Recombinant-activated factor VII as hemostatic therapy in eight cases of severe hemorrhage from esophageal varices.

BACKGROUND AND AIMS: There are several treatment options for gastroesophageal variceal hemorrhage. In severe cases, bleeding persists and is associated with a dismal outcome. The coagulation disorders might be correlated with risk of bleeding in patients with portal hypertension. The administration of activated recombinant factor VII corrects prothrombin time transiently in nonbleeding patients with cirrhosis as well as in bleeding ones. The aim of this study was to assess the hemostatic efficacy of activated recombinant factor VII in bleeding esophageal varices. METHODS: Between May 2001 and September 2002, 112 patients with cirrhosis and an episode of acute esophageal variceal bleeding were admitted. On an open basis with a single intravenous dose of 4.8 mg of recombinant factor VII, we treated 8 patients experiencing severe and active hemorrhage from esophageal varices unresponsive to pharmacologic therapy, endoscopic therapy, or balloon tamponade. RESULTS: Eight (7%) of 112 patients met entry criteria. Hemostasis was achieved in all the cases after recombinant activated factor VII therapy. Rebleeding and mortality rates were 25% and 50% (2 and 4 patients), respectively. CONCLUSIONS: In our experience, recombinant activated factor VII achieves hemostasis in bleeding esophageal varices unresponsive to standard treatment.     

Safety, efficacy and lessons from continuous infusion with rFVIIa

Summary. Continuous infusion with coagulation factor concentrates has only been widely adopted during the last decade and with recombinant activated factor VII (rFVIIa) only during the last 2 years. Still the accumulated number of days on continuous infusion with this product amounts by now to more than one year, 35 patients and 26 surgical procedures. The experience is reviewed here and compared with data from the conventional bolus dose regimen.     

Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII

Eight patients with inhibitors to factor VIII (4 hemophilia A and 4 nonhemophilic) were treated with recombinant activated factor VII (rFVIIa) to control severe abdominal bleeding. The recombinant factor was supplied under an open-label, emergency-use program to patients previously unresponsive to one or more alternative therapies. Therapy with rFVIIa was administered for nine separate bleeding events; one patient was treated for two separate bleeding episodes. Patients were treated for an average of 9 days and received a mean total dose of 5.2 mg of rFVIIa for control of bleeding. Treatment was considered successful and hemostasis adequate in 7 of the 9 episodes (78%). Treatment with rFVIIa was partially successful in one other episode. Four patients in this series experienced serious adverse events; all the adverse events were considered unrelated to rFVIIa therapy. The results of this limited series indicate that rFVIIa is an effective means of managing life-threatening abdominal bleeding in individuals with hemophilia or acquired antibodies to factor VIII.     

Activity of recombinant factor VIIa under different conditions in vitro: effect of temperature, pH, and haemodilution.

Recombinant activated factor VII (NovoSeven; Novo Nordisk A/S, M?l?v, Denmark) is an effective drug for treatment of bleeding in patients with haemophilia A or B and inhibitors. Little is known about physiological conditions influencing the efficacy of recombinant activated factor VII. We investigated the in-vitro effects of pH, temperature, and haemodilution on the activity of recombinant activated factor VII. Samples from eight healthy volunteers were spiked with recombinant activated factor VII (final concentration 1.7 microg/ml) and adjusted to pH 6.0, 6.5, 7.0, and 7.4 or analysed at 30, 33, 37, and 40 degrees C, or diluted 0, 10, 20, 40, and 60% with dextran before analysis. Samples were analysed as rotational thromboelastometry in whole blood (clotting time, clot formation time, and maximum clot firmness) with and without Innovin (tissue factor), and as factor VII coagulant activity in plasma. Significant effects of pH were observed for clotting time, clot formation time, maximum clot firmness, and factor VII coagulant activity in the direction of longer clot formation times and less firm clots with decreasing pH. Temperature had significant effects on clotting time, clot formation time, and factor VII coagulant activity, but no effects on maximum clot firmness indicating that lower temperatures increase clot formation times without affecting clot firmness. Haemodilution had significant effects on clot formation time, maximum clot firmness, and factor VII coagulant activity, but no effects on clotting time indicating that haemodilution does not affect clot formation, but the clot formed at high haemodilution may not be so firm. In conclusion, the activity of recombinant activated factor VII was affected in vitro by pH, temperature, and haemodilution. Additional studies are necessary to demonstrate that these conditions also affect the efficacy of recombinant activated factor VII therapy in vivo.     

Standardization of factor VII/activated factor VII measurement in plasma of patients treated with recombinant factor activated VII.

To improve the standardization of the factor VII clotting activity (FVII:C) assay in patients treated with recombinant activated factor VII (rFVIIa), we conducted a multicentre study on plasma samples from four patients with haemophilia A, before and at various times after injection of a single dose of rFVIIa. FVII:C and prothrombin time were measured with the methods and reagents routinely used in each laboratory. Strong inter-laboratory variability of FVII:C values was found. The main source of variability was the type of thromboplastin. FVII:C values measured using rabbit thromboplastin were very close to activated factor VII clotting activity values (FVIIa:C) measured with a commercial assay (Staclot VIIa-TF). FVII:C values obtained with human placental thromboplastin were about three times lower than those obtained with rabbit and recombinant thromboplastins, and with the FVIIa:C assay. There was a good relationship between FVIIa:C and activated factor VII antigen values measured using a commercial immunoassay (Imubind FVIIa ELISA). In conclusion, rFVIIa at pharmacological concentrations can be easily monitored on the basis of FVII:C, using rabbit and probably also recombinant thromboplastin; equivalent results are obtained with a specific activated factor VII bioassay.     

Prophylactic and therapeutic use of recombinant activated factor VII in patients with cirrhosis and coagulation impairment

Patients with cirrhosis and impaired coagulation often pose major therapeutic problems during bleeding episodes or invasive procedures. Recombinant activated factor VII (rFVIIa), which has been licensed for the treatment of haemophilia patients with factor VIII or IX inhibitors, has been occasionally used in cirrhotic patients. We present five patients with cirrhosis and coagulopathy who received 1-4 recombinant activated factor VII infusions either prophylactically in order to safely undergo an invasive procedure or therapeutically in order to control a severe bleeding episode which did not respond to standard supportive care. In particular, recombinant activated factor VII infusions were given in two patients before a percutaneous liver biopsy, in one patient before teeth extraction and in two patients with haemoperitoneum after an invasive procedure. Infusions of recombinant activated factor VII achieved rapid correction of prothrombin time in all cases allowing the safe performance of invasive procedures or resulting in efficient control of the bleeding episode. In conclusion, recombinant activated factor VII seems to be a rather promising agent for the prevention or treatment of complications of haemostasis impairment in cirrhotic patients. However, its exact role in this setting needs to be evaluated within well-designed, controlled clinical trials.     

Recombinant activated factor VII (rFVIIa): characterization, manufacturing, and clinical development

Recombinant activated coagulation factor VII (rFVIIa) (NovoSeven) was developed for treatment of bleeding in hemophilia patients with inhibitors (antibodies) against factors VIII or IX. rFVIIa initiates the coagulation cascade by binding to tissue factor at the site of injury and causes the formation of sufficient amounts of thrombin to trigger coagulation. Patients with a variety of other coagulation deficiencies than hemophilia characterized by an impaired thrombin generation and life-threatening bleeding have been reported as successfully treated with rFVIIa. Data are now entered into clinical registries established to further monitor this experimental treatment with NovoSeven. rFVIIa is produced free of any added human protein. The amino acid sequence of rFVIIa is identical to plasma-derived FVIIa (pdFVIIa). Posttranslational modifications (i.e., gamma-carboxylations, N- and O-glycosylations) are qualitatively identical in pdFVIIa and rFVIIa although some quantitative differences exist. The activities of rFVIIa and pdFVIIa are indistinguishable. Manufacturing of rFVIIa involves expression in baby hamster kidney (BHK) cells followed by purification, including three ion-exchange and one immunoaffinity chromatography steps. The last anion-exchange chromatography step ensures completion of the autoactivation of recombinant factor VII (rFVII) to rFVIIa. This review describes the mechanism of action, characterization, manufacturing, and preclinical and current clinical evidence for the efficacy and safety of rFVIIa.     

Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors

Summary.  Severe FXI deficiency is a rare injury-related bleeding disorder. In patients with FXI inhibitors, surgeries may be treated using recombinant activated factor VII; however, treatment safety is a major concern and the best dosing regimen as well as mode of administration is still to be defined. We describe four patients with severe factor XI deficiency and inhibitors to FXI, undergoing eight (four major) surgical procedures treated with continuous infusion of rFVIIa. Following acute MI that evolved after surgery of our first patient, all other patients were treated with low-dose bolus rFVIIa followed by low-dose continuous infusion of rFVIIa. Haemostasis was successfully achieved and no further thrombotic complications occurred. To support our clinical results ex-vivo thromboelastography studies were performed, demonstrating the differences of clot formation and lysis between patients with FXI deficiency and healthy controls and suggesting that low-dose rFVIIa corrects coagulation similarly to high-dose rFVIIa in FXI deficiency. Recombinant FVIIa at low doses may effectively induce haemostasis and seems to be a safe treatment mode in patients with FXI deficiency and inhibitors undergoing surgeries.     

Use of recombinant activated factor VII in cardiac surgery for an effective treatment of severe intractable bleeding

Experience gained with administration of supranormal-therapeutic doses (90 microg/kg) of recombinant activated factor VII in 7 cardiac surgery patients is presented. The patients were given recombinant activated factor VII postoperatively for intractable bleeding, 5 of them after surgical revision. Administration of recombinant activated factor VII was associated with significant reduction in blood loss (P < 0.05) and shortening of INR and aPTT in laboratory tests. None of the patients needed reoperation. Administration of recombinant activated factor VII proved highly effective in management of massive hemorrhage in cardiac surgery.     

The international,prospective Glanzmann Thrombasthenia Registry: treatment modalities and outcomes of non-surgical bleeding episodes in patients with Glanzmann thrombasthenia

Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01476423","term_id":"NCT01476423"}}NCT01476423.     

Treatment of Diffuse Alveolar Hemorrhage in Systemic Lupus Erythematosus Patient With Local Pulmonary Administration of Factor VIIa (rFVIIa): A Case Report

Diffuse alveolar hemorrhage (DAH) is a rare serious life-threatening complication in systemic lupus erythematosus (SLE) associated with a high mortality rate.The old standard treatment options include high-dose corticosteroids, cyclophosphamide, and plasmapheresis, which are unspecific, treating the underlying disease rather than the complication itself, and not effective.We report a case of DAH complicating SLE flare-up in a female patient treated with recombinant activated factor VII (rFVIIa) administered via the bronchoscope that showed clinical and radiological improvement.No toxicity or adverse events were observed with rFVII treatment. rFVII may be an effective treatment option for DAH in SLE patient.     

Successful use of activated recombinant factor VII in life threatening bleeding after thoracic surgery

We present three patients in whom life-threatening haemorrhage following lung resection was successfully managed using activated recombinant factor VII (NovoSeven). In one case, activated recombinant factor VII was the only therapy administered to manage bleeding, and in the two remaining cases, activated recombinant factor VII was administered after patients failed to respond to conventional therapy. All patients demonstrated effective haemostasis and improved coagulation parameters as a result of treatment with activated recombinant factor VII. Our experience with the clinical use of rFVIIa suggests that this agent may provide effective hemostasis following lifethreatening postoperative bleeding after major thoracic surgery. Despite these favorable results, randomized, placebo - controlled trials are needed to identify optimal treatment strategy, patient selection, and safety of treatment in patients with massive bleeding following major thoracic surgery.     

Recombinant activated factor VII for non-hemophiliac bleeding patients

THE PURPOSE OF THIS REVIEW: The purpose of this review is to summarize the safety and efficacy of recombinant activated factor VII in diverse clinical settings based on recent published anecdotal experiences and early results from prospective trials. RECENT FINDINGS: Recombinant activated factor VII is increasingly being used for off-label treatment and prophylaxis of bleeding in non-hemophiliac patients. Case reports would suggest that recombinant activated factor VII is an efficacious and safe "universal hemostatic agent". To date, results of several randomized control trials investigating recombinant activated factor VII in non-hemophiliacs have been published as abstracts, supporting recombinant activated factor VII safety, but not its efficacy. SUMMARY: Until the results of additional prospective trials are available, clinicians, who manage patients with challenging hemostatic complications, and transfusion medicine specialists should collaborate to develop local policies for off-label utilization of recombinant activated factor VII.     

Myocardial infarction following recombinant activated factor VII in a patient with type 2A von Willebrand disease.

We describe a 50-year-old man with von Willebrand disease type 2A who suffers from angiodysplasia and has required many transfusions for gastro-intestinal haemorrhage. Various investigative modalities have not demonstrated a single source for this. Following a case report of successful use of recombinant activated factor VII (NovoSeven; Novo Nordisk, Copenhagen, Denmark), the patient was treated with it but suffered a large myocardial infarct. As the patient has risk factors for atherosclerotic disease, we presume the recombinant activated factor VII promoted coagulation at a pre-existing atherosclerotic lesion.     

Evaluation of thromboelastography for monitoring recombinant activated factor VII ex vivo in haemophilia A and B patients with inhibitors: a multicentre trial.

Predicting the clinical effect of bypassing agents such as recombinant activated factor VII in haemophilia patients with inhibitors is hampered by the limited availability of reliable laboratory monitoring tools. This multicentre, open-label trial aimed to explore the dose-response relationship between recombinant activated factor VII concentration and thromboelastography parameters in blood samples from patients with haemophilia A or B with inhibitors in a nonbleeding state. Citrated whole blood samples from 16 patients (>or=16 years) with haemophilia A or B were spiked ex vivo with recombinant activated factor VII (1.2, 1.6, 2.0, 2.6, 3.0, 3.5 microg/ml), corresponding approximately to doses of 90-270 microg/kg. Samples were analysed by Thromboelastograph or Rotation Thromboelastography (three United States and three European centres, respectively) within 30 min (final lipidated recombinant tissue factor 1: 17 000; final CaCl2 15 mM). Thromboelastograph/Rotation Thromboelastography parameters showed large intersubject variation in the baseline profiles. There was a clear effect when recombinant activated factor VII was added; however, a clear concentration-response relationship was only detected for one patient. This is likely due to the fact that the curves were not sufficiently abnormal that led to reduced assay sensitivity. Our preliminary results suggest that thromboelastography may potentially be a clinically useful tool for monitoring changing concentrations of recombinant activated factor VII in haemophilia patients, but only when the baseline curve is significantly abnormal. Thus, test conditions may need to be optimized before Thromboelastograph/Rotation Thromboelastography can be utilized for all inhibitor patients.     

Evaluation of off-label recombinant activated factor VII for multiple indications in children.

Despite a paucity of safety and efficacy data, the use of recombinant activated factor VII in children for off-label indications has now surpassed its use in hemophilia. A retrospective chart review was conducted of 46 subjects (age, 6.7 +/- 6 years; weight, 26 +/- 20 kg) who received recombinant activated factor VII for nonhemophiliac indications between January 1, 2004, and September 1, 2005. Indications for use included prevention (n = 6) or treatment (n = 40) of bleeding due to general surgery, hepatic failure, gastrointestinal bleeding, severe traumatic brain injury, bone marrow transplant, cardiac, acetaminophen overdose, and multiorgan system failure. Decreases in prothrombin time, partial thromboplastin time, and international normalized ratio were observed. No inappropriate thrombotic events were noted. Administration of recombinant activated factor VII was associated with a reduction in coagulation markers without obvious adverse thrombotic events at cost of $4189 per dose. These findings should be confirmed in a prospective trial.     

Differential clot stabilising effects of rFVIIa and rFXIII-A2 in whole blood from thrombocytopenic patients and healthy volunteers

The haemostatic effect of recombinant activated factor VII (rFVIIa;NovoSeven) in thrombocytopenic patients has been a matter of controversy. Haemostasis by rFVIIa occurs via FVIIa-mediated thrombin generation in a platelet-dependent manner and may therefore be suboptimal in patients without functional platelets. Under such conditions, a clot-stabilizing agent, such as factor XIII (FXIII), may supplement the effect ofrFVIIa and improve haemostasis. Recombinant factor XIII (rFXIII-A2) is produced as an A2 homodimer of the FXIII A subunit and is equivalent to cellular FXIII normally found in platelets. The combined effects of rFVIIa andrFXIII-A2 were evaluated in clot lysis assays using factor XIII-deficient plasma and by whole blood thrombelastography (TEG) analysis from normal donors and thrombocytopenic stem cell transplantation patients. Clotting time was shortened by rFVIIa (0.6-10 microg/ml). rFVIIa only modestly improved anti-fibrinolysis,whereas rFXIII-A2 (0-20 microg/ml) enhanced anti-fibrinolysis without effect on clotting time. TEG analysis showed rFVIIa shortened the clotting time, and enhanced clot development, maximal mechanical strength and resistance to fibrinolysis, whereas, rFXIII-A2 enhanced clot development,maximal mechanical strength and markedly enhanced resistance to fibrinolysis. These data illustrate that rFVIIa and rFXIII-A2 contribute to clot formation and stability by different mechanisms suggesting enhanced haemostatic efficacy by combining these agents.     

The use of recombinant factor VIIa in liver diseases

Recombinant activated factor VII, a bypassing hemostatic agent originally developed for the treatment of hemorrhages in hemophilic patients with inhibitors, is increasingly being employed on a compassionate use basis for the treatment of uncontrolled massive bleeding from various causes. In this review, we present the current knowledge on the use of this agent in patients with severe coagulopathy due to end-stage liver disease. In particular, the role of recombinant activated factor VII for treating gastrointestinal bleeding episodes in patients with decompensated cirrhosis or for prophylaxis before liver surgical or invasive procedures will be addressed. The pathogenesis of complex coagulopathy in chronic liver diseases and the mechanisms by which recombinant activated factor VII might improve coagulation in such patients will also be described. Given the paucity of the published data and the lack of randomized trials, there is not enough evidence to support the extensive use of recombinant activated factor VII in any of the clinical indications analyzed. In conclusion, further large randomized, controlled clinical trials are needed to better define the role of recombinant activated factor VII in the treatment of bleeding complications of liver disorders.     

Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic

Summary.  Identifying haemophilia patients with inhibitors for clinical trials is difficult due to the limited number of patients available. Registries are therefore being established as an additional means of data collection. The aim of this study was to investigate the effect of different recombinant activated factor VII (rFVIIa; NovoSeven^®) dose ranges and dosing schedules on the incidence of re-bleeding in haemophilia patients with inhibitors. In this retrospective, uncontrolled study, data on the bleeding patterns of adult haemophilia patients with high responding inhibitors were analysed. Only data from the Czech Republic, obtained by the HemoRec registry, were used. This study analysed 'real-life' clinical data and focused on the collection of the same parameters in different patients: time from bleeding onset to first injection, effect of first injection, number of re-bleedings, total number of injections and total amount of haemostatic drug used. Fifteen patients met the inclusion criteria and were included into the study (128 bleeding episodes). Patients treated within 2 h of bleeding onset experienced less re-bleeding than patients treated after 2 h of bleeding onset (5.2% vs. 13.7%, respectively). In addition, patients who were treated after 2 h of bleeding onset experienced fewer re-bleedings when high-dose rFVIIa was used (15.8% and 0%; <120 μg kg⁻¹ and >250 μg kg⁻¹, respectively). Initial high-dose rFVIIa was also associated with a decline in total rFVIIa consumption. This registry has provided a unique insight into the bleeding patterns of inhibitor patients, highlighting the importance of early treatment initiation and appropriate starting dose.     

A case of acquired hemophilia caused by factor VIII inhibitor with rheumatoid arthritis,successfully treated with immunosuppressive treatment and recombinant activated factor VII

We report the case of a patient who presented with acquired hemophilia associated with rheumatoid arthritis. The patient's factor VIII activity was less than 1% and factor VIII inhibitor was detected. Based on the blood analysis, the patient was diagnosed as having the factor VIII inhibitor. She was successfully treated with prednisolone, cyclophosphamide, and gammaglobulin to suppress the factor VIII inhibitor, and the administration of recombinant activated factor VII was effective in controlling severe bleeding episodes.