Acharya S, Bussel J B
Department of Pediatric Hematology/Oncology, New York Presbyterian Hospital-Cornell Medical Center, New York 10021, USA.
J Pediatr Hematol Oncol. 2000 Jan-Feb;22(1):62-5. doi: 10.1097/00043426-200001000-00012.
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.
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.
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.
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.
丙戊酸钠是治疗儿童难治性癫痫常用的抗惊厥药物，有效率良好且毒性可接受。肝毒性是最广为人知的毒性。随着使用更高的药物剂量来实现充分的癫痫发作控制，血液学毒性越来越常见，小儿血液科医生会在术前或围手术期处理这些问题。本文旨在描述临床中遇到的各种血液学毒性，并提供指导方针以协助管理这些患者。
进行文献综述以确定丙戊酸钠单药治疗或联合治疗时的血液学毒性。搜索中使用的关键词为丙戊酸钠、血液学和出血。
丙戊酸钠可导致直接的骨髓抑制，引起再生障碍性贫血或影响一种或多种细胞系的外周血细胞减少。也曾观察到偶发的致命性骨髓衰竭、骨髓发育异常以及类似急性早幼粒细胞白血病的临床表现。血小板减少、大细胞性贫血、中性粒细胞减少和纯红细胞再生障碍可能发生，但据报道不会危及生命。与丙戊酸钠使用相关的出血素质可能包括血小板减少、异常血小板功能以及获得性I型血管性血友病。
丙戊酸钠的血液学毒性很常见，起病和严重程度各不相同，可复发、短暂或持续，通常在丙戊酸钠血清水平大于100μg/mL时发生。在大多数情况下，即使具有高度临床意义，通过减少剂量也可逆转，很少需要停药。血小板减少和白细胞减少等潜在不良反应可通过实验室监测轻松检测到，至少应每季度无限期持续监测。建议对择期手术谨慎；应进行术前凝血研究，包括血小板功能研究和血管性血友病因子水平检测。在某些情况下，围手术期使用去氨加压素以提高血管性血友病因子水平并改善血小板功能是合适的。
