Local pulmonary administration of factor VIIa (rFVIIa) in diffuse alveolar hemorrhage (DAH) - a review of a new treatment paradigm

Abstract

Background: Diffuse alveolar hemorrhage (DAH) is a clinical syndrome with typical symptoms dyspnea and hemoptysis. DAH is a complication of specific diseases, in some cases with acute catastrophic hemoptysis, while other patients present low grade alveolar bleeding with a need of chronic transfusion as in pulmonary hemosiderosis.

Methods: Current literature in the PubMed database and other sources was reviewed in order to evaluate the current treatment recommendations, efficacy of this treatment, and finally the risk of complications after off-label use of rFVIIa in respect to DAH.

Objectives: (i) To elucidate the clinical aspects of alveolar hemorrhage, (ii) to develop a simple diagnostic algorithm in order to separate DAH from other important pulmonary diseases with similar clinical picture and comparably high mortality. Such an algorithm has important therapeutic consequences because these diseases: acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and bronchiolitis obliterans organizing pneumonia (BOOP) have different therapies, (iii) to evaluate and discuss whether local pulmonary administration may improve outcome and reduce mortality in DAH, and (iv) to suggest a treatment schedule.

Results: Hitherto the diagnosis and treatment of DAH has been based on anecdotal reports. The treatment has relied on different unspecific treatment modalities based on a mixture of treatment of the underlying disease and treatment without evidence targeted to stop the alveolar bleeding. However, recently a number of publications have advocated the use of intrapulmonary rFVIIa. Even in severe bleeding DAH has been shown to respond promptly without thromboembolic complication when FVIIa was administered locally via the air side, because the FVIIa does not penetrate the alveolo-capillary membrane to the blood-side. The incidence of DAH (in the US and Europe is 100,000-150,000, and 50,000 patients annually are at risk of developing DAH following hematopoietic stem cell transplant (HSCT) and autoimmune diseases. Finally 50,000-100,000 patients may be falsely categorized as having acute respiratory distress syndrome/acute lung injury (ARDS/ALI) because DAH and ARDS cannot be separated clinically. A new treatment paradigm of DAH is proposed as no other intervention has been able to ensure pulmonary hemostasis in DAH. The diagnosis of DAH is simple, a series of broncho-alveolar washes which become increasingly bloody. This test should be performed in all patients with pulmonary opacities in order to separate ARDS/ALI from DAH. FVIIa administrated via pulmonary route is "drug of choice", because it stops bleeding in the life-threatening syndrome DAH. Hemostasis is obtained after only one to two small doses of FVIIa (50 μg/kg body weight per dose) and after hemostasis the oxygen transport quickly improves.

Conclusion: Intrapulmonary administration of rFVIIa is recommended as the treatment of choice for DAH and blast lung injury (BLI) because the treatment has been shown to be successful and uncomplicated in spite of the fact that only a small series of DAH has been documented.

Keywords: algorithm; biologics; blast lung injury; bronchoalveolar lavage; coagulation factor FVIIa; diagnosis; diffuse alveolar hemorrhage; hemosiderosis; local pulmonary treatment; new treatment recommendation.

Figure 1

Local pulmonary administration of FVIIa into the airways ensures that the drug reaches its alveolar receptor TF. However, most importantly, taking into account the separation between the two compartments the “air side” and the “systemic side”, there will not be systemic adverse effects in as much as the alveolo-capillary membrane does not allow the transmembranous passage of FVIIa, when inhaled. FVIIa does not pass through the alveolo-capillary membrane either from the (A) alveolus or (B) the blood side. Abbreviation: TF, tissue factor.

Figure 2

The DAH syndrome is the common denominator of multiple diseases and conditions. DAH is the general alveolar response to multiple underlying diseases and conditions. The syndrome DAH manifests itself in three subsets: the acute catastrophic DAH, the chronic DAH and finally as the instant blast lung injury. The acute DAH has been treated with local intrapulmonary FVIIa administration. The two other subsets could potentially also be treated from the air side, an intervention which remains to be shown. Abbreviation: DAH, diffuse alveolar hemorrhage.

Figure 3

The diagnostic algorithm for DAH, BOOP and ARDS. The clinical signs and symptoms of DAH, ALI/ARDS and BOOP are identical, ie, chest film with confluent opacities, acute pulmonary insufficiency with reduced O₂ transport capacity. It is imperative to separate between the specific diagnoses of each of these conditions, in as much as they all have a high mortality; it is of utmost importance to diagnose correctly because the specific therapies are different. The simple algorithmic separation is based on progressively hemorrhagic aliquot of a series of BALF’s either macroscopically which denote a severe DAH syndrome or measurements of an increased hemoglobin concentration in the BALF which corresponds to a slow bleeding DAH like in IPH. Provided there is no bloody return at the BALF the DAH diagnosis is excluded. The remaining two conditions are separated by a simple flow-cytometry on the BALF, where the BOOP is characterized by abundant inflammatory cells, and the ARDS diagnosis is based on a BALF without inflammatory cells or bloody return. Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; BOOP, bronchiolitis obliterans organizing pneumonia; DAH, diffuse alveolar hemorrhage, FC, flow cytometry; IPH, idiopathic pulmonary hemosiderosis.

Figure 4

It is essential to separate cause and the effect of DAH. It is important to separate the treatment of multiple underlying causes of DAH from the common complicating denominator DAH syndrome, because the latter is simply treated with local pulmonary FVIIa. Abbreviations: BLI, blast lung injury; DAH, diffuse alveolar hemorrhage; HSTC, hematopoietic stem cell transplant.

Figure 5

Rationale for local pulmonary treatment of DAH with FVIIa. Intravenous rFVIIa does not reach the alveoli (1) in contrast to the airway route (2) where a direct access to the receptor TF is obtained. The TF-FVIIa complex activates coagulation factor IX and X. Finally the activated TF-FVIIa complex induces a perfect “balanced” hemostasis ie, sufficient fibrin deposition without interference with the oxygen transport. The TFPI are constitutively expressed in the airspace in inflammatory conditions, secondary to alveolar inflammation. The TFPI is usually of less importance as compared to the procoagulatory factors. However, this might be the explanation for the balanced hemostasis. Abbreviations: DAH, diffuse alveolar hemorrhage; TF, tissue factor; TFPI, tissue factor inhibitors.