We present a case of glatiramer acetate-associated refractory immune thrombocytopenic purpura (ITP) in a female patient with multiple sclerosis. A search of MEDLINE/PubMed did not find any connection between glatiramer acetate and thrombocytopenia, specifically ITP. The autoimmune reaction was resistant to conservative ITP treatment, and was eventually managed only by splenectomy. To the best of our knowledge, this is the first report of glatiramer acetate-associated ITP. Physicians should be aware of this condition, and consider performing routine blood counts at the beginning of glatiramer acetate treatment.
Glatiramer acetate; drug associated immune thrombocytopenic purpura; thrombocytopenia.
Glatiramer acetate (Copaxone) is an immunomodulatory agent approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS). It has been proposed that the mechanism of action of glatiramer acetate is by activation of T-lymphocyte suppressor cells and interference with pathological antigen presenting on the myelin sheath. The adverse effects of glatiramer acetate consist mostly of local site injection reactions along with transient systemic reactions. These reactions usually begin 30 sec to 30 min after agent injection, and consist of flushing, chest discomfort, palpitations, dyspnoea and anxiety. They are considered sporadic and self-limiting[1]. In a multi-centric double blind placebo controlled trial comparing glatiramer acetate to placebo, additional adverse events (apart from local and transient systemic reactions) occurred approximately equally in both groups. No routine ECG, laboratory blood counts or chemical tests are recommended for patient monitoring[2].
Immune thrombocytopenia purpura (ITP) is an autoimmune disorder characterized by immunological destruction of otherwise normal platelets, leading to platelet counts of less than 100×109/L. ITP may occur in isolation (primary) or in association with other disorders (secondary) due to viral infections [such as hepatitis C (HCV), cytomegalovirus (CMV) or human immunodeficiency virus (HIV), systemic lupus erythematosus (SLE), lymph proliferative disorders and certain drugs[3]. We present a case of glatiramer acetate-associated refractory ITP in a female patient with multiple sclerosis.
Herein we present the case of a patient who was admitted to hospital due to refractory symptomatic ITP, which was successfully managed only by splenectomy. Treatment for multiple sclerosis with glatiramer acetate had been initiated 2 months before her admission. This was the only treatment she was prescribed before the onset of the thrombocytopenia. Other causes of thrombocytopenia (such as viral infections, haematological and autoimmune conditions) were excluded. Thus, we can refer to this patient as having secondary drug-associated ITP.
Distinguishing between drug-associated ITP and other thrombocytopenia aetiologies may be very challenging for the clinician. The incidence of this phenomenon is 10 cases per 1,000,000 persons per year and there are several possible mechanisms for this condition:
A systemic review of 247 case reports of drug-associated thrombocytopenia identified 98 different potential drugs. The most common drugs associated with thrombocytopenia were quinidine, gold and trimethoprim-sulfamethoxazole. Sporadic reports also mentioned penicillins, cephalosporins, NSAIDs, acetaminophen, digoxin, amiodarone and lithium. Of the 247 patients involved, 9% had a major bleed (defined as intracranial or retroperitoneal haemorrhage) and 0.8% died of bleeding[5].
The clinical presentation of drug-associated ITP is mucocutaneous bleeding that begins 1–2 weeks, sometimes longer, after the patient has taken the sensitizing agent. Severe bleeding such as melena, haematuria and intracranial or retroperitoneal haemorrhage, is unusual and indicates severe thrombocytopenia of less than 20/mm3. The most important differential diagnosis is drug-associated thrombocytopenia (DIT). DIT is characterized by the same clinical features as ITP, starts after exposure to the sensitizing agent for at least a week and can be sometimes accompanied by neutropenia and haemolytic anaemia together with thrombocytopenia. After the suspected agent has been discontinued, the platelet count tends to return to normal within a week.
From the neurological aspect, it is worth mentioning that the association between MS and auto-immune diseases (e.g. diabetes, inflammatory bowel disease, rheumatoid arthritis, etc.) is well established. ITP was found to be 25 times more prevalent among MS patients compared with the general population. In addition, recently there have been reports that ITP can be linked to Interferon beta therapy in MS patients, along with more common haematological adverse effects such as a transient decrease in white blood cell counts. In this instance, the immunomodulatory effect of glatiramer acetate may be associated with the refractory thrombocytopenia in our patient. Unfortunately, since a routine laboratory kit to test for glatiramer acetate-associated antibodies is not available, we cannot establish the definitive diagnosis of immune thrombocytopenia purpura. The fact that cessation of the drug did not result in an instant increase in the platelet count, is another factor against a causal association between glatiramer acetate and thrombocytopenia. Nonetheless, in the absence of any other reasonable aetiology, the clinical suspicion for drug associated ITP still remains very high.