Pancytopenia and Valproic Acid—a Possible Association

Abstract

To the Editor: Valproic acid was approved in the US for use as an antiepileptic in 1978. Pharmacologically it has antiepileptic activity against a variety of seizure types while causing minimal central nervous system side effects.' Although the mechanism of action of valproic acid is unknown, evidence suggests that valproic acid selectively increases concentrations of gamma-aminobutyric acid in synaptic regions.' Valproic acid's psychopharmacological indications have expanded to include use for mood stabilization: a n~i e t y ,~ behavioral dyscontrol? and as an adjunctive modality in the treatment of psychosis.' The most common side effects are gastrointestinal symptoms, including anorexia, nausea, and vomiting. Elevation of hepatic enzymes has been observed in 15 to 30% of patients, often occurring asymptomatically early in the treatment. Heretofore, we were unaware of pancytopenia occurring in adults treated with valproic acid; here we present a case of myelotoxicity associated with valproic acid. Case ReportMr. M is a 66-year-old male, with a confirmed history of bipolar-manic type, hypothyroidism, alcohol abuse, and degenerative joint disease. A decompensation following medication noncompliance led to hospitalization. He was started on haloperidol 2 mg PO bid and 5 mg q hs, valproic acid 500 mg q hs, levothyroxine sodium 0.075 PO qd, and mvt/ thiamine. Valproic acid was increased to 500 mg bid, with serum levels remaining below 60 ng/mL. Admission labs revealed WBC of 4.2, HGB of 10.5, and HCT of 31.3. The hematologic indices fell inversely with increases in valproic acid, reaching WBC of 2.5, HGB of 9.0, and HCT of 27.1. Physical examination found fatigue and weakness without petechiae hemorrhages, ecchymosis, or edema. Hematology consult concluded a pancytopenia secondary to valproic acid, which was immediately discontinued. Within days, all hematologic indices normalized, and symptoms resolved without consequence. DiscussionHematological abnormalities have been reported with valproate use,6 but most studies have been conducted on children and adolescents.' In one hematological study of longterm side effects in 60 patients, 33% developed at least one prominent abnormality. Thrombocytopenia and macrocytosis were the most common findings. None of the patients demonstrated hepatic dysfunction, nor were the hematologic toxicity's severe enough to discontinue therapy.6Aplastic anemia, is attributable to a failure or suppression of pluripotential stem cells, leading to cytopenia of cell lineages. Primary aplastic anemia is without an identifiable cause. Secondary causes of reduction in functional marrow mass may include toxic, radiant, or immunologic injury to stem cells.8 Myelotoxicity is a particular concern for the geriatric population because bone marrow cellular density decreases with advancing age. There is a reduction to approximately 50% cellular density at age 65, with a further reduction in cellularity to about 30% occurring over the next decade.' Age, illness, and medications may create a synergistic v...

Valproate‐induced thrombocytopenia: a prospective monotherapy study

“…Kishi et al (1994) have shown that a high plasma VPA concentration is associated with in vivo and in vitro bone marrow suppression. While the VPA concentration‐dependent thrombocytopenia could be explained by the mechanism of bone marrow suppression, the rare occurrence of pancytopenia suggests that other mechanisms must be involved that renders the platelet cell lineage more vulnerable to VPA suppression or damage (Robinson et al, 1995; Oluboka et al, 2000). It is possible that both immune‐mediated peripheral destruction and VPA concentration‐dependent suppression of platelet precursors may be operating simultaneously.…”

Pancytopenia and Valproic Acid: A Dose‐related Association

“…Robinson et al have proposed that age, illness, and medications may create a synergistic vulnerability to hemopoietic disorders 14 . Duration of exposure and dose of valproic acid may also be significant risk factors in the development of valproic acid‐induced pancytopenia.…”

Acute hemolysis with acute renal failure in a patient with valproic acid poisoning treated with charcoal hemoperfusion

“…Severe valproic acid poisoning primarily affects the cardiovascular and central nervous systems 10–17 . Severe hemolysis has never been reported with valproic acid toxicity.…”

“…[6][7][8][9] Severe valproic acid poisoning primarily affects the cardiovascular and central nervous systems. [10][11][12][13][14][15][16][17] Severe hemolysis has never been reported with valproic acid toxicity. Thrombocytopenia is the most common hematologic abnormality found with acute Valproate toxicity.…”

“…The usual treatment recommended for Valproate poisoning includes supportive care, gastrointestinal decontamination, repeated doses of oral activated charcoal, and, when indicated, hemodialysis-hemoperfusion. 4,5,[10][11][12][13][14][15][16][17]19,20 Charcoal hemoperfusion has been lifesaving in severe Valproate acid toxicity. [19][20][21][22] Reported side effects associated with CH include thrombocytopenia, leukopenia, and hypotension.…”