A case of thrombocytopenia caused by rifampicin and pyrazinamide.

A 32-year-old male patient was diagnosed as having pulmonary tuberculosis and put on category II antitubercular regime since he had a history of antituberculosis treatment 10 years ago. Within 3 weeks, patient presented with ulcers in mouth, and blood picture confirmed thrombocytopenia. Rifampicin-induced thrombocytopenia was suspected and antitubercular treatment stopped. Patient improved and was re-exposed to the drugs one by one. After re-exposure with pyrazinamide, the platelet count decreased drastically and oral mucosal ecchymoses reappeared, while with rifampicin, thrombocytopenia was accompanied with petechiae on legs and forearms. Isoniazid, ethambutol, and streptomycin were continued.

Introduction

Serious and life-threatening adverse drug events with first-line antituberculosis drugs are rare but not unknown. Both rifampicin and pyrazinamide are a part of both category I and II antituberculosis regimes. Pyrazinamide is also included in category IV antituberculosis regime for multidrug-resistant tuberculosis. Unlike other antimicrobial drugs, these drugs are to be taken for a prolonged period of 6–9 months daily or intermittently, thus increasing concerns about the adverse effects of these drugs.

Thrombocytopenia with rifampicin was first documented in 1970,[1] and since then, about 35 case reports have been published, but thrombocytopenia with pyrazinamide is extremely rare and hardly any case reports are available. We present an even rarer adverse event, a case of thrombocytopenia with oral mucosal ecchymoses followed by ulceration and petechiae on legs and forearms caused by both rifampicin and pyrazinamide, which on WHO-UMC Causality Assessment Scale[2] is “certainly” and on Naranjo Adverse Drug Reaction Probability Scale[3] is “definitely” associated with these drugs.

Case Report

A 32-year-old male patient presented on 13/02/2012 in Department of General Medicine with complaints of fever since 1 month and history of antituberculosis treatment in 2002. On chest X-ray examination, the patient was found to have pleural effusion on the right side and was referred to Department of Pulmonary Medicine where 20 ml of straw-colored pleural fluid was aspirated. Pleural fluid was chiefly lymphocytic exudate with adenosine deaminase (ADA) 110 U/L, highly suggestive of tubercular pleural effusion. All routine investigations including complete hemogram, liver function tests (LFTs), renal function tests (RFTs), and complete urine examination were found within normal limits. On 17/02/2012, the patient underwent therapeutic tap with 1 L of straw-colored fluid removed from the pleural cavity and was put on three times a week Category II antituberculosis treatment under DOTS (streptomycin 750 g, isoniazid 600 mg, rifampicin 450 mg, ethambutol 1200 mg, and pyrazinamide 1500 mg) along with daily pyridoxine 10 mg at bed time. After about 20 days, on 10/03/2012, the patient presented in Department of Dermatology, Venereology & Leprosy (DVL) with complaints of ulceration in the mouth. Hemogram revealed hemoglobin (Hb) 8.3 gm%, total leukocyte count (TLC) 9800 cells/mm3, erythrocyte sedimentation rate (ESR) 45 mm/1 h, and platelet count 21,000/mm3. Peripheral smear revealed shift to left with thrombocytopenia, Prothrombin Time Index (PTI) 76.92% and International Normalized Ratio (INR) of 1.43. Enzyme-linked immunosorbant assay (ELISA) for human immunodeficiency virus (HIV) was negative, random blood sugar was within normal limits, and urine was also found normal.

Patient was suspected of having thrombocytopenia due to rifampicin and was referred to the Department of Pulmonary Medicine where all drugs were stopped. On 21/03/2012, the ulcers healed, platelet count increased to 472,000/mm3, International Normalized Ratio (INR) was 1.82, and ESR was 30 mm/1 h. So, after taking informed consent, the patient was again started on the same regime, excluding rifampicin. Next day, the patient again had ulcers in the mouth and the platelet count decreased to 10,000/mm3. Treatment was again stopped and the patient recovered. One month later (on 19/04/2012), the patient returned for treatment. The platelet count (on 03/04/2012) was 505,000/mm3. It was decided that patient will be exposed to medicines one after the other. He was given only isoniazid 300 mg and the treatment was uneventful. On the third day, he was given 750 mg of pyrazinamide under observation. Within 24 h, the patient developed ecchymoses and ulcers in the mouth [Figure 1] and the platelet count decreased to 23,000/mm3, forcing withdrawal of pyrazinamide; isoniazid (300 mg) was continued. Patient recovered, and so, believing that hypersensitivity was because of pyrazinamide and not because of rifampicin, after monitoring the platelet count, the patient was given rifampicin 150 mg along with isoniazid 300 mg on 26/04/2012. Within 6 h, the patient developed petechiae on legs and forearms [Figure 2] and also fever with chills. Platelet count decreased to 25,000/mm3. Rifampicin was stopped and lesions subsided within 48 h. After 2 days, the patient was exposed to ethambutol and then to streptomycin uneventfully. Patient continued with isoniazid 300 mg, ethambutol 1000 mg, and streptomycin 750 mg without any further complaints.

Figure 1

Ecchymoses caused by pyrazinamide

Figure 2

Petechiae caused by rifampicin

Discussion

Drug-induced thrombocytopenia, first reported in 1865 due to quinine,[4] is an increasingly common cause of isolated thrombocytopenia. This may be non-immune–mediated bone marrow suppression or immune-mediated destruction of platelets by specific antibodies directed against the offending drug. Thrombocytopenia caused by myelosuppressive agents is anticipated, dose dependent, and is not difficult to diagnose, but immune-mediated thrombocytopenia is not dependent on dose, sudden in onset, and difficult to diagnose, since most of the time, these patients are taking more than one medicine and facilities for assay of antidrug antibodies are rarely available even in tertiary care hospitals in India and other developing countries.[5] Even when facilities are available, the assays are not conclusive; so, most of the time, the diagnosis is made by exclusion and correlation, by withdrawing the offending drug, and at best by re-challenge which is best avoided if possible.[6]

Many mechanisms have been suggested to be involved in immune-mediated thrombocytopenia like hapten-dependent antibody formation, drug–glycoprotein complex antibody formation, autoantibody formation, ligand-induced binding site creation, drug-specific antibody formation, and immune complex mediated antibody formation.[7] Rifampicin is suggested to act as a hapten and produce antibodies after combining with some molecules in the plasma. These antibodies against rifampicin are suggested to fix a complement on the platelets in the presence of rifampicin resulting in platelet destruction.[8] The mechanism of thrombocytopenia caused by pyrazinamide is not yet clearly elucidated but suggested to be immunological.[9]

The mean delay in onset of thrombocytopenia following exposure to offending medication is 1–2 weeks, but may range from few hours to several years depending on whether the patient has pre-existing antibodies needs to mount an amnestic response because the titer of antibodies produced as a result of previous exposure has fallen below critical levels or in the absence of antibodies.[7] In the present case, the patient presented first time with thrombocytopenia 3 weeks after starting the treatment even when there was a history of exposure to the offending medicines 10 years ago. The symptoms appeared within an hour after exposure, suggestive of amnestic response.

The case study stresses the importance of continuous supervision of patients on antituberculosis treatment since all of them are capable of causing serious thrombocytopenia any time during the course of therapy.