Severe Bleeding Complications during Antiepileptic Treatment with Valproic Acid in Children: A Description of Four Cases.
Authors: Cannizzaro Elvira , Albisetti Manuela , Bergstraesser Eva , Scherer Franziska , Schmitt Bernhard , Wohlrab Gabriele , Schmugge Markus 
Published: October 2019

Abstract
Sodium valproat (VPA) is a commonly used antiepileptic drug in children. It is known to cause a variety of different haematological side effects, including thrombocytopenia, a decrease in plasma fibrinogen, von Willebrand factor (VWF)- and factor XIII, impaired platelet aggregation with ADP and Collagen and prolonged PFA-100 closure times. The mechanisms responsible for such a variety of haematological abnormalities are still poorly understood and controversy exists about their clinical relevance and the risk for significant bleeding. We report on 4 children with severe bleeding complications during VPA treatment that had been followed at our institution.
A first child with a cerebral malformation and no history of bleeding developed a subdural haematoma during VPA treatment without trauma. Additional studies revealed decreased von Willebrand factor levels that persisted with episodes of severe epistaxis also after VPA was stopped. A second infant suffered from herpes encephalitis with generalised seizures and died from an intracranial bleeding a day after a VPA loading dose was administred. Laboratory studies revealed prolonged PFA100 closure times. A third child with a therapeutic VPA serum-levels developed asymptomatic mild thrombocytopenia (around 100 G/l); unexpectedly in this child a tonsillectomy was complicated with sever diffuse haemorrhage that required red cell transfusion and intensive care treatment. Finally, a forth child who had been on VPA therapy for years causing prolonged PFA100 closure times, developed a large spinal epidural haematoma during epidural anaesthesia three days after urological surgery. This child had received VWF containing factor concentrate preoperatively only. For the bleeding additional VWF containing factor concentrate was given, the catheter was removed and the child recovered completely.
Paediatricians, neurologists and anesthesists should be aware of the haemostatic side effects of VPA that can lead to significant bleeding. Before starting VPA therapy, patients should be evaluated for the presence of a congenital bleeding disorder. Preoperatively for any surgical intervention and in case of the occurrence of bleeding symptoms the patients have to be further evaluated for a VPA-induced disorder of the plasmatic haemostasis or an impaired platelet function. Haemostatic side effects of VPA can occur at therapeutic VPA serum levels and are found at any time during the course of VPA treatment. VPA has to be used cautiously in severely ill children and in intensive care patients and the risk of bleeding of any surgical or anesthesiological procedure has to be evaluated. Treatment options for VPA induced haemostatic abnormalities include plasma derived factor concentrates that contain VWF and the use of antifibrinolytic agents. Further studies have to assess the feasibility of standard treatment with the vasopressin analog DDAVP for this group of patients taking into account their high risk for seizures.