Model of altered aspirin pharmacodynamics in ET. Under conditions of normal megakaryopoiesis, low-dose aspirin acetylates COX isozymes in both circulating platelets and BM megakaryocytes, but 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 the peripheral blood throughout the dosing interval. Under conditions of abnormal megakaryopoiesis, an accelerated rate of COX-isozyme resynthesis is biologically plausible in BM 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 the 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COX-2 and peripheral washed platelets from an ET patient stained for COX-2 (from Dragani et al16 and Rocca et al33 and unpublished data). Immunohistochemistry samples in the inserts were analyzed with an Axioskop light microscope (Zeiss) at a numeric aperture of 1.3 in oil. Original magnification ×1000. Images were photographed with a CoolPix 950 digitial camera (Nikon).
