The contribution of cyclooxygenase-1 and -2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy.
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 TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) 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 TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) 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.
Dragani
Alfredo
A
Department of Hematology, Spirito Santo Hospital, Pescara, Italy.
Pascale
Silvia
S
Recchiuti
Antonio
A
Mattoscio
Domenico
D
Lattanzio
Stefano
S
Petrucci
Giovanna
G
Mucci
Luciana
L
Ferrante
Elisabetta
E
Habib
Aida
A
Ranelletti
Franco O
FO
Ciabattoni
Giovanni
G
Davì
Giovanni
G
Patrono
Carlo
C
Rocca
Bianca
B
D000328:Adult; D001241:Aspirin / Q000627:therapeutic use*; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D000077613:Etoricoxib; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*; D013450:Sulfones / Q000627:therapeutic use*; D013920:Thrombocythemia, Essential / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000097:blood / Q000652:urine; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000097:blood / Q000652:urine; D013931:Thromboxanes / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D016896:Treatment Outcome
D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D013450:Sulfones; D013931:Thromboxanes; D013929:Thromboxane B2; D013928:Thromboxane A2; C049235:11-dehydro-thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin; D000077613:Etoricoxib