Clopidogrel

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

An 88-year-old woman developed diffuse alveolar haemorrhage (DAH) during treatment with clopidogrel as anticoagulant [duration of treatment to reaction onset not stated].

The woman presented to the emergency department with worsening shortness of breath, cough and pleuritic chest pain. Her symptoms had begun several months before and had been worsening progressively. She denied night sweats, loss of appetite or loss of weight. Oral ulcers, arthralgias, haemoptysis, haematuria, epistaxis or skin rashes were not reported. Her medical history was significant for heart failure with preserved ejection fraction and a carotid stent placement, following which she was started on clopidogrel [dosage and route not stated]. Three days prior to presentation, she had also received her first dose of COVID-19 mRNA vaccine; however, her symptoms preceded the vaccine. She denied any tobacco use or exposure to animals or unusual plants. On admission, physical examination were as follows: body temperature 36.3°C, BP 141/65mm Hg, respiratory rate 21 breaths/min, pulse oximetry of 91% and heart rate 76 beats/minute. She was slightly tachypneic. No cervical or supraclavicular lymph nodes were detected. Heart sounds were normal. Lung examination demonstrated bilateral lower lung crackles. There was no clinical evidence of volume overload and the rest of the physical examination was normal without clubbing. A chest radiograph revealed bilateral interstitial infiltrates. Investigations were as follows: Hb 102 g/L, WBC 10470 /μL (with predominantly neutrophilic inflammation) and platelets 253000 /μL. Nasopharyngeal swab for respiratory viral panel PCR was found negative for all respiratory viruses and nasopharyngeal swab for COVID-19 PCR was also negative, excluding viral infection.

The woman was initially suspected with community acquired pneumonia and received antibiotics. A possible diastolic congestive heart failure exacerbation was also considered and treated with furosemide. However, her symptoms continued to worsen over the course of the admission. She ended up needing high levels of support with high-flow nasal cannula. A chest CT showed diffuse bilateral ground-glass opacities. On day 7 of admission, she underwent a bronchoscopy with BAL of the right middle lobe and transbronchial biopsies (TBBx) of the right upper lobe. The BAL aliquots were progressively bloodier. Both BAL and TBBx results were suggestive of DAH. BAL and TBBx bacterial, fungal and acid-fast bacilli cultures were all negative; BAL Aspergillus and Histoplasma antigens, Chlamydia psittaci antibodies and urine legionella antigen were also negative ruling out infectious aetiology. Anti-neutrophil cytoplasmic antibody, anti-glomerular basement membrane antibodies, antinuclear antibodies, rheumatoid factor and urinalysis were negative ruling out possible autoimmune aetiology. Transthoracic echocardiogram was essentially normal ruling out mitral stenosis. There was no documented rodent exposure hence Leptospirosis or Hantavirus were also excluded. After the bronchoscopy, she remained intubated for 3 days and was extubated to high-flow nasal cannula. Subsequently, she was started on methylprednisolone for 3 days. Her symptoms had started after placement of a carotid stent, suggesting clopidogrel-induced DAH. Therefore, clopidogrel was discontinued. Afterwards, she improved slowly and was weaned off high-flow nasal cannula in a stepwise manner. Her oxygen requirement improved, but bilateral dry crackles were present until her discharge. Her X-ray findings remained unchanged stating early-developing fibrosis/traction bronchiectasis. A repeat chest CT still showed diffuse ground-glass opacities, reticulation and airway dilatation consistent with diffuse alveolar damage. Methylprednisolone was tapered down, and she was discharged to a rehabilitation facility. In the days to weeks following the discontinuation of clopidogrel, resolution of DAH was noted. She was discharged home and her steroid treatment was tapered off.