Recombinant activated factor VII for diffuse alveolar hemorrhage in microscopic polyangiitis

Introduction

Microscopic polyangiitis is the most common cause for pulmonary-renal vasculitic syndrome. Renal presentation is in the form of rapidly progressive glomerulonephritis, histologically characterized by necrotizing, crescentic glomerulonephritis of pauci-immune type. Pulmonary involvement usually takes the form of diffuse alveolar hemorrhage (DAH) which is seen in 12 to 29%,[1] with respiratory failure being a major complication. The conventional treatment of DAH involves a combination of systemic corticosteroids, cytotoxic medications, and plasmapheresis. However, some cases may be refractory to this regimen and have a high mortality rate of around 31%.[1]

Recombinant factor VIIa is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues and is structurally similar to human plasma derived factor VIIa. It promotes hemostasis by activating the extrinsic pathway of coagulation cascade. This report describes the successful use of recombinant activated factor VII (rFVIIa) for severe pulmonary hemorrhage in a case of microscopic polyangitis.

Case Report

A 23-year-old woman presented to our hospital with one-month history of fever, loss of appetite, and fatigue. On evaluation, she was found to have advanced uremia (serum creatinine 9.8 mg/dl) and severe anemia (hemoglobin 5.2 g/dl). She was started on hemodialysis through internal jugular catheter and packed red cell transfusion was given. Further evaluation revealed active urinary sediments, normal-sized kidneys on ultrasound, and strongly positive myeloperoxidase-antineutrophilic cytoplasmic antibody (MPO-ANCA) (titer>500 u/ml). Renal biopsy was done and treatment with pulse methyl prednisolone and oral cyclophosphamide was started. Renal biopsy revealed necrotizing glomerulonephritis with crescent formation of pauci-immune type with severe chronic glomerular and tubulointerstitial changes. Of 14 glomeruli, 11 were completely sclerosed [Figure 1].

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Figure 1

Section showing a glomerulus with fibro-epithelial crescent. Blood vessels in the vicinity showing medial and intimal thickening with surrounding interstitial fibrosis and tubular atrophy (H and E, ×220)

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On the sixth day of hospital stay, she developed sudden drop in hemoglobin along with dyspnea. Chest X-ray did not reveal any significant abnormality. Computerized tomography (CT) chest showed bilateral pleural effusion with ground glass and nodular opacities without cavitatory lesions. In the next 12 hours she developed respiratory distress, which necessitated mechanical ventilation. Bronchoscopy revealed diffuse hemorrhage. She was started on plasma exchange. However, her condition continued to deteriorate with continuous bleeding from the endotracheal tube and increasing oxygen requirements; hence, it was decided to use recombinant factor VII (Novoseven). She was given two doses of 90 μg/ kg iv bolus at 2 hours interval. This therapy worked dramatically and within 30 minutes of first dose active bleeding stopped. She showed significant respiratory improvement in next 12 hours, and in 72 hours she could be extubated. Plasma exchange was continued and mycophenolate mofetil started. She received five sessions of plasma exchange.

During the hospital stay, she received heparin-free dialysis, antibiotics, prednisolone, and mycophenolate mofetil. However, her platelet counts showed a downward trend, evaluation of which revealed evidence of thrombotic microangiopathy (TMA) (fragmented red blood cells on peripheral smear, high lactate dehydrogenase - 3000 U/l, and normal PT). She was restarted with plasma exchange. She also had an episode of generalized tonic-clonic seizure. Magnetic resonance imaging (MRI) showed features suggestive of posterior reversible encephalopathy syndrome (PRES). She was started on levetiracetam. There was gradual improvement in her general condition and hematological parameters; she was discharged and put on maintenance hemodialysis program.

Discussion

Recombinant factor VIIa promotes hemostasis by activating the extrinsic coagulation pathway. It forms a complex with tissue factor (TF) and activates factor X to Xa, as well as Factor IX to IXa. Factor Xa then converts prothrombin to thrombin, which forms a hemostatic plug by converting fibrinogen to fibrin. A therapeutic dose of FVIIa produces supraphysiological concentrations of FVIIa. This high concentration induces hemostasis by enhancing thrombin generation on the surface of activated platelets, thereby bypassing the traditional FVIIa/TF complex.[2]

Although rFVIIa has been primarily used in patients with hemophilia A/B with Factor VIII or IX inhibitors, its use has been reported in patients with massive pulmonary hemorrhage in a variety of settings like very low birth weight infants,[3] metastatic choriocarcinoma,[4] pneumonia,[5] and blunt thoracic trauma.[6] Betensley and Yankaskas had earlier reported the use of rFVIIa in DAH due to microscopic polyangiitis with good result.[7] Similarly, we found an almost immediate control of pulmonary hemorrhage after rFVIIa injection in the present case. Even intrapulmonary administration of rFVIIa through a bronchoscope has been reported to be effective in DAH.[89]

Other unusual features in our case were the development of TMA and PRES. TMA complicating MPO-ANCA-associated vasculitis is rare and was reported by Yamauchi et al., where it was treated with plasma exchange.[10] We had restarted plasma exchange on finding the features of TMA in the present case and there was gradual improvement of her platelet counts.

PRES is an increasingly diagnosed neurologic disorder with characteristic CT and MRI findings. Classic CT findings are of bilaterally symmetric low attenuation in the posterior parietal and occipital lobes, whereas MRI demonstrates hyperintensity on T2-weighted images. PRES may develop in patients with renal insufficiency, hypertension, or who are on immunosuppressive medications and usually presents with headache, altered alertness, confusion, seizures, and cortical blindness.[11]

Conclusion

This is an unusual case of microscopic polyangiitis with pauci-immune necrotizing glomerulonephritis and massive pulmonary hemorrhage, complicated by TMA and PRES. Use of rFVIIa helped in the rapid control of life-threatening pulmonary hemorrhage and allowed time for conventional therapy to act. Hence, recombinant factor VIIa may be considered as a treatment option in patients with diffuse pulmonary hemorrhage, who otherwise have a very high mortality rate.