IN RESPONSE:
We appreciate Dr. Jonas' thoughtful concerns. The single as yet unconfirmed report that aspirin at ultra-low doses (that is, 0.01 mg/d) may paradoxically reduce bleeding time slightly and transiently without affecting platelet aggregation is interesting [1]. However, this is 1/300th of the lowest dose we studied (3 mg/d) and 1/32 500th of the conventionally recommended aspirin dose for cardiovascular prophylaxis (325 mg/d). Our intent was to determine the threshold dose of gastroduodenal mucosal prostaglandin inhibition in humans because aspirin doses below this threshold may selectively inhibit thromboxane-dependent platelet functions without injuring the gastric mucosa [2]. Our data suggest that aspirin can significantly reduce serum thromboxane B2 at doses of 3 mg/d or 10 mg/d, values substantially below the threshold doses for significant gastric prostaglandin inhibition and acute stomach mucosal injury [2]. Although we did not measure bleeding time or platelet aggregation indices, other investigators have shown that low doses of aspirin (3 to 30 mg/d) significantly inhibit platelet aggregation and prolong bleeding time [3, 4]. More importantly, prospective, placebo-controlled trials are needed to determine whether long-term, low-dose aspirin (3 to 30 mg/d) is effective in preventing thrombotic events while the incidence of gastrointestinal injury remains low.
Because of the sex-related differences in aspirin pharmacokinetics in humans [5], we agree that prospective, long-term studies using low-dose aspirin (3 to 30 mg/d) are needed to ascertain whether these differences are clinically relevant.
1. Doutremepuich C, de Seze O, LeRoy D, Lelanne MC, Anne MC. Aspirin at very ultra low dosage in healthy volunteers: effects on bleeding time, platelet aggregation and coagulation. Haemostasis. 1990; 20:99-105.
2. Lee M, Cryer B, Feldman M. Dose effects of aspirin on gastric prostaglandins and stomach mucosal injury. Ann Intern Med. 1994; 120:184-9.
3. Kallmann R, Nieuwenhuis HK, de Groot PG, van Gijn J, Sixma JJ. Effects of low doses of aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGF1-
excretion in healthy subjects. Thromb Res. 1987; 45:355-61.
4. Fitzgerald GA, Oates JA, Hawiger J, Maas RL, Roberts LJ, Lawson JA, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983; 71:676-88.
5. Buchanan MR, Rischke JA, Butt R, Turpie AG, Hirsh J, Rosenfeld J. The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects. Thromb Res. 1983; 29:125-39.
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