scholarly journals Pharmacologic inhibition of thromboxane synthetase and platelet aggregation: modulatory role of cyclooxygenase products

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1460-1466 ◽  
Author(s):  
V Bertele ◽  
A Falanga ◽  
M Tomasiak ◽  
C Chiabrando ◽  
C Cerletti ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Normal Subjects ◽  
Gas Chromatography Mass Spectrometry ◽  
Thromboxane Synthetase ◽  
High Resolution Gas Chromatography ◽  
Pharmacologic Inhibition

Abstract Dazoxiben , an imidazole-derived selective inhibitor of thromboxane A2 (TxA2) synthetase, prevented TxB2 synthesis in vitro in platelet-rich plasma from 16 normal subjects. Inhibition of TxB2 synthesis was accompanied by increased generation of PGE2, PGF2 alpha, and PGD2, as shown by radioimmunoassay, thin-layer radiochromatography, and high- resolution gas chromatography-mass spectrometry. Even at dazoxiben concentrations (40–80 microM) above those inhibiting TxB2 synthesis, platelet aggregation induced by threshold concentrations of arachidonic acid was inhibited in only 4 of 16 subjects, referred to as responders. The remaining 12 individuals were defined as nonresponders. The aggregating effect of arachidonic acid and of the prostaglandin- endoperoxide analog U-46619 was potentiated by PGE2 and prevented by PGD2 at concentrations within the range of those detected in dazoxiben - treated platelet-rich plasma. The antiaggregating effect of dazoxiben was counteracted by PGE2 (in responders) and was potentiated by PGD2 (in nonresponders). Platelets from responders and nonresponders did not differ in the amount of immunoreactive PGE2 material or in their sensitivity to U-46619 or PGD2. It is concluded that inhibition of thromboxane synthetase does not per se prevent platelet aggregation. The functional result of thromboxane suppression appears to be modulated by an interplay of the prostaglandin-endoperoxides, PGE2 and PGD2, which are formed in excess.

scholarly journals Pharmacologic inhibition of thromboxane synthetase and platelet aggregation: modulatory role of cyclooxygenase products

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1460-1466
Author(s):  
V Bertele ◽  
A Falanga ◽  
M Tomasiak ◽  
C Chiabrando ◽  
C Cerletti ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Normal Subjects ◽  
Gas Chromatography Mass Spectrometry ◽  
Thromboxane Synthetase ◽  
High Resolution Gas Chromatography ◽  
Pharmacologic Inhibition

Dazoxiben , an imidazole-derived selective inhibitor of thromboxane A2 (TxA2) synthetase, prevented TxB2 synthesis in vitro in platelet-rich plasma from 16 normal subjects. Inhibition of TxB2 synthesis was accompanied by increased generation of PGE2, PGF2 alpha, and PGD2, as shown by radioimmunoassay, thin-layer radiochromatography, and high- resolution gas chromatography-mass spectrometry. Even at dazoxiben concentrations (40–80 microM) above those inhibiting TxB2 synthesis, platelet aggregation induced by threshold concentrations of arachidonic acid was inhibited in only 4 of 16 subjects, referred to as responders. The remaining 12 individuals were defined as nonresponders. The aggregating effect of arachidonic acid and of the prostaglandin- endoperoxide analog U-46619 was potentiated by PGE2 and prevented by PGD2 at concentrations within the range of those detected in dazoxiben - treated platelet-rich plasma. The antiaggregating effect of dazoxiben was counteracted by PGE2 (in responders) and was potentiated by PGD2 (in nonresponders). Platelets from responders and nonresponders did not differ in the amount of immunoreactive PGE2 material or in their sensitivity to U-46619 or PGD2. It is concluded that inhibition of thromboxane synthetase does not per se prevent platelet aggregation. The functional result of thromboxane suppression appears to be modulated by an interplay of the prostaglandin-endoperoxides, PGE2 and PGD2, which are formed in excess.

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.

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 Haemodynamic flow conditions at the initiation of high-shear platelet aggregation: a combined in vitro and cellular in silico study

2020 ◽  
Vol 11 (1) ◽  
pp. 20190126 ◽  
Author(s):  
B. J. M. van Rooij ◽  
G. Závodszky ◽  
A. G. Hoekstra ◽  
D. N. Ku
Keyword(s):  
Platelet Aggregation ◽  
In Silico ◽  
Platelet Rich Plasma ◽  
High Shear ◽  
Shear Rates ◽  
Flow Simulations ◽  
In Silico Study ◽  
Platelet Aggregates

The influence of the flow environment on platelet aggregation is not fully understood in high-shear thrombosis. The objective of this study is to investigate the role of a high shear rate in initial platelet aggregation. The haemodynamic conditions in a microfluidic device are studied using cell-based blood flow simulations. The results are compared with in vitro platelet aggregation experiments performed with porcine whole blood (WB) and platelet-rich-plasma (PRP). We studied whether the cell-depleted layer in combination with high shear and high platelet flux can account for the distribution of platelet aggregates. High platelet fluxes at the wall were found in silico . In WB, the platelet flux was about twice as high as in PRP. Additionally, initial platelet aggregation and occlusion were observed in vitro in the stenotic region. In PRP, the position of the occlusive thrombus was located more downstream than in WB. Furthermore, the shear rates and stresses in cell-based and continuum simulations were studied. We found that a continuum simulation is a good approximation for PRP. For WB, it cannot predict the correct values near the wall.

Abstract 4023: Aspirin “Resistance”: Role of Pre-existent Platelet Reactivity and Correlation Between Tests

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Andrew L Frelinger ◽  
Youfu Li ◽  
Matthew D Linden ◽  
Inge Tarnow ◽  
Marc R Barnard ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Function ◽  
Normal Subjects ◽  
Aspirin Resistance ◽  
The Other ◽  
List Type ◽  
Platelet Function Test ◽  
Function Test

Background: Aspirin “resistance” (i.e. hyporesponsiveness to aspirin in a platelet function test) has been widely reported, but the underlying mechanism is unclear. We examined the role of pre-existent platelet hyperreactivity in aspirin “resistance”. We also determined the correlation between aspirin resistance defined by serum thromboxane (TX) B 2 (the most specific test of aspirin’s effect) and other assays of platelet function. Methods: Platelet function measured before and after aspirin 81 mg daily for 7 days was analyzed by Spearman’s rank correlation. Normal subjects (n=165) were studied because virtually all clinically relevant patients are already taking aspirin. An additional advantage of the use of normal subjects is that the platelet response to stimuli is not influenced (with resultant increased scatter of the data) by an underlying disease, e.g. coronary artery disease, which causes platelet hyperreactivity. Results: The proportion of the post-aspirin platelet function predicted by the pre-aspirin platelet function was 28.3 ± 7.5% (mean ± asymptotic standard error) for serum TXB 2 , 39.3 ± 6.8% for urinary 11-dehydro TXB 2 , 4.4 ± 7.7% for arachidonic acid-induced platelet aggregation, 40.4 ± 7.1% for ADP-induced platelet aggregation, 26.3 ± 9.2% for the VerifyNow Aspirin Assay®, and 45.0 ± 10.9% for the TEG® PlateletMapping ™ System with arachidonic acid. Spearman rank order correlations were highly significant for comparisons between assays when both pre-aspirin and post-aspirin results were included in the analysis. However, residual serum TXB 2 levels post-aspirin treatment were not significantly associated with post-treatment results of any of the other assays. Platelet count correlated with pre-aspirin serum TXB 2 and VerifyNow Aspirin Assay, but not with any post-aspirin platelet function test. Conclusions: Aspirin “resistance” (i.e. hyporesponsiveness to aspirin in a laboratory test) is in part unrelated to aspirin but is the result of underlying platelet hyperreactivity prior to the institution of aspirin therapy. Individuals identified as aspirin “resistant” defined by serum TXB 2 are not the same individuals identified by the other tests.

Diabetic Retinopathy And Thromboxane Like Substance

1981 ◽  
Author(s):  
M A Lazzari ◽  
M Gimeno ◽  
N M Sutton ◽  
J R Lopez
Keyword(s):  
Diabetes Mellitus ◽  
Arachidonic Acid ◽  
Diabetic Retinopathy ◽  
Risk Factor ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Thromboxane A2 ◽  
Initial Step ◽  
Platelet Activity

Diabetes Mellitus (DM) is a risk factor in the development of vasculopathies and its complications. It produces also its own microangiopathy. Evidence was reported of increased platelet activity in DM in different assays. Platelets aggregation and the arachidonic cycle could play a key role in the increased tendency to thrombosis. A disorder of ratio TXA2/PGI2, two opposing prostaglandin derivatives, could be the initial step. We intended to evaluate a thromboxane like substance (TLS) produced from platelet rich plasma (PRP) and to compare between normals and diabetic retinopathy (DR) patients. TLS was measured in 16 controls and 16 patients. Assay was done with the aggregating activity developed in PRP (considered TLS) after addition of arachidonic acid (f.c. 2 mM). The supernatant of the PRP (100 μl) was taken 40 sec. after the aggregation started and were added to a normal PRP treated with aspirin (f.c. 40 μl/ml) adjusted to 250.000 - 300.000 pl/μl and the degree of platelet aggregation measured in a Chrono Log Aggregometer. TLS was inactivated after its incubation during 2 min. at 37°C. This finding suggests this activity is due to TXA2.The results obtained (expressed in % of platelet aggregation) were: controls x 16.37% ± 6.28 and DR x 36.00% ± 9.72.The increase detected in the DR group supports previous experimental reports suggesting the role of the thromboxane A2 in vaso occlusive complication of diabetes mellitus.

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.

scholarly journals Monitoring the entry of new platelets into the circulation after ingestion of aspirin

Blood ◽  
1983 ◽  
Vol 61 (6) ◽  
pp. 1081-1085
Author(s):  
G Di Minno ◽  
MJ Silver ◽  
S Murphy
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
In Vitro Experiments ◽  
Early Entry ◽  
Cyclooxygenase Activity ◽  
Aspirin Ingestion ◽  
Thromboxane Formation

There have been reports of a 24–48-hr delay in the recovery of platelet cyclooxygenase activity and platelet function after the ingestion of aspirin. However, these studies employed a single aggregating agent to stimulate enzymatic or functional activity. We investigated the effects of some pairs of aggregating agents on 14 platelet-rich plasmas (PRP) from normal subjects 2 and 4 hr after ingestion of 650 mg aspirin and daily up to 72 hr. We studied platelet aggregation and secretion with a lumiaggregometer and thromboxane-B2 formation by radioimmunoassay. Aggregation and secretion occurred as early as 4 hr after aspirin ingestion in response to combinations of arachidonic acid with epinephrine, collagen, or adenosine diphosphate (ADP). Thromboxane formation was detected as early as 4 hr after ingestion of aspirin in response to 1 mM arachidonic acid in combination with 1 microgram/ml collagen. Up to 72 hr, there was a linear return of thromboxane formation stimulated by this combination, reflecting the entry of new platelets into the circulation. In vitro experiments with mixtures of aspirin-free and aspirin-treated platelets showed that the combination of collagen and arachidonic acid (AA) could produce full aggregation and secretion when only 2.5% of aspirin-free platelets were present. Use of the combination of collagen plus AA demonstrates the early entry into the circulation of platelets originating from megakaryocytes whose cyclooxygenase has not been completely acetylated.

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