Model of altered aspirin pharmacodynamics in ET. Under conditions of normal megakaryopoiesis, low-dose aspirin acetylates COX isozymes in both circulating platelets and bone marrow megakaryocytes, and only negligible amounts of unacetylated enzymes are resynthesized within the 24-hour dosing interval. This pharmacodynamic pattern is associated with virtually complete suppression of platelet TXA2 production in peripheral blood throughout the dosing interval. Under conditions of abnormal megakaryopoiesis, an accelerated rate of COX-isozyme resynthesis is biologically plausible in bone marrow megakaryocytes, accompanied by faster release of immature platelets with unacetylated enzyme(s) during the aspirin dosing interval, and in particular between 12 and 24 hours after dosing. This pharmacodynamic pattern is associated with incomplete suppression of platelet TXA2 production in peripheral blood and time-dependent recovery of TXA2-dependent platelet function during the 24-hour dosing interval. Immunohistochemistry panels depict megakaryocytes from an ET patient stained for COX-1 and from a normal subject stained for COX-2, and peripheral washed platelets from an ET patient stained for COX-2. Reprinted from Pascale et al25 with permission.
