Safety update on the use of recombinant factor VIIa and the treatment of congenital and acquired deficiency of factor VIII or IX with inhibitors

Summary. Recombinant factor VIIa (rFVIIa, NovoSeven^®) has been licensed for treatment of haemophilia with inhibitors in Europe since 1996 and in North America since 1999. Overall, approximately 1.5 million doses have since been administered. Safety data from licensure to April 2003 revealed 25 thromboembolic (TE) adverse events (AE) from over 700 000 doses given, a remarkably low incidence of TE events. Recent reports have cited a higher prevalence of TE events with rFVIIa use, especially when used off‐label. This report reviews the TE and fatal events with use of rFVIIa for congenital and acquired haemophilia A or B from May 2003 to December 2006. Approximately 800 000 standard doses of rFVIIa have been administered during this time frame. All clinical trials, spontaneous and solicited reports, as well as a detailed literature review, were included in the data analysis. There were a total of 30 TE events and 6 TE‐associated fatal events. Spontaneous reports captured 14/71 (20%) TE/AE and 2/34 TE‐associated/total fatal events. From solicited reports, 5/40 (12.5%) were associated with a TE and 1/32 TE‐associated fatal events. Literature review revealed 11/19 (58%) TE events and 3/6 TE‐associated fatal events. Despite the use of high‐dose rFVIIa (270 μg kg^?1) in some clinical trials and registries, rFVIIa appears safe, when used for congenital and acquired haemophilia. The prevalence of TE associated with rFVIIa use is less than 4/100 000 and a TE‐associated fatal event is also extremely rare. However, use of rFVIIa for off‐label indications should continue to be monitored closely via clinical trials and carefully designed registries.     

Recombinant factor VIIa prophylaxis in a patient with severe congenital factor VII deficiency

Use of recombinant factor VIIa (rFVIIa, NovoSeven in patients with congenital FVII deficiency has been reported for the prophylactic management of surgical bleeding and for the treatment of acute bleeding episodes. Because of its short half-life, the use of rFVIIa on a regular prophylactic regimen has not been routinely adopted. In this report, we describe our successful experience with rFVIIa prophylaxis in preventing recurrent target joint bleeding in a severely FVII-deficient adolescent.     

Lack of bleeding in patients with severe factor VII deficiency

Factor VII deficiency, although rare, is now recognized as the most common autosomal recessive inherited factor deficiency. It is usually considered to be associated with bleeding only in the severely affected subject and heterozygotes (>10%) are not considered at risk. The general recommendation for surgery is to achieve a FVII level in excess of 15% (0.15 1U/mL). We present three cases of severe factor VII deficiency, each of whom appeared hemostatically competent based on clinical history. Subject 1 is a 33 year-old African-American female with a baseline FVII of <1%, who had a fractured tibia requiring open reduction with internal fixation without any FVII replacement and subsequently underwent successful laparoscopic knee surgery with a factor VII level measured at 6%. Subject 2 is a 58 year-old African-American female with a factor VII level of 9% who underwent an elective left total hip replacement without any factor replacement and had no excessive bleeding, but who sustained a pulmonary embolism postoperatively. Subject 3 is a 19-year-old African-American male with a baseline FVII of 1% with a history of active participation in football without noticeable injury and who underwent an emergent appendectomy without bleeding. These three cases represent individuals with the severe form of FVII deficiency who did not exhibit excessive bleeding when challenged with surgical procedures. The clinical history would appear the most valuable tool in predicting the likelihood of bleeding in these patients, and we suggest that the presumption that all patients with severe FVII deficiency should receive replacement therapy before surgical procedures may not be valid in all cases.     

Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention

To evaluate the feasibility efficaCy and safety of home treatment with recombinant activated factor VII (rFVIIa), 10 inhibitor patients (all haemophiliacs except one acquired post-partum) self-administered up to four doses of 90 microg/kg rFVIIa every 3+/-1 h. The response was rated by the patient as effective (haemorrhage stopped or decreased substantially), partially, effective (reduced) or ineffective (unchanged or worsened). 45 haemarthroses and eight haematomas were treated within a median time of 1.0 h (range 0.3-11.9) from the onset of bleeding, with a median of two rFVIIa doses per course (range 1-4). rFVIIa was effective in 42 episodes (79%), partially effective in six (11%) and failed in five (10%). Compared with partially effective and ineffective treatments, effective treatments started earlier (median time: 0.6 v 2.7 h, P=0.02) and required a smaller number of doses (median: 1.5 v 3, P=0.007). The risk of a partially effective or ineffective treatment was smaller for treatments started within 6 h from the onset of bleeding than for those which started later (OR 0.24, 95% CI 0.09-0.63). Mild side-effects were reported only after 3/113 self-infusions (2.6%). Early home treatment with rFVIIa is safe, feasible and effective, inducing and maintaining haemostasis with a small number of doses.     

Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial

BACKGROUND & AIMS: Upper gastrointestinal bleeding (UGIB) is a severe and frequent complication of cirrhosis. Recombinant coagulation factor VIIa (rFVIIa) has been shown to correct the prolonged prothrombin time in patients with cirrhosis and UGIB. This trial aimed to determine efficacy and safety of rFVIIa in cirrhotic patients with variceal and nonvariceal UGIB. METHODS: A total of 245 cirrhotic patients (Child-Pugh < 13; Child-Pugh A = 20%, B = 52%, C = 28%) with UGIB (variceal = 66%, nonvariceal = 29%, bleeding source unknown = 5%) were randomized equally to receive 8 doses of 100 microg/kg rFVIIa or placebo in addition to pharmacologic and endoscopic treatment. The primary end point was a composite including: (1) failure to control UGIB within 24 hours after first dose, or (2) failure to prevent rebleeding between 24 hours and day 5, or (3) death within 5 days. RESULTS: Baseline characteristics were similar between rFVIIa and placebo groups. rFVIIa showed no advantage over standard treatment in the whole trial population. Exploratory analyses, however, showed that rFVIIa significantly decreased the number of failures on the composite end point (P = 0.03) and the 24-hour bleeding control end point (P = 0.01) in the subgroup of Child-Pugh B and C variceal bleeders. There were no significant differences between rFVIIa and placebo groups in mortality (5- or 42-day) or incidence of adverse events including thromboembolic events. CONCLUSIONS: Although no overall effect of rFVIIa was observed, exploratory analyses in Child-Pugh B and C cirrhotic patients indicated that administration of rFVIIa significantly decreased the proportion of patients who failed to control variceal bleeding. Dosing with rFVIIa appeared safe. Further studies are needed to verify these findings.     

Recombinant, activated factor VII for surgery in factor VII deficiency: a prospective evaluation - the surgical STER

Excessive bleeding represents a major complication of surgical interventions and its control is especially relevant in patients with Congenital Bleeding Disorders (CBD). In factor VII (FVII) deficiency, scanty data on surgery is available to guide treatment strategies. The STER (Seven Treatment Evaluation Registry) is a multi-centre, prospective, observational, web-based study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Forty-one surgical operations (24 'major' and 17 'minor') were performed in 34 subjects with a carefully characterized FVII deficiency under the coverage of recombinant activated Factor VII (rFVIIa). Bleeding occurred during three major interventions of orthopaedic surgery, but rFVIIa was given at very low dose in each case. An antibody to FVII was observed in one patient who underwent a multiple dental extraction. No thromboses were reported during the 30-d follow up period. Replacement therapy with rFVIIa proved effective when suitable doses were used, which, during the period of maximum bleeding risk (the day of operation), were calculated (Receiver Operated Characteristic analysis) to be of at least 13 μg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.     

Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literature

Summary.  Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven^®) is one of the treatments available for acute life-threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 μg kg⁻¹ bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences.     

Clinical manifestations in 28 Italian and Iranian patients with severe factor VII deficiency

There has been wide variation in the reported haemorrhagic manifestations of factor VII deficiency. We examined type and frequency of clinical manifestations in 28 Iranian and Italian patients with severe deficiency (factor VII coagulant activity 2% or less). The most frequent symptoms were epistaxis and menorrhagia, whereas soft tissue bleeding such as haemarthrosis and muscle haematoma was less frequent. Only 5 of 9 patient who underwent surgery without factor VII replacement therapy had postoperative bleeding severe enough to require blood transfusion. No thrombotic manifestation occurred. A factor VII functional assay based on the use of human thromboplastin was a better predictor of the bleeding tendency of these patients than a rabbit thromboplastin-based functional assay or immunoassay. On the whole, this study shows that in severe factor VII deficiency bleeding in mucosal tracts is not uncommon. Surgery can sometimes be performed without replacement therapy and without haemorrhagic complications.     

Prophylactic effect of recombinant factor VIIa in factor VII deficient patients

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder associated with a bleeding tendency. We describe three patients with congenital FVII deficiency who have been treated with activated recombinant factor VII (rVIIa). Two patients had novel mutations and were treated prophylactically with 1.2 mg rVIIa two to three times a week. Patients 1 and 2 had a severe bleeding tendency. The frequency and severity of bleeding decreased by treatment with rVIIa compared with similar treatment with plasma-derived FVII. The third patient with a moderate bleeding phenotype was treated on demand and showed no change in the frequency of bleeding upon treatment with rVIIa or plasma products. The beneficial effect of rVIIa cannot be explained by the rVIIa half-lives. Pharmacokinetical analysis showed rVIIa activity half-lives of 35, 50 and 54 min for patients 1, 2 and 3, respectively. In conclusion, prophylactic treatment of FVII deficient patients with rVIIa appears to be applicable, safe and successful, although the mechanism of action remains to be elucidated.     

Use of recombinant factor VIIa in surgery in factor-VII-deficient patients

Summary . Patients suffering from severe factor VII deficiency may present with serious bleeding problems. No clear guidelines exist regarding therapy in such patients in case of a large bleeding or surgery. Indeed, it has been postulated that some patients with severe factor VII deficiency may never present with overt bleeding problems. However, in factor-VII-deficient patients who have previously demonstrated a clinical tendency to bleed, surgery is expected to cause excessive bleeding. We present two females suffering from a severe factor VII deficiency (FVII:C < 0.01 U mL^–1) with a distinct history of haemorrhagic diathesis. Due to recurrent bleeding in the past, or for circumstantial reasons, surgery was demanded over a 4-year period on a total of seven occasions. To assist haemostasis during and after joint surgery on five occasions and for embolization and subsequent removal of a large haemangioma of the occipital region, recombinant factor VIIa (NovoSeven) was utilized in doses approximating 20 μg kg^–1 b.w. every 6 h beginning immediately before surgery and continued until 30 h to 13 days postoperatively, depending of the size of the respective procedure. Using this approach, we observed normal haemostasis, and there were no signs of excessive postoperative bleeding or wound haematoma. No adverse reactions or side-effects were observed, and there were no complaints or clinical signs indicative of thrombotic complications. As judged from the clinical course of these seven minor and major surgeries, recombinant factor VIIa appears to be highly efficaceous and safe in the treatment patients with severe factor VII deficiency undergoing surgery.     

Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres

Many patients with haemophilia develop inhibitors to factor VIII and require bypassing agents to provide haemostatic cover for limb- or life-threatening bleeding episodes. Due to the reduced risk of blood-borne pathogen transmission with recombinant products, on-demand recombinant factor VIIa (rFVIIa; NovoSeven is the treatment of choice for children with inhibitors. In haemophiliac patients without inhibitors, primary prophylaxis has been clinical practice for several years. This paper summarises 13 case histories of rFVIIa secondary prophylaxis for haemophilia patients with inhibitors. This was a retrospective survey of adult and paediatric severe haemophilia patients with inhibitors treated with rFVIIa from ten European Haemophilia Centres. There was a wide variation in administered rFVIIa dose, from 200-250 microg kg(-1) per week to 220 microg kg(-1) daily. In many cases, this was lower than the recommended on-demand dose of rFVIIa. In 12/13 cases, prophylaxis with rFVIIa considerably reduced the number of bleeding episodes compared with previous treatment. Eight/nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life (QoL), all were improved, much improved, or significantly improved. In haemophilia patients with inhibitors, prophylaxis with rFVIIa is highly effective in reducing the number of bleeding episodes and results in good patient compliance and improved QoL. Randomised controlled trials are needed to confirm these findings. Results of a recently completed clinical trial on secondary prophylaxis with rFVIIa in frequently bleeding haemophilia patients with inhibitors are expected in late 2006.     

Prophylactic recombinant factor VIIa in haemophilia patients with inhibitors

Prevention of bleeding, especially into joints, with prophylactic factor infusions is the most effective treatment for severe haemophilia patients. Approximately 15-30% of patients with factor VIII deficiency and 3-5% of patients with factor IX deficiency develop neutralizing antibodies (inhibitors) to factor precluding their use. Such patients often have significant bleeding complications including life- and limb-threatening bleeds and severe joint disease. Prophylaxis for such patients is not generally considered because of the fact that the standard (bypassing) agents for such patients are not as effective as natural factor replacement, because of concerns for thrombotic complications and also because of the very high cost of bypassing agents. We treated two patients with high titre inhibitors with prophylactic recombinant factor VIIa (rFVIIa). The first patient was treated as a result of development of a target joint and to reduce the use of agents that can lead to anamnesis of his inhibitor. The second patient had multiple severe bleeds and was hospitalized 20% of the time over a 2-year period. He had a very poor quality of life. Both patients had shown good responses previously to rFVIIa for treatment of bleeds. Both patients had an outstanding response to prophylaxis albeit at a very high cost. Prophylaxis with rFVIIa can be an effective approach in select inhibitor patients with severe complications related to bleeding.     

Surgical Experience with rFVIIa (NovoSeven) in congenital haemophilia A and B patients with inhibitors to factors VIII or IX

Summary. Patients with congenital haemophilia with inhibitors are at risk of peri‐operative bleeding complications, since replacement of the missing coagulation factor is ineffective, presenting a therapeutic challenge in elective or emergency surgery. Therefore, the management of peri‐operative bleeding requires the use of bypassing agents, such as recombinant activated FVII (rFVIIa, NovoSeven^®). This article presents an updated evaluation of the safety and effectiveness of rFVIIa in the treatment of peri‐operative bleeding in this patient population. Surgical and other medical procedures managed with rFVIIa from two randomized clinical trials, the Hemophilia Research Society/Hemophilia and Thrombosis Research Society (HRS/HTRS) registry databases and the medical literature were analysed. There were 395 rFVIIa‐treated procedures (261 surgical, 89 dental and 45 other medical procedures) reported for 263 congenital haemophilia patients with inhibitors. In trials, initial rFVIIa dosing was 35–90 mcg kg^?1 bolus injection or 50 mcg kg^?1 h^?1 continuous infusion. Dosing in the registries and literature was more variable. Recombinant FVIIa effectiveness was comparable across data sources, with an overall rate of 84% (333/395). The incidence of thrombotic events was very low (0.4% of patients and 0.025% of procedures). Prior to the US approval of rFVIIa in 1999, surgical procedures in congenital haemophilia patients with inhibitors were often considered too risky. Recombinant FVIIa has consistently demonstrated effectiveness in treatment of bleeding in these patients during such procedures. Thrombotic events were rare. This analysis confirms the value of corroborating clinical trial results with post‐marketing surveillance registries to assess small patient populations with clinically challenging management decisions.     

Results of the WIRK prospective,non‐interventional observational study of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors and other bleeding disorders

Recombinant activated factor VII (rFVIIa) has been available for the treatment of acute bleeding and for prevention of bleeding during surgery and invasive procedures in patients with congenital haemophilia with inhibitors (CHwI) and acquired haemophilia since 1996. The study objective was to assess the efficacy and safety of rFVIIa in patients with CHwI, acquired haemophilia, congenital FVII deficiency and Glanzmann's thrombasthenia, in a real‐life clinical setting. There were no specific inclusion or exclusion criteria; participation was offered to all German haemophilia centres known to use rFVIIa to treat patients with the above indications. Data on rFVIIa use and efficacy for the treatment of acute bleeding episodes and invasive procedures were recorded. Adverse drug reactions and recurrent bleeding episodes were also monitored. In total, 64 patients (50.0% women) received rFVIIa treatment. Patients experienced 281 evaluable bleeding episodes and underwent 44 invasive procedures. In 252 of 281 (89.7%) bleeding episodes, a stop (66.5%) or a significant reduction (23.1%) in bleeding was observed. No bleeding complications were reported for 42 of 44 (95.5%) invasive procedures covered with rFVIIa. A clear positive association was observed between early initiation of rFVIIa treatment for acute bleeding and efficacy. The total cumulative dose and number of injections were 468.3 ± 545.8 μg kg^?1 and 3.6 ± 4.6 respectively. No drug‐related adverse events were reported. rFVIIa use in Germany provided effective haemostatic cover without associated adverse events in the management of acute bleeds and invasive procedures across a range of bleeding disorders.     

Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors

Summary.  Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 μg kg⁻¹) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly ( P  <   0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P  = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P  =   0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 ( P  =   0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P  =   0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.     

Recombinant factor VIIa to prevent surgical bleeding in factor XI deficiency

Summary.  Factor XI (FXI) deficiency is associated with bleeding after invasive procedures. Risks of human plasma-derived FXI replacement products include transfusion transmitted infection, thrombosis and fluid overload. This study was designed to test the hypothesis that recombinant factor VIIa (rFVIIa) is an effective haemostatic agent in patients with FXI deficiency undergoing surgery. Fourteen FXI deficient patients [five severely deficient (FXI:C <20 U dL⁻¹) and nine partially deficient (FXI:C 20–70 U dL⁻¹] received rFVIIa to prevent surgical bleeding during five major, four minor and six dental procedures. Minor surgical and dental procedures were covered with two doses of rFVIIa (90 μg kg⁻¹ i.v.), the first pre-operatively and the second 4 h postoperatively. Major surgery was covered with 90 μg kg⁻¹ i.v. two hourly for the first 24 h and four hourly for the second 24 h. Oral tranexamic acid was given for 7 days postoperatively. Effective haemostasis was observed in all cases and no alternative haemostatic agents or blood transfusions were required. Three adverse events were recorded; an acute cerebrovascular accident in a patient with a history of cardiovascular disease, an allergic reaction and local phlebitis. In this study, rFVIIa was an effective alternative to plasma-derived FXI replacement for the prevention of surgical bleeding in FXI deficient patients but rFVIIa may not be suitable for patients with pre-existing risk factors for thrombosis.     

Antibodies to factor VIIa in patients with haemophilia and high-responding inhibitors

The haemostatic effect of by-passing agents such as activated prothrombin complex concentrates (aPCC) and recombinant factor VIIa is inadequate in some patients with severe haemophilia and high-responding inhibitors. Theoretically, this could be due to antibody reactivity to procoagulant proteins other than the deficient factor. To evaluate this hypothesis, immunoglobulin (Ig) fractions from six multi-transfused patients (three haemophilia A and three haemophilia B) were purified on protein A sepharose and then subjected to immunoaffinity chromatography on factor IX sepharose and factor VIIa sepharose. All three Ig fractions from the haemophilia B patients, but not commercially available Ig, contained antibodies that bound to both gels. None of the haemophilia A patients had antibodies to factor IX but all three had antibodies towards factor VIIa. The immunoaffinity purified antifactor IX and VIIa antibodies from the haemophilia B patients inhibited thrombin formation in vitro using Feiba as active enzyme, but had no significant effect in the presence of NovoSeven. In contrast, no inhibitory effect was observed with the antifactor VIIa antibodies from the haemophilia A patients. Cross-reactivity to factor IX was seen for the antifactor VIIa antibodies from the patients with haemophilia B. Our findings show that antibody reactivity to other procoagulant factors such as factor VIIa exists in patients with high-responding inhibitors and that these antibodies may have an inhibitory potential that correlates to the amount of active enzyme present. The characterization of the antibody profile may facilitate an optimal treatment with by-passing agents in severe bleeding events.     

Two novel factor VII gene mutations in a Chinese family with factor VII deficiency

We report two novel factor VII (FVII) gene mutations in a Chinese family with FVII deficiency. The proband, a 55-year-old woman. was incidentally found to have right shoulder arthritis consistent with chronic haemophilic arthropathy. FVII studies showed a FVII activity of 0.02 iu/ml and a FVII antigen of 49%. Molecular analysis showed a double heterozygous state, with an exon 4 nonsense mutation (C6003-->A; Cys61-->Term) and an exon 8 missense mutation (T10902-->G; Cys329-->Gly) that disrupted a Cys310/Cys329 disulphide bond. The genotypes and phenotypes were correlated in the patient's daughters. Two daughters were heterozygous for the Cys61-->Term mutation and showed a type 1 FVII gene mutation phenotype consistent with a nonsense mutation. One daughter was heterozygous for the Csy329-->Gly mutation and showed a type 2 mutation phenotype consistent with a missense mutation. These are the first reported FVII gene mutations in the Chinese people.     

Congenital factor VII deficiency: therapy with recombinant activated factor VII – a critical appraisal

Congenital factor VII (FVII) deficiency is a rare bleeding disorder with high phenotypic variability, and optimal management has yet to be determined. Treatment has traditionally involved FVII replacement therapy using fresh frozen plasma, prothrombin complex concentrates or plasma-derived FVII concentrates. Recombinant activated FVII (rFVIIa, NovoSeven(R)), the first recombinant treatment option, has recently been approved in the European Union for use in congenital FVII deficiency, but has been available on an emergency and compassionate use basis since 1988. In FVII deficiency, rFVIIa serves as substitution therapy as it provides the physiological ligand (FVIIa) for tissue factor, its receptor exposed at the site of vascular injury. This paper provides an overview of published and unpublished experience with rFVIIa in patients with congenital FVII deficiency from the NovoSeven compassionate and emergency use programmes (1988-99) and of independent reports in the literature. Recombinant FVIIa has been reported to provide effective haemostasis in patients of all ages and in a range of bleeding situations, including acute central nervous system/life-threatening bleeding episodes (15 episodes in 12 patients), non-life-threatening bleeding episodes (>32 episodes in 17 patients), surgery (>40 interventions in 25 patients) and childbirth (three women). Preliminary reports suggest that it may also be effective prophylactically. The risk of thrombosis in FVII-deficient patients treated with rFVIIa is unknown, as is the occurrence of inhibiting antibodies. A postlicensure pharmacovigilance registry (Seven Treatment Evaluation Registry) has been set up to continue to monitor the efficacy and safety (including alloantibody development) of rFVIIa in patients with FVII deficiency.