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Year : 2006  |  Volume : 9  |  Issue : 4  |  Page : 230-232

Valproate induced thrombocytopenia complicating acute febrile illness

SAT Hospital, Govt. Medical College, Thiruvanathapuram - 695 011, India

Correspondence Address:
K E Elizabeth
Department of Pediatrics, SAT Hospital for Women and Children, Govt. Medical College, Thiruvanathapuram - 695 011, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-2327.29206

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Sodium valproate is a commonly used anticonvulsant. Thrombocytopenia is one of the lesser known adverse effects of valproate. Fever with thrombocytopenia is a frequent clinical presentation especially in tropical countries like India with emerging and reemerging infections like dengue fever. We present here two cases of resistant thrombocytopenia in febrile children which responded dramatically to withdrawing valproate. Both the children had valproate drug level in the normal therapeutic range. Based on the Naranjo adverse drug reaction probability scale a probable association was found between valproate and the thrombocytopenia.

Keywords: Sodium valproate, thrombocytopenia

How to cite this article:
Elizabeth K E, Gopakumar H, Zachariah P, Jacob RG. Valproate induced thrombocytopenia complicating acute febrile illness. Ann Indian Acad Neurol 2006;9:230-2

How to cite this URL:
Elizabeth K E, Gopakumar H, Zachariah P, Jacob RG. Valproate induced thrombocytopenia complicating acute febrile illness. Ann Indian Acad Neurol [serial online] 2006 [cited 2020 Nov 26];9:230-2. Available from:

   Introduction Top

Sodium valproate is a commonly used anticonvulsant with known hematological and liver toxicity, which is usually dose or blood level dependent. During viral infection or acute febrile illness, such toxicity may occur even with normal blood levels. This should be anticipated in sick children with acute febrile illness and in post-operative cases. We report two children on valproate therapy presenting with acute febrile illness and resistant thrombocytopenia with normal blood levels. Both responded promptly to drug withdrawal.

   Case Report Top

A eleven-month-old male child, a diagnosed case of seizure disorder being treated with sodium valproate in a dose of 40 mg/kg/day in two divided doses for six months was admitted with high grade fever and petechial rashes. He had severe thrombocytopenia on admission and developed refractory shock in the absence of any massive bleed. He was treated with antibiotics and supportive measures with an empirical diagnosis of sepsis/dengue shock syndrome. Initial investigations showed Hemoglobin -10.4 g/dl, TC-6000/cumm, DC P24% L76%, PCV 32%, platelet count -33,000/cumm, SGOT -27 IU, SGPT -60 IU, total protein 5.4 g/dl, S Albumin 3.3 g/dl, Plasma urea 15 mg/dl, serum creatinine 0.7 mg/dl, serum Na 143 mEql/l, K, -3 mEl/l. PT -15.5 sec (N value - 11.7 sec) and APTT 42.83 sec (N value-32.5 sec). However repeated blood cultures, Weil's antibody and Dengue IgM were negative. The peripheral smear showed thrombocytopenia. Platelet function tests were not done. Serum valproate level was 81 micrograms/ml (N-50- 100 micrograms /ml). Despite supportive therapy and antibiotics namely IV Crystalline penicillin, IV Cloxacillin and IV ceftriaxone, the repeat platelet count remained persistently low (around 30,000/cmm). The child did not have any drug allergy. In view of persistently low platelet count, the possibility of valproate induced thrombocytopenia was considered and a decision was made to withdraw valproate. This was followed by a dramatic increase in the platelet count in three days. The child was discharged after two weeks of hospitalization on clonazepam. The platelet count at discharge was 120000 /cumm.

A two-year-year old male child on sodium valproate monotherapy in a dose of 30 mg/kg/day in two divided doses for five months for atypical febrile seizures was admitted for evaluation of high grade fever and one episode of malena. On admission the child had thrombocytopenia, platelet count - 90,000/cmm. Other investigations showed Hemoglobin -12 g/dl, TC -4000/ cumm, DC P51% L49%, ESR 20 mm/Hr, PCV 36%. Renal and liver functions were normal. The peripheral smear showed lymphocytosis and thrombocytopenia. Work up for sepsis, Weil's antibody and dengue serology were negative. The child was on IV Crystalline penicillin and supportive measures. The child did not have any allergies. Platelet function test was not done. Serum valproate level was 97.9 micrograms /ml. Despite supportive management and antibiotics, the platelet count reduced to 30,000/cumm. On withdrawing sodium valproate the thrombocytopenia improved remarkably in 2 days. On discharge, the platelet count was 1, 72,000/ cu mm and the child was placed on intermittent diazepam prophylaxis for febrile seizure.

On follow-up for a year, both the patients have had stable hematological parameters.

   Discussion Top

Sodium valproate is a commonly used anticonvulsant in the management of childhood refractory epilepsy with good response rates and acceptable toxicity. Hepatotoxicity is the most widely recognized toxicity. With the use of higher drug levels to achieve adequate seizure control, hematological toxicity is being increasingly encountered.[1],[2] Valproate associated thromobocytopenia has been reported ranging from 1 to 21%.[3],[4],[5],[6] However, severe clinically significant thrombocytopenia as seen in patient one is rare.[7] Valproate can cause direct bone marrow suppression leading to aplastic anemia or peripheral cytopenia affecting one or more cell lines.[1] Occasional fatal bone marrow failure, myelodysplasia and a clinical picture resembling acute promyelocytic leukemia[8] have also been seen. Thrombocytopenia, macrocytosis, neutropenia and pure red cell aplasia can occur, but are not reported to be life-threatening.[1] A bleeding diathesis associated with valproate use may include thrombocytopenia, abnormal platelet function,[9] megakaryocyte dysplasia,[10] acquired Von Willebrand disease type I[11] and a deficiency of factor XIII.[12]

Hematological toxicities of valproate are common, vary in onset and severity, are recurrent, transient or persistent and usually occur with a serum valproate level greater than 100 microgms/mL. In most situations, even when clinically significant, they can be reversed with dosage reduction; drug discontinuation is rarely required.[13] Potential adverse effects such as thrombocytopenia and leukopenia are easily detected by laboratory monitoring, which should be continued indefinitely at least on a quarterly basis. Caution for elective surgery is advised; preoperative coagulation studies should be done, including platelet function studies and Von Willebrand factor levels. Perioperative use of DDAVP to increase Von Willebrand factor levels and improve platelet function is appropriate in some cases.

In both the above patients, in view of the presentation, the initial clinical diagnosis made was of Dengue fever/sepsis resulting in thrombocytopenia. However, the negative diagnostic work up and resistant thrombocytopenia which responded remarkably to valproate withdrawal suggested drug toxicity as the predisposing cause. Neither of the children had a previous history of allergic drug reactions. Hematological parameters done prior to starting valproate were documented to be normal in both the children. An objective causality assessment using the Naranjo Adverse Drug Reaction (ADR) probability scale showed a probable association (score =7) between valproate and the thrombocytopenia.[14] In developing countries with large patient population and inadequate resources, regular follow-up and earlier detection of this complication in asymptomatic children may not happen. Hence, the need to consider valproate drug toxicity in the differentials for thrombocytopenia even in children with clinical presentations that may be more suggestive of an infective etiology is emphasized. Viral infections have been suggested as etiological agents for clinically significant episodic thrombocytopenia in patients treated with valproate.[15] This may occur when the valproate drug levels are in the normal range as in our cases.

   References Top

1.Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol 2000;22:62-5.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Brichard B, Vermylen C, Scheiff JM, Ninane J, Cornu G. Haematological disturbances during long-term valproate therapy. Eur J Pediatr 1994;153:378-80.  Back to cited text no. 2  [PUBMED]  
3.Allarakhia IN, Garofalo EA, Komarynski MA, Robertson PL. Valproic acid and thrombocytopenia in children: A case-controlled retrospective study. Pediatr Neurol 1996;14:303-7.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Conley EL, Coley KC, Pollock BG, Dapos SV, Maxwell R, Branch RA. Prevalence and risk of thrombocytopenia with valproic acid: Experience at a psychiatric teaching hospital. Pharmacotherapy 2001;21:1325-30.  Back to cited text no. 4  [PUBMED]  
5.Ko CH, Kong CK, Tse PW. Valproic acid and thrombocytopenia: Cross-sectional study. Hong Kong Med J 2001;7:15-21.  Back to cited text no. 5    
6.Delgado MR, Riela AR, Mills J, Browne R, Roach ES. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J Child Neurol 1994;9:311-4.  Back to cited text no. 6  [PUBMED]  
7.Ganick DJ, Sunder T, Finley JL. Severe hematologic toxicity of valproic acid. A report of four patients. Am J Pediatr Hematol Oncol 1990;12:80-5.  Back to cited text no. 7    
8.Bottom KS, Adams DM, Mann KP, Ware RE. Trilineage hematopoietic toxicity associated with valproic acid therapy. J Pediatr Hematol Oncol 1997;19:73-6.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Verrotti A, Greco R, Matera V, Altobelli E, Morgese G, Chiarelli F. Platelet count and function in children receiving sodium valproate. Pediatr Neurol 1999;21:611-4.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Gesundheit B, Kirby M, Lau W, Koren G, Abdelhaleem M. Thrombocytopenia and megakaryocyte dysplasia: An adverse effect of valproic acid treatment. J Pediatr Hematol Oncol 2002;24:589-90.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.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;17:41-3.  Back to cited text no. 11    
12.Teich M, Longin E, Dempfle CE, Konig S. Factor XIII deficiency associated with valproate treatment. Epilepsia 2004;45:187-9.  Back to cited text no. 12    
13.Lackmann GM. Valproic-acid-induced thrombocytopenia and hepatotoxicity: Discontinuation of treatment? Pharmacology 2004;70:57-8.  Back to cited text no. 13    
14.Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al . A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 14    
15.Vadney V. Unusual clusters of valproate-associated thrombocytopenia. J Epilepsy 1992;5:186-90.  Back to cited text no. 15    


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