Immune-mediated thrombocytopaenia secondary to pulmonary tuberculosis: Diagnostic and therapeutic dilemma.

INTRODUCTION

A myriad of haematological manifestations are reported with tuberculosis (TB) such as anaemia, leucocytosis and pancytopenia. Thrombocytopenia occurring in association with TB can be immune mediated, often induced by anti-tubercular drugs. Immune-mediated thrombocytopenia due to TB itself is extremely rare. Isolated thrombocytopenia has been reported in 23–43% of patients with disseminated TB.[1] Newly diagnosed immune thrombocytopenia in TB is rare; only 27 cases have been reported so far.[2]

When a patient with TB presents with haemoptysis to the Intensive Care Unit (ICU), one should rule out coexisting thrombocytopenia. Untreated thrombocytopenia may result in dreaded complications such as retro-orbital, retro-peritoneal and intracranial haemorrhage.

CASE REPORT

A 30-year-old male presented with epistaxis and haemoptysis to the casualty. He was diagnosed with sputum positive pulmonary TB 1-week before and was on category one intermittent anti-tubercular treatment (ATT) regimen. On examination, his pulse rate was 90/min; blood pressure was 116/78 mm Hg, and respiratory rate was 22 breaths/min. Trachea was central, dull note was heard in right infra-clavicular, mammary, infra-axillary and inter-scapular areas along with bronchial breath sounds. Other systemic examinations were within normal limits.

His haemoglobin (Hb) was 9.2 g%, white blood cell count 6700 cells/mm3, and platelet count was 8000/mm3. Other routine investigations along with serum bilirubin, liver enzymes, prothrombin time and activated partial thromboplastin time were unremarkable. Peripheral smear showed normocytic, normochromic blood picture with thrombocytopenia. Chest X-ray showed homogenous opacity in right lower zone with fluffy shadows in right upper zone [Figure 1]. Patient was shifted to ICU, 3 units of random donor platelet (RDP) concentrates were transfused and epistaxis subsequently stopped. Meanwhile, he was evaluated for secondary causes of thrombocytopenia. The dengue NS1 antigen, PF/PV antigen, HIV, hepatitis B surface antigen, hepatitis C virus, anti-nuclear antibody, antiglycoprotein and anticardiolipin antibody were negative. The anti-platelet antibody was strongly positive. Isoniazid and rifampicin were stopped to prevent drug-induced thrombocytopenia. Patient was started on tablet levofloxacin 750 mg orally, and rest of the first line ATT was continued.

Figure 1

Chest X-ray showing homogenous opacity in right lower zone with fluffy shadows in right upper zone

On 2nd day, patient again had a bout of epistaxis and haemoptysis. His platelet count was 22,000/mm3. Two units of RDP were transfused and injection dexamethasone 8 mg twice daily was started.

Patient improved symptomatically along with mild improvement in platelet count over the next 2 days. His platelet counts were 20,000/mm3 and 41,000/mm3 on day 3 and day 4 respectively. Bone marrow biopsy picture was within normal limits with normal numbers and normal shaped megakaryocytes. On 4th day, patient developed left hemiparesis. Patient was haemodynamically stable. Computed tomography (CT)/magnetic resonance imaging done showed a small haematoma in right frontal lobe. Patient's muscle power improved gradually over next 2 days.

However, on 7th day, he deteriorated suddenly with an episode of generalized tonic-clonic seizures followed by loss of consciousness. Patient was intubated and mechanically ventilated with controlled mandatory ventilation mode using continuous infusions of injection vecuronium, injection midazolam and injection fentanyl. Injection phenytoin 20 mg/kg loading dose was administered intravenously (IV) followed by 100 mg IV every 8 h. Injection mannitol 40 mg IV was administered every 8 h. Arterial blood gas analysis showed combined metabolic and respiratory acidosis, which were corrected using sodium bicarbonate and by optimizing his minute ventilation. Repeat CT brain showed large haematoma in left frontal and parietal lobe with midline shift and uncal herniation [Figure 2]. His Hb and platelet count were 8.7 g% and 6000/mm3, respectively. Further administration of platelet concentrates did not improve his platelet count. As patient's haemodynamics started deteriorating, injection noradrenaline and injection dopamine IV infusions were started in titrated doses. However, patient succumbed to death on 8th day.

Figure 2

Computed tomography scan brain repeated on day 6 showing large haematoma in left frontal and parietal lobe with midline shift and uncal herniation

DISCUSSION

Immune thrombocytopenia in association with or as a presenting manifestation of TB is very rare. Immunological basis of TB-induced thrombocytopenia can be confirmed by the presence of either platelet antigen-specific antibodies or platelet surface membrane immunoglobulin G (IgG). It is postulated that Mycobacterium TB could stimulate a clone of B lymphocytes directed against autologous platelets and produce anti-platelet antibodies.[1]

Tuberculosis may involve bone marrow in the form of fibrosis, granulomatosis, amyloidosis, and necrosis and can cause thrombocytopenia along with a decrease in other cell lines. Other causes of non-immune thrombocytopenia in association with TB include hypersplenism, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura and haemophagocytic syndrome.[3] Thrombocytopenia can also be a complication of therapy with anti-tubercular drugs such as rifampicin and isoniazid.[4] In our case, there was sufficient reason to contemplate that thrombocytopenia was due to the immune mechanism. Normal bone marrow examination excluded production defect or haemophagocytic syndrome. Absence of hepatosplenomegaly ruled out platelet consumption as a possible cause to suggest that thrombocytopenia was not co-existent with TB but was causally related to it. Immune-mediated thrombocytopenia can be either because of ATT or due to TB per se. Drug-induced thrombocytopenia cannot be conclusively ruled out in our case. Still, ATT-induced thrombocytopenia was not considered since drugs known to cause thrombocytopenia were given only for a short period and were stopped immediately following onset of bleeding. Furthermore, steroids were started, and the patient did not have any skin rashes/purpura or eosinophilia and also had two episodes of the major bleed, which would not have happened when adequately treated with steroids. In spite of all these measures, thrombocytopenia did not improve.

Idiopathic thrombocytopenic purpura (ITP) in conjunction with TB has not been reported frequently. A study done in Saudi Arabia of 846 TB patients reported that only 1% had ITP as the presenting feature.[5] Ghobrial and Albornoz have reported a case of disseminated TB with bleeding manifestations due to ITP. In this case, the bleeding manifestations resolved only after ATT was added to the ongoing immunotherapy for ITP.[6] During literature search, it was found that immune-mediated thrombocytopenia resolved in most of the patients who were treated with steroids along with ATT.[567] However, it can be resistant to steroids and in such cases, IV Ig should be promptly started without any delay. IV Ig could not be given in the present case as it was not available in hospital stores, and patient could not afford the purchase from other pharmacy sources.

CONCLUSION

Medical fraternity should consider TB as a treatable secondary cause of immune-mediated thrombocytopenia, when patient with TB presents with bleeding manifestations. After ruling out secondary causes of thrombocytopenia, isoniazid, and rifampicin should be stopped temporarily, and alternate ATT should be continued along with steroids.