Case Series on Rifampicin-induced Thrombocytopenia with Daily Regimen: Clinical Insights and Management Strategies

ABBREVIATIONS USED IN THIS ARTICLE

AFB = Acid-fast bacilli; APTT = Activated partial thromboplastin time; ATT = Anti-tubercular therapy; BT = Bleeding time; CBC = Complete blood count; CECT = Contrast-enhanced computed tomography; CT = Clotting time; CT = Computed tomography; CXR = Chest X-ray; FDC = Fixed-dose combination; GM-CSF = Granulocyte-macrophage colony-stimulating factor; Hb = Hemoglobin; INR = International normalized ratio; IVIG = Intravenous immunoglobulin; L = Lymphocytes; LFT = Liver function tests; N = Neutrophil; PRBC = Packed red blood cells; PT = Prothrombin time; RE = Routine examination; RIT = Rifampicin-induced thrombocytopenia; SOB = Shortness of breath; TLC = Total leukocytes count.

INTRODUCTION

Rifampicin, a key anti-tubercular drug that inhibits bacterial DNA-dependent RNA polymerase, can cause gastrointestinal (nausea, vomiting, hepatitis), dermatological (rashes, pruritus, flushing), and hematological (thrombocytopenia, neutropenia, hemolytic anemia) side effects. Rifampicin-induced thrombocytopenia, an immune-mediated reaction, typically appears within 5–7 days but may occur rapidly in individuals with pre-existing antibodies, leading to potentially life-threatening platelet destruction.

We present a series of four cases of rifampicin induced thrombocytopenia presenting to our department and their management (Table 1).

DISCUSSION

Tuberculosis (TB), a chronic granulomatous infection caused by Mycobacterium tuberculosis, primarily manifests as pulmonary disease. Despite a declining incidence, India reported around 25% of the 10.6 million global TB cases in 2021 (Global TB Report 2023), highlighting its ongoing public health significance.¹ Newly diagnosed tuberculosis patients are initially treated with an effective regimen comprising four drugs: isoniazid, rifampicin, pyrazinamide, and ethambutol. None of the antitubercular drugs are devoid of risk, and the World Health Organization (WHO) advocates for the monitoring and reporting of suspected or confirmed adverse drug reactions associated with these medications.

Effective chemotherapy is essential for tuberculosis management, but first-line drugs such as isoniazid, rifampicin, ethambutol, and pyrazinamide can cause side effects like hepatotoxicity, nausea, vomiting, rashes, allergies, peripheral neuropathy, and optic neuritis. Anti-tubercular therapy (ATT) may also lead to various hematological abnormalities. Rifampicin, in particular, can cause gastrointestinal issues, drug-induced hepatitis, rash, flushing, flu-like syndrome, and blood disorders like thrombocytopenia, neutropenia, and hemolytic anemia.

The introduction of rifampicin in 1965 revolutionized TB treatment by initiating the era of short-course chemotherapy. This breakthrough drastically reduced the duration of anti-TB therapy from 12–24 months to just 6 months.² Despite advancements, TB treatment remains a challenging endeavor for physicians due to the prolonged treatment duration, adverse drug effects, suboptimal medication adherence, and emergence of drug resistance.

Thrombocytopenia, often defined as a platelet count below 150 × 10⁹/L, is more clinically significant below 100 × 10⁹/L. Causes include viral infections, autoimmune diseases, lymphoproliferative disorders, and various medications.

Rifampicin-induced thrombocytopenia (RIT), first reported by Blajchman et al. in 1970, is a reversible condition if detected early.³ It involves anti-rifampicin antibodies (ARA), mainly IgM, forming immune complexes with rifampicin, leading to platelet destruction via complement fixation (type III hypersensitivity) and the production of antiplatelet and anti-erythrocyte antibodies (type II hypersensitivity). Discontinuation of rifampicin usually normalizes blood counts. Other drugs causing thrombocytopenia include quinine, chloroquine, sulfonamides, and aspirin. Adverse reactions to first-line antituberculous drugs vary widely, from 8.0 to 85%, but are usually mild. Rifampicin-induced thrombocytopenia, though rare, is a potentially life-threatening complication of anti-tuberculosis therapy, often associated with high-dose intermittent regimens (1,200 mg twice-weekly). Daily treatment or cases following therapy interruptions are infrequent. The TB Research Center in Chennai reported only one case in over 8,000 patients treated over 30 years.⁴ Thrombocytopenia can arise with any of the primary antitubercular medications.

Prior to diagnosing thrombocytopenia, it’s essential to exclude pseudothrombocytopenia, which may arise from factors such as inadequate anticoagulation in blood tubes, thrombocyte aggregation, or the use of abciximab. George et al. conducted a comprehensive collection of case reports concerning drug-induced thrombocytopenia, establishing standard criteria to elucidate the association between drugs and thrombocytopenia (Table 2).⁵

If the suspected drug fulfils all criteria, the level of evidence is considered definite. Meeting the first three criteria denotes a probable association, while fulfilling only the first criterion indicates a possible link. Failure to meet the first criterion suggests an unlikely causative relationship.

Epidemiological data on drug-induced immune thrombocytopenia (DITP) are limited, with an estimated incidence of about 10 cases per 1,000,000 people annually, likely an underestimate. DITP arises from two mechanisms: suppression of platelet production and platelet destruction. Destruction occurs via hapten-dependent antibodies, platelet-reactive autoantibodies, and drug-dependent antibodies (DDabs). Pool et al. found a strong link between rifampicin-dependent antibodies and adverse reactions, especially with a 1,200 mg twice-weekly regimen.⁶ According to WHO-UMC Causality Categories, rifampicin is a “Probable/Likely” cause of this adverse drug reaction. Ferguson and the Hong Kong trial reported thrombocytopenia even with daily rifampicin, occurring from the first to the fourteenth month of therapy.^7,8 A literature search identified around 35 cases of rifampicin-induced thrombocytopenia, including 15 case reports. Larbaoui et al. noted a patient with generalized purpura after four months of therapy.⁹ Doyle et al. found adverse effects, including fever, in 28 of 74 patients on high-dose rifampicin (1,800 mg) twice-weekly.¹⁰ Bansal et al. reported thrombocytopenia following re-exposure to rifampicin a decade later, indicating long-lasting drug sensitivity.¹¹ Mehta et al. documented three cases of rifampicin-induced thrombocytopenia with antiplatelet antibodies showing increased binding in the presence of rifampicin, indicating it as the causative agent.¹² Despite its rarity, rifampicin-induced thrombocytopenia is potentially fatal. Banu Rekha VV et al. reported only one case among 8,000 patients treated over 30 years at the Tuberculosis Research Centre.⁴

Diagnosing drug-induced thrombocytopenia is primarily based on exclusion. Immune thrombocytopenia and secondary forms often occur with various immune disorders. Direct assays for platelet-bound antibodies have a sensitivity of 49–66%, specificity of 78–92%, and a positive predictive value of 80–83%. However, a negative result does not conclusively exclude the diagnosis. Diagnosing drug-induced immune thrombocytopenia involves clinical assessment of bruising, petechiae, and bleeding, along with reviewing the suspected drug. Essential tests include total blood count and peripheral blood smear to rule out pseudothrombocytopenia, and platelet serology tests. Thrombocytopenia can occur up to 14 months after starting treatment and is less frequent with daily regimens due to continuous drug presence of neutralizing antibodies. Intermittent therapy allows antibody accumulation during drug-free periods, intensifying reactions upon reinitiation, though daily regimens can still result in thrombocytopenia.

Corticosteroids have been employed in cases where thrombocytopenia arises from an immune-mediated mechanism, although their efficacy remains unproven. Platelet transfusion is warranted in instances of severe thrombocytopenia or wet purpura due to the heightened risk of intracranial hemorrhage. Plasmapheresis and intravenous immunoglobulin (IVIG) have been employed in the management of drug-induced thrombocytopenia. However, the efficacy of these interventions remains contentious. The immediate cessation of the offending drug is considered the paramount step in treatment.

After stopping the causative drug, platelet counts typically normalize within 7–10 days, often without needing further treatment. Platelet transfusion may be required if counts fall below 20,000/mm³. Reintroducing rifampicin must be strictly avoided to prevent immune reactions, even in small doses, following purpura onset. Immediate cessation of rifampicin and avoiding re-administration are critical.

In our experience, these cases underscore a rare complication of daily rifampicin therapy, which exhibited a favorable response to discontinuation of the implicated drug alongside supportive measures, resulting in gradual amelioration of symptoms and normalization of blood cell counts. Patients are currently managed on alternative regimens comprising isoniazid, ethambutol, pyrazinamide, and levofloxacin, with diligent monitoring of complete blood counts (CBCs) to ensure therapeutic efficacy and safety.

CONCLUSION

Thrombocytopenia, although uncommon with rifampicin, can range from minor bleeding to severe complications such as gastrointestinal hemorrhage or acute subdural hematoma. It can occur even without prior rifampicin exposure. Regular monitoring for blood and liver abnormalities is essential during tuberculosis treatment. Immediate discontinuation of rifampicin upon suspicion is crucial. Patients should avoid using rifampicin again to prevent recurrence, as re-introduction poses risks in cases of rifampicin-induced thrombocytopenia.

REFERENCES

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