Clinical Pharmacology

"Adverse Drug Event of the month"

Probable valproic acid induced thrombocytopenia


Case report:

A 7-year-old boy was brought to the emergency department with complaints of echymotic patches over the right forearm, back and continuous bleeding through a wound on left knee for the past 15 days. The patient was apparently alright 15 days back when he started developing echymotic patches all over the body spontaneously. There was no history of fever, trauma, joint swelling, jaundice or ascites. He was a known case of seizure disorder and was taking Syrup valproic acid 20 mg/kg/day (5 ml twice a day) for past year. There was no significant past, personal or family history. He had no past history of any drug reactions/allergic diathesis. At the time of admission to the hospital, his general condition was fair, he was afebrile with a heart rate of 90/min. On local examination echymotic patches were seen on the right forearm and back. A thorough systemic examination revealed no abnormality. The investigations done on the day of admission revealed the hemoglobin count of 10.4 mg%, total leukocyte count of 9500/mm3 and platelet count was 13,000 per mm3. Peripheral smear for malaria parasites was negative. Total serum proteins were 8.3 gm/dl, albumin 5.23gm/dl; total bilirubin was 0.36mg/dl, SGOT- 42 IU/L, SGPT-18 IU/L and blood group A positive.

Treatment Details

Syrup valproic acid was stopped immediately after admission into the hospital and he was given injection Vitamin K 5mg per day for three days intravenously. He was also transfused with 2 pints of platelets. Each pint is intended to raise the platelet count by 8000 to 10000 per mm .
His blood levels for valproic acid were 16.18ug/ml with normal range being 50-100 ug/ml.
Investigations on the day 3-revealed hemoglobin count 11.1mg%, reticulocyte count 3.5mg%, total leukocyte count of 10100/mm3 and platelet count of 40,000 per mm3. He was discharged on day 5 with the advice to do the platelet count every weekly for first 4 weeks and then bi-weekly for next three months. His parents were also instructed to report to the emergency medical services department of this hospital if the count is seen to be less than 20,000/mm3

Discussion:
We assessed the relationship between the event thrombocytopenia and the drug valproic acid using Naranjo's algorithm (1) as well as modified James N George et al (2) criteria. The George scale is used for assessing reports of drug induced thrombocytopenia and levels of evidence for a causal relation between the drug and thrombocytopenia (Table 1). Naranjo's algorithm (1) established a possible causal relationship with score of 6 points and modified James N George et al (2) criteria established a probable relationship between thrombocytopenia and valproic acid in our patient. There was no rechallenge with valproic acid.

Thrombocytopenia has been reported in 6-33% of adults within a few months of valproic acid use, but a lower platelet count was seen in all most all patients and appeared to be dose related (3,4). Thrombocytopenia associated with valproic acid therapy has been reported to resolve without interruption of valproic acid treatment and has been also reported to endure over time or to have an erratic course. (5) Valproic acid (VPA) may cause impaired platelet function, thrombocytopenia and, occasionally, severe bleeding. Controversy exists both as to the mechanism of this alteration in hemostasis and as to whether these adverse effects are either dose-related or idiosyncratic. (6)

A prospective study was carried out to evaluate whether valproic acid (VPA) can cause thrombocytopenia and impaired platelet function in 20 children before and after 6 months of Valproate monotherapy. Fifteen healthy sex and age matched children served as control subjects. Results showed that the platelet counts were significantly lower in the patients than in the control subjects. VPA can cause a decreased platelet count and aggregation and ATP release impairment. These side effects can appear after a few months of therapy and with plasma Valproate levels within the normal range. They do not seem to be associated with clinical symptoms, and drug discontinuation is not necessary. (7)

Different etiologies have been suggested, such as circulating antibodies of immunoglobulin M (IgM), stem cell suppression, or direct drug toxicity. (8) The diagnosis of drug induced thrombocytopenia remains one of exclusion. Immune thrombocytopenia and secondary forms of the thrombocytopenias occur in association with systemic lupus erythematosus, the antiphospholipid syndrome, immunodeficiency states (IgA deficiency and common variable hypogammaglobulinemia), lymphoproliferative disorders (chronic lymphocytic leukemia, large granular lymphocytic leukemia, and lymphoma), infection with human immunodeficiency virus and hepatitis C virus. The direct assay for the measurement of platelet-bound antibodies has an estimated sensitivity of 49 to 66 percent, an estimated specificity of 78 to 92 percent, and an estimated positive predictive value of 80 to 83 percent. A negative test cannot be used to rule out the diagnosis (9).
The table 2 gives the list of drugs causing thrombocytopenia and their mechanisms.

Table 1: Criteria for Assessing Reports of Drug-Induced Thrombocytopenia and Levels of Evidence for a Causal Relation between the Drug and Thrombocytopenia (modified from James N George et al 2)

Table 2 : Drugs causing thrombocytopenia and their mechanisms(2)

Drug Name	Mechanism
Abciximab	IM
Acetaminophen	IM
Acetazolamide	IM?
Allopurinol	IM?
Amiodarone	IM?
Amphotericin B	BM?
Ampicillin	IM
Amrinone	PA
Antineoplastics	BMG
Aspirin	IM?
Captopril	IM?
Carbamazepine	IM
Ceftazidime	IM
Ceftriaxone	IM
Cefuroxime	IM
Chlorothiazide	BMS, IM?
Cimetidine	IM, BM?
Ciprofloxacin	IM?
Clarithromycin	IM?
Cocaine	IM?
Cyclosporine	IM?
Diazepam	IM
Diazoxide	IM?
Digoxin	IM
Diltiazem	IM?
Enalapril	IM?
Ethambutol	IM?
Ethanol	BMS
Famotidine	IM?
Fluconazole	Unknown
Furosemide	IM?
Ganciclovir	BM
Gentamicin	IM?
Haloperidol	IM
Heparin	PA, IM
Heparin, low-molecular-weight	PA, IM
Hydralazine	IM?
Hydrochlorothiazide	IM?
Interferon-alpha	BMG
Iocetamic acid (contrast agent)	IM?
Iopanoic acid (contrast agent)	IM?
Isoniazid	IM?
Itraconazole	Unknown
Lidocaine	IM?
Methyldopa	IM
Milrinone	PA
Minoxidil	IM?
Morphine	IM
Nifedipine	IM
Nitroglycerin	IM?
Nitroprusside	IM?
Octreotide	IM?
Ondansetron	IM?
Penicillin	IM
Phenobarbitol	IM?
Phenytoin	IM?
Piperacillin	IM
Prednisone	IM?
Procainamide	IM
Prochlorperazine	IM?
Protamine	PA
Pyrazinamide	IM?
Quinidine	IM
Ranitidine	IM?
Rifampin	IM
Ticlopidine	Unknown
Tobramycin	IM?
Trimethoprim-sulfamethoxazole	BMS?, IM
Valproic acid	IM?
Vancomycin	IM?

References:
1. 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.
2. James N George et al. Drug-induced thrombocytopenia. A systematic review of published case reports. Ann Intern Med 1998; 129: 886-90.
3. Neophytides AN, Nutt JG, Lodish JR: Thrombocytopenia associated with valproate treatment. Annl Neurol 1979; 5:389-90.
4. Covanis A, Gupta AK, Jeavons PM: Sodium valproate monotherapy and polytherapy. Epilepsia 1982; 23:693-720.
5. Eastham RD, Jancar J sodium valproate and platelet counts (letter). Br Med J 1980; 280:186.
6. Gidal B, Spencer N, Maly M, Pitterle M, Williams E, Collins M, et al. Valproate-mediated disturbances of hemostasis: relationship to dose and plasma concentration. Neurology 1994 Aug; 44(8): 1418-22.
7. Verrotti A, Greco R, Matera V, Altobelli E, Morgese G, Chiarelli F. Platelet count and function in children receiving sodium valproate. Pediatr Neurol. 1999 Sep; 21(3): 611-14.
8 Oluboka OJ, Haslam D, Gardner DM. Pancytopenia and valproic acid: a dose related association. J Am Geriatr Soc 2000; 48:349-50.
9 Lori D, Wazny et al. Evaluation and management of drug-induced thrombocytopenia in the acutely ill patient. Pharmacotherapy 2000; 20: 292-307.