Effects of different aspirin formulations on platelet aggregation times and on plasma salicylate concentrations

BACKGROUND: Early aspirin treatment is widely used to inhibit platelet activity and to reduce morbidity and mortality in patients presenting with an acute myocardial infarction or a stroke. A number of different aspirin formulations have been used for this purpose; however, a comparison of their effectiveness in inhibiting early platelet aggregation has not been determined. METHODS: In this study, we determined plasma salicylate concentrations and platelet inhibitory activities at various times after ingestion of three commonly used aspirin formulations: soluble aspirin (Alka-Seltzer), 325 mg, chewed baby aspirin, 324 mg, and whole compressed non-enteric coated aspirin, 324 mg. Twenty-four healthy volunteers, 18-39 years of age, participated in the prospective single-blinded triple-crossover study. Plasma salicylate concentrations and inhibition of arachidonic acid-induced platelet aggregation were determined on post-dose blood samples collected at 2.5, 5.0, 7.5, 10, 15, 20, 25, 30, and 40 min. All subjects crossed over to the other two formulations with at least 2 weeks between ingestions. RESULTS: The median platelet inhibition times for the chewed, soluble, and whole aspirin formulations were 7.5, 7.5, and 10.0 min, respectively. Soluble and chewed aspirin were found to inhibit platelet aggregation faster than whole aspirin (p<0.001); however, there were no significant differences in platelet aggregation times between the soluble and chewed formulations (p<0.163). Inhibition of platelet aggregation was found to occur at an average plasma salicylate concentration of 2.46 microg/mL, regardless of method of ingestion. CONCLUSION: The results indicate that soluble and chewed aspirin inhibit platelet aggregation in a shorter period of time than does whole aspirin. The results suggest that chewing baby aspirin or taking soluble buffered aspirin may be the preferred route of administration for early platelet inhibition.     

Aspirin kinetics and inhibition of platelet thromboxane generation-relevance for a solution of the "aspirin dilemma"

Six healthy male volunteers received aspirin (ASA) in a compressed (320 mg) and an enteric-coated (800 mg) formulation as single oral doses ten days apart. Ten plasma samples were obtained from each volunteer between 5 and 120 min after compressed ASA, and seven between 10 and 240 min after enteric-coated ASA. ASA was undetectable (less than 100 ng/ml) in plasma from three subjects receiving compressed ASA and two receiving the enteric-coated preparation. Plasma levels and kinetic parameters of salicylate were the same in subjects with undetectable and detectable ASA plasma levels. More than 98% inhibition of pre-drug serum TXB2 was noted in all samples collected one and four hours after either ASA preparation. TXB2 generation recovered on average by 3.5% at 24 hr with both preparations. Thus inhibition of platelet TXB2 generation occurred independently of the amount of ASA reaching the peripheral circulation. If this is due to inhibition of platelet function in the enterohepatic circulation followed by extensive first-pass deacetylation of ASA, vascular PGI2 synthesis could be spared. A better knowledge of the kinetic parameters of ASA for each of the formulations used in thrombosis prevention trials might help in solving the "aspirin dilemma".     

Measurement of aspirin concentrations in portal and systemic blood in pigs: effect on platelet aggregation, thromboxane and prostacyclin production

Low doses of enteric-coated aspirin were administered orally to pigs. Plasma aspirin concentrations measured in blood obtained simultaneously from permanent catheters in a systemic artery and portal vein for 6 hours after dosage showed a large variation in the plasma aspirin concentration: time profile between pigs. After 50 mg single dose the ratio of the arterial: portal area under the plasma concentration versus time curve (AUC) was 0.63 +/- 0.08 (mean +/- SE, n = 6). In three pigs which received all three dosage regimens, the arterial: portal AUC ratios were 0.48 +/- 0.05 after 50 mg single dose, 0.52 +/- 0.02 after 100 mg single dose and 0.47 +/- 0.02 after 100 mg daily for 1 week. Platelet aggregation in response to sodium arachidonate (1.65 mM) was completely abolished after chronic aspirin administration of 100 mg daily. Thromboxane production (pg/10(6) platelets) induced by this stimulus decreased from 536 +/- 117 before aspirin to 57 +/- 14 after aspirin (mean +/- SE, n = 4; p = 0.03). Aortic prostacyclin synthesis, measured as 6-keto PGF1 alpha (ng/disc after 10 min incubation), was 1.66 +/- 0.28 (mean +/- SE, n = 4) in untreated pigs and 0.95 +/- 0.25 (n = 5) in treated pigs (p = 0.07). Results from this study support the idea that a difference between aspirin concentrations in the portal and systemic circulations can be achieved. Whether this can be translated into a clinically useful differential effect on the vessel wall compared to the platelet remains to be determined.     

Why single daily dose of aspirin may not prevent platelet aggregation

The effect of different doses of aspirin on the synergistic activity of sodium arachidonate plus platelet activating factor (paf) ADP or collagen in platelet aggregation was studied in human volunteers. Aggregation studies in platelet rich plasma (PRP) showed that aspirinated platelets, unresponsive to arachidonate, when stirred with threshold concentrations of paf, ADP or collagen, reacted differently according to the dose of aspirin and the time elapsed since ingestion. After a single or daily 50 mg dose for 7-10 days independent of elapsed time until blood withdrawal, a complete synergistic activity was obtained. In PRP samples obtained 24 hours after the last aspirin intake, a complete synergistic aggregation was achieved after a single dose or after 7-10 days of 500 mg aspirin ingestion; synergistic effect did not appear when blood was drawn 2.5 hours after intake. The thromboxane B2 concentrations were very low in all samples after PRP stimulation with sodium arachidonate or paf or both. As rationale is that platelet activation in vivo occurs in response to several stimuli, the therapeutic implications of our results is that aspirin may not prevent the agonist potentiation effect when low dose or daily high dose (500mg) are administrated. This may explain the erratic results of most aspirin trials in which this drug was used to suppress platelet function.     

Effects of low dose aspirin on platelet function in patients with recent cerebral ischemia

We tested the antiplatelet effects of low-dose aspirin in patients with occlusive cerebrovascular disease, because conventional dosage aspirin inhibits vascular synthesis of prostacyclin at the same time that it inhibits platelets. The effects on platelet function and thromboxane A2 synthesis of 40 mg of aspirin daily or 40 mg aspirin plus dipyridamole were measured in 23 patients starting within a week after the onset of cerebral ischemia. All patients had normal baseline platelet aggregation responses to four stimuli: arachidonate, epinephrine, adenosine diphosphate and collagen. The generation of thromboxane A2 by platelets, measured as serum thromboxane B2, was also normal. After 3 to 7 days of low dose aspirin therapy, platelet aggregation responses were suppressed to the extent observed with higher dosage aspirin. Serotonin release during platelet aggregation was inhibited by more than 95% and thromboxane B2 levels in clotted blood fell by more than 95%. Responses to aspirin treatment were similar in patients with transient ischemic attacks and in those with stroke and were also similar in both sexes. No differences in platelet responses were observed between patients receiving aspirin alone and aspirin plus dipyridamole. Thus 40 mg aspirin daily inhibited platelet responses as effectively as higher doses of aspirin in patients who had recent cerebral ischemia and showed a cumulative antiplatelet effect.     

The antiplatelet effect of daily low dose enteric-coated aspirin in man: A time course of onset and recovery

We have studied the onset and recovery of inhibition of platelet function by low dose aspirin. Enteric-coated aspirin 50mg daily was administered to five human volunteers for five weeks and then 100mg daily was given for a further five weeks. We studied platelet aggregation and thromboxane formation in response to a range of stimuli: ADP, adrenaline, arachidonate and collagen, and also measured thromboxane formation after coagulation of whole blood (serum thromboxane). The onset of inhibition of platelet aggregation was progressive over several days for each of the four platelet stimuli, and was synchronous with the inhibition of thromboxane formation. Maximum inhibition occurred by day three for the weak stimuli ADP and adrenaline, by day five for the stronger stimuli arachidonate and collagen, but did not occur until day eight for serum thromboxane. Further inhibitory effects on both aggregation and thromboxane generation were observed after 100mg daily. Two weeks after the cessation of aspirin the responses to collagen and arachidonate and serum thromboxane had returned to normal. Platelet aggregation in response to the weaker stimuli, ADP and adrenaline, still showed detectable inhibition two weeks after cessation of aspirin, but had returned to normal by four weeks. These experiments provided no evidence for an effect of aspirin on platelets separate to its effect on cyclooxygenase. The onset and recovery of inhibition of platelet function by low dose aspirin was dependent on the strength of the stimulus studied.     

Effect of the combination of antiplatelet agents in man : Combination of aspirin, trapidil, ticlopidine and dipyridamole

An study of how platelet aggregation would be inhibited by the combination of aspirin or ticlopidine irreversibly inhibitory to platelet aggregation and trapidil or dipyridamole reversibly inhibitory, was carried out. The measured 50% inhibition concentrations indicated that aspirin was most inhibitory to collagen-induced platelet aggregation, followed by trapidil, ticlopidine and dipyridamole in decreasing sequence of inhibition. The combination of either aspirin or ticlopidine with trapidil inhibited platelet aggregation more intensely than the combination of either agent with dipyridamole. Thus, in clinical use of aspirin or ticlopidine, it may be expected that the lower dosage of aspirin or ticlopidine with lower frequencies of side effects inhibits platelet aggregation effectively with the combination of trapidil rather than dipyridamole.     

Dose- and time-dependent antiplatelet effects of aspirin

Aspirin is widely used, but dosages in different clinical situations and the possible importance of "aspirin resistance" are debated. We performed an open cross-over study comparing no treatment (baseline) with three aspirin dosage regimens--37.5 mg/day for 10 days, 320 mg/day for 7 days, and, finally, a single 640 mg dose (cumulative dose 960 mg)--in 15 healthy male volunteers. Platelet aggregability was assessed in whole blood (WB) and platelet rich plasma (PRP). The urinary excretions of stable thromboxane (TxM) and prostacyclin (PGI-M) metabolites, and bleeding time were also measured. Platelet COX inhibition was nearly complete already at 37.5 mg aspirin daily, as evidenced by >98% suppression of serum thromboxane B2 and almost abolished arachidonic acid (AA) induced aggregation in PRP 2-6 h after dosing. Bleeding time was similarly prolonged by all dosages of aspirin. Once daily dosing was associated with considerable recovery of AA induced platelet aggregation in WB after 24 hours, even after 960 mg aspirin. Collagen induced aggregation in WB with normal extracellular calcium levels (hirudin anticoagulated) was inhibited <40% at all dosages. TxM excretion was incompletely suppressed, and increased <24 hours after the cumulative 960 mg dose. Aspirin treatment reduced PGI-M already at the lowest dosage (by approximately 25%), but PGI-M excretion and platelet aggregability were not correlated. Antiplatelet effects of aspirin are limited in WB with normal calcium levels. Since recovery of COX-dependent platelet aggregation occurred within 24 hours, once daily dosing of aspirin might be insufficient in patients with increased platelet turnover.     

Effect of sodium arachidonate on thrombin generation through platelet activation--inhibitory effect of aspirin

BACKGROUND: Sodium arachidonate was used in this study to determine its capacity to generate thrombin through platelet activation. Whether aspirin prevent this effect was also investigated. METHODS AND RESULTS: Seventeen healthy volunteers without and after 160 mg/day aspirin intake for 3-5 days were studied. Lag-time and TG at basal condition and after platelet stimulation by sodium arachidonate (AA) were measured in normal non-aspirinated as well as "in vivo" aspirinated platelet rich plasma. (PRP). The lag-time was statistically significant shorter in non-aspirinated PRP activated with AA compared with non-activated PRP. This effect was inhibited by aspirin. In non-aspirinated PRP, there was an increase of TG at 4 and 6 min. incubation when platelets were activated with AA but the difference disappeared after 8 min. incubation, (84 +/- 71; 148 +/- 58 and 142 +/- 92 nmol/L respectively) compared with non-aspirinated. non-activated platelets (16 +/- 23; 55 +/- 56 and 111 +/- 76 nmol/L at 4,6 and 8 min, p < 0.0001, p < 0.0001 and p = 0.292, respectively). The AUCo-->22 min were 520.6 +/- 545.5 in non-aspirinated, non-stimulated PRP and 808.9 +/- 617, in non-aspirinated PRP activated with sodium arachidonate (p = 0.014). Aspirin administered in vivo produced a decrease of TG in PRP activated with AA. CONCLUSION: Platelet activated by AA trigged TG. This effect was inhibited by aspirin and could be an additional beneficial effect of aspirin in the prevention of thrombosis.     

Abciximab treatment in vitro after aspirin treatment in vivo has additive effects on platelet aggregation, ATP release, and P-selectin expression

To prevent arterial thrombosis, abciximab is administered together with aspirin. However, whether or not there are benefits to combine abciximab with aspirin is not yet well defined. Healthy volunteers were studied for the effect of aspirin+abciximab using sodium arachidonate and adenosine diphosphate (ADP) alone or in combination to induce platelet activation/aggregation. Abciximab produced complete inhibition of platelet aggregation induced with ADP but only 40% inhibition of aggregation induced by 0.75-mmol/l sodium arachidonate. Abciximab added in vitro to platelet-rich plasma (PRP) from platelets from aspirin-treated donors produced an almost complete inhibition of platelet aggregation. Aspirin, and abciximab alone, did not inhibit adenosine triphosphate (ATP) release as thoroughly as aspirin+abciximab did. Abciximab (3–5 μg/ml) produced inhibition of P-selectin expression induced with 5 (from 46.2±6.0% to 27.4±7.0%, P=.002) and 20-μmol/l ADP (from 53.1±8.1% to 35.1±11.0%, P=.019), but no effect was observed when 0.75-mmol/l sodium arachidonate was used (P=.721). Aspirin diminished P-selectin expression in sodium arachidonate-stimulated platelets (from 77.7±11.8% to 40.2±3.6%, P<.0001) in non-aspirinated and platelets from aspirin-treated donors, respectively. Abciximab (3, 4, and 5 μg/ml) added to platelets from aspirin-treated donors decreased P-selectin expression in platelets stimulated with sodium arachidonate from 40.2±8.6% to 25.6±11.5% (P=.027), to 20.5±3.5% (P<.0001), and to 22.5±1.8% (P<.0001). We concluded that the antiplatelet effect of abciximab is greatly increased by aspirin.     

Danish very-low-dose aspirin after carotid endarterectomy trial

The effect of very-low-dose aspirin as an antithrombotic agent was evaluated blindly in 301 patients who had recently undergone carotid endarterectomy. After randomization, 150 patients received aspirin and 151 received placebo. The two groups were comparable with regard to age, sex, blood pressure, previous cerebrovascular events, and smoking habits. The effect of the study medication on platelet aggregation was measured twice in each patient during the first 2 months and at each follow-up visit; the dose was individually adjusted. In 76% of the patients receiving aspirin, 50 mg/day gave satisfactory platelet inhibition, 13% needed 60 mg/day, 8% needed 70 mg/day, and 3% needed 100 mg/day. Platelet aggregation was found to be inhibited in only 1.2% of the measurements in the patients receiving placebo. Observation during treatment averaged 21 months; total intention-to-treat follow-up averaged 25 months. For the combined outcome events of transient ischemic attack, stroke, acute myocardial infarction, and vascular death, aspirin reduced risk by 11% (95% confidence limits: -38% to 48%, p greater than 0.1). Thus, there was no significant effect of very-low-dose aspirin in our trial.     

Individual variation in platelet aggregability and serum thromboxane B2 concentrations after low-dose aspirin

The effects of low daily oral doses of aspirin (40 mg/day) on platelet aggregability and serum thromboxane B2 concentrations were studied in 19 poststroke patients. Although platelet aggregation was reduced significantly after 1 week, there was wide individual variation in the inhibition of platelet function in spite of marked decreases of serum thromboxane B2 concentrations by greater than 90% (from 224 +/- 58 to 8 +/- 8 ng/ml). There was no correlation between collagen-induced platelet aggregability and serum thromboxane B2 concentration before aspirin administration in the range 100-350 ng/ml, but after 1 week of repeated administration of aspirin, there was a correlation between platelet aggregability and serum thromboxane B2 concentrations of less than 25 ng/ml (r = 0.68, p less than 0.01). However, platelet inhibition was insufficient even in some patients with markedly decreased thromboxane B2 concentrations (less than 5 ng/ml). Our results suggest that individual variation of platelet aggregability in response to low-dose aspirin may be due to variation not only in the degree of inhibition of thromboxane A2 production but also in the relative dependence of platelet aggregation on extra-arachidonic pathways.     

Synergistic actions of paf-acether and sodium arachidonate in human platelet aggregation. 2. Unexpected results after aspirin intake

The effect of sodium arachidonate and paf-acether on the activation of human platelet rich plasma from volunteers 2.30 to 36 hours after 500 mg of aspirin intake was studied. Concentrations of paf-acether which induce a reversible aggregation in platelet rich plasma (PRP) (0.29-0.029 microM) and concentrations of sodium arachidonate (AA) which don't produce aggregation (0.75-1mM) on the PRP from these volunteers, induced full aggregation when added together. But no cooperation activity was achieved in the 2.30 hours sample. Contrarily to the in vitro studies performed in human normal PRP, ASA (200 micrograms/ml) or indomethacin(12 microM) added to the PRP were unable to suppress the cooperative aggregation effect; neither did apyrase (12U/ml), esculetin (10 microM) or nordihydroguaiaretic acid (0.1 microM) have any action on the activated platelets but the synergistic action is completely suppressed by BW 755C (0.1 mM). TXB2 formation is very low in all these activated samples and insufficient to cause platelet aggregation. These results suggest 2 behaviors of platelets: synergistic activity of paf-acether and exogenous AA in vitro on normal human PRP is mediated mainly through active metabolites of AA formed via cyclooxygenase, as was previously published. When cyclooxygenase is inhibited in vivo by administration of 500 mg ASA, the cooperative effect of agonists is still present but the active aggregating product(s) is probably, formed through a pathway different of that of the cyclooxygenase or lypoxygenase.     

Effects of aspirin and alcohol on platelet thromboxane synthesis and vascular prostacyclin synthesis

We have studied interactions between aspirin and alcohol in vitro with regard to their effects on platelet thromboxane synthesis and vascular prostacyclin synthesis. Alcohol did not affect the inhibition by aspirin of platelet thromboxane synthesis. However, low concentrations of alcohol (0.05-0.15%, v/v) reversed the inhibition by aspirin of vascular prostacyclin synthesis. Since the effects on prostacyclin and thromboxane synthesis would favour bleeding rather than haemostasis, the observations reported herein may explain previous reports of a potentiation by alcohol of the aspirin-induced increase in bleeding time.     

Synergistic actions of PAF-acether and sodium arachidonate in human platelet aggregation. 1. Studies in normal human platelet rich plasma

The effect of sodium arachidonate and paf-acether in the activation of human platelet was studied. Concentrations of paf-acether which induced a reversible aggregation in normal human platelet rich plasma (0.029-0.0029 microM) and subthreshold concentrations of sodium arachidonate (0.25-0.35 mM), produced full aggregation when added together. Pre-exposition of platelets to paf-acether that renders them insensitive to paf-acether supresed the synergism. With full aggregation a markedly increase of thromboxane synthesis was detected by RIA. In vitro addition of aspirin (200 micrograms/ml) or indomethacin (12 microM) prevented aggregation and thromboxane formation by the joint action of sodium arachidonate plus paf-acether. Specific inhibition of 12-lipoxygenase by esculetin (10 microM) did not affect the synergistic action of paf-ace-ther and sodium arachidonate. These findings suggest that synergism between both agonists is mediated by active derivatives of arachidonic acid via cyclooxygenase.     

Combination therapy with low-dose aspirin and ticlopidine in cerebral ischemia

We compared combination therapy with low-dose aspirin plus ticlopidine to therapy with aspirin alone or ticlopidine alone in patients suffering transient ischemic attack or cerebral infarction. In 17, 24, and 23 patients, respectively, 300 mg/day aspirin, 200 mg/day ticlopidine, and 81 mg/day aspirin plus 100 mg/day ticlopidine were administered orally. Aspirin alone markedly inhibited platelet aggregation induced by arachidonic acid, partially inhibited platelet aggregation induced by adenosine diphosphate, and did not inhibit platelet aggregation induced by platelet activating factor. Ticlopidine alone inhibited platelet aggregation induced by adenosine diphosphate and platelet activating factor, but did not inhibit platelet aggregation induced by arachidonic acid. Combination therapy with aspirin plus ticlopidine markedly inhibited platelet aggregation induced by all three agonists. Plasma concentrations of beta-thromboglobulin and platelet factor 4 remained unchanged by aspirin alone, were slightly reduced by ticlopidine alone, and were markedly reduced by aspirin plus ticlopidine. Plasma concentration of thromboxane B2 was reduced by aspirin alone or with ticlopidine, but not by ticlopidine alone. The level of 6-ketoprostaglandin F1 alpha was reduced only by aspirin alone. Bleeding time was significantly prolonged by aspirin alone and by ticlopidine alone, although the greatest prolongation was produced by aspirin plus ticlopidine. Our results indicate that the combination of aspirin plus ticlopidine is a potent antiplatelet strategy, although the clinical importance of the changes observed need to be determined by a properly designed and controlled prospective study.     

Unexpected effects of aurin tricarboxylic acid on human platelets.

Aurin tricarboxylic acid (ATA) is a potent inhibitor of ristocetin-mediated platelet agglutination and of shear-induced, von Willebrand factor (vWf)-mediated platelet aggregation, probably via inhibition of vWf interaction with glycoprotein Ib (GPIb). We examined the effects of ATA (both the sodium salt and a solution of ATA in ethanol) on platelet functions in citrated plasma (PRP) and in suspensions of washed platelets in Tyrode-albumin solution (contains 2 mM Ca2+). ATA (42-211 micrograms/ml) blocked aggregation and release of granule contents induced by thrombin (0.15 U/ml in PRP; 0.03 U/ml in platelet suspension). Responses to higher concentrations of thrombin were not inhibited. ATA also prolonged thrombin-induced clotting of fibrinogen. Since ATA had no effect on fibrinogen-induced responses of chymotrypsin-treated platelets, ATA probably acts on thrombin rather than on fibrinogen. In PRP and platelet suspensions, ATA (acid form 106 micrograms/ml; sodium salt 122 micrograms/ml) had little effect on ADP-induced platelet aggregation. The sodium salt of ATA (61-122 micrograms/ml) enhanced collagen-induced aggregation and release by platelets in citrated plasma and by washed platelets; the enhancement was extensively inhibited by aspirin. With platelet suspensions, ATA significantly enhanced aggregation and release caused by low concentrations of sodium arachidonate (15-50 microM); aggregation and release caused by higher concentrations of arachidonate were somewhat inhibited by ATA. Arachidonate-induced aggregation and release were also enhanced by ATA in PRP. ATA enhanced aggregation and release induced by the calcium ionophore A23187; aspirin had little effect on the enhancement.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of platelet aggregation by abciximab but not by aspirin can be detected by a new point-of-care test, the hemostatus.

We have investigated the type of platelet defect that can be detected with the Hemostatus test performed with the Hepcon/HMS instrument (Medtronic) designed to investigate platelet function during and after surgery. This assay is based on the comparison of the activated clotting time of whole blood measured in cartridges containing kaolin or kaolin and platelet-activating factor in different concentrations. Addition of platelet-activating factor shortened the blood activated clotting time when the platelet counts were normal. However, when platelet counts were below 70000/microL, the activated clotting time was prolonged in all channels including those without platelet-activating factor showing the influence of platelets in the formation of the clot under the conditions tested. Inhibition of platelet aggregation with c7E3 (abciximab, ReoPro) also induced a much-prolonged activated clotting time, and a similar finding was seen with blood from a patient with Glanzmann's thrombasthenia confirming the need for platelet aggregation and/or the glycoprotein (GP) IIb-IIIa complex. In contrast, the interaction of GP Ib with von Willebrand Factor was not of major importance, since inhibition of this interaction with the anti-GP Ib murine monoclonal antibody, ALMA-12, did not modify the activated clotting time. Furthermore, the activated clotting time measured for patients with an acquired defect in von Willebrand Factor activity were unchanged. Finally, inhibition of thromboxane A2 formation by aspirin did not influence the results of this test. Globally, the Hemostatus test was able to detect major abnormalities of GP IIb-IIIa function in the presence or absence of platelet-activating factor.     

Inhibition of platelet aggregation in whole blood by dipyridamole and aspirin

We have examined the effects of dipyridamole on platelet aggregation in whole blood both in vitro and after administration to man. The effects of dipyridamole ex vivo were compared with those of aspirin and a combination of dipyridamole and aspirin. In vitro dipyridamole was most effective as an inhibitor of platelet aggregation induced by platelet activating factor (PAF) and low concentrations of arachidonic acid (AA). Its inhibitory effect was always potentiated by adenosine suggesting that its effect on aggregation may be via inhibition of adenosine uptake into blood cells. Ex vivo, dipyridamole, aspirin and the combination of these drugs inhibited the platelet aggregation induced by PAF and AA. Again, adenosine increased the degree of inhibition. These results stress the importance of measuring platelet aggregation in the natural whole blood environment for detection of the inhibitory effects of dipyridamole and suggest a mode of action for the drug.     

Effect of increasing doses of aspirin on platelet aggregation among stroke patients

BACKGROUND AND PURPOSE: Aspirin has been shown to reduce the risk of myocardial infarction and stroke. Some investigators believe that low-dose aspirin inhibits platelet aggregation to the same degree as high-dose aspirin. Our study aimed to assess the effect of increasing doses of aspirin on the degree of platelet aggregation induced by collagen and adenosine diphosphate (ADP) among stroke patients. METHODS: Sixteen poststroke patients were prescribed aspirin at daily doses of 40, 80, 160, 325, 650, and 1,300 mg, each dose to be taken for 14 days (total duration 12 weeks). Platelet aggregation studies using 2 microgram/ml collagen and 2 microM ADP were performed on platelet-rich plasma at baseline and on the 14th day of each dose. RESULTS: Platelet aggregation studies using 2 microgram/ml collagen at the start of treatment and at the 14th day of each dose revealed dose-dependent inhibition by aspirin starting at 40 mg/day, but was optimal at 80- 160 mg/day. ADP-induced platelet aggregation inhibition appears to be dose dependent up to 1,300 mg/day. CONCLUSION: Inhibition of collagen-induced platelet aggregation by aspirin appears to be optimal at 80-160 mg/day, while ADP-induced platelet aggregation inhibition by aspirin appears to be dose dependent up to 1,300 mg/day in our poststroke patients, albeit to a less remarkable degree at higher doses.