Valproate-Associated Dysmyelopoiesis in Elderly Patients

Chi-chiu So, MRCPath, Kit-fai Wong, MD

Disclosures

Am J Clin Pathol. 2002;118(2) 

In This Article

Case Reports

A 62-year-old woman had a long history of primary generalized epilepsy. Valproate monotherapy was started in 1989. Results of a baseline CBC count were normal. Isolated mild thrombocytopenia of 120 to 130 103/µL (120-130 109/L; reference range, 145-370 103/µL [145-370 109/L]) soon developed and persisted as shown by serial blood monitoring. The serum valproate levels remained in the therapeutic range.

In January 1997, her epileptic control worsened, and the dose of valproate had to be increased from 1,500 mg once daily to 1,500 mg twice daily. Severe pancytopenia developed after 1 month with a hemoglobin level of 8.1 g/dL (81 g/L; reference range 13.4-17.1 g/dL [134-171 g/L]); a mean corpuscular volume of 98 µm3 (98 fL; reference range, 82-97 µm3 [82-97 fL]); a WBC count of 1,800/µL (1.8 109/L; reference range, 3,700-9,200/µL [3.7-9.2 109/L]) with 61% neutrophils (0.61), 27% lymphocytes (0.27), and 12% monocytes (0.12); and a platelet count of 10 103/µL (10 109/L).

Neutrophils with pseudo-Pelger-Huët anomaly were found on peripheral blood smear examination Figure 1A. Examination of bone marrow aspirates showed normal cellularity with active megaloblastoid erythropoiesis, relatively reduced and left-shift granulopoiesis, and adequate megakaryopoiesis. Many megakaryocytes with multiple separate nuclei were found Figure 1B. Some erythroblasts had irregular to lobulated nuclei Figure 1C. Blasts were not increased, and there were no ringed sideroblasts. A diagnosis of dysmyelopoiesis was made and the possibility of valproate-related hematologic toxic effects was suggested.

(Case 1) A, Two circulating neutrophils with pseudo-Pelger-Huët anomaly (May-Grünwald-Giemsa, 1,000). B, Two dysplastic megakaryocytes (arrows) in the bone marrow aspirate smear showing nuclear segregation (May-Grünwald-Giemsa, 1,000). C, An erythroblast in the bone marrow aspirate showing nuclear irregularity (May-Grünwald-Giemsa, 1,000).

(Case 1) A, Two circulating neutrophils with pseudo-Pelger-Huët anomaly (May-Grünwald-Giemsa, 1,000). B, Two dysplastic megakaryocytes (arrows) in the bone marrow aspirate smear showing nuclear segregation (May-Grünwald-Giemsa, 1,000). C, An erythroblast in the bone marrow aspirate showing nuclear irregularity (May-Grünwald-Giemsa, 1,000).

(Case 1) A, Two circulating neutrophils with pseudo-Pelger-Huët anomaly (May-Grünwald-Giemsa, 1,000). B, Two dysplastic megakaryocytes (arrows) in the bone marrow aspirate smear showing nuclear segregation (May-Grünwald-Giemsa, 1,000). C, An erythroblast in the bone marrow aspirate showing nuclear irregularity (May-Grünwald-Giemsa, 1,000).

The serum valproate level was markedly elevated to 1,447 µmol/L (therapeutic level, 347-693 µmol/L). Valproate therapy was stopped, and carbamazepine therapy was started. Her blood counts normalized 6 weeks after cessation of therapy. In 1999, valproate had to be reintroduced at a reduced dose of 300 mg twice daily in addition to carbamazepine because of poor seizure control. Mild thrombocytopenia recurred, and serial blood monitoring revealed that it remained stable at around 100 103/µL (100 109/L).

A 62-year-old man had a cerebrovascular accident that was complicated by seizure attacks. He was given 200 mg of valproate twice daily for seizure control. Two weeks after commencement of therapy, mild pancytopenia was detected by blood count monitoring, with a hemoglobin level of 12.9 g/dL (129 g/L); a mean corpuscular volume of 98.5 µm3 (98.5 fL); a WBC count of 2,200/µL (2.2 109/L) with 63% neutrophils (0.63), 27% lymphocytes (0.27), and 10% monocytes (0.10); and a platelet count of 109 103/µL (109 109/L). The serum valproate level was 363 µmol/L. Examination of the peripheral blood smear showed no dysplastic features. Examination of the bone marrow aspirate showed normal cellularity with megaloblastoid erythropoiesis and normal granulopoiesis. Megakaryocytes were adequate in number, with occasional ones showing multiple separate nuclei Figure 2. Toxic effects of valproate were suspected, and the drug was withheld. His blood cell counts normalized 12 days afterward.

(Case 2) A dysplastic megakaryocyte in the bone marrow aspirate smear showing nuclear segregation (May-Grünwald-Giemsa, 1,000).

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