Severe Bleeding Complications during Antiepileptic Treatment with Valproic Acid in Children[*]

Abstract

Valproic acid (VPA) is an antiepileptic drug frequently used in children. Although VPA can cause a variety of laboratory abnormalities affecting haemostasis, controversy exists about the clinical relevance of such haematological abnormalities. We report on 4 children with severe bleeding complications while on VPA therapy; two presented with intracranial bleeding, while two suffered from severe bleeding postoperatively. Diagnostic and therapeutic measures are discussed that help to avoid severe bleeding complications in children with VPA treatment.

Key words

Epilepsy - valproic acid - von Willebrand factor - platelets - coagulation

1 Presented in part at the 47nd annual meeting of the American Society of Haematology, Atlanta, Georgia, December 2005.

References

• 1 Anderson GD, Temkin NR, Chandler WL, Winn HR. Effect of valproate on haemostatic function in patients with traumatic brain injury.  Epilepsy research. 2003;  57 111-119
• 2 Argyriou AA, Tsota I, Solomou E, Marangos M, Kalogeropoulou C, Petsas T. et al . Intracerebral haemorrhage as a rare complication of HSV-1 meningoencephalitis: Case report and review of the literature.  Scand J Infect Dis. 2006;  38 63-66
• 3 Banerjea MC, Diener W, Kutschke G, Schneble HJ, Korinthenberg R, Sutor AH. Pro- and anticoagulatory factors under sodium valproate therapy in children.  Neuropaediatrics. 2002;  33 215-220
• 4 Chambers HG, Weinstein CH, Mubarak SJ, Wenger DR, Silva PD. The effect of valproic acid on blood loss in patients with cerebral palsy.  J Paediatr Orthop. 1999;  19 792-795
• 5 Gerstner T, Teich M, Bell N, Longin E, Dempfle C, Brand J. et al . Valproate-associated coagulopathies are frequent and variable in children.  Epilepsia. 2006;  47 1136-1143
• 6 Gidal B, Spencer N, Maly M, Pitterle M, Williams E, Collins M. et al . Valproate-mediated disturbances of haemostasis.  Neurology. 1994;  44 1418-1422
• 7 Harrison P. The role of PFA-100 testing in the investigation and management of haemostatic defects in children and adults.  B J Haematol. 2005;  130 3-10
• 8 Konig S, Scheffner D, Rauterberg-Ruland I, Kochen W, Hofmann WJ, Wokittel E. et al . Fatal hepatic failure in a normally developed 5-year-old boy by VPA monotherapy.  Monatsschr Kinderheilkd. 1987;  135 310-313
• 9 Kreuz W, Linde R, Funk M, Meyer-Schrod R, Föll E, Nowak-Göttl U. et al . Valproate therapy induces von Willebrand disease type I.  Epilepsia. 1992;  33 178-184
• 10 Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R. et al . Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans-retinoic acid.  Blood. 2004;  104 1266-1269
• 11 Larkin D, Murphy D, Reilly DF, Cahill M, Sattler E, Harriott P. et al . ICln, a novel integrin α_IIbβ₃-associated protein, functionally regulates platelet activation.  J Biol Chem. 2004;  279 27286-27293
• 12 Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.  CNS Drugs. 2002;  16 695-714
• 13 Peterson GM, Naunton M. Valproate: a simple chemical with so much to offer.  J Clinical Pharmacy and Therapeutics. 2005;  30 417-421
• 14 Pohlmann-Eden B, Peters CAN, Wennberg R, Dempfle CE. Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding.  Acta Neurol Scand. 2003;  108 142-145
• 15 Rosenberg HK, Ortega W. Haemorrhagic pancraetitis in a young child following valproic acid therapy. Clinical and ultrasonic assessment.  Clin Paediatr (Phila). 1987;  26 98-101
• 16 Sleiman C, Raffy O, Roué C, Mal H. Fatal pulmonary haemorrhage during high-dose valproate monotherapy [letter].  Chest. 2000;  117 613
• 17 Verrotti A, Greco R, Matera V, Altobelli E, Morgese G, Chiarelli F. Platelet count and function in children receiving sodium valproate.  Paediatr Neurol. 1999;  21 611-614
• 18 Zeller JA, Schlesinger S, Runge U, Kessler C. Influence of valproate monotherapy on platelet activation and hematologic values.  Epilepsia. 1999;  40 186-189

1 Presented in part at the 47nd annual meeting of the American Society of Haematology, Atlanta, Georgia, December 2005.

Correspondence