Valproate treatment and platelet function: The role of arachidonate metabolites

Purpose: Valproate (VPA) is an extensively used drug in the therapy of epil epsies. One of the most frequently reported side effects of VPA is hemorrha gic diathesis. Some authors emphasized the decreased platelet count as the basis of VPA-induced hemorrhagic diathesis, but some reports suggested that a significant proportion of patients with normal platelet count may still have an altered platelet function. The mechanism of the VPA-induced platele t dysfunction has not yet been elucidated. A determining element of platele t functions is the arachidonate cascade. Present ex vivo experiments were d esigned to determine whether a relation exists between the incidence of hem ostasis caused by VPA and the effect of this drug on the arachidonate casca de of platelets. Methods: Platelets were isolated from patients receiving long-term VPA trea tment (serum level, 36.04 +/- 16.12 mu g/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24 +/- 2.67 mu g/ml; n = 10) and were labeled wi th [C-14]arachidonic acid. (CBZ-treated patients were chosen as a control g roup, because CBZ causes blood dyscrasias similar to those elicited by VPA, but there has been no report that CBZ induces a platelet dysfunction.) The C-14-eicosanoids were separated by means of overpressure thin-layer chroma tography and determined quantitatively by liquid scintillation. Results: Even when the mean plasma concentration of the drug was low, VPA t reatment reduced the activity of the arachidonate cascade in platelets. VPA effectively inhibited the cyclooxygenase pathway and the synthesis of the strong platelet aggregator thromboxane A(2). Conclusions: Inhibition of the platelet arachidonate cascade may contribute to the platelet-function alterations caused by VPA.