The Effect of Valproate Therapy on Thrombin Generation Determined by Calibrated Automated Thrombography

Abstract

Background: There is some evidence for coagulation disorders, e. g. decreased coagulation factor activity or thrombocytopenia, related to the use of antiepileptic drugs, mainly associated with valproate. The aim of our study was to evaluate the influence of valproate on thrombin generation.

Method: Patients with epilepsy receiving multiple anticonvulsant medications either with, or without, valproate were compared. The study group included 90 samples from patients with epilepsy, aged 1.3–20.1 years. Antiepileptic combination therapy without valproate was administered in 50 cases and therapy including valproate in 40 cases. The reference group consisted of 50 non-epileptic patients. Thrombin generation in platelet poor plasma was measured by calibrated automated thrombography.

Results: No differences were measured for thrombin generation parameters between controls and patients without valproate therapy. In epileptic patients with valproate therapy, peak height and lag time were significantly lower in comparison to non-epileptic patients. In comparison to epileptic patients without valproate therapy, significant differences were found for lag time and peak time. Patients with valproate therapy had a significantly lower fibrinogen concentration. Platelet counts were decreased in a dose dependent manner.

Conclusion: No major differences in thrombin generation were found between children on antiepileptic therapy with and without valproate. The decreased fibrinogen levels result in shorter lag time and peak time.

Zusammenfassung

Hintergrund: Für verschiedene Antiepileptika, insbesondere für Valproat, sind Gerinnungsstörungen als Nebenwirkung beschrieben, wie z. B. eine verminderte Faktoraktivität oder Thrombozytopenie. Ziel unserer Studie war es, die Wirkung von Valproat auf die Thrombingenerierung durch Messung des endogenen Thrombinpotenzials zu untersuchen.

Patienten: Für die Untersuchung wurden jeweils Epilepsiepatienten, die mit und ohne Valproat behandelt wurden, miteinander verglichen. 90 Epilepsiepatienten im Alter von 1,3–20,1 Jahren wurden eingeschlossen. 50 Patienten erhielten eine Therapie ohne Valproat, 40 eine Kombinationstherapie mit Valproat. Die Referenzgruppe bestand aus 50 Kindern ohne Epilepsie.

Methode: Die Thrombingenerierung wurde im plättchenarmen Plasma nach der Methode von Hemker gemessen.

Ergebnisse: Im Vergleich zur Kontrollgruppe Konnte für alle Kurvenparameter der Thrombingenerierung kein signifikanter Unterschied gefunden werden. Bei den Patienten mit Valproat-therapie waren im Vergleich zu den Patienten ohne Valproat Lag-Phase und die Zeit bis zum Erreichen des Peakmaximums geringfügig, aber signifikant erniedrigt. Die Patienten mit Valproat zeigten signifikant niedrigere Fibrinogenspiegel. Die Thrombozytenanzahl war dosisabhängig erniedrigt.

Schlussfolgerung: Die antiepileptische Therapie mit und ohne Valproat zeigte keine wesentlichen Unterschiede in Bezug auf die Thrombingenerierung im plättchenarmen Plasma. Erniedrigte Fibrinogenspiegel führen zu einer kürzeren Lag-Phase und Peakzeit.

thrombin - valproate - ETP - antiepileptic therapy - endogenous thrombin potential - fibrinogen

Thrombin - Valproat - ETP - Antiepileptika - endogenes Thrombinpotenzial - Fibrinogen

References

• 1 Banerjea MC, Diener W, Kutschke G. et al . Pro- and anticoagulatory factors under sodium valproate-therapy in children.  Neuropediatrics. 2002;  33 215-220
• 2 Bernhard H, Rosenkranz A, Petritsch M. et al . Phospholipid content, expression and support of thrombin generation of neonatal platelets.  Acta Paediatr. 2009;  98 251-255
• 3 Cannizzaro E, Albisetti M, Wohlrab G. et al . Severe bleeding complications during antiepileptic treatment with valproic acid in children.  Neuropediatrics. 2007;  38 42-45
• 4 Carney BT, Minter CL. Is operative blood loss associated with valproic acid? Analysis of bilateral femoral osteotomy in children with total involvement cerebral palsy.  J Pediatr Orthop. 2005;  25 283-285
• 5 De Berardis D, Campanella D, Matera V. et al . Thrombocytopenia during valproic acid treatment in young patients with new-onset bipolar disorder.  J Clin Psychopharmacol. 2003;  23 451-458
• 6 Duchemin J, Pan-Petesch B, Arnaud B. et al . Influence of coagulation factors and tissue factor concentration on the thrombin generation test in plasma.  Thromb Haemost. 2008;  99 767-773
• 7 Eberl W, Budde U, Bentele K. et al . Acquired von Willebrand syndrome as side effect of valproic acid therapy in children is rare.  Hamostaseologie. 2009;  29 137-142
• 8 Eisert S, Hovermann M, Bier H. et al . Preoperative screening for coagulation disorders in children undergoing adenoidectomy (AT) and tonsillectomy (TE): does it prevent bleeding complications?.  Klin Padiatr. 2006;  218 334-339
• 9 Gerstner T, Teich M, Bell N. et al . Valproate-associated coagulopathies are frequent and variable in children.  Epilepsia. 2006;  47 1136-1143
• 10 Halimeh S, Angelis G, Sander A. et al . Multiplate whole blood impedance point of care aggregometry: preliminary reference values in healthy infants, children and adolescents.  Klin Padiatr. 2010;  222 158-163
• 11 Hemker HC, Al Dieri R, De Smedt E. et al . Thrombin generation, a function test of the haemostatic-thrombotic system.  Thromb Haemost. 2006;  96 553-561
• 12 Hemker HC, Giesen P, AlDieri R. et al . The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability.  Pathophysiol Haemost Thromb. 2002;  32 249-253
• 13 Koenig S, Gerstner T, Keller A. et al . High incidence of vaproate-induced coagulation disorders in children receiving valproic acid: a prospective study.  Blood Coagul Fibrinolysis. 2008;  19 375-382
• 14 Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: a prospective monotherapy study.  Epilepsia. 2008;  49 438-445
• 15 Rosenkranz A, Hiden M, Leschnik B. et al . Calibrated automated thrombin generation in normal uncomplicated pregnancy.  Thromb Haemost. 2008;  99 331-337
• 16 Rosenkranz A, Koestenberger M, Novak M. et al . Pediatric patients with congenital heart disease: thrombin generation measured by calibrated automated thrombography.  Blood Coagul Fibrinolysis. 2008;  19 389-393
• 17 Schadlich D, Friebel D, Schallner J. et al . Evaluation of haemostasis in children treated with valproic acid.  Hamostaseologie. 2010;  30 S132-S137
• 18 Streif W, Knofler R, Eberl W. Inherited disorders of platelet function in pediatric clinical practice: a diagnostic challenge.  Klin Padiatr. 2010;  222 203-208
• 19 von Voss H, Petrich C, Karch D. et al . Letter: Sodium valproate and platelet function.  Br Med J. 1976;  2 179

Correspondence