SICKLE-CELL VASOOCCLUSIVE CRISIS IS ASSOCIATED WITH ABNORMALITIES IN THE RATIO OF VASOCONSTRICTOR TO VASODILATOR PROSTANOIDS

Plasma levels of 6-keto-prostaglandin F-1 alpha (6kPGF(1 alpha)) and t hromboxane (Tx) B-2 have been assessed in sickle cell disease (SCD) wi th discrepant results. Inasmuch as direct measurement of plasma prosta noids is fraught with the problem of interfering substances, we assess ed plasma 6kPGF(1 alpha) and TxB(2) levels in patients with SCD by RIA after extraction of eicosanoids and separation by HPLC. We demonstrat e that the 6kPGF(1 alpha) and TxB(2) levels in children with SCD in st eady state as well as in vaso-occlusive crisis (VOC) are significantly lower when compared with those from age-matched controls. The VOC pla sma 6KGF(1 alpha) and TxB(2) levels were, however, significantly eleva ted when compared with those from children in steady state. Changes si milar to those noted with unpaired plasma samples were also observed w hen paired steady state and VOC plasmas from the same patients were as sessed. The ratio of TxB(2) to 6kPGF(1 alpha) was, however, significan tly elevated in patients with SCD in crisis when compared with eicosan oid ratios obtained during steady state. In an attempt to understand w hether the abnormality in 6kPGF(1 alpha) was due to an impairment in e ndothelial cell prostacyclin-regenerating ability, we compared the abi lity of plasma from controls and children with SCD to activate arachid onic acid (AA) release and prostacyclin production by [C-14]AA-prelabe led bovine aortic endothelial cells. Our results suggest that the decr eased 6kPGF(1 alpha) levels in plasma from children with SCD was not d ue to an effect on substrate AA release but rather a modulatory effect of sickle plasma components on endothelial cell cyclooxygenase activi ty. Although a decreased production of prostacyclin has previously bee n suggested to play a role in the initiation and/or propagation of vas o-occlusion in SCD, our study demonstrates a relative increase during VOC of 6kPGF(1 alpha) levels over those observed in steady state. Howe ver, the rise in 6kPGF(1 alpha) is accompanied by an increase in level s of TxB(2) such that the ratio of TxB(2) to 6kPGF(1 alpha) is signifi cantly increased during VOC. The imbalance in the production of vasoac tive eicosanoids, TxA(2) and prostacyclin, could potentially play a ro le in the potentiation of VOC in patients with SCD.