Valproate Treatment and Platelet Function: The Role of Arachidonate Metabolites

Abstract

Summary:Purpose: Valproate (VPA) is an extensively used drug in the therapy of epilepsies. One of the most frequently reported side effects of VPA is hemorrhagic 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 platelet dysfunction has not yet been elucidated. A determining element of platelet functions is the arachidonate cascade. Present ex vivo experiments were designed to determine whether a relation exists between the incidence of hemostasis caused by VPA and the effect of this drug on the arachidonate cascade of platelets.Methods: Platelets were isolated from patients receiving long-term VPA treatment (serum level, 36.04 f 16.12 pg/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24 + 2.67 yg/ml; n = 10) and were labeled with ['4C]arachidonic acid. (CBZ-treated patients were chosen as a control group, 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-eicosanoids were separated by means of overpressure thin-layer chromatography and determined quantitatively by liquid scintillation.Results: Even when the mean plasma concentration of the drug was low, VPA treatment 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,.Conclusions: Inhibition of the platelet arachidonate cascade may contribute to the platelet-function alterations caused by VPA.

Different resuscitation strategies and novel pharmacologic treatment with valproic acid in traumatic brain injury

“…Acute VPA overdose results in hypotension, respiratory depression, thrombocytopenia, and metabolic disorders (Manoguerra et al, 2008). In addition, chronic VPA use ( > 4 weeks) has been associated with thrombocytopenia, platelet dysfunction (Davidson et al, 2011;Gesundheit, Kirby, Lau, Koren, & Abdelhaleem, 2002;Gidal et al, 1994;Kis et al, 1999;Manoguerra et al, 2008), and acquired von Willebrand disease (Serdaroglu, Tutuncuoglu, Kavakli, & Tekgul, 2002;Verrotti et al, 1999). A dose as low as 60 mg/kg a day has been found to be biologically active in cancer studies, which led to our hypothesis that lower doses might also be beneficial for trauma patients.…”

Considerations in perioperative assessment of valproic acid coagulopathy

“…The mechanism of VPA-induced coagulopathy is not well-identified and may include multiple mechanisms. [2122] As shown in the above-described studies, the causal relationship between plasma VPA levels, duration of therapy and incidence of VPA induced coagulopathy in patients receiving VPA may vary. These blood coagulation disturbances may be of clinical importance in VPA treated patients, therefore, special attention to this side-effect in the pre-operative assessment would be highly recommended.…”

Occurrences of thrombocytopenia with valproic acid used for psychiatric indication

“…26,27 Another interesting hypothesis is that hypersensitivity to VPA may lead to the development of drug-induced platelet antibodies and, consequently, thrombocytopenia and alteration of the bleeding time: drug-induced platelet antibodies usually belong to the immunoglobulin G (IgG) class, but occasionally IgM and/or IgA antibodies may be present. 28,29 The limitations of this study were the relatively small number of subjects and lack of control group.…”