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Ann Thorac Surg 2007;83:725
© 2007 The Society of Thoracic Surgeons

Correspondence

Valproic Acid and Bleeding: Caution Required

John P. Veinot, MDa, Marc Ruel, MD, MPHb

a Pathology and Laboratory Medicine, University of Ottawa, Ottawa Hospital, Civic Campus, 1053 Carling Ave, Ottawa, Ontario, K1Y 4E9 Canada
b Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7 Canada

(Email: jpveinot{at}ottawahospital.on.ca).

To the Editor:

We read with interest the recent article proposing valproic acid as a neuroprotective agent for use in cardiac surgery 1]. The canine hypothermic circulatory arrest model demonstrated improved clinical, histologic, and biochemical measurements with pretreatment with this medication. Although this is promising, caution may be warranted for future human studies.

An association between valproic acid and increased surgical bleeding is well described in the orthopedic and neurological literature [2, 3]. The affected individuals are usually children with chronic administration of the drug, mainly for seizure or neurologic disorders. Valproic acid has been described to affect the platelet count and function, thus affecting the bleeding time, and it also may affect coagulation factors such as fibrinogen and factor VIII. It is not known whether these effects are dose related or idiosyncratic [4, 5].

We recently had the unfortunate clinical experience of a patient with unexplained severe postoperative bleeding after routine coronary artery bypass grafting and aortic valve replacement. This individual had been receiving chronic valproic acid for a well-controlled seizure disorder, as well as acetylsalicylic acid aspirin for coronary artery disease related angina. At the end of an uneventful procedure the left ventricle surface had fatal uncontrollable bleeding. Complete autopsy, including detailed heart examination, found no underlying myocardial cause, and the grafts and valve prosthesis were uncomplicated. Preoperative thrombocytopenia was not present.

We recognize that acute administration and chronic administration of a drug are entirely different circumstances. Nonetheless we believe that this interaction of valproic acid with bleeding is not well known in the cardiac surgical literature. It is also not known if this interaction is dose related or idiosyncratic [4]. Because the procedure of cardiopulmonary bypass itself may have effects on platelet function and coagulation, the combination deserves careful study. Cerebral protection in cardiac surgery is an ongoing challenge. Valproic acid certainly deserves further study with caution and attention to investigation of the blood measurements.


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  1. Williams JA, Barreiro CJ, Nwakanma LU, et al. Valproic acid prevents brain injury in a canine model of hypothermic circulatory arrest: a promising new approach to neuroprotection during cardiac surgery Ann Thorac Surg 2006;81:2235-2242.[Abstract/Free Full Text]
  2. Pohlmann-Eden B, Peters CNA, Wennberg R, et al. Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding Acta Neurologica Scandinavica 2003;108:142-145.[Medline]
  3. 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.[Medline]
  4. Winter SL, Kriel RL, Novacheck TF, et al. Perioperative blood loss: the effect of valproate Pediatr Neurol 1996;15:19-22.[Medline]
  5. Gidal B, Spencer N, Maly M, et al. Valproate-mediated disturbances of hemostasis: relationship to dose and plasma concentration Neurology 1994;44:1418-1422.[Abstract/Free Full Text]

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Jason A. Williams and William A. Baumgartner
Ann. Thorac. Surg. 2007 83: 725-726. [Extract] [Full Text] [PDF]



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J. A. Williams and W. A. Baumgartner
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Ann. Thorac. Surg., February 1, 2007; 83(2): 725 - 726.
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