Coagulation abnormalities and acquired von Willebrand's disease type 1 in children receiving valproic acid

Valproic acid is commonly used in the management of childhood epilepsy. The known hematologic side effects of the drug are hemorrhagic diatheses, thrombocytopenia, and hypofibrinogenemia. We studied coagulation parameters in 29 epileptic children receiving valproic acid for at least 6 months. Their ages ranged between 2 and 18 years (10.2 +/- 4.9 years). The total valproic acid dose was 250 to 1000 mg/day equivalent to 20 to 30 mg/kg/day. Treatment duration ranged from 6 to 57 months. These children had not previously had a hemostatic defect and had no family history of bleeding disorders. Platelet count, prothrombin time, activated partial thromboplastin time, bleeding time, fibrinogen, platelet aggregation assays, and ristocetin cofactor activity levels were determined in all of the patients, but von Willebrand's factor antigen levels could be determined in only 14 patients. The values of von Willebrand's factor antigen ranged from 53 to 218% (104.1 +/- 42.3), and ristocetin cofactor activity levels ranged from 11.5 to 218% (94.5 +/- 43.1). Six of the 29 children (20.7%) had decreased values of ristocetin and cofactor activity and were considered to have acquired von Willebrand's disease. The decreases in coagulation parameters were not dependent on either valproic acid dose or treatment duration. Two patients with low ristocetin cofactor activity values had mild epistaxis, which did not require discontinuation of therapy. In patients receiving valproic acid therapy, this side effect must be considered, especially before surgical intervention and serious traumatic conditions.