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

Figures & data

Table 1 DAH – the key points

Clinical picture DAH is characterized clinically by alveolar bleeding, from mild with chronic transfusion need to the catastrophic alveolar bleeding with hemoptysis.

The DAH presents with three subsets Macroscopic bleeding – mortality of >70%. Chronic microscopic alveolar bleeding, falling hematocrit, sputum filled with hemosiderin laden macrophages. The mortality is low, however, the life expectancy is reduced due to pulmonary fibrosis. Blast lung injury after a major blast. The subset seemingly has a “window of opportunity” of 3 hours.

The diagnosis of DAH Bronchoalveolar lavage with aliquot with successive lavage fluid bloodier macro/microscopically than the previous one. In this way DAH may be separated from ARDS/ALI and BOOP.

Treatment of DAH Alveolar bleeding may be treated successfully provided the DAH syndrome is treated locally intrapulmonarily, by lavage or inhalation. Prophylaxis of DAH is only based on the specific optimization of the multiple underlying diseases and conditions.

Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; BOOP, bronchiolitis obliterans organizing pneumonia; DAH, diffuse alveolar hemorrhage.

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.

Table 2 Overview of diseasesyndromes and other causes leading to DAH and the classical options of treatment

Syndromes	Clinical presentations	Classic options of treatment^Citation22
Pulmonary capillaritis or autoimmune diseases	Systemic lupus erythematosus	Immunosuppressants Steroids Methotrexate Retuximab Removal of autoantibodies Plasmapheresis Procoagulation Plasma Tranexamic acid Platelet transfusion Coagulation factors
	Goodpasture’s syndrome
	Antiphospholipid syndrome
	Wegner’s granulomatosis
	Scleroderma rheumatoid arthritis
	Henoch Schönlein purpura
	Acute lung allograft rejection
	Bone marrow transplantation
Diffuse alveolar damage	Radiation therapy
	Cytotoxic drugs
	ARDS
Traumatic alveolocapillary membrane	Blast lung injury
Mixed	Multiple myeloma
	Subacute bacterial endocarditis
	Negative pressure pulmonary edema
	Mitral stenosis
	Idiopathic pulmonary hemosiderosis
	Coagulation disorders
	Pulmonary veno-occlusive disease
Drug induced alveolocapillary membrane	Warfarin
	Isocyanates	+ Discontinuation of treatment
	Nitrofurantoin
	Propylthiouracil
	Clopidogrel
	Fibrinolytics
	Aspirin
	Amiodarone
	Phenytoin
Infections	Bacteria
	Pseudomonas aeruginosa	+ Broad spectrum antibiotics and antiviral therapy
	Leptospirosis
	Mycoses
	Aspergillus spp.
	Virus infections
	CMV and herpes pneumonitis

Abbreviations: ARDS, acute respiratory distress syndrome; CMV, cytomegalovirus; 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.

Table 3 Overview of BLI – a dynamic condition²³

Definition and pathogenesis	The traumatic DAH secondary to primary blast BLI is a special form of DAH but triggered By a “blast wave” secondary to a high explosive detonation. The expanding high pressure wave induces destructive interaction between the pressure wave, the lung tissue and pulmonary vasculature leading to a disruption of tissues at the air-blood interface. Wth a subsequent resonance inducing hemolysis of the intra-alveolar space.
Natural course of BLI	From the early phase with bleeding over mild hemolysis to the end stage with irreversible lung injury based on insufficient iron clearance. Reversible provided therapy is initiated within the first 3 hours – “the window of opportunity.
Treatment window	The blast injury secondary to high-explosives is life-threatening and the window of opportunity is narrow which means that time for treatment is of essence. The time window for intervention is only 3 hours. Preemptive* inhalation of FVIIa can eliminate the risk of mortality or permanent lung dysfunction secondary to BLI.
Battlefield and homeland security	Inhalation of FVIIa implies that BLI casualties may be evacuated from the war zone by helicopter and ensure a safe home transport to acquire final treatment in an allied hospital.

Note:

* Preemptive is predefined prophylaxis based on (i) a major blast exposure within the 3 hours open window, most preferably 30 minutes after the exposure.

Abbreviations: BLI, blast lung injury; DAH, diffuse alveolar hemorrhage.

Table 4 After a major blast the three phases have their own distinct problems^24–26

Timing	Pathophysiology of the post blast pulmonary injury phases
Phase 1 0–3 hours	Hemorrhagic phase Transmigration of inflammatory leucocytes, inflammatory stress and destruction of integrity Window of opportunity
Phase 2 4–12 hours	Alveolar inflammation Extravasation of blood with transmigration of inflammatory leucocytes into the hemorrhagic Subsequent biodegradation of hemoglobin with deposition of iron in alveoli accompanied by degranulation of neutrophils
Phase 3 13–56 hours	Pulmonary destruction Increased transferrin – bound Fe (3+) and non-transferrin complexes of Fe (3+) Subsequently disruption of alveolar capillary network and necrotic changes in the pulmonary epithelial cells

Table 5 Diffuse alveolar hemorrhage – the treatment paradigm

DAH subtype	Clinical signs and symptoms	Route of administration	Effective dose
Macroscopic alveolar bleeding	Hemoptysis and severely reduced oxygen transport capacity and confluent opacities on chest films	Bronchoalveolar lavage with 25 mL saline via each main bronchusa	75 μg/kg FVIIa^Citation31^–^Citation34
Microscopic alveolar bleeding or hemosiderosis	Chronic transfusion requirement and hemosiderin laden macrophages in expectorate	Inhaled FVIIab	75 μg/kg FVIIa^Citation31
Blast lung injury	Initial dyspnea after the blast	No information	–
	Increasing symptoms and eventually leading to hemoptysis or microscopic DAH	Animal proof of concept at DSTL
	Window of opportunity of 3 hours	Most likely the intervention would be inhalation of FVIIa, at least as a prehospital treatment

Notes:

a The total effective dose is dissolved in 50 mL;

b Using a micropump nebulizer interference with the two active sites of FVIIa is avoided. This treatment option was effectively administered in one patient who presented with recurrent bleeding after extubation; no further published experience exists. Note that the treatment regime is based on a limited number of patients.

Abbreviation: DSTL, British Defence Science and Technology Laboratory.

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.

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