Hematologic toxicity of sodium valproate.

PURPOSE

Sodium valproate is a commonly used anticonvulsant in the management of childhood refractory epilepsy with good response rates and acceptable toxicity. Hepatotoxicity is the most widely recognized toxicity. With the use of higher drug levels to achieve adequate seizure control, hematologic toxicity is being increasingly encountered, and the pediatric hematologist is consulted for these problems in the pre- or perioperative setting. The purpose of this article is to characterize the various hematologic toxicities encountered in a clinical setting and to provide guidelines to assist in the management of these patients.

METHODS

A literature review was undertaken to identify the hematologic toxicities of valproate used as monotherapy or polytherapy. Key words used in the search were valproate, hematology, and bleeding.

RESULTS

Valproate can cause direct bone marrow suppression leading to aplastic anemia or peripheral cytopenia affecting one or more cell lines. Occasional fatal bone marrow failure, myelodysplasia, and a clinical picture resembling acute promyelocytic leukemia have also been seen. Thrombocytopenia, macrocytosis, neutropenia, and pure red cell aplasia can occur but are not reported to be life-threatening. A bleeding diathesis associated with valproate use may include thrombocytopenia, abnormal platelet function, and acquired von Willebrand disease type I.

CONCLUSIONS

Hematologic toxicities of valproate are common, vary in onset and severity, are recurrent, transient, or persistent, and usually occur with a serum valproate level greater than 100 microg/mL. In most situations, even when highly clinically significant, they can be reversed with dosage reduction; drug discontinuation is rarely required. Potential adverse effects such as thrombocytopenia and leukopenia are easily detected by laboratory monitoring, which should be continued indefinitely at least on a quarterly basis. Caution for elective surgery is advised; preoperative coagulation studies should be done, including platelet function studies and von Willebrand factor levels. Perioperative use of DDAVP to increase von Willebrand factor levels and improve platelet function is appropriate in some cases.