Once daily aspirin dose insufficient for platelet COX activity inhibition

Aspirin suppressed serum TXB2 by more than 98% but patients had significant recovery of platelet function 24 hours after dosing.

Issue: August 1, 2006

New research showed that one daily dose of aspirin may be insufficient for patients with increased platelet turnover and that two daily doses might be more effective.

According to a new study, aspirin provides only a weak inhibition of platelet aggregation in whole blood with normal calcium levels, despite effective platelet cyclooxygenase (COX) inhibition.

Paul Hjemdahl, MD, PhD, professor at the Karolinska Institute and University Hospital in Stockholm, Sweden, told Hem/Onc Today that 10% of platelets in circulation are normally renewed each day, but the number can be higher with increased platelet turnover.

Harry S. Jacob, MD, FRCPath(Hon) [photo]
Harry S. Jacob

“Also, it has been shown that one needs virtually complete COX-1 inhibition for full blockade of thromboxane mediated platelet aggregation,” Hjemdahl said.

Researchers examined aspirin’s limitations as an antithrombotic agent and analyzed the long-standing debate about the optimal clinical dosage.

Different regimens

Researchers performed an open-label cross-over study comparing no treatment with three aspirin dosage regimens: 37.5 mg/day for 10 days, 320 mg/day for 7 days and a single 640 mg dose. There was a cumulative dose of 960 mg on the last day. The study was conducted on 15 healthy male volunteers, all of whom were nonsmokers, aged 22 to 39 years and who had a body mass index of 22.9.

Hjemdahl and colleagues observed platelet aggregation in platelet-rich plasma and in whole blood. They measured the urinary excretion of thromboxane and prostacyclin metabolites as well as thromboxane B2 (TXB2) generation in whole blood clotting. They also used hirudinized blood to avoid artifactual enhancement by thrombin of the thromboxane dependence of platelet aggregation, which is seen when citrate is used as anticoagulant and extracellular calcium levels are low.

Additionally, the researchers examined the time dependence of the effects of different aspirin doses to determine if there was significant recovery of COX-dependent platelet function during the normal dosing interval of 24 hours.

Insufficient dosing

“When there is need of really full COX inhibition, and when platelet turnover is increased, once daily dosing of aspirin may be insufficient,” said Hjemdahl.

His research revealed that one daily dose might be insufficient even though there is nearly complete inhibition of platelet COX activity early after dosing. Aspirin treatment suppressed TXB2 in serum by more than 98%. It also abolished arachidonic acid-induced platelet aggregation in platelet-rich plasma already at a low dose level, but there was significant recovery of platelet function 24 hours after dosing.

This was also true with high doses of aspirin. There was also incomplete suppression of thromboxane excretion in urine. After the 960 mg aspirin dose, there was a larger reduction of prostacyclin excretion more than four hours after dosing, but, there was a significant recovery after the first 24 hours.

Treatment with 37.5 mg aspirin was found to decrease the sensitivity to stimulation by adenosine diphosphate (ADP; Sigma Chemical Co.) in platelet-rich plasma, but that effect was less pronounced after higher doses of aspirin.

Bleeding time increased similarly after all dosages of aspirin and was not related to changes in the urinary excretion of prostacyclin.

The study appeared in the Journal of Thrombosis and Haemostasis.

Optimal testing

According to the study, there is no single or accepted platelet function test that is optimal for monitoring aspirin treatment. This was illustrated in the study with different effect parameters yielding different results, Hjemdahl said.

Although using urinary TXM and whole blood aggregometry in combination may be the most suitable approach for the evaluation of in vivo effects of aspirin treatment, researchers said that arachidonic acid–induced aggregation in platelet-rich plasma may provide the best assessment of platelet COX inhibition. However, the study did note that neither approach has been evaluated in relation to clinical outcomes during aspirin treatment.

Hjemdahl said the next step is to investigate other aspirin dosage regimens and see if those results follow accordingly.

Platelet studies

Joel Moake, MD [photo]
Joel Moake

“These results help explain earlier work by Laurence Harker, MD, [from Emory University School of Medicine in Atlanta] who demonstrated suboptimal inhibition of platelet aggregation/consumption in baboons fitted with Teflon vascular implants with once daily aspirin,” said Harry S. Jacob, MD, FRCPath(Hon), chief medical editor of HemOnc Today. “Complete inhibition of excessive platelet removal by the implants required two to three daily doses of aspirin (with dipyrimadole). I personally have found aspirin given three times daily (with dipyrimadole) to completely prevent transient ischemic attacks in three patients with vasculitis when daily aspirin was without effect.”

Hjemdahl’s study highlights the difficulty in correlating in vitro and in vivo observations of platelet activation, according to Joel Moake, MD, professor at Baylor College of Medicine and Rice University, and Platelet Disorders & Physiology section editor for HemOnc Today.

“Platelet aggregation tests are done in vitro using platelet-rich plasma or whole blood in different anticoagulants and under non-physiological stirring conditions (very low shear rates),” Moake said. “In contrast, in vivo platelet adhesion/aggregation in small arteries: occurs in blood flowing at high shear (flow) rates; and is dependent on large von Willebrand factor (VWF) forms to induce the platelet adhesion/ aggregation process. High shear, VWF-mediated platelet adhesion/aggregation is not inhibited by acetyl salicylic acid.

“These facts emphasize that the mechanism of the modest anti-arterial thrombotic effects of aspirin may not, in fact, be established with as much certainty as often presumed. Are other proteins involved in hemostasis and thrombosis acetylated and altered by acetyl salicylic acid — in addition to COX-1 that generates thromboxane A2, and COX-2 that produces prostacyclin (PGI2)? The extent of aspirin effects in vivo is unlikely to be completely understood. It is not surprising, therefore, that the search continues for both the quantity and frequency of acetyl salicylic acid required to achieve optimum anti-arterial thrombotic effects.”

In response, Hjemdahl said that his team also examined the effects of aspirin treatment on fibrin gel permeability and found that per- meability was most markedly increased with the lowest dose of aspirin. This finding agreed with an earlier one of his studies that found greater effects of 75 mg daily aspirin compared with 325 mg daily aspirin daily.

“This may be related to acetylation of fibrinogen and reduced cross-linking in the fibrin clots that are formed. It may enhance fibrinolysis.” Hjemdahl said. “The inverse dose-response for aspirin regarding this response is of interest.” – by Angelo Milone

For more information:

Perneby C, Wallen N, Rooney C, et al. Dose- and time-dependant antiplatelet effects of aspirin. Thromb Haemost. 2006;95:652-658.

Antovic A, Perneby C, Ekman GJ, et al. Marked increase of fibrin gel permeability with very low dose ASA treatment. Thromb Res. 2005;116:509-517.

Williams S, Fatah K, Hjemdahl P, et al. Better increase in fibrin gel porosity by low dose than intermediate dose acetylsalicylic acid. Eur Heart J. 1998;19:1666-1672.