Valproic Acid and Augmentation of Fetal Hemoglobin in Individuals With and Without Sickle Cell Disease

To the Editor: pliance with therapy. Annual rates of vaso-occlusive crisis were calculated as previously described by dividing the number of crises by the number of years of therapy (for example, 2 crises Increased synthesis of fetal hemoglobin may ameliorate the cliniin 6 months Å 4 crises per year). The number of days spent in cal severity of sickle cell disease; both chemotherapeutic and nonhospital and the number of red blood cell transfusions adminischemotherapeutic agents have been shown to augment fetal hemotered were calculated in a similar manner. Compliance with valglobin synthesis in selected populations of affected patients. Some proic acid was monitored by the Medication Event Monitoring studies have suggested that the fatty acid analogue valproic acid (nSystem, a bottle with a computer chip in the lid that determines dipropylacetic acid) may increase the synthesis of fetal hemoglobin. the timing and frequency of bottle openings, and by determinaA study of 36 patients with epilepsy treated with valproic acid (10 tions of concentrations of serum valproic acid obtained at clinic to 46 mg/kg body weight per day) reported that the percentage of visits. red blood cells containing fetal hemoglobin (F cells) was signifiThe changes observed during therapy with valproic acid over 5.8 cantly higher in these individuals than in 293 patients not receiving { 0.9 (3.2 to 9.0) months are shown in Table 1. Data are presented this therapy; parallel changes in fetal hemoglobin were not reported. as the mean { standard deviation. A study of four adults with sickle cell disease treated with valproic Compliance with valproic acid was 93% { 7% drug taken of that acid (15 to 40 mg/kg/d) reported a threefold increase in fetal hemoprescribed. Mean trough serum levels (561 { 115 mmol/L) were globin in three patients, with no corresponding decrease in the frewithin the therapeutic range (350 to 750 mmol/L; 50 to 100 mg/mL). quency of vaso-occlusive crises, over 2 to 13 weeks. Finally, a No changes in liver function tests were observed; in one patient, the study in which 10 patients with sickle cell disease received treatment platelet count decreased to 98 1 10/L, prompting discontinuation with hydroxyurea followed by valproic acid (20 mg/kg/d) reported of valproic acid. Review of this patient’s medical records showed no difference in the concentrations of fetal hemoglobin, frequency that he had chronic low-grade thrombocytopenia before the initiation of vaso-occlusive crises, or adverse drug effects in patients treated of valproic acid; this finding has persisted after withdrawal of valwith either agent. proic acid. Bone marrow aspiration showed abundant megakaroWe examined the changes in fetal hemoglobin synthesis in indicytes. The relationship between thrombocytopenia in this patient viduals without sickle cell disease and receiving valproic acid for and valproate therapy, acknowledged to induce thrombocytopenia epilepsy to determine whether previously reported valproic acidin 21% to 60% of treated patients who have serum concentrations induced changes in F-cells are associated with measurable increases exceeding 100 to 140 mg/mL, is unclear. in fetal hemoglobin. In parallel, we evaluated laboratory and clinical Because of the lack of clinical improvement and frequent hospital responses associated with valproic acid therapy in seven patients admissions during valproic acid, one patient requested discontinuawith sickle cell disease. One hundred and six consecutive patients attending the Neurology Clinic at The Hospital for Sick Children, Toronto, with a diagnosis of seizure disorder, none of whom had sickle cell disease or trait, were studied. Fifty-seven patients, aged (mean { SD) 9.3 { 4.4 Table 1. Clinical and Laboratory Characteristics of Seven Patients years, were receiving therapy with carbamazepine (Tegretol), With Sickle Cell Disease Treated With Valproic Acid whereas 49 patients, aged 9.9 { 5.2 years, had been treated with Prevalproic acid (15 to 50 mg/kg/d) for 4.0 { 0.5 years. Although a Valproic PostP significant mean increase in mean red blood cell volume (from 84 Parameter Acid Valproic Acid Value { 5 fL before treatment with valproic acid to 90 { 5 fL; P õ Hemoglobin (g/dL) 8.3 { 0.9 9.3 { 1.2 .05 .01) had been observed in the latter group, the percentage of fetal Hemoglobin F (%) 6.4 { 2.6 8.4 { 4.3 .05 hemoglobin (mean { SEM, 0.9% { 0.1%) in patients with therapeuHemoglobin F (g/dL) 5.4 { 2.2 7.9 { 4.5 .05 tic serum drug concentrations of valproic acid did not differ signifiMean cell volume (fL) 83 { 8.0 86 { 7.0 NS cantly from that of the carbamazepine-treated patients (0.8% { Annual rate of 0.1%; P Å NS). Vaso-occlusive crises 3.1 { 3.1 5.8 { 9.0 NS In parallel, seven patients, aged 16.5 { 10 years, with severe Blood transfusions 1.1 { 3.0 0.3 { 0.7 NS sickle cell disease, defined as three or more hospitalizations in In-patient hospital days 31 { 28 37 { 53 NS the year before treatment, were offered valproic acid at 15 { 3 (range, 9 to 20) mg/kg/d. Complete blood counts were obtained Data obtained at evaluation before beginning valproic acid were compared with those at the completion of the study using the Stutwice monthly. Patients were reviewed by a physician twice a month and questioned regarding adverse effects of treatment, dent’s t-test for paired data. All tests were two-tailed; a significance level of .05 was used to indicate statistical significance. sickle cell disease-related pain, admissions to hospital, and com-