© 2002 American Thoracic Society
Factor viia for alveolar hemorrhage in microscopic polyangiitisTo the Editor:Diffuse alveolar hemorrhage (DAH) is a potentially fatal complication of microscopic polyangiitis (MPA), with a prevalence of 12–29% (1). Respiratory failure is a major complication, and mechanical ventilation is required frequently. Treatment includes systemic corticosteroids, cytotoxic medications, and plasmapheresis. Often, bleeding is refractory to therapy, and the mortality rate is 31% (1). We report the case of a 52-year-old man who presented with dyspnea, temperature of 38.1°C, and room air saturation (SaO2) of 90%. Auscultation revealed bilateral inspiratory crackles. Sputum was bloody and chest radiograph showed diffuse alveolar infiltrates. White blood cell count was 18.1 x 109/L without eosinophilia. Hemoglobin was 10.1 g/dl, platelets 441 x 109/L, and ESR 68 mm/hour. PT and aPTT were normal. Creatinine was 1.1 mg/dl. ANA, anti-GBM, and anti-myeloperoxidase were negative, with anti–proteinase 3 positive at 151.7 U/ml. Urine showed 1+ protein and 4+ blood with RBC casts. Echocardiogram was normal. On hospital Day 2, bronchoalveolar lavage returned increasingly bloody specimens on sequential aliquots. Methylprednisolone (600 mg IV) was administered and plasmapheresis with FFP replacement was performed. On hospital Day 3 plasmapheresis was repeated, but dyspnea continued to worsen, hemoglobin was 8.3 g/dl, and PaO2 was 44 mm Hg on 1.0 fraction of inspired oxygen (FIO2) by mask. The patient was intubated and large amounts of bright red blood immediately poured from the endotracheal tube. PaO2 was 58 mm Hg with FIO2 of 1.0 and 14 cm H2O positive end-expiratory pressure (PEEP). Death from hypoxemic respiratory failure appeared imminent, and activated Factor VII (NovoSeven; Novo Nordisk, Princeton, NJ) was administered (80 µg/kg IV bolus). Within 30 minutes, tracheal aspirates changed from bloody to clear. Three additional doses were given over the following 9 hours (protocol slightly modified from the manufacturer's recommendations for patients with hemophilia). Within 12 hours of intubation, the FIO2 was decreased to 0.60, while maintaining an SaO2 of more than 90%. Chest radiograph showed partial resolution of the bilateral infiltrates. The patient was treated with two additional doses of prednisolone (600 mg IV), four more cycles of plasmapheresis, prednisone (60 mg PO QD), Mycophenolate Mofetil (1,000 mg PO BID), and cyclophosphamide (0.5 g/m2 IV x 1 dose). Plasma Factor VII activity level before administration of FVIIa was within the normal range for our institution. Renal biopsy revealed a pauci-immune focal necrotizing and sclerosing glomerulonephritis with 35% crescents. The patient was extubated on hospital Day 9 and discharged on hospital Day 14. Chest radiograph 6 days after hospital discharge showed complete resolution of pulmonary infiltrates. After 2 months of corticosteroids and monthly cyclophosphamide, symptoms had not recurred, creatinine was 0.9 mg/dl, ESR was 9 mm Hg, anti–proteinase 3 was 36.9 U/ml, and urine showed only trace protein and trace blood. Although high-dose FVIIa has been used extensively in patients with hemophilia A/B with Factor VIII or IX inhibitors, its use has rarely been reported in patients with normal factor levels. Our case is the first reported use in DAH associated with systemic vasculitis. High concentrations of FVIIa have been shown to induce hemostasis by enhancing thrombin generation on the surface of activated platelets, thereby bypassing the traditional FVIIa/tissue factor (TF) complex (2). The localization on activated platelets is believed to restrict the activity of high-dose FVIIa to the site of endothelial injury (3). TF pathway inhibitor (TFPI) is a potent inhibitor of the FVIIa/TF catalytic complex. Plasma levels of TFPI are increased in systemic vasculitis (4), and TFPI levels are increased 20-fold in bronchoalveolar lavage fluid from patients with acute lung injury, presumably due to local synthesis by activated alveolar macrophages (5). Because high concentrations of FVIIa induce coagulation by a TF independent mechanism, high-dose FVIIa treatment is thereby resistant to the TFPI inhibition that may be significantly enhanced in systemic vasculitis. Some hypothesize that high levels of FVIIa bind to exposed TF at the site of bleeding to initiate hemostasis (6, 7). This mechanism does not explain the requirement for the high dose that gives plasma levels at least an order of magnitude above the Kd for binding to TF (2). In DAH associated with systemic vasculitis, this may be due to ability to bypass TFPI. The temporal relationship between the FVIIa infusion and our patient's improvement supports our belief that FVIIa treatment was necessary to halt the severe alveolar bleeding. We cannot rule out the possibility that improvement was due to steroids or plasmapheresis, but his condition was clearly deteriorating despite these therapies. The time course was consistent with the known pharmacokinetics of FVIIa, as human studies have shown that peak effects of a single intravenous bolus dose of FVIIa occur within 10 minutes of delivery (8). Although more than 6,500 patients have received recombinant FVIIa, only 17 patients have been reported to have experienced a thrombotic event (3). Regardless, caution should be used in the administration of FVIIa, especially since TF is found in atherosclerotic plaques and some types of tumor cells (9) and might initiate pathological thrombosis. In summary, we conclude that high-dose FVIIa treatment can temporarily halt refractory, life-threatening bleeding in DAH associated with systemic vasculitis. It should be considered as a temporizing measure in refractory cases to allow more time for standard treatment regimens to control the underlying inflammation and capillary wall injury. Further investigation is warranted to determine if it should be considered as standard therapy.
University of North Carolina Chapel Hill, North Carolina REFERENCES
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