COPD 2017_Evaluation of the Maximal Respiratory Pressure in Children and Adolescents with Asthma between 7 and 14 Years Old_ Clemax Couto Sant´Anna

Novel anticoagulants such as rivaroxaban, a direct factor Xa inhibitor, have presented advancement in management of venous thromboembolism and atrial fibrillation. The most common complication of rivaroxaban treatment is bleeding with a relative risk (when compared to warfarin) of non-major bleeding of 0.99 and a relative risk for fatal bleeding of 0.48 [1]. Diffuse alveolar hemorrhage (DAH) related to rivaroxaban has only been reported in two cases [2,3]. Other causes of DAH incude systemic vasculitides, connective tissue diseases, infections, toxins and drugs. Diagnosis is confirmed by bronchoscopy with bloody fluid return on irrigation. Data regarding the overall incidence of DAH were lacking. We present four cases (Table 1) of rivaroxaban associated alveolar hemorrhage. Alveolar hemorrhage should be considered in patients receiving anticoagulation who develop hemoptysis, respiratory failure, or bilateral ground glass opacities on chest X-ray.

Case Presentation

 Case 1

The patient is a 45-year-old woman with a past medical history of systemic lupus erythematosis (SLE) complicated by lupus nephritis, antiphospholipid syndrome (APS) with aortic and renal artery thrombosis, and autoimmune hemolytic anemia. There was no evidence of pulmonary involvement of SLE prior to presentation. Her renal function was stable with a glomerular filtration rate of 51 ml/ min. She was prescribed 20 mg of rivaroxaban daily for the preceding 19 days. She presented with complaints of dyspnea and hemoptysis. Her condition deteriorated quickly and she required mechanical ventilation. Chest imaging revealed bilateral opacification of the lungs. Laboratory studies showed an acute anemia with hemoglobin level of 5.8 g/dl (baseline of approximately 8.5 g/dl). Bronchoscopy was performed and confirmed the diagnosis of DAH. Rivaroxaban was discontinued and she was treated with red blood cell transfusion, high dose steroids, and intra-pulmonary activated factor VII concentrate. Her renal function declined and it was felt that this was partly due to worsening lupus nephritis for which cyclophosphamide was started. The patient recovered and has been stable on follow up visits for several months. She was not restarted on oral anticoagulation as she developed hemoptysis with a challenge dose of rivaroxaban of 20 mg.

Case 2

 This patient is an 80-year-old man with a past medical history significant for adenocarcinoma of the lung (treated with partial left lobectomy two years prior), atrial fibrillation, chronic obstructive pulmonary disease, and chronic hypoxemic respiratory failure with tracheostomy. The patient was receiving rivaroxaban 20 mg daily. He developed worsening hypoxia and hemoptysis and required mechanical ventilation. Chest radiograph revealed bilateral infiltrates. His hemoglobin decreased from 10.6 g/dl to 7.4 g/dl, so rivaroxaban was discontinued. Bronchoscopy confirmed the diagnosis of DAH. The patient and family opted for a palliative care approach and he expired.

Case 3

This patient is a 79-year-old woman with history of lymphangioleiomyomatosis (LAM) and recent diagnosis of deep venous thrombosis and bilateral pulmonary embolism two weeks prior. She was treated with rivaroxaban 20 mg daily. She presented with dyspnea, cough, and hemoptysis. Chest radiography showed bilateral infiltrates with a right-sided pleural effusion. Laboratory studies showed an acute anemia with fall in hemoglobin from 10.5 g/dl on presentation to 7.6 g/dl one day later. Her respiratory status declined and she required intubation and mechanical ventilation. Rivaroxaban was held and a thoracentesis was performed on a right-sided pleural effusion revealing grossly bloody fluid. A bronchoscopy was performed which confirmed the diagnosis of DAH. An inferior vena cava filter was placed, and the patient recovered with supportive treatment. She was discharged after fifteen days in the hospital. This patient was not restarted on anticoagulation and unfortunately was lost to follow-up.

Methods

 We aimed to identify additional cases of anticoagulation-related DAH and the incidence thereof at our centre. We performed a search of our electronic medical record (EMR) during a one year time period of July 1, 2014 and June 30, 2015 for cases of alveolar haemorrhage including DAH, massive haemoptysis and pulmonary haemorrhage. This search returned 22 cases of significant alveolar haemorrhage that was not considered simple haemoptysis or blood-streaked sputum. In the same time period as the EMR search, we also queried the inpatient pharmacy for the number of unique patients rivaroxaban was dispensed to.

Results

 Rivaroxaban accounted for 13.6% (n=4) of all cases of clinically significant pulmonary hemorrhage and drug related pulmonary hemorrhage accounted for half of cases. There were additional cases of pulmonary hemorrhage on anticoagulants (one on dabigatran and two on warfarin). There were also cases of antiplatelet associated alveolar hemorrhage with one observed on prasugrel and three with clopidogrel. The remainder of the cases were accounted for by Wegener’s granulomatosis (one), malignancy (six), infectious (three), and post-procedural (four)**. We found 1,060 unique individuals were dispensed Rivaroxaban, resulting in the rate of alveolar hemorrhage associated with Rivaroxaban of approximately 0.0028 to 0.0037, or about 3 cases in 1,000. The rate of DAH associated with warfarin was 0.0013 (2 cases in 1,561 patients given warfarin).

Discussion:

 Alveolar hemorrhage associated with rivaroxaban is an apparently rare complication. There were no reported cases of DAH in the ROCKET-AF study [1]. We identified two additional cases in the literature, both of which included patients with underlying lung conditions [2,3]. The patients identified in this case series all have underlying chronic medical conditions. Case one identified a woman with SLE and APS. APS is associated with alveolar hemorrhage, either as a primary etiology or in combination with other connective tissue disorders such as SLE. The incidence of DAH associated with APS is unknown, but 22 cases were presented in one series [4]. The patient was treated with Rivaroxaban for an arterial thrombosis, which is not an approved indication [5]. She also had a worsening renal function during hospitalization which might contribute to the decrease in the rivaroxaban clearance leading to higher level of the drug in the system. The patient in case two had no recognized risk factors for DAH, however he was diagnosed with chronic lung disease, resected adenocarcinoma, recurrent infections, and chronic respiratory failure. In case three, we present a patient with lymphangioleimyomatosis. This condition exclusively affects females and its incidence is not well established, though it estimated that there are about 1,300 cases of LAM in North America [6]. LAM has an association with clinically insignificant bleeding on biopsy and we could identify only two cases of spontaneous alveolar hemorrhage in LAM [7,8]. Finally, the fourth patient had an underlying diagnosis of myelodysplastic syndrome.

Conclusions:

 We identified four cases of rivaroxaban associated alveolar hemorrhage. We encourage cautious use of rivaroxaban in patients with underlying lung conditions or factors that predispose to alveolar hemorrhage. Further research to clarify the risk of diffuse alveolar hemorrhage (DAH) in at-risk patients receiving oral anticoagulants is recommended.

 

 

Author(s): Clemax Couto Sant´Anna

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