Lung DOI 10.1007/s00408-015-9720-z
Use of Activated Factor VII in Patients with Diffuse Alveolar Hemorrhage: A 10 Years Institutional Experience Vikas Pathak1 • Judy Kuhn1 • Don Gabriel2 • Jennifer Barrow1 • J. Charles Jennette3 David C. Henke1
•
Received: 11 February 2015 / Accepted: 16 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Introduction Diffuse alveolar hemorrhage (DAH) is a lifethreatening condition with an obscure etiology and pathogenesis. It is associated with many drugs and diseases including chemotherapy, hematopoietic stem cell transplantation, and autoimmune disorders. This retrospective study reports our experience with 23 patients who had DAH and received intravenous recombinant activated Factor VIIa (rFVIIa). Methods We performed a retrospective chart review of patients who received intravenous rFVIIa for DAH at a tertiary care university hospital between January 1, 2003 and May 31, 2013. We report demographics, etiology of DAH, frequency and total dose of intravenous rFVIIa, effect of rFVIIa on DAH, and morbidity and mortality. Results Mean age was 47 ± 19 years. There were 13 men and 10 women. Nine patients had Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, two had systemic lupus erythematosus, three had Good pasture’s syndrome, seven were post-bone marrow transplant, one had idiopathic thrombocytopenic purpura, and one had cryoglobulinemia. Treatment in the ICU was required for 22 patients of whom 18 were intubated and on mechanical ventilation; one patient was treated on general medical
& Vikas Pathak [email protected] 1
Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina School of Medicine, 130 Mason Farm Road, Chapel Hill, NC 27599, USA
2
Division of Hematology and Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
3
Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
service. All patients received 35–120 mcg/kg rFVIIa every 2 h until hemostasis was achieved or treatment was judged to be inadequate. In 22/23 patients, bleeding resolved with rFVIIa therapy. The mean dose to control bleeding was 5 ± 3 mg. Eight patients died (36 %) of their underlying condition; six of them had received bone marrow transplant, while two had ANCA vasculitis. Deaths were due to multiorgan failure, sepsis, and progressive underlying disease. No overt, clinically obvious adverse thrombotic events were observed with the use of rFVIIa. Conclusion Activated Factor VII can achieve hemostasis in patients with diffuse alveolar hemorrhage. Keywords Diffuse alveolar hemorrhage (DAH) Factor VII Activated Factor VII
Introduction Diffuse alveolar hemorrhage (DAH) is a clinical syndrome characterized by hemoptysis, pulmonary infiltrates (most often diffuse and bilateral), and hypoxic respiratory failure [1]. Etiology of DAH is diverse, which includes pulmonary capillaritis (Figs. 1, 2) from systemic vasculitis, drugs, toxins, and infections. It can also occur in patients with allogeneic hematopoietic stem cell transplant (HSCT) or it could be bland pulmonary hemorrhage from coagulation abnormalities [1]. It is a life-threatening condition with high mortality rate. In fact, in patients with HSCT, the mortality ranges from 64 to 100 %, particularly for the ones who require mechanical ventilation [2]. Activated recombinant Factor VII is a hemostatic agent that is currently approved for the treatment of hemophilia A and B patients who have acquired antibodies to Factor VII and IX [3]. It has thus far not been approved for use in
123
Lung
As a vasculitis and bone marrow transplant center, we encounter lot of patients with DAH. We have used Factor VII in patients with life-threatening DAH. This is a retrospective analysis of the patients we treated with Factor VII in the last 10 years and their outcomes.
Materials and Methods Setting This study was undertaken at University of North Carolina Hospital, a tertiary care teaching hospital located in Chapel Hill, North Carolina, USA. Study Design
Fig. 1 ANCA-related alveolar capillaritis and diffuse alveolar hemorrhage. Red blood cells (red) in the alveolar lumen and inflammatory cells (blue)
Fig. 2 Anti-GBM disease (Good pasture’s syndrome) with severe intra alveolar hemorrhage (red) but without capillaritis and neutrophils (blue)
patients with bleeding due to a variety of etiologies [3]. However, there have been several case reports [4, 5] wherein Factor VII was able to stop the bleeding in patients DAH secondary to bone marrow transplantation. Due to the lack of a randomized controlled trial, Factor VII has been used in patients with severe pulmonary hemorrhage as a final effort to stop bleeding.
123
The study design was an Institutional Review Board approved retrospective analysis of cases. All the patients who were diagnosed with DAH and received intravenous rFVIIa from January 1, 2003 through May 31, 2013 were included. All the patients who had bilateral infiltrates on chest radiograph underwent bronchoscopy to confirm DAH. Bronchoalveolar lavage was performed in the area corresponding to the dense infiltrate seen on chest radiograph prior to the procedure. Patients with increasingly darker/ bloody aliquots on bronchoalveolar lavage were considered to have diffuse alveolar hemorrhage. None of the patients reported in this study were reported in previous manuscript. A retrospective review of all available medical records and radiographs was conducted. All the laboratory tests including coagulation profile were noted. The dose, frequency, outcomes, and adverse effects of rFVIIa were noted. The choice of the dose was on physician’s discretion. The dose used was between 35 and 120 mcg/kg rFVIIa every 2 h for total of four doses per day. Usually, the starting dose in majority of the patients was 75 mcg/kg. All the patients received all other standard treatments (Table 1) while receiving Factor VII (plasmapheresis, steroids, and cytotoxic drugs). The treatment was deemed successful if we were able to achieve complete hemostasis with the use of rFVIIa. Successful hemostasis was defined by stable hematocrit, stable infiltrate on the chest radiograph, stabilizing or improving oxygenation (defined by stable ventilator parameters over 24 h, PEEP and FIO2 if the patient was on ventilator and stable FIO2 if the patient was not on ventilator). Subjects All patients who had DAH and received rFVIIa were included.
Other treatments The corticosteroids used was methylprednisone; cytotoxic drugs used were either cyclophosphamide or rituximab based on the severity of illness
Resolved In one patient with Good pasture’s syndrome, bleeding did not stop and the patient died
18/23 23 Total
ANCA anti-neutrophil cytoplasmic antibody, SLE systemic lupus erythematosus, ITP idiopathic thrombocytopenic purpura, IVIG intravenous immunoglobulin
8/23
0
0
15
Plasmapheresis, corticosteroids, and cytotoxic drugs
02
1/1 Resolved 60
01
No Resolved 57
Cryoglobulinemia
ITP
SLE
01
Resolved 24
Yes
No
Platelet transfusion, IVIG, and corticosteroids
1/3
0 5.5
Yes
02
Yes Resolved
Resolved1 42 03 Good pasture’s syndrome
Bone marrow transplant
07
44
Yes
2/2
Plasmapheresis, platelet transfusion, and corticosteroids
6/7
3.5 3/3
Plasmapheresis, corticosteroids, and cytotoxic drugs
11 6/7
Platelet transfusions and corticosteroids
1/9 Plasmapheresis, corticosteroids, and cytotoxic drugs 09 6/9 Resolved ANCA vasculitis
09
48
Yes
RFVIIa dose (mean) (mg) ICU admission Alveolar hemorrhage Mean age (years) No. of patients Diagnosis
Table 1 Outcomes of patients with DAH who received rFVIIa
Results
Intubation
Other treatments
Mortality
Lung
The mean age of the patients in the study was 47 years ± 19 (SD). There were 13 men and 10 women, 22 Caucasian and one African American patient. Mean INR was 1.4 ± 0.4 SD. Mean hematocrit was 26 ± 7. All the 23 patients underwent bronchoscopy. Nine patients had ANCA vasculitis, two had systemic lupus erythematosus, three had Good pasture’s syndrome, seven were post-bone marrow transplant, one had idiopathic thrombocytopenic purpura, and one had cryoglobulinemia (Fig. 3). Treatment in the ICU was required for 22 patients of whom 18 were intubated and on mechanical ventilation; one patient was treated on a floor service. All patients received 35–120 mcg/kg rFVIIa every 2 h until hemostasis was achieved or treatment was judged to be inadequate. In 22/23 patients, bleeding resolved with rFVIIa therapy. The mean dose to control bleeding was 5 ± 3 mg. Eight patients died (36 %) of their underlying condition; six of them had received bone marrow transplant, while two had ANCA vasculitis. Deaths were due to multiorgan failure, sepsis, and progressive underlying disease. No adverse thrombotic events were observed with the use of rFVIIa. In addition to rFVIIa, patients were treated with any combination of cyclophosphamide, steroids, rituximab, and plasmapheresis depending on underlying cause and severity of the disease.
Discussion This is the largest series of patients treated with rFVIIa and reported so far. We were able to show that we were able to successfully stop bleeding after administration of rFVIIa in majority of these patients. This gave us time to treat the underlying disease process (cytotoxic drugs, plasmapheresis, and corticosteroids). Our study also showed that although we were able to control bleeding in almost all the
Eology of DAH 4% 4%
ANCA vasculis
9% 39%
Bone marrow transplant Good pasture's syndrome
13%
SLE
31%
ITP Cryoglobulinemia
Fig. 3 Etiology of diffuse alveolar hemorrhage
123
Lung
Fig. 4 Mechanism of action of rFVIIa. Zymogen coagulation factor IX (FIX) bound to the activated platelet surface is bound and activated by activated coagulation factor VIIa (FVIIa). Once activated, FVIIa dissociates and the Activated FIX then binds activated FVIIIa (FVIIIa) to form the tenase complex that can then activate coagulation factor X (FX) to activate it (FXa). FXa can then bind to FVa forming the prothrombinase complex that generates a burst of thrombin
patients with DAH, patients with vasculitis-induced DAH did better in terms of survival. Out study also confirmed the fact that patients with HSCT and DAH have high mortality, particularly if they are on mechanical ventilator despite controlling their bleeding. Recombinant activated Factor VII has been used increasingly to achieve hemostasis in non-hemophiliac bleeding patient. It has unique mechanism of action (Fig. 4). As already known, the injury of the vessel wall leads to contact between blood and tissue Factor (TF). Factor VII binds with the TF and is converted to activated Factor VII (FVIIa) which in turn initiates a cascade of reaction leading to thrombin burst and fibrin formation at the site of injury. Recombinant Factor VII was initially intended to be used for patients with hemophilia A and B who also had inhibiting antibodies against Factor VIII and Factor IX, respectively. In the absence of TF and at higher doses, rFVIIa directly activates Factor X which is bound to the surface of activated platelets. Factor X then converts prothrombin to thrombin which in turn converts fibrinogen to fibrin [3, 6, 7]. There have been numerous reports over the years about the successful use of rFVIIa in non-hemophiliac patients with bleeding. Recombinant FVIIa has been used for various nonFDA approved indications like postcardiac surgery, prostatectomy, von willebrand disease, and DAH with some success [3, 7]. Nonparenteral use of rFVIIa has also been reported [6]. Heslet et al. [6] administered rFVIIa directly into the alveoli using bronchoscope. They reconstituted 50 mcg/kg of rFVIIa in 50 ml of sodium chloride and then instilled 25 ml in each of the main bronchi and the dose was repeated in 24 h if patient continued bleeding. All the six patients who received this treatment had good responses to
123
the intrapulmonary administration of rFVIIa. The rationale behind the use was the fact that tissue Factor is expressed in abundance in the inflamed alveoli, and giving rFVIIa locally would enhance the process of coagulation and achieve hemostasis faster. The major concern in the use of rFVIIa as highlighted by Henke et al. [7] is the generation of harmful thrombosis. It is therefore imperative to select the patient carefully and weigh the risk versus benefit with its use. Recombinant Factor VII should not be used in patients who have had recent surgery or a history of thrombotic events. Caution should be exercised in patients with liver disease, history of myocardial infarction, stroke, pulmonary embolus or deep venous thrombosis, and congenital or acquired thrombophilic conditions. We also feel that an adequate anti-thrombin III level should be maintained during rFVIIa use [8–10]. At our center, we used rFVIIa very carefully, particularly in patients with increased likelihood of thrombosis. All our patients were in hypoxic respiratory failure, bleeding stopped in almost all the patients, which helped us treat the underlying disease. We did not observe any adverse effect for rFVIIa use. Bone marrow transplant patients with DAH do poorly once they are on mechanical ventilation. The overall mortality is high despite treatment [7]. Clinical judgment should be used as Factor VII does not resolve the underlying disease process and is quite expensive (about $1500 for 1 mg). The limitation of this study includes its retrospective nature, single institute, and small sample size. In future, randomizing patient into the treatment and control group would help us getting more information about the use of rFVIIa in patients with DAH and come to a definite conclusion.
Conclusion Activated recombinant Factor VII seems to have achieved hemostasis in patients with diffuse alveolar hemorrhage. This gives us time to treat the underlying cause of DAH. However, a randomized controlled multi-center trial needs to be done to expand the use of rFVIIa in other etiologies of bleeding disorder.
Conflict of interest of interest.
The authors report no real or potential conflict
References 1. Lara AR, Schwarz MI (2010) Diffuse alveolar hemorrhage. Chest 137(5):1164–1171
Lung 2. Afessa B et al (2002) Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166(10):1364–1368 3. Carr ME Jr, Martin EJ (2004) Recombinant Factor VIIa: clinical applications for an intravenous hemostatic agent with broadspectrum potential. Expert Rev Cardiovasc Ther 2(5):661–674 4. Hicks K, Peng D, Gajewski JL (2002) Treatment of diffuse alveolar hemorrhage after allogeneic bone marrow transplant with recombinant factor VIIa. Bone Marrow Transplant 30(12):975–978 5. Meijer K et al (2000) Successful treatment of massive hemoptysis in acute leukemia with recombinant factor VIIa. Arch Intern Med 160(14):2216–2217 6. Heslet L et al (2006) Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage. Crit Care 10(6):R177
7. Henke D, Falk RJ, Gabriel DA (2004) Successful treatment of diffuse alveolar hemorrhage with activated factor VII. Ann Intern Med 140(6):493–494 8. Levy JH et al (2006) Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 46(6):919–933 9. O’Connell KA et al (2006) Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 295(3):293–298 10. Rudisill CN et al (2006) Implementing guidelines for the institutional use of factor VIIa (recombinant): a multidisciplinary solution. Am J Health Syst Pharm 63(17):1641–1646
123
Use of Activated Factor VII in Patients with Diffuse Alveolar Hemorrhage: A 10 Years Institutional Experience Vikas Pathak1 • Judy Kuhn1 • Don Gabriel2 • Jennifer Barrow1 • J. Charles Jennette3 David C. Henke1
•
Received: 11 February 2015 / Accepted: 16 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Introduction Diffuse alveolar hemorrhage (DAH) is a lifethreatening condition with an obscure etiology and pathogenesis. It is associated with many drugs and diseases including chemotherapy, hematopoietic stem cell transplantation, and autoimmune disorders. This retrospective study reports our experience with 23 patients who had DAH and received intravenous recombinant activated Factor VIIa (rFVIIa). Methods We performed a retrospective chart review of patients who received intravenous rFVIIa for DAH at a tertiary care university hospital between January 1, 2003 and May 31, 2013. We report demographics, etiology of DAH, frequency and total dose of intravenous rFVIIa, effect of rFVIIa on DAH, and morbidity and mortality. Results Mean age was 47 ± 19 years. There were 13 men and 10 women. Nine patients had Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, two had systemic lupus erythematosus, three had Good pasture’s syndrome, seven were post-bone marrow transplant, one had idiopathic thrombocytopenic purpura, and one had cryoglobulinemia. Treatment in the ICU was required for 22 patients of whom 18 were intubated and on mechanical ventilation; one patient was treated on general medical
& Vikas Pathak [email protected] 1
Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina School of Medicine, 130 Mason Farm Road, Chapel Hill, NC 27599, USA
2
Division of Hematology and Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
3
Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
service. All patients received 35–120 mcg/kg rFVIIa every 2 h until hemostasis was achieved or treatment was judged to be inadequate. In 22/23 patients, bleeding resolved with rFVIIa therapy. The mean dose to control bleeding was 5 ± 3 mg. Eight patients died (36 %) of their underlying condition; six of them had received bone marrow transplant, while two had ANCA vasculitis. Deaths were due to multiorgan failure, sepsis, and progressive underlying disease. No overt, clinically obvious adverse thrombotic events were observed with the use of rFVIIa. Conclusion Activated Factor VII can achieve hemostasis in patients with diffuse alveolar hemorrhage. Keywords Diffuse alveolar hemorrhage (DAH) Factor VII Activated Factor VII
Introduction Diffuse alveolar hemorrhage (DAH) is a clinical syndrome characterized by hemoptysis, pulmonary infiltrates (most often diffuse and bilateral), and hypoxic respiratory failure [1]. Etiology of DAH is diverse, which includes pulmonary capillaritis (Figs. 1, 2) from systemic vasculitis, drugs, toxins, and infections. It can also occur in patients with allogeneic hematopoietic stem cell transplant (HSCT) or it could be bland pulmonary hemorrhage from coagulation abnormalities [1]. It is a life-threatening condition with high mortality rate. In fact, in patients with HSCT, the mortality ranges from 64 to 100 %, particularly for the ones who require mechanical ventilation [2]. Activated recombinant Factor VII is a hemostatic agent that is currently approved for the treatment of hemophilia A and B patients who have acquired antibodies to Factor VII and IX [3]. It has thus far not been approved for use in
123
Lung
As a vasculitis and bone marrow transplant center, we encounter lot of patients with DAH. We have used Factor VII in patients with life-threatening DAH. This is a retrospective analysis of the patients we treated with Factor VII in the last 10 years and their outcomes.
Materials and Methods Setting This study was undertaken at University of North Carolina Hospital, a tertiary care teaching hospital located in Chapel Hill, North Carolina, USA. Study Design
Fig. 1 ANCA-related alveolar capillaritis and diffuse alveolar hemorrhage. Red blood cells (red) in the alveolar lumen and inflammatory cells (blue)
Fig. 2 Anti-GBM disease (Good pasture’s syndrome) with severe intra alveolar hemorrhage (red) but without capillaritis and neutrophils (blue)
patients with bleeding due to a variety of etiologies [3]. However, there have been several case reports [4, 5] wherein Factor VII was able to stop the bleeding in patients DAH secondary to bone marrow transplantation. Due to the lack of a randomized controlled trial, Factor VII has been used in patients with severe pulmonary hemorrhage as a final effort to stop bleeding.
123
The study design was an Institutional Review Board approved retrospective analysis of cases. All the patients who were diagnosed with DAH and received intravenous rFVIIa from January 1, 2003 through May 31, 2013 were included. All the patients who had bilateral infiltrates on chest radiograph underwent bronchoscopy to confirm DAH. Bronchoalveolar lavage was performed in the area corresponding to the dense infiltrate seen on chest radiograph prior to the procedure. Patients with increasingly darker/ bloody aliquots on bronchoalveolar lavage were considered to have diffuse alveolar hemorrhage. None of the patients reported in this study were reported in previous manuscript. A retrospective review of all available medical records and radiographs was conducted. All the laboratory tests including coagulation profile were noted. The dose, frequency, outcomes, and adverse effects of rFVIIa were noted. The choice of the dose was on physician’s discretion. The dose used was between 35 and 120 mcg/kg rFVIIa every 2 h for total of four doses per day. Usually, the starting dose in majority of the patients was 75 mcg/kg. All the patients received all other standard treatments (Table 1) while receiving Factor VII (plasmapheresis, steroids, and cytotoxic drugs). The treatment was deemed successful if we were able to achieve complete hemostasis with the use of rFVIIa. Successful hemostasis was defined by stable hematocrit, stable infiltrate on the chest radiograph, stabilizing or improving oxygenation (defined by stable ventilator parameters over 24 h, PEEP and FIO2 if the patient was on ventilator and stable FIO2 if the patient was not on ventilator). Subjects All patients who had DAH and received rFVIIa were included.
Other treatments The corticosteroids used was methylprednisone; cytotoxic drugs used were either cyclophosphamide or rituximab based on the severity of illness
Resolved In one patient with Good pasture’s syndrome, bleeding did not stop and the patient died
18/23 23 Total
ANCA anti-neutrophil cytoplasmic antibody, SLE systemic lupus erythematosus, ITP idiopathic thrombocytopenic purpura, IVIG intravenous immunoglobulin
8/23
0
0
15
Plasmapheresis, corticosteroids, and cytotoxic drugs
02
1/1 Resolved 60
01
No Resolved 57
Cryoglobulinemia
ITP
SLE
01
Resolved 24
Yes
No
Platelet transfusion, IVIG, and corticosteroids
1/3
0 5.5
Yes
02
Yes Resolved
Resolved1 42 03 Good pasture’s syndrome
Bone marrow transplant
07
44
Yes
2/2
Plasmapheresis, platelet transfusion, and corticosteroids
6/7
3.5 3/3
Plasmapheresis, corticosteroids, and cytotoxic drugs
11 6/7
Platelet transfusions and corticosteroids
1/9 Plasmapheresis, corticosteroids, and cytotoxic drugs 09 6/9 Resolved ANCA vasculitis
09
48
Yes
RFVIIa dose (mean) (mg) ICU admission Alveolar hemorrhage Mean age (years) No. of patients Diagnosis
Table 1 Outcomes of patients with DAH who received rFVIIa
Results
Intubation
Other treatments
Mortality
Lung
The mean age of the patients in the study was 47 years ± 19 (SD). There were 13 men and 10 women, 22 Caucasian and one African American patient. Mean INR was 1.4 ± 0.4 SD. Mean hematocrit was 26 ± 7. All the 23 patients underwent bronchoscopy. Nine patients had ANCA vasculitis, two had systemic lupus erythematosus, three had Good pasture’s syndrome, seven were post-bone marrow transplant, one had idiopathic thrombocytopenic purpura, and one had cryoglobulinemia (Fig. 3). Treatment in the ICU was required for 22 patients of whom 18 were intubated and on mechanical ventilation; one patient was treated on a floor service. All patients received 35–120 mcg/kg rFVIIa every 2 h until hemostasis was achieved or treatment was judged to be inadequate. In 22/23 patients, bleeding resolved with rFVIIa therapy. The mean dose to control bleeding was 5 ± 3 mg. Eight patients died (36 %) of their underlying condition; six of them had received bone marrow transplant, while two had ANCA vasculitis. Deaths were due to multiorgan failure, sepsis, and progressive underlying disease. No adverse thrombotic events were observed with the use of rFVIIa. In addition to rFVIIa, patients were treated with any combination of cyclophosphamide, steroids, rituximab, and plasmapheresis depending on underlying cause and severity of the disease.
Discussion This is the largest series of patients treated with rFVIIa and reported so far. We were able to show that we were able to successfully stop bleeding after administration of rFVIIa in majority of these patients. This gave us time to treat the underlying disease process (cytotoxic drugs, plasmapheresis, and corticosteroids). Our study also showed that although we were able to control bleeding in almost all the
Eology of DAH 4% 4%
ANCA vasculis
9% 39%
Bone marrow transplant Good pasture's syndrome
13%
SLE
31%
ITP Cryoglobulinemia
Fig. 3 Etiology of diffuse alveolar hemorrhage
123
Lung
Fig. 4 Mechanism of action of rFVIIa. Zymogen coagulation factor IX (FIX) bound to the activated platelet surface is bound and activated by activated coagulation factor VIIa (FVIIa). Once activated, FVIIa dissociates and the Activated FIX then binds activated FVIIIa (FVIIIa) to form the tenase complex that can then activate coagulation factor X (FX) to activate it (FXa). FXa can then bind to FVa forming the prothrombinase complex that generates a burst of thrombin
patients with DAH, patients with vasculitis-induced DAH did better in terms of survival. Out study also confirmed the fact that patients with HSCT and DAH have high mortality, particularly if they are on mechanical ventilator despite controlling their bleeding. Recombinant activated Factor VII has been used increasingly to achieve hemostasis in non-hemophiliac bleeding patient. It has unique mechanism of action (Fig. 4). As already known, the injury of the vessel wall leads to contact between blood and tissue Factor (TF). Factor VII binds with the TF and is converted to activated Factor VII (FVIIa) which in turn initiates a cascade of reaction leading to thrombin burst and fibrin formation at the site of injury. Recombinant Factor VII was initially intended to be used for patients with hemophilia A and B who also had inhibiting antibodies against Factor VIII and Factor IX, respectively. In the absence of TF and at higher doses, rFVIIa directly activates Factor X which is bound to the surface of activated platelets. Factor X then converts prothrombin to thrombin which in turn converts fibrinogen to fibrin [3, 6, 7]. There have been numerous reports over the years about the successful use of rFVIIa in non-hemophiliac patients with bleeding. Recombinant FVIIa has been used for various nonFDA approved indications like postcardiac surgery, prostatectomy, von willebrand disease, and DAH with some success [3, 7]. Nonparenteral use of rFVIIa has also been reported [6]. Heslet et al. [6] administered rFVIIa directly into the alveoli using bronchoscope. They reconstituted 50 mcg/kg of rFVIIa in 50 ml of sodium chloride and then instilled 25 ml in each of the main bronchi and the dose was repeated in 24 h if patient continued bleeding. All the six patients who received this treatment had good responses to
123
the intrapulmonary administration of rFVIIa. The rationale behind the use was the fact that tissue Factor is expressed in abundance in the inflamed alveoli, and giving rFVIIa locally would enhance the process of coagulation and achieve hemostasis faster. The major concern in the use of rFVIIa as highlighted by Henke et al. [7] is the generation of harmful thrombosis. It is therefore imperative to select the patient carefully and weigh the risk versus benefit with its use. Recombinant Factor VII should not be used in patients who have had recent surgery or a history of thrombotic events. Caution should be exercised in patients with liver disease, history of myocardial infarction, stroke, pulmonary embolus or deep venous thrombosis, and congenital or acquired thrombophilic conditions. We also feel that an adequate anti-thrombin III level should be maintained during rFVIIa use [8–10]. At our center, we used rFVIIa very carefully, particularly in patients with increased likelihood of thrombosis. All our patients were in hypoxic respiratory failure, bleeding stopped in almost all the patients, which helped us treat the underlying disease. We did not observe any adverse effect for rFVIIa use. Bone marrow transplant patients with DAH do poorly once they are on mechanical ventilation. The overall mortality is high despite treatment [7]. Clinical judgment should be used as Factor VII does not resolve the underlying disease process and is quite expensive (about $1500 for 1 mg). The limitation of this study includes its retrospective nature, single institute, and small sample size. In future, randomizing patient into the treatment and control group would help us getting more information about the use of rFVIIa in patients with DAH and come to a definite conclusion.
Conclusion Activated recombinant Factor VII seems to have achieved hemostasis in patients with diffuse alveolar hemorrhage. This gives us time to treat the underlying cause of DAH. However, a randomized controlled multi-center trial needs to be done to expand the use of rFVIIa in other etiologies of bleeding disorder.
Conflict of interest of interest.
The authors report no real or potential conflict
References 1. Lara AR, Schwarz MI (2010) Diffuse alveolar hemorrhage. Chest 137(5):1164–1171
Lung 2. Afessa B et al (2002) Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166(10):1364–1368 3. Carr ME Jr, Martin EJ (2004) Recombinant Factor VIIa: clinical applications for an intravenous hemostatic agent with broadspectrum potential. Expert Rev Cardiovasc Ther 2(5):661–674 4. Hicks K, Peng D, Gajewski JL (2002) Treatment of diffuse alveolar hemorrhage after allogeneic bone marrow transplant with recombinant factor VIIa. Bone Marrow Transplant 30(12):975–978 5. Meijer K et al (2000) Successful treatment of massive hemoptysis in acute leukemia with recombinant factor VIIa. Arch Intern Med 160(14):2216–2217 6. Heslet L et al (2006) Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage. Crit Care 10(6):R177
7. Henke D, Falk RJ, Gabriel DA (2004) Successful treatment of diffuse alveolar hemorrhage with activated factor VII. Ann Intern Med 140(6):493–494 8. Levy JH et al (2006) Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 46(6):919–933 9. O’Connell KA et al (2006) Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 295(3):293–298 10. Rudisill CN et al (2006) Implementing guidelines for the institutional use of factor VIIa (recombinant): a multidisciplinary solution. Am J Health Syst Pharm 63(17):1641–1646
123
