Toward Optimised Intrapulmonary and Systhemic Hemostatic Interventions in Diffuse Alveolar Hemorrhage, a Single Center Experience
Authors: Udvardy Miklos , Selmeczi Anna , Egyed Miklos , Szucs Attila , Illes Arpad , Gergely Lajos , Balla Joseph , Matyus Janos 
Published: October 2019

Abstract
Background: We observed diffuse alveolar hemorrhage (DAH) relatively frequently at our Bone Marrow Transplant and Nephrology Units (ANCA positive vasculitis + DAH). We tried to refine DAH medical treatments, cooperating with intensive care specialists. During the last 3 years we treated 14 DAH cases (4 posttransplant, 1 cirrhosis, and 9 pulmonary vasculitis).
Patients, treatments
The patient cohorts according to the underlying disease, DAH severity (micro or macro DAH according to Uptodate recommendations), hemostatic drug dose, way of application, responses are summarised in Table I. Table 1.Patient cohortsDAH severityrFVIIa dose way of applicationintratraecheal tranexamic acid doserepeatedreponse commentBone marrow transplant related DAH (amyloidosis, AML, CNS lymphoma)macro 3 micro 150 ug/kg in 10 ml bronchoscopy500 mg in 5 ml bronchoscopy1 day later 1x, few days later 2x inhalationbleeding stopped combined with iv rFVIIa + tranexamic acid in 2 cases with systhemic bleedingPrimary biliary cirrhosis, liver failuremacro50 ug/kg 10 ml bronchoscopy500 mg in 5 ml bronchoscopyinhalation 1 day later 1xbleeding stoppedANCA positive vasculitis induced DAHmacro 3 micro 450 ug/kg 10 ml bronchoscopy 40 ug/kg rFVIIa,500 mg in 5 ml bronchoscopyinhalation 1 day later 1x 2 hoursbleeding stopped bleeding stopped
The diagnostic evaluation of DAH was run according to international standard requirements, based upon repeated bronchoalveolar lavage. Platelet transfusions and factor supplementation were applied according to the recommendations. Standard non-specific DAH related intensive care was provided for all cases
The basis of our DAH drug treatment approach was intrapulmonary (bronchoscopical/intratracheal or inhalatory) or systhemic (iv) recombinant FactorVIIa (Novoseven) application, combining with systhemic or local tranexamic acid. Novoseven (rFVIIa) has received Orphan Drug Status from FDA and EMA recently. Novoseven is usually combined in severe systhemic bleedings with tranexamic acid, however, there is very limited information available on the combined approach in DAH.
Results, discussion
All of our DAH bleeding was stopped or impressively reduced after rFVIIa+tranexamic acid interventions. However, overall survival was determined mostly by the underlying condition (i.e. amyloid heart disease, refractory AML, etc.)
The pattern of bleeding was somewhat different according to etiology: posttransplant and hematological background predisposed to more macro DAH, bleeding cessation could be well achieved, usually repeated interventions were necessary. Patients with non malignant disease (vasculitis, liver failure) had both micro and macro DAH, bleed slightly less, interventions seemed to produce more durable responses.
DAH seemed to be less modifyed by systhemic hemostatic parameters, than some other bleeds. Platelet transfusion alone rarely achieved significant improvement. We did not observe thrombotic events in our cases following intratracheal or iv treatments..
In conclusion: if DAH develops, the combined application of systhemic (iv) and/or intrapulmonary rFVIIa/tranexamic acid combination achieves a relatively quick bleeding cessation and improvement of respiration, allowing time for other interventions to improve underlying conditions and outcome. For micro DAH iv rFVIIa (40 ug/kg, repeated 2 hourly if needed) +tranexamic acid seems to be safe and effective. For fulminant macro DAH we do suggest to apply rFVIIa 50 ug/kg+tranexamic acid 50 mg in 10-15 ml volume, which stops bleeding quickly, improves respiration and can be life saving. This intervention might be repeated after 24 hours, usually by inhalation. In less severe makro DAH the inhalatory approach might be useful.
We do support to register DAH treatment approaches to further optimalise results.

Disclosures
No relevant conflicts of interest to declare.