Case Report
A Case Report of Thrombocytopenia Associated with Initiation of Dimethyl-Fumarate in a Patient with Multiple Sclerosis
Allison Jordan1, Michael K Racke1 and Jaime Imitola1,2*
1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
2Department of Neuroimmunology and Multiple Sclerosis, Comprehensive Multiple Sclerosis Center, OH, USA
*Corresponding author: Jaime Imitola, Department of Neuroimmunology and Multiple Sclerosis, Ohio State University Wexner Medical Center, 460W12th Ave, Biomedical Research Tower, Room 688, Columbus, OH 43321, USA
Published: 06 May, 2017
Cite this article as: Jordan A, Racke MK, Imitola J. A Case
Report of Thrombocytopenia Associated
with Initiation of Dimethyl-Fumarate in a
Patient with Multiple Sclerosis. Ann Clin
Case Rep. 2017; 2: 1350.
Abstract
This is a case report of a 44-year-oldwoman with a past medical history of idiopathic thrombocytopenia purpura (ITP), with previous stable platelet counts, who developed drug induced thrombocytopenia after starting dimethyl fumarate for her Relapsing Remitting Multiple Sclerosis (RRMS). Her platelet count returned to baseline without any intervention except for cessation of the drug. To date, thrombocytopenia has not been described as a side effect of dimethyl fumarate. Treatment of Multiple Sclerosis (MS) patients with dimethyl fumarate in the setting of concomitant Idiopathic thrombocytopenic purpura (ITP) should prompt close platelet monitoring.
Keywords: Dimethyl-fumarate; Idiopathic thrombocytopenic purpura
Introduction
Dimethyl fumarate (Tecfidera), was first approved by the FDA in 2013 for relapsing remitting multiple sclerosis. While its exact mechanism of action has not been fully elucidated, Tecfidera has been shown to selectively reduce circulating CD4+ and CD8+ lymphocytes [1]. Lymphopenia is a well characterized side effect of dimethyl fumarate, with increased incidence and severity in patients older than fifty-five [2]. Fumaric acid esters, which include dimethyl fumarate, have also been shown to cause eosinophilia after initiation of treatment [3]. Case reports of eosinophilic fasciitis like disorder [4] and eosinophilic cardiac injury [5] have been reported with dimethyl fumarate therapy. Additional commonly reported side effects of this medication include flushing and gastrointestinal side effects such as nausea, diarrhea, and abdominal pain [6]. While dimethyl fumarate has been shown to affect other hematopoietic cell lines, thrombocytopenia has not been observed. Here we present a case of a forty-four-year-old woman with past medical history significant for Idiopathic Thrombocytopenia Purpura (ITP) who developed severe thrombocytopenia after starting dimethyl fumarate for her relapsing remitting multiple sclerosis.
Case Presentation
The patient is a 44-year-old African American woman with a past medical history of ITP,
depression, GERD and migraines. She was first diagnosed with ITP in 2013 by a hematologist at The
Ohio State University. Diagnosis of ITP was given based on her clinical presentation and other wise
negative laboratory evaluation. At time of presentation she was started on a short course of IVIG
and was maintained on prednisone until November 2013. She did not require any further steroid
therapy until her diagnosis of multiple sclerosis in May 2014.
She was diagnosed with relapsing remitting multiple sclerosis in May 2014 with optic neuritis
as her first presenting symptom. Diagnosis was based on the 2010 McDonald criteria for Multiple
Sclerosis. At time of diagnosis she was given methylprednisolone 1 gram IV for 3 days and
completed a prednisone taper over the course of 2 weeks. After investigating the literature for any
contraindications with the use of Dimethyl fumarate in ITP patients, she was started on Dimethyl
fumarate in August 2014 as a first line disease modifying therapy.
Given the patient’s diagnosis of ITP, a complete blood count (CBC) was obtained every few
months for routine surveillance. Her last routine blood draw prior to drug initiation was on 7/31/14,
which showed a platelet count of seventy-seventy thousand, which was her normal baseline. The
patient started dimethyl fumarate on 8/20/14. Her platelet count was checked after initiation of the drug (on 8/29/14) with a result of seventy-four thousand. The
patient tolerated initiation of dimethyl fumarate well, with only a
report of mild nausea which improved when the patient took the
medication with food. A CBC was ordered on 9/25/14 as part of a
routine lab check, and platelets were found to be twenty thousand.
This number was confirmed by two independent labs. The first lab
draw was completed at The Ohio State University, and the second
lab draw was completed a day later on 9/26/14 at the patient’s local
laboratory. Dimethyl fumarate was immediately discontinued by the
patient on 9/25/14. After discontinuation of the drug, the patient’s
platelet counts slowly returned to baseline without need for steroid
intervention (Figure 1).
Figure 1
Discussion
Drug induced platelet destruction is thought to be antibody
mediated [7]. Onset of platelet destruction typically occurs after
a week or more of therapy with the offending agent, but can occur
as early as 1-2 days [7]. The decline in this patient’s platelet count
after initiating dimethyl fumarate, combined with return to baseline
platelet count after discontinuation of dimethyl fumarate, strongly
suggests drug induced thrombocytopenia. Additionally, the time
from drug initiation to platelet nadir (in this case occurring sometime
between 9 and 36 days after drug initiation) closely matches the typical
time line of drug-induced thrombocytopenia. One could argue that
the patient’s drop in platelet count could be secondary to her known
ITP, but platelet decline in the setting of an ITP flare would not likely
resolve without steroid treatment.
It is also possible that dimethyl fumarate directly caused
thrombocytopenia by impairing platelet maturation. Dimethyl
fumarate has been shown to activate NRF2, a transcription factor
integral to megakaryocyte proliferation [8]. Platelet maturation requires an increased ratio of the transcription factor P45 to NRF2
[8]. Through the activation of NRF2, it is possible that dimethyl
fumarate could hinder megakaryocyte maturation resulting in
underproduction of mature platelets.
Given the popularity of dimethyl fumarate in the treatment of
MS, this case report aspires to make the medical community aware
of the possibility of drug induced thrombocytopenia with dimethyl
fumarate. It is likely that our patient was at higher risk of this side
effect given her co-diagnosis of MS and ITP. In one population based
study in Maryland, patients with ITP were 25 times more likely to
have MS than the general population [9], showing co-diagnoses is
not rare. When starting dimethyl fumarate,heightened monitoring is
suggested in patients with co-diagnoses of MS and ITP.
In summary, this is a case of a 44-year-old woman who developed
drug-induced thrombocytopenia after initiation of Dimethyl
fumarate for relapsing remitting multiple sclerosis.
References
- Longbrake EE, Ramsbottom MJ, Cantoni C, Ghezzi L, Cross AH, Piccio L. Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler. 2016;22(8):1061-70.
- Longbrake EE, Naismith RT, Parks BJ, Wu GF, Cross AH. Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance. Mult Scler J Exp Transl Clin. 2015;1:2055217315596994.
- Harries MJ, Chalmers RJ, Griffiths CE. Fumaric acid esters for severe psoriasis: a retrospective review of 58 cases. Br J Dermatol. 2005;153(3):549-51.
- Sheu J, Kattapuram SV, Stankiewicz JM, Merola JF. Eosinophilic fasciitis-like disorder developing in the setting of multiple sclerosis therapy. J Drugs Dermatol. 2014;13(9):1144-7.
- Brown W, Suksaranjit P, Khor LL. Eosinophil-Mediated Cardiac Injury Possibly Due to Dimethyl Fumarate. JACC Cardiovasc Imaging. 2016;9(6):752-3.
- Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-107.
- Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med. 2007;357(6):580-7.
- Motohashi H, Kimura M, Fujita R, Inoue A, Pan X, Takayama M, et al. NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation. Blood. 2010;115(3):677-86.
- Segal JB, Powe NR. Prevalence of immune thrombocytopenia: analyses of administrative data. J Thromb Haemost. 2006;4:2377-83.