Valproate‐induced thrombocytopenia: a prospective monotherapy study

Abstract

SUMMARYPurpose: The frequency of valproate (VPA)-induced thrombocytopenia varied widely in previous studies, due to methodological differences. Our objective was to evaluate the relationship between trough VPA plasma levels and platelet counts and assess risk factors for the development of thrombocytopenia. Methods: Patients with refractory partial epilepsy were enrolled in this double-blind, multicenter, concentration-response trial that evaluated the efficacy and safety of high versus low trough plasma VPA concentrations following administration of divalproex sodium as monotherapy. Trough VPA concentrations and concomitant platelet counts were drawn at baseline and intermittently throughout the 24-week trial. Bivariate correlations and multivariate stepwise regression analysis were performed between platelet counts and multiple variables. A logistic regression analysis was done to determine the probability of developing thrombocytopenia at various VPA levels.Results: A total of 851 VPA levels and concomitant platelet counts were analyzed in 265 patients. Of these, 17.7% of patients experienced at least one episode of thrombocytopenia (platelet count ≤ 100,000/μl) after exposure to divalproex sodium. A significant negative correlation was found between VPA levels and platelet counts. Women were significantly more likely to develop thrombocytopenia. The probability of developing thrombocytopenia substantially increased at trough VPA levels above 100 μg/ml in women and above 130 μg/ml in men. Discussion: Our data strongly support a causal relationship between rising plasma VPA levels and reduced platelet counts, with additional risk factors including female gender and lower baseline platelet counts.

2010–2016 yılları arasında çocuk acil polikliniğinde valproik asit intoksikasyonu nedeniyle takip ve tedavi edilen olguların değerlendirilmesi

“…Mechanism of vaproic acid-related thrombocytopenia is not clear. Thrombocyte antibodies formed by VPA or its metabolytes cause peripheral thrombocyte destruction or dose-dependent bone marrow suppression (18). Sixteen of our patients in our study had thrombocytopenia during referral.…”

How I evaluate and treat thrombocytopenia in the intensive care unit patient

“…17,60,64 In contrast to DTP, DITP typically presents with an abrupt platelet count fall evolving within 1 to 2 days, which usually begins 5 to 14 days after starting a new drug, and a nadir below 20 3 10 9 /L, which is nearly always accompanied by mucocutaneous bleeding. 59,[65][66][67][68][69] Table 3 summarizes typical mechanisms and drugs of DTP and DITP. [61][62][63]65,70 More than 10% of patients treated with valproic acid develop DTP.…”

“…59 Older age, female sex, higher valproic acid dosage, and lower baseline platelet counts are associated with an increased risk of DTP. 59,66,67 However, valproic acid can also induce immune-mediated DITP. In both DTP and DITP, cessation of the drug is most important and usually sufficient.…”

“…In both DTP and DITP, cessation of the drug is most important and usually sufficient. 59,[65][66][67][68][69] Recovery of the platelet count will occur thereafter and is often not very helpful for differentiation between DTP and DITP. In our patient, the platelet count started to increase ;48 hours after stopping valproic acid, but also in DITP, platelet count recovery usually begins 5 to 7 half-times after cessation of the drug (half-time for valproic acid 5-7 hours 5 expected recovery after ;50 hours).…”

Epilepsy and Brain Tumors

“…Hemato-logic abnormalities vary between 13.7% and 28.2% and include coagulation disorders, particularly diminished platelet aggregation and thrombocytopenia in children and the elderly. Thrombocytopenia occurs in approximately 17.7% of patients, usually asymptomatic and particularly seen with supratherapeutic drug levels (Nasreddine and Beydoun, 2008). The mechanism probably depends on dosedependent suppression of platelet production in the bone marrow.…”