Diffuse alveolar haemorrhage secondary to warfarin therapy for atrial fibrillation: a case report and literature review

Abstract

Alveolar haemorrhage is a rare and serious medical emergency with many causes. Diffuse alveolar haemorrhage due to warfarin therapy has been rarely reported in the literature. In this paper, we describe the case of 62-year-old woman with a history of chronic atrial fibrillation treated with warfarin, who was admitted to our institution with haemoptysis and dyspnoea. Alveolar haemorrhage was suspected clinically and subsequently confirmed by bronchoscopy. The patient required aggressive treatment with fresh frozen plasma, vitamin K and mechanical ventilation with a successful outcome. We emphasise the need for early diagnosis and fast therapeutic intervention, especially with over-anticoagulation (INR >9), in patients with this rare and potentially lethal condition.

BACKGROUND

Diffuse alveolar haemorrhage (DAH) is a rare occurrence in clinical practice. It can be caused by many conditions such as lung infections, pulmonary embolism, Wegener’s granulomatosis, Goodpasture’s syndrome, systemic lupus erythematosus and Behçet’s syndrome. A few drugs, including the widely used anticoagulant warfarin, have been documented to cause this potentially lethal condition.

Recently, a patient with haemoptysis and dyspnoea was admitted to our institution. She had chronic atrial fibrillation and was being treated with warfarin. We will describe her presentation, diagnosis, management and follow-up.

Even though DAH secondary to warfarin use for atrial fibrillation is still relatively rare, we think its incidence is likely increase with the use of anticoagulation therapies (including warfarin) in an increasingly aging population. Health care professionals in general and physicians in particular need to be vigilant and act swiftly when this condition is detected.

CASE PRESENTATION

A 64-year old woman with a past medical history of hypertension, atrial fibrillation and haemorrhoids, was admitted to our institution complaining of haemoptysis and shortness of breath over the previous 24 h.

On examination, she was noted to be in mild respiratory distress and was coughing up blood-tinged sputum. Her vital signs were: temperature 37.4°C, pulse 103 bpm and irregular, respiratory rate 20 per minute, blood pressure 132/68 mm Hg and oxygen saturation 93% on room air. Skin examination revealed multiple ecchymoses on the trunk and extremities. She had normal heart sounds with irregular rhythm. She also had diffuse wet crackles over both lung fields. The rest of her physical examination was unremarkable.

The patient’s medications on the day of admission were: amlodipine 5 mg PO daily, warfarin 5 mg PO every other day (4 days/week), warfarin 2.5 mg PO every other day (3 days/week), digoxin 0.25 mg PO daily, bisoprolol 5 mg PO daily and ethamsylate 750 mg PO three times a day.

INVESTIGATIONS

The patient’s laboratory findings were: WBC 17.2, haemoglobin 118 g/l, haematocrit 34%, platelets 316, INR >9, PT >94 s, aPTT 94.9 s, random glucose 11.4 mmol/l, serum sodium 128 mmol/l and serum creatinine 57 μmol/l. Urinalysis showed a moderate number of RBCs without RBC casts. The rest of the laboratory results, including D-dimer level and cardiac enzymes, were unremarkable.

Chest x ray (fig 1) showed alveolar opacities in both lungs, especially in the perihilar and pericardiac zones.

Figure 1.

Chest x ray on admission.

High resolution CT of the chest (fig 2) showed bilateral patchy airspace disease.

Figure 2.

Computed tomography of the chest on admission.

DIFFERENTIAL DIAGNOSIS

The presence of haemoptysis and bilateral lung infiltrate suggests several differential diagnoses: elevated pulmonary capillary pressure (as seen with mitral stenosis or significant left ventricular failure), community acquired pneumonia, TB, immune disorders including Goodpasture’s syndrome, idiopathic pulmonary haemosiderosis, lupus pneumonitis, Wegener’s granulomatosis, or a coagulopathy secondary to the use of anticoagulants. However, the acute presentation, the absence of mitral stenosis murmur or signs of left ventricular failure, and the presence of coagulopathy raised the possibility of diffuse pulmonary haemorrhage. The patient was started empirically on moxifloxacin for possible community acquired pneumonia. Serum levels of C-ANCA, P-ANCA, ANA and anti ds-DNA were investigated. Echocardiogram showed normal left ventricular function and no valvular disease.

TREATMENT

The patient’s coagulopathy was corrected with fresh frozen plasma and vitamin K. She had to be mechanically ventilated as her dyspnoea and hypoxaemia worsened. A bronchoscope was wedged into a sub-segmental bronchus and the diagnosis of DAH was confirmed as the lavage became progressively more haemorrhagic, with no evidence of massive bleeding or end-bronchial pathology. Iron stains were not performed in the bronchoalveolar lavage (BAL).

OUTCOME AND FOLLOW-UP

The patient required 14 days of mechanical ventilation and was extubated successfully.

A repeat CT scan of the chest 7 weeks after presentation showed complete resolution of the previous findings (fig 3). The vasculitis work-up was negative and the patient was started back on warfarin to maintain an INR between 2 and 3. BAL stain for AFB, bacterial and fungal pathogens and BAL culture were negative. The final diagnosis was DAH induced by warfarin treatment for atrial fibrillation.

Figure 3.

CT of the chest 7 weeks after admission.

DISCUSSION

DAH is the result of widespread bleeding on the acinar portion of the lung. Depending on the aetiology of the haemorrhage, there may be associated pulmonary capillaritis, neutrophil infiltration, interalveolar septal capillary thrombi, and even capillary wall necrosis.¹ Some of the disorders that can cause this condition include Churg-Strauss syndrome,² Wegener’s granulomatosis,³ systemic lupus erythematosus,⁴ Goodpasture’s syndrome,⁵ acute post-streptococcal glomerulonephritis,⁶ and potentially any pulmonary renal syndrome.⁷ DAH can also be idiopathic without any inflammatory process. It is rarely seen in the adult population.⁸

Less common conditions causing DAH include idiopathic thrombocytopenic purpura,⁹ sarcoidosis,¹⁰ blood transfusion,¹¹ HELLP sydrome,¹² scuba diving,¹³ and even ascending aorta dissection.¹⁴

Many drugs can also cause DAH, including inhaled cocaine,¹⁵ diphenyl-hydantoin,¹ sirolimus¹⁶ and leflunomide.¹⁷

Anticoagulant-induced bleeding in the alveolar space is rare. In 1962 Jaques reported evidence of pulmonary haemorrhage caused by dicumarol in animal models.¹⁸ The first case of diffuse intrapulmonary haemorrhage caused by coumadin intoxication was reported clinically and radiologically by Brown et al in 1965.¹⁹ Since then few cases have been described in the literature.^20,21

The tools used to diagnose DAH have evolved over time. Initially, the clinical presentation and plain chest radiography were enough to suggest the diagnosis. More recently, CT scans of the chest are frequently used to better visualise parenchymal lung findings.²² However, flexible fibre-optic bronchoscopy, which has been for almost four decades, offers a better diagnostic tool for DAH²³ and BAL confirms the diagnosis by showing the presence of stainable haemosiderin within the alveolar macrophages.^24,25 It is worth adding that, paradoxically, bronchoscopy itself can cause massive pulmonary bleeding.²⁶ Warfarin-induced bleeding in the alveolar space is usually severe and can be fatal.²⁷

Even though DAH induced by anticoagulation agents remains rare, its incidence may increase because of (i) the use of newer, more potent agents such as abciximab²⁸ and eptifibatide²⁹ and (ii) the use of warfarin and these agents in an increasingly elderly population with co-morbidities and polypharmacy.

Various lessons can be learned from this case. Firstly, it is very important is to establish an early diagnosis as the patient is literally drowning in their own blood, and anaemia, hypoxaemia, respiratory failure and death can follow. Bronchoscopy is instrumental in confirming the diagnosis of DAH as blood visualised in the airways is highly suggestive of the diagnosis. Positive iron studies of BAL will confirm the condition. Secondly, prompt two-pronged therapy should be initiated. The first aim is coagulopathy reversal with conventional fresh frozen plasma and vitamin K, or even with clotting factor concentrate if necessary.³⁰ The other goal is to assist the patient’s breathing with good oxygenation and mechanical ventilation when needed. In our case, we believe that the rapid diagnosis using fibre-optic bronchoscopy and swift therapeutic interventions were instrumental in saving this woman’s life.

Our patient had very high INR, PT and aPTT. It is worth mentioning that warfarin induces elevation of both PT and aPTT. In their prospective study, Kearon et al showed that for each increase of 1.0 in the INR, the aPTT increased by 16 s.³¹ Another study showed good linear correlation between PT elevation and aPTT elevation while taking warfarin.³² Another additional explanation of the patient’s severe coagulopathy is a possible warfarin–digoxin interaction.³³ Her other medications have no known interaction with warfarin.

CONCLUSION

DAH is rare and dangerous and can be caused by warfarin which is used for the treatment of atrial fibrillation among other pathologies. Greater use of this medication and growth in the aging population will probably result in more cases of DAH. The diagnosis may be suspected clinically and radiologically but must be confirmed by bronchoscopy. Either visualisation of fresh blood in the airways or positive histopathological BAL results will confirm the diagnosis. Early intervention is vital: warfarin must be stopped, warfarin-induced coagulopathy must be addressed, and the patient must be provided with adequate oxygenation and ventilation.

LEARNING POINTS

• Early diagnosis of diffuse alveolar haemorrhage secondary to warfarin therapy is extremely important.

• Bronchoscopy will confirm the diagnosis suggested by radiological investigation.

• Swift reversal of anticoagulation is required after diagnosis.

• Respiratory support must be provided when there is respiratory failure.

• Physicians and health care professionals must prescribe and administer warfarin with care in view of potential complications and act rapidly in cases of diffuse alveolar haemorrhage.