Aspirin-induced Platelet Inhibition Research Articles

Fibrin clot permeability (Ks) in patients on left ventricular assist device

Patients on left ventricular assist devices (LVAD) are prone to excessive hemostasis disturbances due to permanent contact of artificial pump surfaces with blood components. We aimed to investigate if fibrin clot permeability is altered in patients on long-term continuous-flow LVAD therapy and if the clot permeability is associated with clinical characteristics and adverse events. We investigated 85 end-stage heart failure patients (90.6% men, age 48.6–63.8 years) scheduled for continuous flow long-term LVAD support according to current clinical indications. The patients were assessed periodically: prior to LVAD implantation (T1), 3–6 months (T2) after LVAD implantation, 6–12 months after (T3) and then every 6 months. We tested the first three blood samples (T1-T3) and the last available blood sample (T4), but no longer than 5 years after LVAD implantation. We assessed hemostasis parameters (Activated Partial Thromboplastin Time (APTT) Prothrombin Time, Activated Partial Thromboplastin Time, Fibrinogen, d-dimer, Antithrombin, Thrombin Time, Factor VIII, and von Willebrand Factor, aspirin-induced platelet inhibition, adenosine-diphosphate test) changes during the study period. Fibrin Clot Permeability was evaluated using a pressure system and Permeability Coefficient (Ks) was calculated. We observed a decrease in fibrin clot permeability (Ks) between T1, T2, T3 and T4 time periods; P < 0.01 for each comparison. Fibrin clot permeability was negatively correlated with fibrinogen concentration: r = − 0.51, P < 0.001, factor VIII activity r = − 0.42, P < 0.001. There was no association of Ks with age, Left Ventricular Ejection Fraction (LVEF) and medications P > 0.001, however cumulative measurements in patients on aspirin showed shortening of Ks in this group P = 0.0123. Major adverse cardiac and cerebrovascular events (MACCE) occurred in 36.5% patients, bleeding events in 25.9%, Net Adverse Clinical Events (NACE) in 62.4%; 31.7% patients died, and 17.6% underwent transplantation. The transplantation was considered as the endpoint. Discrepancies in Ks were observed between patients with MACCE, bleeding, and NACE, and patients without adverse events. Ks showed a constant trend towards normalization (P < 0.01) only in patients without adverse events. Patients with advanced heart failure have disturbed clot structure. A trend towards normalization of the Ks values is associated with fewer thromboembolic and bleeding complications in this group of patients.

Individual predictors of platelet response to aspirin therapy in pregnancy

Aspirin (81mg daily) reduces the risk of preeclampsia in high-risk individuals, however, up to 30% of treated high-risk individuals still develop preeclampsia. Aspirin response in non-pregnant adults can vary widely. The objective of this study is to identify individual factors predictive of response to aspirin therapy in pregnancy. PFA-100 closure time is a measure of platelet response to epinephrine and is a quantitative measure of aspirin induced platelet inhibition. We conducted a prospective cohort study at Thomas Jefferson University Hospital of 130 patients with a singleton pregnancy at risk for preeclampsia and recommended aspirin therapy, 81mg daily initiated ≤16 weeks. PFA-100 closure time was analyzed at baseline and then 2-4 weeks after aspirin initiation. The primary outcome was PFA-100 closure time at follow-up #1. Predictors were evaluated with multivariable least squares model with stepwise variable selection using R package. 114 participants completed follow-up visit #1 with complete data for all variables. Average gestational age at baseline was 12.6±1.5 and at follow-up#1 was 16.0 ±2.3 weeks’ (p< 0.001). There was a significant increase in mean PFA-100 from baseline to follow-up #1 (131±39 vs 170±61, p< 0.001). In multivariable logistic regression, obesity and pre-gestational diabetes were associated with reduced aspirin response (lower PFA-100). Those with diabetes or obesity had lower mean PFA-100 at follow up in unadjusted and adjusted analyses (Figure). In contrast, Black race was associated with increased platelet response to aspirin therapy (MD 29 (95% CI 7-51), p=0.01) (Table). Baseline PFA-100 was also positively associated with follow-up PFA-100 (Table). Individuals with pre-gestational diabetes or obesity have a reduced platelet response to aspirin therapy. This is consistent with findings in non-pregnant adults. Aspirin dosing in pregnancy may need to be adjusted based on individual characteristics.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Time to peak effect of aspirin-induced platelet inhibition and ex vivo effects of desmopressin: an observational study

Objective: To investigate time to maximal platelet inhibition after an oral loading dose of ASA. The effect of ex vivo reversal platelet inhibition by desmopressin (DDAVP) was also studied. Methods: Ten healthy volunteers were given a 300 mg ASA-tablet. Blood was sampled at 0, 15, 30, 60, 120 and 180 minutes. DDAVP was added to the samples taken at 120 minutes. Samples were analysed with a Multiplate® platelet aggregometer (MEA) using arachidonic acid (AA), collagen and thrombin aggregation agonists. Results: Platelet inhibition was observed in the sample activated by AA at 15 minutes but not until 120 minutes in the samples activated by collagen. No platelet inhibition was seen in the samples activated by thrombin. The median time to maximal AA-induced platelet inhibition of <30 U was 30 (interquartile range 15-90) minutes. Ex vivo DDAVP did not reverse platelet inhibition. Subgroup analysis did not show any gender differences. Conclusions: ASA induces a strong platelet inhibition within 30 minutes of oral ingestion, with no gender differences. Ex vivo DDAVP did not reverse ASA’s platelet inhibition. (Less)

Morphine Interaction with Aspirin: a Double-Blind, Crossover Trial in Healthy Volunteers

Aspirin is a cornerstone in the antiplatelet therapy for acute coronary syndromes. Coadministration of morphine may potentially influence the intestinal absorption, pharmacokinetics, and pharmacodynamics, as seen with P2Y12 inhibitors. In this trial, healthy volunteers were randomized to receive morphine (5 mg, i.v. bolus injection) at one of seven different time points before, after, or with aspirin (162 mg, p.o.) in a double-blind, placebo-controlled fashion. After a 14-day washout, subjects received placebo instead of morphine. Pharmacokinetics were determined by liquid chromatography, and aspirin's effects were measured by platelet function tests (whole-blood platelet aggregation: multiplate, platelet plug formation: PFA-100). Morphine increased the total acetylsalicylic acid exposure by 20% compared with placebo when given simultaneously with aspirin, whereas Cmax and tmax were not altered. Morphine had no significant effect on aspirin-induced platelet inhibition. In contrast to coadministration with P2Y12 inhibitors, morphine appears to have negligible interaction with aspirin.

Aspirin responsiveness changes in obese patients following bariatric surgery.

Bariatric surgery has emerged as a promising treatment option for weight loss and to counter the metabolic consequences of obesity. Obesity has been linked to a hyperaggregable state, as well as a blunted response to aspirin. This pilot study assessed the hypothesis that bariatric surgery would lead to an improvement in aspirin-induced platelet inhibition and a reduction in platelet aggregability. Fifteen patients scheduled to undergo bariatric surgery were administered two 7-day courses of aspirin 81mg: the first course administered before surgery and the second was 3months following surgery. Platelet aggregation was measured before and after each aspirin course using VerifyNow-Aspirin. The primary endpoint was the change in on-treatment aspirin reactive units (ARU) pre- and postsurgery. Data from bariatric surgery study patients were compared to data of normal weighted subjects gathered in a previous study. Roux-en-Y gastric bypass was performed in 80%, and 20% underwent sleeve gastrectomy. The mean starting body mass index (BMI) was 46.9kg/m2 . Patients lost on average 24.5kg, resulting in a postsurgical BMI of 38.5kg/m2 . Postbariatric surgery, off-treatment ARU was significantly reduced from presurgery levels (602±59 vs 531±78; P=.035). On-aspirin platelet reactivity was also significantly reduced following surgery (469±60 vs 432±143, P=.03). There was a significant correlation between the extent of weight loss and the degree of improvement in on-aspirin platelet reactivity (r2 =.49, P=.024). Presurgery on-aspirin platelet reactivity was significantly higher in obese patients compared to normal weighted subjects (469±60 vs 419±52; P=.016) and reduced to the baseline after the surgery (432±63 vs 419±52; P=.54). Aspirin-induced platelet inhibition may be more potent following bariatric surgery. The mechanisms behind this improvement require further investigation.

12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition.

BackgroundAspirin is one of the most widely used non-steroidal anti-inflammatory drugs (NSAIDs). It is also a commonly used anti-platelet drug, which inhibits the formation of the platelet activator, thromboxane A2 (TxA2) via inhibition of cyclooxygenase-1 (COX-1). However, the presence of a patient subset that fails to respond to aspirin despite reduced TxA2 concentrations suggests that the effect of aspirin might be more complex than exclusive COX-1 inhibition.MethodsIn this study we evaluated the impact of in vivo oral administration of a standard anti-platelet dose (75 mg) of aspirin in healthy volunteers on the acute impact of in vitro collagen-mediated platelet aggregation and generation of platelet-derived TxA2 and the 12-lipoxygenase (LOX) metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The eicosanoids were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).ResultsLow-dose aspirin administration not only inhibited TxA2 generation but also decreased the production of 12-HETE. Furthermore, a significant correlation was observed between the levels of 12-HETE and collagen-induced platelet aggregation. Pre-treatment of platelets with the 12-LOX inhibitor, baicalein, prior to activation attenuated platelet aggregation.ConclusionsThese findings support a role for 12-HETE as a pro-aggregatory eicosanoid in platelet function and suggest a role for 12-HETE in variable sensitivity to aspirin. The study also highlights a potentially important mechanism by which aspirin impacts upon eicosanoid generation.

12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition

12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition

Diabetic Platelets Are Not Resistant to Aspirin Inhibition

AbstractAbstract 3324A daily aspirin in patients with myocardial infarctions (MI) effectively reduces the risk of occlusive vascular disease by 25%. This protective effect is reduced or absent in diabetics possibly because aspirin induced inhibition of platelet function is diminished. We tested the hypothesis that the amount of aspirin induced inhibition of platelets in diabetics is decreased. Methods:Each subject was evaluated at 2 time points: off-aspirin and 2-hours after observed ingestion of a 325mg aspirin tablet. Platelets were stimulated in a light aggregometer with platelet prostaglandin agonist (PPA). The slope of the PPA aggregation curve decreases with aspirin inhibition and is a sensitive measure of the amount of aspirin induced platelet inhibition (Schwartz J. Lab Clin Med 2002;139:227). Light aggregometry with arachidonic acid was used to verify that the patients had or had not taken aspirin. Maximal aspirin induced decrease in platelet function was defined as the difference between the PPA aggregation curve slopes at the 2 time points, off-aspirin and 2-hours post aspirin ingestion. 187 adult subjects (62% male 38% female) divided into four groups were studied, MI patients without diabetes n=98, diabetics with an MI n=41, diabetics without an MI n=9, and normal subjects n=39. Results:Comparisons of the PPA slopes of the 4 groups showed that diabetics had higher slopes than non-diabetics. Platelets from diabetics with and without an MI had significantly (p<0.05) increased off aspirin platelet reactivity (PPA slope) compared to normals. At the 2 hr time point patients with diabetes and an MI had a significantly higher PPA slope than the MI without diabetes group. Maximum aspirin induced decrease in platelet function was negatively correlated with age (r=-0.32, p=0.002). When controlled for age, there was no difference in the maximum decrease in platelet function among the 4 groups. Conclusions:1. Platelets from diabetic patients with and without MI have increased platelet reactivity to PPA. 2. The maximum decrease in platelet function observed in diabetic patients with and without an MI was similar to that observed in MI patients without diabetes and in normals. This suggests that the decreased protection from future vascular events observed with aspirin in diabetic patients is not because of an intrinsic resistance to aspirin inhibition of platelets. Disclosures:No relevant conflicts of interest to declare.

Low-Dose Aspirin May Prevent Growth and Later Surgical Repair of Medium-Sized Abdominal Aortic Aneurysms

Experimental data suggest that aspirin-induced platelet inhibition may retard growth of abdominal aortic aneurysms. In this article, whether low-dose aspirin use is associated with reduced aneurysm progression and subsequent need for surgery is examined. In this observational cohort study within a screening trial, 148 patients with small aneurysms (maximum diameter 30-48 mm) annually are followed. Patients were referred for surgery when the aneurysmal diameter exceeded 50 mm. Median follow-up time was 6.6 years. Among patients whose abdominal aortic aneurysms were initially 40 to 49 mm in size, the abdominal aortic aneurysm expansion rate for low-dose aspirin users compared with nonusers was 2.92 mm/y versus 5.18 mm/y (difference 2.27 mm/y, 95% CI, 0.42-4.11). No difference in expansion rates and risk ratios for operative repair was found for patients with abdominal aortic aneurysms <40 mm. For medium-sized abdominal aortic aneurysms, low-dose aspirin may prevent abdominal aortic aneurysm growth and need for subsequent repair, but residual confounding cannot be excluded.

Non-Compliance Is the Predominant Cause of Aspirin Resistance.

Classifying patients as resistant to aspirin is an arbitrary designation with up to 60% of patients reported to be aspirin resistant. Our previous publication showed that 16 or 9% of 192 patients with a history of M.I. could be labeled as aspirin resistant and that all of these patients were aspirin resistant because of non-compliance. This report compares the relative frequency of aspirin resistance between known compliant and non-compliance subjects to demonstrate that non-compliance is the predominant cause of aspirin resistance. Platelet prostaglandin agonist (PPA) stimulated light aggregometry was used to measure amount of aspirin induced platelet inhibition and arachidonic acid (AA) stimulated platelet aggregation to classify platelets as either aspirin inhibited or not. After not taking aspirin for 7 days blood for aggregation studies was drawn, off aspirin time point, which was followed by observed ingestion of 365mg of aspirin. Two hours after observed aspirin ingestion aggregation studies were repeated, on aspirin time point. The difference in the slopes of the PPA light aggregation curves on and off aspirin was defined as the net aspirin response. After supposedly refraining from aspirin for 7 days, 45 subjects were judged non-compliant with the protocol and removed from the study. Of the remaining 185 subjects 39 were normals and 146 had a past history of myocardial infarction (MI). There was no difference in net aspirin response between normal and MI subjects. The net aspirin response in known compliant patients was statistically normally distributed. Only 4% of complaint subjects (2 normals and 5 MI) had a net aspirin response of less than one standard deviation which would qualify as a conservative designation of aspirin resistance. Of the 230 enrolled subjects 16 were noncompliant with their daily prescribed aspirin, 45 were non-compliant with the protocol not to take aspirin for 7 days and one patient had NANSAID interference with aspirin's effect. In total a maximum of 30% of the 230 patients could be classified as aspirin resistant and or non-compliant with 9% aspirin resistant because of non-compliance 18% non-compliant with the protocol and only 3% because of a decreased net aspirin response in known compliant patients. We conclude that:1.the predominant cause of aspirin resistance is noncompliance;2.net aspirin response in compliant patients is normally distributed;3.in compliant patients no difference in net aspirin response is observed between normals and MI patients; and4.PPA stimulated light aggregometry measured off aspirin and 2 hours after observed aspirin ingestion is a useful technique for measuring net aspirin response.

Aspirin resistance among long-term aspirin users after carotid endarterectomy and controls: Flow cytometric measurement of aspirin-induced platelet inhibition

Numerous studies have indicated that some patient subpopulations do not respond to the antithrombotic effects of aspirin. The objective of this study was to evaluate aspirin-induced inhibition of platelet cyclooxygenase (COX) using a flow cytometric technique in long-term aspirin users after carotid endarterectomy (CEA) and controls with newly diagnosed carotid stenosis not taking aspirin and to compare these results with platelet function analyzer measurements. The study included 86 patients with a history of CEA on long-term aspirin therapy (100 mg daily) and 29 age-matched patients with newly diagnosed carotid artery stenosis not taking aspirin. Platelet-rich plasma diluted with phosphate-buffered saline was incubated with arachidonic acid (ARA) at a final concentration of 80 micromol/L. After staining with phycoerythrin-labeled anti-P-selectin (CD62p) antibody, platelet CD62p-antigen expression was measured on a flow cytometer. Flow cytometric measurement of ARA-induced platelet activation showed an inhibition of ARA-induced platelet stimulation in all patients on aspirin therapy, whereas all but two controls (95%) showed expected platelet reactivity. In contrast, results of the platelet function analyzer measurements were normal in 16% of aspirin-treated patients. Flow cytometric measurement of CD62p expression on platelets after incubation with ARA proved to be a practicable tool to monitor aspirin-induced inhibition of platelet COX. Results in patients on long-term low-dose aspirin therapy show that the inability of aspirin to inhibit platelet COX for both symptomatic and asymptomatic patients with high-grade internal carotid artery stenosis is a very rare event. So-called aspirin resistance detected quite frequently by platelet function analyzer measurement is most likely from COX-independent mechanisms.

Aspirin-induced platelet inhibition in patients undergoing cardiac surgery

Platelet function and response to pharmacological inhibition are altered by cardiac surgery. For example, aggregation is increased early after aortic valve replacement (AVR) and platelet response to aspirin is often insufficient after coronary artery bypass grafting (CABG). We hypothesized that the effect of aspirin administration after cardiac surgery might be impaired due to platelet activation. Therefore, the antiplatelet effect of aspirin was compared in patients (n = 20 per group) after CABG and AVR surgery (bileaflet prosthesis). Arachidonic acid-induced aggregation (turbidimetry) and thromboxane formation (radioimmunoassay) were determined before and 1, 5, and 10 days after surgery. In CABG-patients, antiplatelet treatment had been discontinued 10 days before surgery. Oral aspirin was started on day 1 after CABG. AVR-patients did not receive oral aspirin. Before surgery, platelet aggregation and thromboxane formation were significantly higher in patients with aortic stenosis. After CABG, thromboxane formation was not significantly changed from control values before surgery (66 ± 13% on day 10) despite oral aspirin treatment, whereas thromboxane formation in patients undergoing AVR significantly increased compared to values before surgery (216 ± 29% on day 10). In both groups of patients, 100 µmol/l aspirin in vitro largely inhibited platelet function before surgery, with markedly attenuated effects after surgery. In conclusion, thromboxane formation increased after AVR but not after CABG. The antiplatelet effect of aspirin, therefore, may be impaired after CABG by increased platelet activity. An additional in vitro “resistance” of platelets was seen after both CABG and AVR.

Minimal Frequency of Aspirin Resistance after Observed Aspirin Ingestion.

Poor compliance is an important cause of aspirin resistance. Our goal was to investigate amount of aspirin induced inhibition of platelets independent of compliance. We investigated the net amount of aspirin induced inhibition of platelets by comparing Platelet Prostaglandin Agonist (PPA) stimulated platelet aggregations before, off aspirin, with the platelet inhibition that occurred 2 hours after observed aspirin ingestion. 217 post-myocardial infarction patients who had taken aspirin for at least 30 days were evaluated at two time points. The first time point was 7 days after they had signed informed consent to stop taking aspirin as well as nonsteroidal anti-inflammatory drugs (NSAIDs). The second time point was 2 hrs after they were observed to ingest 325mg of aspirin. Platelets were evaluated using 2 different agonists in a light aggregometer. Arachidonic acid (AA) was used as a qualitative check to see if the patients at the first time point had really refrained from taking aspirin and NSAIDs for 7 days and PPA which mainly activates platelets via the prostaglandin pathway and can detect degrees of aspirin induced platelet inhibition. The slope of the PPA stimulated aggregation curve was used to measure aspirin induced platelet inhibition. The net aspirin response was calculated by determining the paired difference between the PPA slopes at the two time points. Compliance with the directive of not taking aspirin or NSAIDs before the first time point was checked with AA stimulated aggregometry and 45 patients were judged to be noncompliant. We defined aspirin resistance as a minimal change in PPA slope of 15 or less. Of the patients who had complied with the directive not to take aspirin or NSAIDs for 7 days as determined by AA aggregometry only 7 (3.2%) were aspirin resistant. The net aspirin response was directly related to the PPA slope off aspirin (p<0.001). When the 45 patients who were judged by AA aggregometry to be noncompliant with the directive to refrain from taking aspirin or NSAIDs were removed from the analysis, the direct relationship between the slope of the off aspirin PPA aggregation and the net aspirin response remained significant (p<0.001). The amount of platelet inhibition in the compliant group 42±16 was significantly larger than the platelet inhibition in the noncompliant group 36±16 (p=0.02). We conclude that: 1. a small percent of patients, 3.2%, whose net amount of aspirin induced platelet inhibition was less than 15 may be resistant to aspirin because of mechanisms unrelated to compliance and 2. The net amount of aspirin induced inhibition of platelets is directly related to the slope of the “off” aspirin PPA stimulated aggregation curve.

Relation of Aspirin Resistance to Coronary Flow Reserve in Patients Undergoing Elective Percutaneous Coronary Intervention

Previous studies have shown that more complete platelet inhibition improves the coronary flow reserve (CFR), a measure of microvascular integrity, in patients undergoing percutaneous coronary intervention (PCI). We hypothesized that patients with aspirin resistance would have impaired CFR after elective PCI. We used VerifyNow Aspirin to determine the response to aspirin in 117 consecutive patients who underwent elective single-lesion PCI. The assay results are expressed quantitatively in Aspirin Reaction Units based on the degree of platelet aggregation. All patients received a 300-mg loading dose of clopidogrel >12 hours before and a 75-mg maintenance dose the morning of PCI. CFR was estimated using the Thrombolysis In Myocardial Infarction frame count method. Of the 117 patients, 22 (18.8%) were aspirin resistant. The clinical, angiographic, and procedural characteristics of the aspirin-sensitive and -resistant patients were balanced. All patients underwent successful PCI with <50% residual diameter stenosis and Thrombolysis In Myocardial Infarction grade 3 flow after PCI. Aspirin-resistant patients had a lower CFR than the aspirin-sensitive patients (1.42 +/- 0.35 vs 1.80 +/- 0.64, p = 0.018). Univariate correlates of CFR included the Aspirin Reaction Unit (r = -0.227, p = 0.014) and post-PCI creatine kinase-MB elevation (p = 0.048). Multivariate linear regression analysis revealed the Aspirin Reaction Unit to be the only independent determinant of CFR after PCI (r2 = 0.051, p = 0.014). Thus, aspirin resistance was associated with impaired CFR in patients who underwent elective PCI, implicating insufficient aspirin-induced platelet inhibition as a cause of microvascular dysfunction by distal atherothrombotic embolization and/or spasm.

Effects of Non-Steroidal Anti-Inflammatory Drugs and COX-2 Inhibitors on Aspirin-Induced Platelet Inhibition.

Low dose aspirin has been widely used as a cardiac protective drug. It acts by inhibiting platelet activation and aggregation through the cyclooxygenase-1 pathway. However, such effects may be affected by short-term use of other drugs such as non-steroidal anti-inflammatory drugs (NSAIDs). We have conducted a multiple-dose, single-blind, parallel-group study to investigate the effects of over-the-counter NSAIDs and COX-2 inhibitors on arachidonic-induced platelet aggregation and thromboxane B2 (TxB2) production. We recruited 87 healthy individuals of 40-75 years of age, who met the inclusion and exclusion criteria by pretest screening. All subjects received 81 mg of aspirin (non-enteric coated and chewable) daily for eight days. Two hours after the 81 mg aspirin dose, the subjects received one of following drugs: acetaminophen (4 doses of 1000 mg daily), ibuprofen (3 doses of 400 mg daily), naproxen sodium (440 mg morning and 220 mg evening), a higher dose of aspirin (4 doses of 650 mg daily), celecoxib (2 doses of 200 mg daily) and rofecoxib (1 dose of 25 mg daily). Control individuals received only 81 mg of aspirin. Citrated blood was obtained before the treatment and at 2, 6, 12, and 24 hr during the first day and an identical schedule after 7 days of dosing (Day 8 of treatment). Platelet function was measured by arachidonic acid-induced platelet aggregation and serum levels of TxB2. We found that the maximal inhibitory effect (more than 85% reduction in aggregation) of 81 mg aspirin was reached more than 24 hr after initial drug intake; whereas it was observed within 6 hr in subjects receiving randomized 2600 mg of aspirin (but only took 1300 mg at time of blood draw). Similar to the higher dose of aspirin, both ibuprofen and naproxen sodium also significantly accelerated the inhibitory effects of low dose aspirin on platelet aggregation (Paired Student t test, p < 0.01). In comparison, acetaminophen and two COX-2 inhibitors showed no additive effects with 81 mg of aspirin. Consistent with aggregation studies, the inhibition of TxB2 production was significantly greater than those with 81 mg of aspirin only at 6, 12, and 24 hr after initial drug intake for 2600 mg of aspirin, ibuprofen, and naproxen, but not for acetaminophen, celecoxib, and rofecoxib. Contrary to a report by Catella-Lawson et al, we found that ibuprofen did not interfere, but rather slightly enhanced, aspirin-induced inhibition of platelet aggregation. The reason for the discrepancy remains unknown, but may be attributed to the type of aspirin used (enteric-coated vs. non-enteric-coated) and different schedules of drug intakes between the two studies. Finally, it may also be due to the fact that our subjects were in their normal environments and not in a clinical research unit. In conclusion, we found that acetaminophen and COX-2 inhibitors did not affect the course of the low-dose aspirin action on platelets. Although ibuprofen and naproxen have had no additive effects, they accelerated the action of 81 mg of aspirin on platelet aggregation.