dose- and time-dependent antiplatelet effects of aspirin christina perneby, n. håkan wallén, cathy...

Dose- and time-dependent Dose- and time-dependent antiplatelet effects of aspirinantiplatelet effects of aspirinDose- and time-dependent Dose- and time-dependent

antiplatelet effects of aspirinantiplatelet effects of aspirin

Christina Perneby, N. Håkan Wallén, Cathy Christina Perneby, N. Håkan Wallén, Cathy Rooney, Desmond Fitzgerald, Paul HjemdahlRooney, Desmond Fitzgerald, Paul Hjemdahl

Published in Published in Thrombosis and HaemostasisThrombosis and Haemostasis 20062006

www.theplatelet.org

• Aspirin (ASA) has variable antiplatelet activity when assessed by different Aspirin (ASA) has variable antiplatelet activity when assessed by different methods, and the poorly defined phenomenon of “aspirin resistance” is often methods, and the poorly defined phenomenon of “aspirin resistance” is often discussed. discussed.

• Using various test methods, the range of patients among different studies Using various test methods, the range of patients among different studies judged not to have optimal antiplatelet effects during ASA treatment was judged not to have optimal antiplatelet effects during ASA treatment was between 5-57%.between 5-57%.

• Among such patients, several authors have reported an increased risk of Among such patients, several authors have reported an increased risk of suffering major cardiovascular events in post hoc analyses.suffering major cardiovascular events in post hoc analyses.

• However, prospective studies validating the clinical utility of identifying However, prospective studies validating the clinical utility of identifying biochemical or functional “aspirin resistance” are lacking.biochemical or functional “aspirin resistance” are lacking.

• At low dosages, first pass hepatic metabolism of aspirin limits the systemic At low dosages, first pass hepatic metabolism of aspirin limits the systemic exposure of the patients to COX inhibition, thus preserving the vasodilating exposure of the patients to COX inhibition, thus preserving the vasodilating and antiplatelet effects of endothelial prostacyclin. and antiplatelet effects of endothelial prostacyclin.

• Higher doses of ASA may attenuate this potentially antithrombotic mechanism.Higher doses of ASA may attenuate this potentially antithrombotic mechanism.

• Aspirin (ASA) has variable antiplatelet activity when assessed by different Aspirin (ASA) has variable antiplatelet activity when assessed by different methods, and the poorly defined phenomenon of “aspirin resistance” is often methods, and the poorly defined phenomenon of “aspirin resistance” is often discussed. discussed.

• Using various test methods, the range of patients among different studies Using various test methods, the range of patients among different studies judged not to have optimal antiplatelet effects during ASA treatment was judged not to have optimal antiplatelet effects during ASA treatment was between 5-57%.between 5-57%.

• Among such patients, several authors have reported an increased risk of Among such patients, several authors have reported an increased risk of suffering major cardiovascular events in post hoc analyses.suffering major cardiovascular events in post hoc analyses.

• However, prospective studies validating the clinical utility of identifying However, prospective studies validating the clinical utility of identifying biochemical or functional “aspirin resistance” are lacking.biochemical or functional “aspirin resistance” are lacking.

• At low dosages, first pass hepatic metabolism of aspirin limits the systemic At low dosages, first pass hepatic metabolism of aspirin limits the systemic exposure of the patients to COX inhibition, thus preserving the vasodilating exposure of the patients to COX inhibition, thus preserving the vasodilating and antiplatelet effects of endothelial prostacyclin. and antiplatelet effects of endothelial prostacyclin.

• Higher doses of ASA may attenuate this potentially antithrombotic mechanism.Higher doses of ASA may attenuate this potentially antithrombotic mechanism.

Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8. Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirineffects of aspirin: Study BackgroundStudy Background

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirineffects of aspirin: Study BackgroundStudy Background

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Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Study Designeffects of aspirin: Study Design

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Study Designeffects of aspirin: Study Design

ASA treatment with 37.5mg/day for 10 daysASA treatment with 37.5mg/day for 10 days(half tablet of Trombyl(half tablet of Trombyl®® 75mg) 75mg)

Blood Sampling on 10Blood Sampling on 10thth day at day at 1.5-2h (9am), 1.5-2h (9am), 6h (1pm) and 24 hours after last 6h (1pm) and 24 hours after last dosedose

ASA treatment with 37.5mg/day for 10 daysASA treatment with 37.5mg/day for 10 days(half tablet of Trombyl(half tablet of Trombyl®® 75mg) 75mg)

Blood Sampling on 10Blood Sampling on 10thth day at day at 1.5-2h (9am), 1.5-2h (9am), 6h (1pm) and 24 hours after last 6h (1pm) and 24 hours after last dosedose

ASA treatment with 320 mg/day for 7 days ASA treatment with 320 mg/day for 7 days (1 tablet Alka Seltzer (1 tablet Alka Seltzer ®®))

Blood Sampling on 10th day at 1.5-2h (9am), Blood Sampling on 10th day at 1.5-2h (9am), 6h (1pm) and 24 hours after 6h (1pm) and 24 hours after last doselast dose

ASA treatment with 320 mg/day for 7 days ASA treatment with 320 mg/day for 7 days (1 tablet Alka Seltzer (1 tablet Alka Seltzer ®®))

Blood Sampling on 10th day at 1.5-2h (9am), Blood Sampling on 10th day at 1.5-2h (9am), 6h (1pm) and 24 hours after 6h (1pm) and 24 hours after last doselast dose

Open cross-over study, measurements at baseline and during treatment with 3 different aspirin Open cross-over study, measurements at baseline and during treatment with 3 different aspirin dosagesdosages

15 Males, Ages 22-39 years, non-smokers,15 Males, Ages 22-39 years, non-smokers,Body Mass Index of 22.9 (range 20-26)Body Mass Index of 22.9 (range 20-26)

Avoidance of antiplatelet drugs for 2 weeks before first visitAvoidance of antiplatelet drugs for 2 weeks before first visit

Open cross-over study, measurements at baseline and during treatment with 3 different aspirin Open cross-over study, measurements at baseline and during treatment with 3 different aspirin dosagesdosages

15 Males, Ages 22-39 years, non-smokers,15 Males, Ages 22-39 years, non-smokers,Body Mass Index of 22.9 (range 20-26)Body Mass Index of 22.9 (range 20-26)

Avoidance of antiplatelet drugs for 2 weeks before first visitAvoidance of antiplatelet drugs for 2 weeks before first visit

Single dose 640mg ASA (2 tablets Alka Seltzer Single dose 640mg ASA (2 tablets Alka Seltzer ®®); 1-2h after last 320 mg dose); 1-2h after last 320 mg doseBlood Sampling at 4h and 24h after Blood Sampling at 4h and 24h after

Single dose 640mg ASA (2 tablets Alka Seltzer Single dose 640mg ASA (2 tablets Alka Seltzer ®®); 1-2h after last 320 mg dose); 1-2h after last 320 mg doseBlood Sampling at 4h and 24h after Blood Sampling at 4h and 24h after


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Dose- and time- dependent antiplatelet effects Dose- and time- dependent antiplatelet effects of aspirin: Methodsof aspirin: Methods

Dose- and time- dependent antiplatelet effects Dose- and time- dependent antiplatelet effects of aspirin: Methodsof aspirin: Methods

• Whole Blood Aggregometry:Whole Blood Aggregometry:- An impedence aggregometer was used to - An impedence aggregometer was used to

study platelet aggregation in whole blood (ie, Chrono-study platelet aggregation in whole blood (ie, Chrono-log model 570-VS Four Sample, Chrono-log Corp)log model 570-VS Four Sample, Chrono-log Corp)

- Agonists used were collagen type I at final - Agonists used were collagen type I at final concentrations of 1, 3 or 5 µM and arachidonic acid concentrations of 1, 3 or 5 µM and arachidonic acid (AA) dissolved in ethanol at final concentrations of 0.2, (AA) dissolved in ethanol at final concentrations of 0.2, 0.5 or 1 mM.0.5 or 1 mM.• Aggregometry in Platelet Rich Plasma (PRP):Aggregometry in Platelet Rich Plasma (PRP):

- A four-channel platelet aggregation - A four-channel platelet aggregation profiler was used to study platelet aggregation in PRP profiler was used to study platelet aggregation in PRP (ie, PAP-4, Bio-Data Corporation)(ie, PAP-4, Bio-Data Corporation)


www.theplatelet.org Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8. Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: AA-induced aggregationeffects of aspirin: AA-induced aggregation

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: AA-induced aggregationeffects of aspirin: AA-induced aggregation

Comparison of AA-induced aggregation Comparison of AA-induced aggregation (Impedence in (Impedence in ΩΩ))

• There was neither a dose-There was neither a dose-response relationship for platelet response relationship for platelet aggregation induced by 0.2-1aggregation induced by 0.2-1mmM M AA in whole blood nor a AA in whole blood nor a significant diurnal variability significant diurnal variability without ASA treatment.without ASA treatment.

• The 37.5mg ASA suppressed The 37.5mg ASA suppressed aggregation at low AA aggregation at low AA concentrations; inhibitory effects concentrations; inhibitory effects of the low-dose ASA were of the low-dose ASA were attenuated after 24h compared to attenuated after 24h compared to 6h (p<0.01).6h (p<0.01).

• After 320 and 960mg of ASA, After 320 and 960mg of ASA, platelet aggregation was almost platelet aggregation was almost completely inhibited (p<0.001 for completely inhibited (p<0.001 for both) when using 0.2 mM AA, but both) when using 0.2 mM AA, but there was less complete there was less complete inhibition with higher inhibition with higher concentrations of AA, and concentrations of AA, and significant recovery 24h after significant recovery 24h after high-dose ASA.high-dose ASA.

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•All doses of aspirin (37.5mg, 320mg and 960mg) All doses of aspirin (37.5mg, 320mg and 960mg) inhibited AA-induced platelet aggregation almost inhibited AA-induced platelet aggregation almost completely (to <1%), indicating good compliance and completely (to <1%), indicating good compliance and effective platelet COX inhibition.effective platelet COX inhibition.

•Three individuals had small aggregatory responses (3-Three individuals had small aggregatory responses (3-5%) to AA after 37.5mg aspirin, which were abolished 5%) to AA after 37.5mg aspirin, which were abolished after 320 and 960mg.after 320 and 960mg.


Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Aggregometry in PRPeffects of aspirin: Aggregometry in PRPDose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet

effects of aspirin: Aggregometry in PRPeffects of aspirin: Aggregometry in PRP

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Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Urinary excretion of TxMeffects of aspirin: Urinary excretion of TxM

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Urinary excretion of TxMeffects of aspirin: Urinary excretion of TxM


Urinary excretion of TxM expressed as ng/mmol Urinary excretion of TxM expressed as ng/mmol creatinine after different doses of aspirin.creatinine after different doses of aspirin.

• There was no significant diurnal There was no significant diurnal variability of urinary TxM excretion. variability of urinary TxM excretion. • After 37.5mg ASA, nocturnal TxM After 37.5mg ASA, nocturnal TxM excretion was reduced by 74.0±2.0% excretion was reduced by 74.0±2.0% (p<0.001).(p<0.001).• After 320mg ASA the degree of After 320mg ASA the degree of inhibition was 82.0±1.8% (p<0.001 inhibition was 82.0±1.8% (p<0.001 vs. baseline, and 37.5mg). vs. baseline, and 37.5mg). • Four hours after 960mg ASA, TxM Four hours after 960mg ASA, TxM excretion was reduced by 83.9±2.8% excretion was reduced by 83.9±2.8% (p<0.001 vs. baseline, and 37.5 mg), (p<0.001 vs. baseline, and 37.5 mg), but there was significant recovery but there was significant recovery after <24h to 78.5±1.4% inhibition after <24h to 78.5±1.4% inhibition (TxM excretion increased from (TxM excretion increased from 9.4±1.1 to 14.8±1.5 ng/mmol 9.4±1.1 to 14.8±1.5 ng/mmol creatinine; p<0.001). creatinine; p<0.001). •TxBTxB2 2 production in serum was production in serum was inhibited by 98.5±0.7% (n=8) after inhibited by 98.5±0.7% (n=8) after 37.5mg ASA, and by 98.9±0.5% (n=9) 37.5mg ASA, and by 98.9±0.5% (n=9) after 320mg ASA.after 320mg ASA.

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Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Urinary excretion of PGI-Meffects of aspirin: Urinary excretion of PGI-M

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Urinary excretion of PGI-Meffects of aspirin: Urinary excretion of PGI-M

• Urinary PGI-M excretion was Urinary PGI-M excretion was 16.5±1.6 and 14.6±1.0 ng/mmol 16.5±1.6 and 14.6±1.0 ng/mmol creatinine in nocturnal and 1 PM creatinine in nocturnal and 1 PM samples, respectively, without samples, respectively, without treatment. treatment.

• Nocturnal PGI-M excretion Nocturnal PGI-M excretion decreased by 25±7% (p<0.05) after decreased by 25±7% (p<0.05) after 37.5mg ASA, and by 28±14% 37.5mg ASA, and by 28±14% (p=0.066) after 320mg. (p=0.066) after 320mg.

•PGI-M excretion during the day PGI-M excretion during the day tended to decrease (by 18±8%; tended to decrease (by 18±8%; p=0.055) with 37.5mg ASA, and was p=0.055) with 37.5mg ASA, and was reduced by 26±10% (p<0.05) 4h after reduced by 26±10% (p<0.05) 4h after 960mg ASA, but recovered (from 960mg ASA, but recovered (from 10.6±1.5 to 13.9±2.0 ng/mmol 10.6±1.5 to 13.9±2.0 ng/mmol creatinine; p<0.05) in the ensuing creatinine; p<0.05) in the ensuing nocturnal sample.nocturnal sample.

Urinary excretion of PGI-M expressed as ng/mmol Urinary excretion of PGI-M expressed as ng/mmol creatinine after different doses of aspirin.creatinine after different doses of aspirin.


www.theplatelet.org Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8. Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.Perneby et al., Thromb Haemost. 2006 Apr; 95(4):652-8.

Dose- and time- dependent antiplatelet effects of Dose- and time- dependent antiplatelet effects of aspirin: Platelet inhibition by ASAaspirin: Platelet inhibition by ASA

Dose- and time- dependent antiplatelet effects of Dose- and time- dependent antiplatelet effects of aspirin: Platelet inhibition by ASAaspirin: Platelet inhibition by ASA

Comparison of platelet inhibition afforded by ASA at Comparison of platelet inhibition afforded by ASA at different dosages (37.5-960mg) using different different dosages (37.5-960mg) using different platelet function assays (% inhibited by ASA)platelet function assays (% inhibited by ASA)

• The parameter most sensitive to The parameter most sensitive to inhibition by aspirin was AA inhibition by aspirin was AA induced aggregation in PRP, induced aggregation in PRP, followed by serum TxBfollowed by serum TxB22..• TxM excretion was less TxM excretion was less markedly, but dose-dependently markedly, but dose-dependently reduced by ASA treatment. reduced by ASA treatment. • A dose related but weak A dose related but weak inhibition of collagen induced inhibition of collagen induced aggregation in hirudinized whole aggregation in hirudinized whole blood was found with the lowest blood was found with the lowest collagen concentration, and some collagen concentration, and some inhibition of PGI-M excretion.inhibition of PGI-M excretion.•Platelet aggregation in whole Platelet aggregation in whole blood stimulated by low AA blood stimulated by low AA concentrations was correlated to concentrations was correlated to serum TxBserum TxB22 levels after 37.5mg levels after 37.5mg ASA (eg, r=0.73, p<0.05, at 0.2 mM ASA (eg, r=0.73, p<0.05, at 0.2 mM AA); correlations disappeared with AA); correlations disappeared with higher AA concentrations and higher AA concentrations and aspirin dosages.aspirin dosages.

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Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Discussioneffects of aspirin: Discussion

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Discussioneffects of aspirin: Discussion

•Aspirin treatment suppressed TxBAspirin treatment suppressed TxB²² in serum by more in serum by more

than 98% and abolished AA-induced platelet aggregation in than 98% and abolished AA-induced platelet aggregation in PRP already at a very low dose level (37.5mg daily).PRP already at a very low dose level (37.5mg daily).

•Even when using high dosages of ASA, there was Even when using high dosages of ASA, there was significant recovery of platelet function 24 hours after significant recovery of platelet function 24 hours after dosing.dosing.

•Thus there was incomplete suppression of TxM excretion Thus there was incomplete suppression of TxM excretion in urine, and AA-induced platelet aggregation could still in urine, and AA-induced platelet aggregation could still occur in whole blood.occur in whole blood.

•Furthermore, treatment with 37.5mg aspirin decreased Furthermore, treatment with 37.5mg aspirin decreased the sensitivity to stimulation by ADP in platelet rich plasma.the sensitivity to stimulation by ADP in platelet rich plasma.

•In accordance with earlier results, this effect was less In accordance with earlier results, this effect was less pronounced (non-significant) after higher doses of aspirin.pronounced (non-significant) after higher doses of aspirin.


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Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Discussion cont.effects of aspirin: Discussion cont.

Dose- and time- dependent antiplatelet Dose- and time- dependent antiplatelet effects of aspirin: Discussion cont.effects of aspirin: Discussion cont.

•The low 37.5mg dose of aspirin, which appears to be The low 37.5mg dose of aspirin, which appears to be subtherapeutic, effectively inhibited platelet-dependent subtherapeutic, effectively inhibited platelet-dependent thromboxane formation with very modest effects on aggregation thromboxane formation with very modest effects on aggregation in whole blood.in whole blood.

•Nucleated cells are capable of regenerating the COX-1 Nucleated cells are capable of regenerating the COX-1 enzyme after a couple of hours and provide PGHenzyme after a couple of hours and provide PGH

²² to platelets to to platelets to

bypass the inhibition of platelet COX-1.bypass the inhibition of platelet COX-1.•These findings of dose- and time-dependent recovery of These findings of dose- and time-dependent recovery of

platelet function within 24h after dosing of aspirin are of platelet function within 24h after dosing of aspirin are of relevance for the inability of 100mg ASA every other day to relevance for the inability of 100mg ASA every other day to reduce cardiac events in the Women’s Health Study, as such a reduce cardiac events in the Women’s Health Study, as such a dose regimen may provide incomplete COX-1 inhibition during dose regimen may provide incomplete COX-1 inhibition during at least part of the dosing interval.at least part of the dosing interval.


dose- and time-dependent antiplatelet effects of aspirin christina perneby, n. håkan wallén, cathy...

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