7-year-old boy was diagnosed to have absence epilepsy. VPA (20-mg/kg body weight/day) was started. Three days later, he presented with multiple ecchymotic patches and epistaxis. Hemoglobin was 11.4 mg%, and platelet count-3,52,000/cu.mm. Bleeding time (BT) was >15 minutes. Platelet aggregometry showed normal aggregation with ristocetin and reduced aggregation with epinephrine and collagen. Clotting time (CT), prothrombin time (PT) and partial thromboplastin time (PTT) were normal. Plasma VPA level was 54 µg/ml. VPA-therapy was withdrawn. Fresh platelet concentrates were transfused. Child improved and platelet aggregometry repeated after six weeks was normal.

15-year-old girl presented with excessive bleeding from traumatic compound tibial fracture. Twelve hours after surgery, she developed re-bleeding from surgical site. She was on VPA (30 mg/Kg/day) for nine months for epilepsy. Plasma VPA level was 120 µg/mL. Hemoglobin was 9.2 g%, and platelet count-2,10,000/cumm. BT, CT, PT and PTT were normal. Urea clot lysis test was positive, suggesting Factor XIII deficiency. Past history did not suggest prolonged bleeding from umbilical stump after birth, therefore VPA therapy as an acquired cause for factor XIII deficiency was suspected and withdrawn. Cryopreci-pitates were transfused and bleeding stopped. Clot lysis test repeated after ten weeks was normal.

The commonest hematologic abnormality with VPA therapy is thrombocytopenia, however, our patients had normal platelet counts. Frequency of valproate-induced thrombo-cytopenia is 21%, however 90% remain asymptomatic(1). The incidence of thrombo-cytopenia is related to VPA dose and plasma drug levels, as 1200-3000 mg/day resulted in thrombocytopenia(2). Most had plasma VPA level >140 micrograms/mL Platelet counts normalized after dose reduction(1). Plasma drug levels were within therapeutic range in our patients. The incidence of thrombo-cytopenia was also related to VPA-treatment duration(1). Thrombocytopenia results due to combination of peripheral antibody-mediated platelet destruction and bone marrow depression. Platelet dysfunction also occurs with VPA therapy. In a 4-month-old, bleeding from venepuncture sites and multiple ecchymoses occurred two days after starting VPA therapy(3). The cause was platelet dysfunction and hypofibrogenemia. Case 1 had platelet aggregation defect, and onset of symptoms was similar. Platelet aggregation defects correlate well with VPA dose and plasma concentration.

VPA-related factor XIII deficiency (seen in case 2) has been reported earlier(4). Acquired von Willebrand’s disease may be the other mechanism of bleeding(5).

In conclusion, the risk of clinical bleeding with VPA therapy appears to be extremely low despite high incidence of laboratory abnormalities. Hematologic toxicities may be reversed by dosage reduction and discontinua-tion of VPA may not be required.

Sudhir Kumar,
Consultant Neurologist,
Department of Neurological Sciences,
Christian Medical College,
Vellore, Tamilnadu 632 004,
India.
E-mail: [email protected]

1. Delgado MR, Riela AR, Mills J, Browne R, Roach ES. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J Child Neurol. 1994; 9: 311-314.

2. Neophytides AN, Nutt JG, Lodish JR. Thrombocytopenia associated with sodium valproate treatment. Ann Neurol. 1979; 5: 389-390.

3. Raghuveer TS, Srinivasa R, Chandrasekhara MK. Valproate induced bleeding. Indian Pediatr. 1989; 26: 596-597.

4. Teich M, Longin E, Dempfle CE, Konig S. Factor XIII deficiency associated with valproate treatment. Epilepsia. 2004; 45: 187-189.

5. Serdaroglu G, Tutuncuoglu S, Kavakli K, Tekgul H. Coagulation abnormalities and acquired von Willebrand’s disease type 1 in children receiving valproic acid. J Child Neurol. 2002; 17: 41-43.