−12 (2.2–14.6 × 10−12) mol/l after sodium arachidonate, 7.8 × 10−12 (2.2–16.3 × 10−12) mol/l after thrombin and 12.2 × 10−12 (4.8–32.1 × 10−12) mol/l after adrenaline. 3. An arginine vasopressin level of 18 × 10−12 mol/l, which can be achieved physiologically, increased the sensitivity of platelets to adenosine 5′-pyrophosphate and collagen in vitro; the same concentration of arginine vasopressin caused a potentiation of the effect of catecholamines on the response of platelets to sodium arachidonate. 4. These results indicate that intraplatelet arginine vasopressin is released during aggregation and suggest that a local release of arginine vasopressin could occur after complete platelet aggregation in vivo.

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