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Inhibition of thromboxane formation in vivo and ex vivo: implications for
therapy with platelet inhibitory drugs
IA Reilly and GA FitzGerald
The capacity of platelets to generate thromboxane A2, reflected by
measurement of serum thromboxane B2 (TxB2), greatly exceeds the systemic
production of thromboxane in vivo. Thus, it is possible that substantial
but incomplete inhibition of thromboxane formation ex vivo would still
allow marked augmentation of thromboxane production in vivo. To address
this hypothesis, we administered aspirin 120 mg, a selective inhibitor of
thromboxane synthase (TxSl), 3-(1H-imidazol-1-yl-
methyl)-2-methyl-1H-indole-1-propanoic acid (UK-38, 485) 200 mg, and a
combination of both drugs to 12 healthy volunteers and measured the effects
on serum TxB2 and urinary 2,3-dinor-thromboxane B2 (Tx-M), an index of
endogenous thromboxane biosynthesis. Although serum TxB2 was maximally
inhibited by 94 +/- 1% after aspirin and 96 +/- 2% after the TxSl, maximal
depression of Tx-M was only 28 +/- 8% and 37 +/- 9%, respectively.
Combination of aspirin with the TxSl resulted in a small but significant
increase in inhibition of thromboxane generation ex vivo (98 +/- 1% v 94
+/- 1%; P less than 0.05), but a disproportionately greater fall in
thromboxane synthesis in vivo (58 +/- 7%; P less than 0.01). Consistent
with further inhibition of platelet thromboxane synthesis, addition of the
TxSl abolished the transient decline in prostacyclin formation after
aspirin alone. Administration of a lower dose of aspirin (20 mg) to 6
healthy subjects caused a small reduction in Tx-M (12 +/- 4%; P less than
0.05) and inhibited serum TxB2 by 48 +/- 2%. The relationship between
inhibition of platelet capacity to form thromboxane ex vivo (serum TxB2)
and synthesis in vivo (Tx-M) departed markedly from the line of identity.
When total blockade of the capacity of platelets to generate thromboxane is
approached, minor decrements in capacity result in a disproportionate
depression of actual thromboxane biosynthesis. These results imply that
pharmacologic inhibition of serum TxB2 must be virtually complete before
thromboxane- dependent platelet activation is influenced in vivo.
Volume 69,
Issue 1,
pp. 180-186,
01/01/1987
Copyright © 1987 by The American Society of Hematology
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