Thrombosis Research Society Registry Research Articles

Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study.

The Hemostasis and Thrombosis Research Society Registry was used to monitor the postapproval use and safety of recombinant activated factor VII (rFVIIa). The objective of this article is to evaluate the data from the Hemostasis and Thrombosis Research Society Registry related to rFVIIa-treated bleeding episodes in patients with acquired hemophilia. For each rFVIIa-treated bleeding episode, the initial dose, total dose, average infused dose, number of doses, and treatment duration were calculated. Efficacy was assessed on a three-point scale. Out of the 166 registered patients with acquired hemophilia, 110 patients were treated for 237 bleeding episodes (139 rFVIIa treated); the majority (70%) were in patients older than 60 years. The most frequently reported bleeding locations were subcutaneous (40%) and mucosal (32%). Subcutaneous bleeding episodes were more commonly reported in women (55% vs. 40% men) and white patients (44 vs. 27% black). Of the 139 rFVIIa-treated bleeding episodes, rFVIIa was used as first-line treatment in 127 bleeding episodes. The median initial dose was 90 μg/kg; the median total dose per episode was 333.5 μg/kg. Physician-rated efficacy of rFVIIa for each bleeding episode was reported as ‘bleeding stopped’ in 85% of bleeding episodes, ‘bleeding slowed’ in 11% of bleeding episodes, ‘no improvement’ in 4% of bleeding episodes, and was not documented in 1 bleeding episode. One thromboembolic event was reported; transient neurologic symptoms were reported in a 31-year-old postpartum patient after 110 doses of rFVIIa. Adequate hemostasis was provided for most rFVIIa-treated bleeding episodes at doses largely conforming to the package insert. No major safety concerns were reported.

Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry

Assessment of acquired hemophilia patient demographics in the United States: the Hemostasis and Thrombosis Research Society Registry

Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study

Use of recombinant activated factor VII for acute bleeding episodes in acquired hemophilia: final analysis from the Hemostasis and Thrombosis Research Society Registry acquired hemophilia study

US experience with recombinant factor VIIa for surgery and other invasive procedures in acquired haemophilia: analysis from the Hemostasis and Thrombosis Research Society Registry.

Acquired haemophilia (AH) is a rare disorder caused by autoantibodies against factor VIII. The Hemostasis & Thrombosis Research Society (HTRS) Registry was used to monitor the safety of recombinant FVII (rFVIIa). This study aims to report data from the HTRS Registry regarding safety and efficacy of rFVIIa for haemostatic management of surgeries and other invasive procedures in patients with AH. For each rFVIIa-treated procedure, the initial dose, total dose, average infused dose, number of doses and treatment duration were calculated. Efficacy was assessed on a 4-point scale. Of 166 registered patients with AH, 37 patients underwent 58 procedures [30 (51%) rFVIIa-treated]. The median (range) age of all patients undergoing procedures was 70 (13-93) years; for rFVIIa-treated patients, 74 (28-89) years. Approximately 67% (39/58) of all procedures were elective. Overall, the most common procedures were endoscopy (12) and central venous access device (10); rFVIIa was used preoperatively (11), postoperatively (13) and during six follow-up procedures during ongoing postoperative rFVIIa treatment. The median (range) initial dose was 90.0 (44-187) μg kg(-1) preoperatively and 106.0 (56-270) μg kg(-1) postoperatively. For rFVIIa-treated episodes with a reported outcome, 20 (91%) were rated excellent/good or no additional agents used and 2 (9%) were rated as poor/ineffective requiring a switch to another bypassing agent. No thromboembolic events were reported. Adequate haemostasis was provided for 91% of rFVIIa-treated procedures at doses largely conforming to the package insert. No safety concerns were reported.

Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO

A United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) guideline approved by the British Committee for Standards in Haematology Peter W Collins, Elizabeth Chalmers, Daniel Hart, Ian Jennings, Ri Liesner, Savita Rangarajan, Kate Talks, Michael Williams and Charles R. M. Hay School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Royal Hospital for Sick Children, Glasgow, Royal London Hospital, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK NEQAS Blood Coagulation, Sheffield, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, and Manchester University Dept of Haematology, Manchester Royal Infirmary, Manchester, UK

Use of Recombinant Factor VIIa (rFVIIa) for Acute Bleeding Episodes in Acquired Hemophilia: Final Analysis From the Hemostasis and Thrombosis Research Society (HTRS) Registry AH Study

AbstractAbstract 4624 Introduction:Acquired hemophilia (AH) is a rare disorder marked by the development of autoantibodies to factor VIII. Patients typically present with bleeding and a prolonged aPTT that does not correct with mixing with normal plasma. Recombinant factor VIIa (rFVIIa) is the only FDA approved bypassing agent for treatment of bleeding in AH. The Hemostasis and Thrombosis Research Society Registry was established as an IRB-monitored web-based platform with informed consent in 1999 to support the society's research needs and monitor rFVIIa use after its FDA approval. AH surveillance was initiated in October 2006. Methods:Data on bleeding episodes entered between January 2004-November 2011 were analyzed. For each rFVIIa-treated bleed, the initial dose, total dose, mean dose per infusion, number of doses, and treatment duration were calculated. Results:Of 166 registered AH patients, 110 had bleeding episodes reported. Of 237 bleeds, 17 (7%) occurred in patients aged ≤40, 54 (23%) in ages 41–60, and 166 (70%) with age >60. The most common sites were subcutaneous (40%), mucosal (32%), muscle (20%) and joint (11%). Subcutaneous bleeds were more commonly reported in females (55% vs. 40% males) and white patients (44% vs. 27% black). Mucosal bleeds were more common in black patients (49% vs. 25%) and muscle bleeds more common in white patients (14% vs. 23%). There were 139 (59%) rFVIIa-treated bleeds (89 rFVIIa alone, 50 rFVIIa plus other agents/blood components); 127 were treated with rFVIIa first-line. There were 75 episodes (43 patients) treated with other hemostatic agents or blood components only, 21 episodes (18 patients) recorded with no treatment for the episode, and 2 episodes (2 patients) with no treatment data recorded. For rFVIIa-treated episodes, 71 were in males and 68 females; 101 were Caucasian and 30 were black. Mean (median) age at bleeding was 67 (69) years. rFVIIa-treated bleeds were spontaneous (95), traumatic (30), surgical/procedure-related (7), dental (2) or other (4). Median (IQR) initial rFVIIa dose was 90 (88–100) mcg/kg, and average dose per injection was 90 (88–99). The total dose per episode was 334 (166–1383) mcg/kg administered as 3 (2–14) injections over 1 (0–2.75) day. Median (IQR) data for rFVIIa dosing by treatment sequence, bleed location and type is described below:First line n=127Second line n=12Subcutaneous n=52Mucosa n=45Initial dose (mcg/kg)90 (87–100)90 (87–100)90 (90–97)90 (87–100)Mean dose (mcg/kg)90 (88–99)90 (90–97)90 (90–97)90 (88–99)Total dose (mcg/kg)300 (119–1345)577 (275–3430)577 (275–3430)300 (119–1345)# doses3 (1–13.5)7 (3.5–25)7 (3.5–25)3 (1–13.5)Duration (days)1 (0–4)7.5 (0.8–13.5)1.5 (0.8–4.1)1 (0–2.5)Spontaneous n=95Traumatic n=30Other Medical Procedures n=5Surgery n=3Initial dose (mcg/kg)90 (83–93)93.5 (90–101)96 (78–100)90 (90–105)Mean dose (mcg/kg)90 (85–92)91.4 (90–100)96 (78–100)109 (100–115)Total dose (mcg/kg)290 (110–1132)314 (180–1430)900 (810–1152)9600 (5520–9885)# doses3 (1–12)3.5 (2.0–14.8)9 (6–12)88 (50–101)Duration (days)1 (0–2.5)1 (0.2–2.0)2.3 (0–3)10 (6–10.5)Efficacy of rFVIIa, physician-rated for each regimen, was reported as “bleeding stopped” in 117 (85%) episodes; “bleeding slowed” in 15 (11%) episodes (stopped with other agents in 3 episodes); “no improvement” in 5 (4%) episodes (no bleed stop date identified in 4, stopped with other agent in 1), and was not documented in 1. Considering only the 4 rFVIIa treatment failures where bleeding stopped after switching to another agent, overall rFVIIa efficacy was 97%. The only thromboembolic event was transient neurologic symptoms in a 31-year-old post-partum patient after 110 doses of 90 mcg/kg every 2 hours. The neurologist reported it most likely related to eclampsia and vasculitis. Conclusions:The HTRS registry final analysis represents the 2nd largest data set in AH. While subcutaneous bleeding as a first bleed location was uncommon outside of Caucasians, it represents the most common bleed location of recorded bleeds in all race/ethnicity groups. As this registry was originally intended in part to track the safety of rFVIIa, the proportion of bleeds treated with rFVIIa (59%) and associated data derived from those bleeds may be somewhat biased and selective. Nevertheless, they are certainly indicative that rapid and safe hemostasis can be achieved with rFVIIa in an aging population with AH where thrombogenicity is of concern. Disclosures:Ma:Novo Nordisk Inc.: Consultancy, Speakers Bureau. Kessler:Novo Nordisk: Consultancy, Research Funding. Fisher:Novo Nordisk Inc.: Employment. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Exposure and safety of higher doses of recombinant factor VIIa ≥250 μg kg−1 in individuals with congenital haemophilia complicated by alloantibody inhibitors: the Haemophilia and Thrombosis Research Society Registry experience (2004-2008)

Recombinant factor VIIa (rFVIIa) is a well-established treatment for managing bleeding episodes in individuals with congenital haemophilia complicated by alloantibody inhibitors (CHwI). The safety and efficacy of standard dosing (90-120 μg kg(-1) every 2-3 h) are well-established; however, the desire to optimize therapy with one or more higher doses instead of multiple lower doses has created a need for evidence of the safety and efficacy of such regimens. Analysis of data from the Haemophilia and Thrombosis Research Society (HTRS) Registry was performed on episodes where doses of ≥250 μg kg(-1) were reported. From 2041 rFVIIa-treated bleeds, 172 bleeding episodes were identified in 25 individuals with CHwI who were treated with ≥1 higher doses (≥250 μg kg(-1) , ≥270 μg kg(-1) or ≥300 μg kg(-1) ) of rFVIIa between January 2004 and November 2008. Bleeds occurred in individuals ranging in age from 0.4 to 41.7 years who were predominantly non-Hispanic and white (40%) with haemophilia A (88%). Bleed types most frequently treated with higher doses of rFVIIa were spontaneous (62-65%) or traumatic (27-32%). Bleed locations most frequently treated with higher doses of rFVIIa were joint (60-68%) or muscle (20-25%). A total of 1521 rFVIIa doses were administered (median, three doses per bleed); 26% were 250 μg kg(-1) or higher (initial dose, 82%). Bleeding stopped in 93% (160/172) of bleeds treated with rFVIIa 250 μg kg(-1) or higher. No serious adverse drug-related events or thrombotic complications were reported. This data analysis from the HTRS Registry provides evidence of the safe and effective use of higher doses of rFVIIa (≥250 μg kg(-1) ) in US practice.

Recombinant activated factor VII safety and efficacy in the treatment of cranial haemorrhage in patients with congenital haemophilia with inhibitors: an analysis of the Hemophilia and Thrombosis Research Society Registry (2004–2008)

Cranial haemorrhage (CH) is a potentially serious complication in patients with severe congenital haemophilia with inhibitors (CHwI). Treatment includes bypassing agents, such as recombinant activated factor VII (rFVIIa). To examine the US experience in treating CH with rFVIIa, a retrospective review of the Hemophilia and Thrombosis Research Society 2004-2008 database was conducted. Among 29 patients with CHwI, 56 of the reported haemorrhages met the study criteria. Of these, 75% were traumatic and 80% were extracranial (ECH). The majority (8/11, 73%) of intracranial haemorrhages (ICHs) developed spontaneously. Conversely, most ECHs (39/45, 87%) followed trauma. ICHs were treated with a median/mean of 23/58 rFVIIa infusions over a median/mean of 7/9 days while ECHs were treated with a median/mean of 1/3 infusions (P = 0.011) over a median/mean of 1/1 day. The median/mean initial rFVIIa doses for all CHs were 106/137 microg kg(-1), and were similar for ICHs and ECHs. All ECHs were effectively controlled with rFVIIa; 44/45 bleeds were controlled within 24 h, one bleed was successfully treated perioperatively, and 27 ECHs required only a single dose. Nine out of 11 ICHs were effectively treated with rFVIIa; six ICHs were controlled within 24 h, one within 72 h and in two cases haemostasis was achieved during the perioperative period. No serious treatment-associated adverse events were reported. One patient died as a result of ICH despite the reported control of bleeding. In conclusion, standard dosing of rFVIIa was found to be safe and effective in treating CH with an efficacy rate of 100% for ECH and 82% for ICH.

Use of Single Dose of rFVIIa in Congenital Hemophilia: Analysis of Data Capture from the Hemophilia and Thrombosis Research Society Registry (2004–2008)

The recommended dose of recombinant factor VIIa (rFVIIa, NovoSeven®) is 90 mcg/kg every 2–3 hours. The Home Treatment Study demonstrated an average of 2.2 doses of 90 mcg/kg were required to treat mild to moderate bleeds. Since it is recognized that a single dose administered shortly after a bleed, if equally effective, would be more convenient and possibly could reduce bleeding morbidity, this study examined the experience registered with the use of single rFVIIa doses in the United States.The HTRS database contains patient data relating to hemophilia treatment and related disorders, and in particular the treatment of acute bleeding episodes in individuals with hemophilia complicated by anti-factor VIII (FVIII) or IX (FIX) alloantibody inhibitors. Between January 2004 and March 2008, the database contained information on over 5,000 bleeding episodes. The data for patients receiving only a single bolus intravenous dose of rFVIIa and no additional treatment were evaluated. The parameters assessed included patient demographics, bleed location, bleed type (specifically joint and muscle bleeds), and dose.Of 2,532 patients who received rFVIIa, 70 with congenital hemophilia A (n=63) or B (n=7) and inhibitors experienced 508 bleeding episodes that were treated solely with a single dose of rFVIIa. The mean (median, range) age at the time of bleed was 12.7 years (8.2, 0.6–60.4). Mean titers for anti-FVIII and anti-FIX were 62.2 BU (15.0, 0–1408) and 6.8 BU (1.3, 0–31.7), respectively. The bleed sites recorded were joints (271 bleeds [53%], including 55 in target joints [20.2% of joint bleeds]), muscle (78, 15%), mucosal (45, 9%), intracranial (25, 5%), and subcutaneous (21, 4%). Joint bleeds occurred primarily in the ankles (124 bleeds), elbows (61 bleeds) and knees (53 bleeds).For 508 bleeds treated with a single dose of rFVIIa, the mean (median, range) dose was 119.5 mcg/kg (100, 25–500) with 20 of those doses ≥270 mcg/kg. Patients with joint bleeds were treated with 123.1 mcg/kg (100, 25–500), target joint bleeds with 155.3 (140, 50–393), and those with the muscle bleeds received 120.1 mcg/kg (100, 50–500). The most common single dose regimen overall and for the joint and muscle bleeds was 90 mcg/kg rFVIIa.The majority of bleeds (424, 82.7%) were treated at home, but bleeds were also treated at Hemophilia Treatment Centers (61, 12.0%) and in the emergency room (15, 3.0%). Overall, physician reported “bleeding stopped” in 97% of the 494 bleeds, 97% of hemarthroses, 96% of target joint hemarthroses and 96% of muscle bleeds. For the remaining 14 episodes, although documentation did not indicate “bleeding stopped”, no other medications were recorded.There were no serious adverse drug reactions.Registry data can only demonstrate the treatment reported in selected bleeds captured, and the analysis here specifically examined bleeds treated with only a single dose either because of bleed resolution or by physician/patient choice. The data analyzed here demonstrate single doses of rFVIIa of up to 500 mcg/kg (mean 119 mcg/kg) for mild to moderate bleeds effectively resolved bleeds in 97%, including hemarthrosis, target joints hemarthrosis, and muscle bleeds. These data support the possibility that rFVIIa can be administered in a single bolus dose with equivalent or superior efficacy as multiple lower doses for bleeding episodes treated as part of a home therapy regimen. While 3 randomized trials have examined the equivalence of a single dose of 270 mcg/kg with 3 doses of 90 mcg/kg, these data suggest that single doses of rFVIIa therapy in the real world often were empirically titrated on a patient specific basis, according to the severity and site of the bleeding episode. These registry data provide justification for prospective, randomized, single dose titration trials of rFVIIa or future analogues.

Recombinant Activated Factor VII (rFVIIa) Dosing and Efficacy in the Treatment of Cranial Hemorrhage in Hemophilia Patients with Inhibitors: An Analysis of the Hemophilia and Thrombosis Research Society Registry (HTRS) (2004–2008).

Patients with severe hemophilia are at risk for developing neutralizing antibodies (inhibitors) in response to treatment with factor concentrates. Inhibitors develop in >30% of patients with factor VIII (FVIII) deficiency, in 3–6% of patients (pts) with factor IX (FIX) deficiency, and significantly increase the disease-related morbidity. Cranial hemorrhage is a serious bleeding complication in the presence of high titer inhibitors. Treatment strategies include bypassing agents such as activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa). For rFVIIa, 90–120μg/kg every 2–3hr represents the standard initial dosing regimen, although higher doses have been studied. Despite its licensure in 1999 for treatment of hemophilia patients with inhibitors, little has been published on rFVIIa dosing and efficacy in such pts with cranial bleeding. To examine the US experience with this therapeutic challenge, we conducted a retrospective review of the HTRS 2004–2008 database that includes >5000 bleeding episodes in hemophilia inhibitor pts collected retrospectively from 2000 onwards. This analysis included congenital hemophilia inhibitor (CHI) pts treated at least partially with rFVIIa for “head” bleeds designated as either spontaneous or traumatic and either intra- (ICH) or extracranial (ECH). Each cranial hemorrhage was analyzed with respect to initial, initial 24 hour and total infused dose of FVIIa, total number of doses and days of therapy and investigator-assigned outcome.In all, 29 CHI pts with 56 cranial bleeding episodes met study criteria; 27 had FVIII and 2 had FIX deficiency. Mean ages (years) at spontaneous and traumatic bleeding were 12.2 and 3.7 respectively for FVIII pts; 16 and 1.5 respectively in FIX pts. Most cranial bleeds were traumatic (75%) and extracranial (80%). Importantly, 8/11 ICHs developed spontaneously while 39/45 ECHs were traumatic. In all, 51/56 cranial hemorrhages were treated exclusively with rFVIIa. In 4, therapy included a single aPCC dose. In 1 case, rFVIIa followed a 2 week course of FVIII, on which the pt developed an inhibitor.ICHs were treated with a mean of 58 infusions over 8.9 days (median: 23 infusions, 7 days); ECHs were treated with a mean of 6 infusions over 1.3 days (median: 1 infusion, 1 day) (p=.011). The mean/median initial infusion dose for all cranial bleeds were with 137/106μg/kg and varied little by location and nature of the hemorrhage. All ICHs were initially treated in hospital settings, while ⅔ of ECHs were initially treated at home. However, initial treatment setting did not impact initial dose. Interestingly, higher initial doses of rFVIIa were used to treat cranial hemorrhage through 2005 (mean 150 μg/kg; range 60–400 μg/kg) than were used from 2006–08 (103 μg/kg; range 80–170 μg/kg). The mean total dose/treatment course was 1,751 μg/kg (median: 240μg/kg, range 70–35,025μg/kg), but varied according to bleed location. As expected, pts with ICHs received higher total doses (mean: 7,279μg/kg; median of 2,250μg/kg) when compared with ECHs (mean: 400μg/kg; median of 140μg/kg 190μg/kg) (p=.06). Overall 78% of the total dose per treatment course was administered within the first 24 hours; however this differed between ICH (34% total/24 hrs) and ECH (88% total/24 hrs).All ECH was stopped effectively with rFVIIa; 44/45 bleeds were controlled within 24 hours (hrs) and in one hemostasis was achieved within 72 hrs. Twenty-seven episodes required a single treatment dose. Of the 11 ICH bleeds, 6 were reported to be controlled within 24 hrs; one within 72 hrs. Two pts required surgery to control hemostasis. In 2 cases, control of hemorrhage was not explicitly confirmed. One patient with spontaneous ICH died despite reported control of hemostasis. There were no serious adverse drug reactions associated with the rFVIIa treatment.In summary, in this retrospective review of the US experience accumulated between 2004 and 2008, standard dosing of rFVIIa was found to be safe and effective in the treatment of cranial hemorrhage with an efficacy rate of 100% for ECH and 82% for ICH. The limitations of this study include potential adverse outcome and complications underreporting. Furthermore, neurological and other morbidity data is unavailable. We advocate further prospective documentation of treatment and outcomes.

Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal

Acquired haemophilia is a rare bleeding disorder usually caused by the spontaneous formation of inhibitory antibodies to coagulation FVIII. The disease occurs most commonly in the elderly, and although acquired haemophilia may be associated with a variety of underlying conditions, up to 50% of reported cases are idiopathic. Treatment options have traditionally involved human FVIII or FIX replacement therapy (if the inhibitor titre allows), porcine FVIII or the use of activated pro-thrombin complex concentrates. Recombinant activated coagulation FVII (rFVIIa) was available on an emergency and compassionate use basis from 1988 to 1999 at sites in Europe and North America. It has been registered in Europe for use in treating acquired haemophilia since 1996 and has recently been licensed for this indication in the United States. By directly activating FX on the surface of activated platelets at the site of injury (thereby bypassing FVIII and FIX), rFVIIa can circumvent the actions of inhibitory antibodies present in acquired haemophilia patients. This paper provides an overview of experiences with rFVIIa for the treatment of acquired haemophilia from the NovoSeven compassionate and emergency use programmes (1989-1999), the Hemophilia and Thrombosis Research Society Registry, and independent published reports from January 1999 to September 2005. rFVIIa has been reported to provide safe and effective haemostasis as a first line therapy in patients of all ages for a variety of surgical and non-surgical bleeding situations.

Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry

Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg(-1) every 2-3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90-300 mcg kg(-1). High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100-150, 150-200 and >200 mcg kg(-1). Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1-55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg(-1) (range: 40-4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P < 0.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100-150, 0% for 150-200, <1% for >200 mcg kg(-1) dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346 mcg kg(-1) appear to be well-tolerated. Additionally, rFVIIa doses >200 mcg kg(-1) appear to significantly increase efficacy (97% in the high-dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high-dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.