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CASE REPORT
Year : 2019  |  Volume : 36  |  Issue : 6  |  Page : 534-539  

Warfarin-induced diffuse alveolar hemorrhage: Case report and a review of the literature


1 Department of Cardiology, Sawai Man Singh Medical College, Jaipur, Rajasthan, India
2 Department of Chest and Tuberculosis, Sawai Man Singh Medical College, Jaipur, Rajasthan, India

Date of Web Publication31-Oct-2019

Correspondence Address:
Dr. Rajeev Bagarhatta
530, Opposite Ram Mandir, Mahaveer Nagar, Tonk Road, Jaipur - 302 018, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/lungindia.lungindia_8_19

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   Abstract 


Diffuse alveolar hemorrhage (DAH) refers to the intra-alveolar accumulation of blood originating from the pulmonary microvasculature. This life-threatening condition is a medical emergency as patients often develop acute respiratory failure requiring invasive mechanical ventilation. This mandates for an early diagnosis with prompt and aggressive management strategies. A host of clinical disorders are known to cause DAH; however, warfarin-induced alveolar hemorrhage is a distinct clinical rarity. A search of the literature reveals few reports documenting this entity. A 27-year-old male presented with complaints of recent-onset hemoptysis and dyspnea. One month back, he was diagnosed with lower-limb deep-venous thrombosis and pulmonary embolism. He had been taking oral anticoagulants irregularly since then without monitoring of prothrombin time. Chest radiograph, done on presentation, revealed bilateral upper-lobe infiltrates, whereas computed tomography of the chest was suggestive of bilateral upper-lobe ground-glass opacities. Serial bronchoscopic alveolar lavage yielded samples which became progressively bloodier, whereas cytological evaluation of the sample revealed numerous alveolar macrophages with intracytoplasmic hemosiderin. A diagnosis of DAH due to warfarin was made, and the patient was administered Vitamin K followed by infusion of fresh frozen plasma. There was a marked clinical recovery, and the patient has been asymptomatic since then.

Keywords: Bronchoscopic alveolar lavage, computed tomography of the chest, diffuse alveolar hemorrhage, fiber-optic bronchoscopy, warfarin


How to cite this article:
Kunal S, Bagarhatta R, Singh S, Sharma SK. Warfarin-induced diffuse alveolar hemorrhage: Case report and a review of the literature. Lung India 2019;36:534-9

How to cite this URL:
Kunal S, Bagarhatta R, Singh S, Sharma SK. Warfarin-induced diffuse alveolar hemorrhage: Case report and a review of the literature. Lung India [serial online] 2019 [cited 2019 Nov 14];36:534-9. Available from: http://www.lungindia.com/text.asp?2019/36/6/534/270092




   Introduction Top


Diffuse alveolar hemorrhage (DAH) is a rare clinical entity which refers to bleeding into the acinar portion of the lung from the pulmonary microvasculature.[1] This occurs as a result of the disruption of the alveolar–capillary basement membrane, leading to the intra-alveolar collection of red blood cells. The prognosis of patients with DAH is often dismal, and the in-hospital mortality ranges widely from 20% to 100%.[2] A strong clinical suspicion is often required for making an early diagnosis to prevent disease progression and reduce the mortality rate.[1]

A wide spectrum of clinical conditions are known to cause DAH. This includes immunological mediated conditions such as systemic vasculitis (granulomatosis with polyangitis [Wegner's granulomatosis], microscopic polyangitis), rheumatoid arthritis, systemic lupus erythematosus (SLE), antiglomerular basement membrane antibody disease (Goodpasture syndrome), antiphospholipid syndrome, and Bechet's disease. The nonimmunological mediated conditions include drugs, toxins, bleeding disorders, and malignancy.[1],[3]

Anticoagulants are increasingly being used in a variety of clinical conditions, and bleeding forms an important adverse effect of anticoagulant use. DAH due to warfarin is an uncommon clinical entity and has been infrequently documented in the literature.[4] The paucity of the literature on the subject prompted this report of a young male who presented with hemoptysis and was subsequently diagnosed with DAH as a result of warfarin therapy.


   Case Report Top


A 27-year-old, HIV-negative, never-smoker male presented to the emergency department with complaints of hemoptysis along with shortness of breath for the past 3 days. His clinical course was characterized by multiple bouts of coughing out bright red blood around 200 ml/day for 3 days. Hemoptysis was not accompanied with malena, bleeding diathesis, and gum or nasal bleed. In addition, he also had symptoms of dyspnea at rest, which were not associated with wheezing. One month prior to presentation, he had complained of exertional dyspnea accompanied with pain and swelling in the right leg for which he underwent a computed tomography scan of the chest. At that point, a diagnosis of pulmonary embolism along with right lower-limb deep-venous thrombosis was made. He was started on oral anticoagulants (tablet warfarin: 5 mg/day) after an adequate overlap with low-molecular-weight heparin. However, the patient had been taking the drug erratically without adequate monitoring for a month prior to presentation. General physical examination revealed a young male in respiratory distress with a saturation of 90% while breathing ambient room air. There was an asymmetry in the girth of the lower limbs, with right limb girth being larger. Chest auscultation revealed vesicular breath sounds of equal intensity with bibasilar fine-end inspiratory crepitation.

Investigations

On admission, the hemoglobin levels were 14.2 gm% which subsequently fell to 10.6 gm% over the course of 3 days. Liver and renal function tests as well as the urine routine analysis were within the normal limits. The prothrombin time (PT) values done on admission were deranged with an international normalized ratio (INR) of 7.2. A review of the past records revealed PT values of 22 and an INR of 2.05 at the time of discharge. Chest radiograph done on presentation revealed bilateral upper-zone infiltrates (right > left). Contrast-enhanced computed tomography of the chest revealed bilateral eccentric filling defects in the pulmonary artery suggestive of pulmonary thromboembolism [Figure 1]a. In addition, the high-resolution computed tomography of the chest showed bilateral upper-lobe ground-glass opacities with a mosaic attenuation pattern [Figure 1]b. Compression ultrasound (CUS) along with Doppler of the right lower limb revealed partial recanalized thrombus in the right common femoral vein with streaky irregular patchy flow. In view of the presence of diffuse alveolar infiltrates, the patient's consent was taken for a fiber-optic bronchoscopy which revealed a normal tracheobronchial tree. Serial bronchoscopic alveolar lavage (BAL) was done from the right upper lobe, with each of the five sequential 20-mL aliquots of BAL being bloodier than the previous [Figure 2]. Cytological evaluation of the BAL sample revealed numerous brown intracytoplasmic hemosiderin pigment-laden macrophages on hematoxylin and eosin stain [Figure 3]a and bluish cytoplasmic granules on Pearls stain [Figure 3]b. Stains and cultures of the BAL were negative for Mycobacterium tuberculosis and other aerobic organisms as well as pathogenic fungi. Subsequent workup included a negative test for antineutrophil cytoplasmic antibodies, antinuclear antibody, antiglomerular basement membrane, and antiphospholipid antibodies. A diagnosis of anticoagulant (warfarin)-induced DAH was made based on (a) clinical presentation; (b) radiology; and confirmed on (c) BAL as well as BAL fluid cytology.
Figure 1: (a) Contrast-enhanced computed tomography of the chest (mediastinal window: coronal section) showing eccentric filling defects in the right and left main pulmonary arteries suggestive of pulmonary thromboembolism. (b) High-resolution computed tomography of the chest (lung window: axial section) showing bilateral upper-lobe ground-glass opacities with a mosaic attenuation pattern

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Figure 2: Serial broncho-alveolar lavage showing progressive hemorrhagic nature of the broncho-alveolar lavage fluid

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Figure 3: (a) High-power view (H and E, ×40) of the patient's broncho-alveolar lavage fluid cytology specimen showing numerous brown intracytoplasmic hemosiderin pigment-laden macrophages (black arrows). (b) High-power view (Pearls, ×40) of the patient's broncho-alveolar lavage fluid cytology specimen showing hemosiderin-laden macrophages. Hemosiderin is demonstrated as blue cytoplasmic granules

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Management

Warfarin was immediately stopped, and the patient was placed on high-flow oxygen and 10-mg intravenous Vitamin K injection was administered followed by transfusion of four units of fresh frozen plasma. In a couple of days, the patient had improvement in his symptoms, and he was weaned off the supplemental oxygen. A repeat chest radiograph done on day 4 showed clearance of the radiological opacities. As the patient was unable to afford newer oral anticoagulants, he was discharged on a lower dose of warfarin with an advice of strict INR monitoring in further follow-ups.


   Discussion Top


The clinical presentation in patients with DAH includes cough, hemoptysis, dyspnea, and chest pain.[1] Hemoptysis may be absent in one-third of patients with DAH.[5] Respiratory failure is usually the most severe form of presentation requiring ventilatory support and entailing high mortality rate. The diagnosis of DAH is mainly clinical in an appropriate setting and is usually supported by radiological and bronchoscopic findings.[3] Clinical history forms an important diagnostic armamentarium in patients with DAH, as apart from establishing a diagnosis, it often elicits the etiology. Radiological features in DAH are usually nonspecific and include patch/diffuse ground-glass opacities, “crazy-paving” pattern, or frank consolidation. These findings are often seen in acute pulmonary edema, acute respiratory distress syndrome (ARDS), congestive heart failure, and infections.[1] BAL often confirms the diagnosis based on (1) progressively bloodier return on sequential BAL samples and (2) hemosiderin-laden macrophages on BAL cytology.[1],[3]

Based on the histological pattern, the causes of DAH may be grouped as: (1) those associated with pulmonary capillaritis; (2) associated with bland pulmonary hemorrhage; and (3) associated with diffuse alveolar damage.[1] Pulmonary capillaritis refers to the neutrophilic infiltration of the pulmonary capillaries leading to loss of structural integrity and bleeding into the alveolar spaces. This is usually seen in DAH associated with systemic vasculitis, Goodpasture syndrome, rheumatoid arthritis, some drugs (diphenylhydantoin, propylthiouracil, and all–trans-retinoic acid), and the rare entity of idiopathic pulmonary capillaritis. In patients with bland pulmonary hemorrhage, there occurs bleeding into the alveolar spaces without affecting the interstitial compartment. This is often seen in patients with mitral stenosis, bleeding disorders, and anticoagulant therapy. Diffuse alveolar damage is usually seen in patients with SLE, cytotoxic drug intake, and ARDS.[6]

Anticoagulant-induced DAH is a rare clinical entity and has been infrequently documented in the medical literature. Warfarin is a Vitamin K antagonist and a very potent and widely used anticoagulant. Systemic bleeding is often an important complication with warfarin therapy.[7] The risks of bleeding further increase because factors such as diet, concurrent medications, poor compliance, and alcohol consumption lead to fluctuating INR levels.[8] A search of the literature using PubMed, Cochrane, IndMed, Google, and other databases with the keywords “warfarin,” “acenocoumarol,” “Vitamin K antagonist,” and “diffuse alveolar haemorrhage” revealed 18 studies [4],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] documenting 22 patients, which has been depicted in [Table 1]. Brown et al.[9] in 1965 for the first time reported DAH caused due to warfarin in a 64-year-old male who presented with hemoptysis and hematuria. He had accidentally ingested 35 mg of warfarin leading to DAH, a diagnosis of which was made clinicoradiologically. Nearly, a decade later, Finley et al.[10] reported three patients with warfarin-induced “occult pulmonary hemorrhage,” the diagnosis of which was established on BAL. Following this, isolated reports have come up highlighting this rare clinical entity.[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25] A recent retrospective study from Japan [24] described the clinical features and outcome of DAH caused by antithrombotic therapy. In this study, 14/39 patients had DAH due to warfarin, with eight on monotherapy, whereas the remaining six were on other antithrombotic agents too. Of the eight patients on warfarin monotherapy, only four had DAH due to the offending drug, whereas the remaining four had other causes too (vasculitis and heart failure).
Table 1: Tabulated review of anticoagulant-induced diffuse alveolar hemorrhage

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Management of warfarin-induced DAH is usually supportive, with withdrawal of the offending drug being the most important treatment strategy followed by administration of Vitamin K and fresh frozen plasma which serves as an effective antidote.[1],[3],[4] Since DAH is often a life-threatening condition, a prompt diagnosis and early treatment is often required to decrease the mortality. Intravenous corticosteroids and ventilatory support are often required in cases with severe hypoxemia and respiratory failure. In a recent report,[20] extracorporeal membrane oxygenation has been used as a bridge to therapy in severe cases of DAH caused due to warfarin therapy with promising results.

Our case highlights two important features related to the diagnosis and management of drug-induced DAH. First, a high index of clinical suspicion is warranted for an early and prompt diagnosis as was seen in our case. BAL is often considered to be the gold standard and was used in our case to confirm the diagnosis. Second, DAH has a high mortality rate and hence, therapy should be instituted as early as possible, with reversal of anticoagulation being the cornerstone of the management strategy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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2.
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Klenner AF, Friesecke S, Schäper C, Ewert R, Gläser S. Diffuse alveolar hemorrhage with acute respiratory distress syndrome associated with phenprocoumon therapy. Blood Coagul Fibrinolysis 2008;19:813-5.  Back to cited text no. 15
    
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Lee JH, Kim SW. Successful management of warfarin-exacerbated diffuse alveolar hemorrhage using an extracorporeal membrane oxygenation. Multidiscip Respir Med 2013;8:16.  Back to cited text no. 20
    
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Uysal E, Çevik E, Solak S, Acar YA, Yalimol M. A life-threatening complication of warfarin therapy in ED: Diffuse alveolar hemorrhage. Am J Emerg Med 2014;32:690.e3-4.  Back to cited text no. 21
    
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Otoshi T, Kataoka Y, Nakagawa A, Otsuka K, Tomii K. Clinical features and outcomes of diffuse alveolar hemorrhage during antithrombotic therapy: A Retrospective cohort study. Lung 2016;194:475-81.  Back to cited text no. 24
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]



 

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