The contribution of cyclooxygenase-1 and -2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy

• Published in: Blood Vol. 115; no. 5; pp. 1054 - 1061
• Main Authors: Dragani, Alfredo, Pascale, Silvia, Recchiuti, Antonio, Mattoscio, Domenico, Lattanzio, Stefano, Petrucci, Giovanna, Mucci, Luciana, Ferrante, Elisabetta, Habib, Aida, Ranelletti, Franco O., Ciabattoni, Giovanni, Davì, Giovanni, Patrono, Carlo, Rocca, Bianca
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 04.02.2010; Americain Society of Hematology
• Subjects: Adult; Aspirin - therapeutic use; Biological and medical sciences; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - therapeutic use; Drug Therapy, Combination; Etoricoxib; Female; Hematologic and hematopoietic diseases; Humans; Immunohistochemistry; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Platelet Aggregation Inhibitors - therapeutic use; Pyridines - therapeutic use; Sulfones - therapeutic use; Thrombocythemia, Essential - drug therapy; Thrombocythemia, Essential - metabolism; Thrombocythemia, Essential - pathology; Thromboxane A2 - biosynthesis; Thromboxane A2 - blood; Thromboxane A2 - urine; Thromboxane B2 - analogs & derivatives; Thromboxane B2 - biosynthesis; Thromboxane B2 - blood; Thromboxane B2 - urine; Thromboxanes - biosynthesis; Thromboxanes - blood; Thromboxanes - urine; Treatment Outcome; Prostaglandin-endoperoxide synthase; Hematology; Enzyme; Arachidonic acid derivatives; Cyclooxygenase 2; Cyclooxygenase 1; Enzyme inhibitor; Malignant hemopathy; Biosynthesis; Acetylsalicylic acid; Antiplatelet agent; Myeloproliferative syndrome; Essential thrombocythemia; Treatment; Eicosanoid; Oxidoreductases; Salicylates; Thromboxane; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2009-08-236679

We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange–positive platelets (r = 0.71, P < .001). The rate of TXA2 biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB2 (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB2, were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB2 was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB2. Fourteen of the 41 patients were studied again 21 (± 7) months after the first visit. Serum TXB2 was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50μM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA2 biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.