Recombinant human factor VIIa for alveolar hemorrhage following allogeneic stem cell transplantation

Abstract

The mortality rate of alveolar hemorrhage (AH) after allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high-dose steroid therapy. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor VIIa (rFVIIa) as a therapeutic adjunct for AH. Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range [IQR], 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 μg/kg (IQR, 39 to 62 μg/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [IQR, 141 to 262]); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P = .50), duration of mechanical ventilation (P = .89), duration of oxygen supplementation (P = .55), or hospital mortality (P = .27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (ie, worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa.

Keywords: Diffuse alveolar hemorrhage; Glucocorticoids; Hematopoietic stem cell transplantation; Recombinant human factor VIIa.

Figure 1. Survival in Patients Treated with rFVIIa Compared to Conventional Therapy for Alveolar Hemorrhage

Kaplan-Meier survival curves depicting outcomes in the first 180 day following the onset of the first episode of alveolar hemorrhage. rFVIIa plus conventional therapy (—), conventional therapy (---).

Figure 2. Extent of Radiographic Pulmonary Pathology at the Onset of Alveolar Hemorrhage

(A-E) Representative surface renderings of pulmonary parenchymal pathology at the onset of alveolar hemorrhage are shown from five different patients treated with rFVIIa and conventional therapy. (A) Patient 8; 8%, (B) Patient 21; 20%, (C) Patient 5; 25%, (D) Patient 13; 37%, and (E) Patient 11; 47%. Total lung volume is outlined in blue and pathological areas are highlighted in light green.

Figure 3. Effect of rFVIIa on ICU Length of Stay, Duration of Mechanical Ventilation, Resolution of Alveolar Hemorrhage, and Duration of Supplemental Oxygen Use

In patients treated with rFVIIa plus conventional therapy (■) compared to patients treated with conventional therapy alone ( ), there was no difference in ICU length of stay due to alveolar hemorrhage (AH; episodes included in analysis: rFVIIa n = 23/43, conventional therapy n = 8/14; p = 0.63), duration of mechanical ventilation (MV) due to AH (rFVIIa n = 25/43, conventional therapy n = 7/14; p = 0.89), time to resolution of AH (rFVIIa n = 30/43, conventional therapy n = 10/14; p = 0.50); or duration of supplemental oxygen use from the onset of the initial episode of AH (rFVIIa n = 23/23, conventional therapy n = 14/14; p = 0.55).

Figure 4. Survival in Patients with Diffuse Alveolar Hemorrhage (DAH) and Infection-Associated Alveolar Hemorrhage (IAH)

Kaplan-Meier survival curves depicting outcomes in the first 180 day following the onset of the first episode of alveolar hemorrhage in the subgroup of patients with (A) DAH and (B) IAH. rFVIIa plus conventional therapy (—), conventional therapy (---).

Figure 5. Autopsy Sections of Representative Lung Histopathology

(A) Hematoxylin-eosin stain (magnification, 20X) shows accumulation of red blood cells, fibrin, and hemosiderin-laden macrophages in alveolar spaces. (B) Iron stain (magnification, 20X) highlights hemosiderin-laden macrophages within the alveolar and interstitial space. C4d stain (magnification, 20X) highlights predominantly large-caliber vessels (C) and hyaline membranes (D).