ASPIRIN INCREASES THE BLEEDING SIDE-EFFECTS IN ESSENTIAL THROMBOCYTHEMIA INDEPENDENT OF THE CYCLOOXYGENASE PATHWAY - ROLE OF THE LIPOXYGENASE PATHWAY

Acetylsalicylic acid (ASA) is currently recommended as an antithrombot ic for patients with essential thrombocythemia (ET) who are at an incr eased risk of thrombotic events. However, ASA is also associated with an increased risk of bleeding in these patients as compared to the ris k of bleeding in other patients treated with ASA. Recent data suggest that while ASA inhibits platelet thromboxane A(2) (TxA(2)) synthesis i n all individuals, ASA has little effect or inhibits the lipoxygenase pathway (i.e., 12-hydroxyeicosatetranoic acid or 12-HETE synthesis) in some individuals, and enhances 12-HETE synthesis in others. These dif ferential effects are associated with a pronounced prolongation of the bleeding time vs. no prolongation of the bleeding time, respectively, i.e., in ASA responders and ASA nonresponders, respectively. To deter mine if the increased risk of ASA-induced bleeding seen in ET patients is associated with an effect on 12-HETE synthesis, we compared the re lative effects of ASA on the bleeding time, platelet TxA(2) and 12-HET E synthesis, and platelet aggregation and adhesion in ET patients and healthy volunteers. ASA (300 mg, taken orally) prolonged the bleeding time in 82% of the ET patients but only 27% of the healthy volunteers although platelet TxA(2) synthesis and ADP- and collagen-induced aggre gation were inhibited significantly in both groups. In contrast, plate let 12-HETE synthesis was unchanged and platelet adhesion was decrease d in those patients and volunteers whose bleeding times were prolonged by ASA, whereas platelet 12-HETE synthesis was increased significantl y and platelet adhesion was unaffected in those patients and volunteer s whose bleeding times were not prolonged, and in some cases shortened by ASA. These results confirm previous data that demonstrate that ASA has different effects on platelet 12-HETE synthesis and platelet adhe sion in different individuals, i.e., inhibitory or no effect in ASA re sponders (in whom ASA prolonged bleeding) vs. enhancing effects in ASA nonresponders (in whom ASA did not prolong bleeding). These results a lso indicate that there is a greater percentage of ASA responders in p atients with ET than that seen in the general population, a difference that is associated with an effect of ASA on the lipoxygenase pathway. This may explain the increased bleeding side effects seen in the ET p atient population. Am. J. Hematol. 57:277-282, 1998. (C) 1998 Wiley-Li ss, Inc.