Experience of four UK comprehensive care centres using FEIBA® for surgeries in patients with inhibitors

Summary. Increasing evidence indicates that factor VIII (FVIII) inhibitor bypassing agents (FEIBA^® and NovoSeven^®) can provide effective peri‐operative haemostasis in haemophilia patients with high‐responding inhibitors. We report the collected experience of all major and minor surgeries, conducted between December 1998 and September 2008, at four UK haemophilia Comprehensive Care Centres with FEIBA^® as the first‐line bypassing agent in patients with inhibitors. A total of 26 surgical procedures were performed in 18 patients of ages 34–83 years including five patients with acquired FVIII inhibitors. A single pre‐operative infusion of FEIBA was followed by 6–12 h interval dosing for major surgeries at the discretion of the physician to approximate a maximum of 200 U kg^?1 day^?1, with tapering when postoperative haemostasis and wound healing permitted. Haemostatic outcomes were retrospectively reviewed against European consensus thresholds for blood loss and duration of treatment compared with expectations for equivalent procedures in non‐inhibitor patients. Peri‐operative haemostatic outcome with FEIBA was rated excellent or good in 78% of 18 major surgeries in 12 patients, including 11 major orthopaedic procedures. Haemostatic outcome was rated excellent in all seven procedures in five patients with acquired FVIII inhibitors and in all eight minor surgical procedures in six patients. FEIBA was well tolerated with no intra‐operative haemostatic complications. A single, transient postoperative thrombotic adverse event occurred in a patient with cerebrovascular disease. This case series adds significantly to existing evidence that FEIBA can provide adequate, well‐tolerated, peri‐operative haemostatic cover for a wide variety of major and minor surgical procedures.     

Low incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A treated with octanate®: Final report from a prospective study

Introduction

Octanate^® is a human, plasma‐derived, von Willebrand factor‐stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A.

Aim

This prospective, open‐label study aimed to assess the immunogenicity of octanate^® in previously untreated patients (PUPs).

Methods

The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate^® for the prevention and treatment of bleeds and in surgical procedures were also assessed.

Results

Five (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate^® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on‐demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as “excellent” in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated “very good” in 99.9% of infusions.

Conclusion

In PUPs with severe haemophilia A, octanate^® demonstrated haemostatic efficacy with a low rate of inhibitor development.     

Long‐term tolerability,immunogenicity and efficacy of Nuwiq® (human‐cl rhFVIII) in children with severe haemophilia A

Introduction

Nuwiq^® (human‐cl rhFVIII, simoctocog alfa) is a 4th generation recombinant human FVIII, without chemical modification or fusion with any other protein, produced in a human cell line.

Aim/Methods

This study (GENA‐13) was an extension of the GENA‐03 study in which previously treated children aged 2‐12 years with severe haemophilia A received Nuwiq^® prophylaxis for ≥6 months. GENA‐13 examined long‐term tolerability, immunogenicity and efficacy of Nuwiq^® prophylaxis in children.

Results

Of 59 patients enrolled in GENA‐03, 49 continued Nuwiq^® prophylaxis in GENA‐13 for a median (range) of 30.0 (9.5‐52.0) months. No patient withdrew due to drug‐related adverse events or developed inhibitors. Only 2 of 20 518 infusions were associated with possibly related adverse events (dyspnoea, fever). The estimated annualized bleeding rate (ABR) was 0.67 (95% CI: 0.44, 1.02) for spontaneous and 2.88 (95% CI: 1.86, 4.46) for all bleeds. Younger children (2‐5 years) had lower ABRs than children aged 6‐12 years. Annualized bleeding rates were reduced in GENA‐13 vs GENA‐03, especially for spontaneous bleeds in younger children (71% reduction; ABR ratio 0.29 [95% CI: 0.11, 0.74]). Nuwiq^® efficacy was rated as excellent/good in the treatment of 83.0% of 305 evaluated breakthrough bleeds. Surgical prophylaxis with Nuwiq^® was rated as excellent for all 17 assessed procedures.

Conclusion

Long‐term treatment with Nuwiq^® for the prevention of bleeds in children with severe haemophilia A was well tolerated, effective and reduced spontaneous bleeding by up to 70% compared with GENA‐03.     

Safety and efficacy of turoctocog alfa (NovoEight®) during surgery in patients with haemophilia A: results from the multinational guardian™ clinical trials

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prevention and treatment of bleeding episodes in patients with haemophilia A. The present investigations from the multinational, open‐label guardian^? clinical trials assessed the haemostatic response of turoctocog alfa (NovoEight^®), a rFVIII product, in patients with severe haemophilia A (FVIII ≤ 1%) undergoing surgery. All patients had a minimum of 50 exposure days to any FVIII product prior to surgery and no history of inhibitors. A total of 41 procedures (13 orthopaedic, 19 dental and 9 general) were performed in 33 patients aged 4–59 years. Of the 41 procedures, 15 were major surgeries in 13 patients and 26 were minor surgeries in 21 patients. The success rate for haemostatic response was 100% (success was defined as ‘excellent’ or ‘good’ haemostatic outcome). Turoctocog alfa consumption on the day of surgery ranged from 27 to 153 IU kg^?1. The mean daily dose declined over time, while retaining adequate FVIII coverage as measured by trough levels. Overall, no safety issues were identified. No thrombotic events were observed and none of the patients developed FVIII inhibitors. In conclusion, the present results show that turoctocog alfa was effective in controlling blood loss by obtaining a sufficient haemostatic response in patients with severe haemophilia A undergoing surgery.     

Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment

Introduction

Patients with Von Willebrand disease (VWD) are regularly treated with VWF‐containing concentrates in case of acute bleeding, trauma and dental or surgical procedures.

Aim

In this multicentre retrospective study, current perioperative management with a von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate (Haemate^® P) in patients with VWD was evaluated.

Patients/Methods

Patients with VWD undergoing minor or major surgery between 2000 and 2015, requiring treatment with a VWF/FVIII concentrate (Haemate^® P), were included. Achieved VWF activity (VWF:Act) and FVIII during FVIII‐based treatment regimens were compared to predefined target levels in national guidelines.

Results

In total, 103 patients with VWD (148 surgeries) were included: 54 type 1 (73 surgeries), 43 type 2 (67 surgeries) and 6 type 3 (8 surgeries). Overall, treatment resulted in high VWF:Act and FVIII levels, defined as ≥0.20 IU/mL above predefined levels. In patients with type 1 VWD, respectively, 65% and 91% of trough VWF:Act and FVIII levels were higher than target levels. In patients with type 2 and type 3 VWD, respectively, 53% and 57% of trough VWF:Act and 72% and 73% of trough FVIII levels were higher than target level. Furthermore, FVIII accumulation over time was observed, while VWF:Act showed a declining trend, leading to significantly higher levels of FVIII than VWF:Act.

Conclusion

High VWF:Act and accumulation of FVIII were observed after perioperative FVIII‐based replacement therapy in patients with VWD, both underlining the necessity of personalization of dosing regimens to optimize perioperative treatment.     

Experience of recombinant activated factor VII usage during surgery in patients with haemophilia with inhibitors

Inhibitor development is one of the most challenging complications of haemophilia management. Haemostatic control in patients with haemophilia with inhibitors can be difficult, and is especially risky in those undergoing surgical interventions. Most haemophilia patients with inhibitors suffer from chronic joint disease requiring surgical correction due to recurrent bleeding episodes. The aim of this study was to assess the use of recombinant activated factor VII (rFVIIa) as haemostatic therapy during orthopaedic surgery in haemophilia patients with inhibitors. A series of case reports was retrospectively collected to describe clinical experience of rFVIIa use in inhibitor patients undergoing a range of orthopaedic surgical procedures at a single centre. All surgeries were performed using standard methods. All patients received rFVIIa at a starting dose of 120 μg kg^?1 with the subsequent regimens depending on the type of surgery. rFVIIa provided effective haemostasis in 23 patients with haemophilia A and inhibitors (15 with high inhibitor titres) undergoing orthopaedic surgery. The majority (70%) of surgical procedures were major (joint and extra‐articular surgery). The doses and intervals of rFVIIa treatment used varied depending on the severity of bleeding, and the type (major or minor) or site of surgery. In all cases, administration of rFVIIa achieved good haemostasis. In all 23 patients with haemophilia with inhibitors, rFVIIa treatment in orthopaedic interventions proved to be an efficient haemostatic agent, providing effective intra‐operative and postoperative haemostasis.     

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis,on‐demand treatment and surgical procedures,with Octanate®: interim report from an ongoing prospective clinical study

Summary. For patients with haemophilia A (HA), lifelong replacement therapy with factor VIII (FVIII) concentrates is the treatment of choice. Octanate^® is a plasma‐derived, human, von Willebrand factor‐stabilized FVIII product with demonstrated haemostatic efficacy in patients with HA. The aim of this ongoing study is to assess the immunogenicity of Octanate^® in previously untreated patients (PUPs), monitoring for development of FVIII inhibitors. Interim data on 39 PUPs treated for bleeding, prophylactically and for surgical coverage are reported. Two of 39 subjects (5.1%) developed clinically relevant inhibitor titres over the course of the study. Another two displayed inhibitors that disappeared spontaneously without Octanate^® dose change. All inhibitors developed under on‐demand treatment and before exposure day (ED) 50. Remarkably, no inhibitor was observed in PUPs receiving prophylaxis with Octanate^®. Of 39 subjects, 30 had exceeded 50 EDs at the time of this analysis. All inhibitor subjects were found to have large FVIII gene defects, either intron 22‐inversions or large deletions. Octanate^® was well‐tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy of Octanate^® in prophylaxis and treatment of bleeding were generally rated as ‘excellent’, and no complication was reported for surgery. Notable FVIII activity was present in blood at 15 min postadministration, and levels remained high at 1 h. Mean incremental in vivo recovery (IVR) was 2.0 (±0.6) % IU^?1kg^?1. These interim results indicate Octanate^® to be an efficacious, well‐tolerated human FVIII product for management of HA in PUPs, associated with a minimal risk of inhibitors.     

Long-term immunogenicity,efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients

Background

The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq^®) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A.

Methods

Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study.

Results

Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%–88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0–0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0–1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported.

Conclusion

No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.     

An ultrapure plasma‐derived monoclonal antibody‐purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies

Summary. Nonafact^®, an ultrapure, monoclonal antibody‐purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half‐life, in vivo response and recovery of Nonafact^® were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL^?1 per IU kg^?1 b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high‐risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow‐up study, 26 previously treated patients (PTP) were included with a median follow‐up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow‐up studies the investigators rated the effect of Nonafact^® as excellent/good in 95% of major bleedings. Surgeries for which Nonafact^® was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact^® were used during almost 120 person‐years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact^® is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact^® is cost saving compared to other FIX products.     

Safety and efficacy of plasma‐derived coagulation factor IX concentrate (AlphaNine® SD) in patients with haemophilia B undergoing surgical intervention: a single institution retrospective analysis

Summary. While coagulation factor replacement is essential in surgical intervention in haemophilia B patients, few studies are available on the safety and efficacy of plasma‐derived factor IX (FIX) for haemostasis during surgery. This retrospective study examined outcomes in these patients. A total of 20 patients who underwent 29 surgical procedures at the Hemophilia Treatment Center at Orthopaedic Hospital in Los Angeles, California, were identified and their inpatient charts were reviewed and abstracted. Outcomes included pre‐ and postoperative FIX dosing, recovery of FIX, blood loss, use of blood products, safety and haemostatic response. Identified patients had mild (10%), moderate (15%) or severe (75%) haemophilia B, and average age at surgery was 48.5 years. All surgical procedures were major (orthopaedic 89.7%; abdominal 10.3%), all were completed under general anaesthesia, and average time in surgery was 3.25 h. Average hospital length of stay was 11.0 days [standard deviation (SD) = 8.5] and all patients were discharged home. All patients were treated with AlphaNine^® SD at an average dose of 254.9 IU kg^?1 (SD = 65.4) on the day of surgery and the dose was adjusted over the course of hospital stay. Mean perioperative blood loss was 255.5 mL (SD = 283.1) and blood replacement was required in only two surgeries (6.9%). FIX recovery analysis performed preoperatively related well to FIX levels obtained. Identified patients had little blood loss perioperatively and had no bleeding related complications. Plasma‐derived FIX pre‐ and postoperatively appeared to be a safe and effective treatment in haemophilia B patients undergoing surgery.     

Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin‐free recombinant factor VIII product (ADVATE®)

Summary. Previous studies have suggested that development of inhibitors in previously treated patients (PTPs) may be attributable to a switch in factor VIII (FVIII) therapeutic product. Consequently, it is widely recognized that inhibitor development must be assessed in PTPs following the introduction of any new FVIII product. Following a national tender process in 2006, all patients with haemophilia A in Ireland changed their FVIII treatment product en masse to a plasma and albumin‐free recombinant full‐length FVIII product (ADVATE^®). In this study, we retrospectively reviewed the case records of Irish PTPs to evaluate risk of inhibitor formation following this treatment switch. One hundred and thirteen patients participated in the study. Most patients (89%) had severe haemophilia. Only one of 96 patients with no inhibitor history developed an inhibitor. Prior to the switch in his recombinant FVIII (rFVIII) treatment of choice, this child had only experienced three exposure days (EDs). Consequently, in total he had only received 6 EDs when his inhibitor was first diagnosed. In keeping with this lack of de novo inhibitor development, we observed no evidence of any recurrent inhibitor formation in any of 16 patients with previously documented inhibitors. Similarly, following a previous en masse switch, we have previously reported that changing from a Chinese hamster ovary cell‐produced to a baby hamster kidney cell‐produced rFVIII was also associated with a low risk of inhibitor formation in PTPs. Our cumulative findings from these two studies clearly emphasizes that the risk of inhibitor development for PTPs following changes in commercial rFVIII product is low, at least in the Irish population.     

Efficacy of a sucrose-formulated recombinant factor VIII used for 22 surgical procedures in patients with severe haemophilia A.

A sucrose-formulated recombinant FVIII (rFVIII-SF) was investigated under clinical trial conditions during surgical procedures in previously treated patients (PTPs). Fifteen PTPs with severe haemophilia A (FVIII < or = 1%) underwent 22 surgical procedures. The procedures performed cover a spectrum from minor to major surgery. Haemostatic outcome was assessed by the investigators to be excellent in 16 procedures and good in the remaining six procedures. It is concluded that rFVIII-SF is efficacious and safe in severe haemophilia A patients undergoing minor or major surgery.     

Surgery in patients with haemophilia and high responding inhibitors: Izmir experience

Summary. This report evaluates the haemostatic efficacy of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) in patients with haemophilia and high responding inhibitors who underwent major and minor surgery. Data pertaining to surgeries from 2001 to 2009 at a single centre were retrospectively analysed. During this period, 53 surgical procedures were performed in 30 haemophiliacs with high responding inhibitors. Mean age was 16.2 ± 9.4 years. Eleven major surgeries in 4 patients, 41 radioisotope synovectomies (RS) and one circumcision classified as minor surgery in 28 patients were performed. Among the major surgery procedures, four were treated with rFVIIa, five with APCC and two with sequential use of APCC and rFVIIa. We used rFVIIa at the dosage of 80–120 μg kg^?1 every 2 h and APCC 100 IU kg^?1 every 12 h for the major surgery. When performing RS, we used rFVIIa in 18 patients with 26 target joints and APCC in 9 patients with 15 target joints. Three consecutive doses of rFVIIa (90 μg kg^?1) were used at 2‐h intervals followed by additional three doses at 6‐h intervals. The initial dose of APCC was 75 IU kg^?1 followed by a second and third dose of 50 IU kg^?1 at 12‐h intervals. APCC and rFVIIa demonstrated excellent efficacy in our major and minor surgical interventions [100% (22/22) and 94% (31/33), respectively]. We had only two bleeding complications with rFVIIa. There were no thromboembolic complications. APCC and rFVIIa provide an effective and safe first line haemostatic therapy for inhibitor‐positive haemophiliacs, allowing both major and minor surgery to be successfully performed.     

Long‐acting recombinant factor IX Fc fusion protein (rFIXFc) for perioperative management of subjects with haemophilia B in the phase 3 B‐LONG study

In the phase 3 B‐LONG (Recombinant Factor IX Fc Fusion Protein [rFIXFc] in Subjects With Haemophilia B) study, rFIXFc demonstrated a prolonged half‐life compared with recombinant factor IX (rFIX), and safety and efficacy for prophylaxis and treatment of bleeding in subjects with moderately‐severe to severe haemophilia B. In this B‐LONG sub‐analysis, rFIXFc was evaluated for efficacy in subjects requiring major surgery. Dosing was investigator‐determined. Assessments included dosing, consumption, bleeding, transfusions and haemostatic response. A population pharmacokinetics model of rFIXFc was used to predict FIX activity. Twelve subjects underwent 14 major surgeries (including 11 orthopaedic surgeries); most subjects (11/12) received rFIXFc prophylaxis before surgery (range, ~2 weeks–12 months). Investigators/surgeons rated haemostatic responses as excellent (n = 13) or good (n = 1). In most surgeries (85·7%), haemostasis from the pre‐surgical dose until the end of surgery was maintained with a single rFIXFc infusion. Blood loss was consistent with similar surgeries in subjects without haemophilia. The strong correlation (R² = 0·9586, P < 0·001) between observed and population pharmacokinetic model‐predicted FIX activity suggests surgery did not impact rFIXFc pharmacokinetics. No unique safety concerns or inhibitors were observed. In conclusion, rFIXFc was safe and efficacious, with prolonged dosing intervals and low consumption, when used perioperatively in haemophilia B. Surgery did not appear to alter rFIXFc pharmacokinetics.     

Successful surgical haemostasis in patients with von Willebrand disease with Koate®DVI

Summary. This report describes our experience with Koate^®DVI, a factor VIII (FVIII) concentrate containing von Willebrand factor (VWF) for surgery in patients with von Willebrand’s disease (VWD). Twenty‐one patients underwent 26 procedures, 10 of which were major and 16 were minor. The median age was 27 years (3–55) and the mean weight was 52 kg (16–88). Among the ten patients (type 2–5; type 3–5) who underwent major procedures, the pre‐operative dose was 35 IU kg^?1 of FVIII followed by 10–20 IU kg^?1 once daily depending on FVIII:C levels. The mean total dose of FVIII used per procedures was 106 IU kg^?1 (30–190) over a mean duration of 7 days (3–11). In this group, pre‐infusion FVIII:C, VWF:Ag and VWF: ristocetin cofactor (RCoF) level that were 19.5% (1–64), 20 U dL^?1 (0–96) and 12% (0–66) increased to 72% (54–198), 131 U dL^?1 (68–206) and 68% (27–108) postinfusion, respectively. Sixteen minor procedures were performed in 11 patients (type 1–3, type 2–6, type 3–2). The preparative dose of FVIII was 10–20 IU kg^?1. The average duration of factor support was 2 days (1–3) for a mean total dose of 23 IU kg^?1 (9–60). The pre‐infusion levels of FVIII:C, VWF:Ag and VWF:ristocetin cofactor (RCo) which were 31% (22–64), 25.5 U dL^?1 (0–63) and 21% (0–76), respectively, increased to 76% (27–111), 73 U dL^?1 (30–137) and 45% (2–106) postinfusion. Whereas surgical haemostasis was achieved in all patients, minor postoperative bleeding occurred after one procedure in each group. Both were controlled with additional doses of factor replacement. We conclude that Koate^®DVI in modest doses provide adequate haemostasis for surgery in patients with VWD.     

The clinical efficacy and safety of the FVIII/VWF concentrate,BIOSTATE®, in children with von Willebrand disorder: a multi‐centre retrospective review

Summary. Factor replacement with BIOSTATE^®, a factor VIII (FVIII)/von Willebrand factor concentrate, forms the mainstay of treatment for children with von Willebrand disorder (VWD) in Australia and New Zealand. However, published data on the clinical efficacy and safety of BIOSTATE in the VWD paediatric population are limited. We retrospectively assessed the efficacy and safety of BIOSTATE in 43 children with VWD who received treatment for surgery, non‐surgical bleeds or continuous prophylaxis at eight paediatric haemophilia centres in Australia and New Zealand. Data were collected on patient demographics, disease history, treatment history, dosage, administration, adverse reactions, concomitant medications and excessive bleeding events. BIOSTATE provided excellent/good haemostatic efficacy in 90% of surgical procedures (n = 42) with a mean daily FVIII dose of 47 IU FVIII:C kg^?1 and a median treatment duration of 3 days. Excellent/good haemostatic efficacy was achieved in 94% of non‐surgical bleeding events (n = 72) with a mean FVIII dose of 45 IU FVIII:C kg^?1 day^?1 and a median treatment duration of 1 day. There were no bleeding events attributable to lack of efficacy. One case of nausea, possibly related to BIOSTATE administration, was reported. These results suggest that BIOSTATE is safe and effective for the treatment and prophylaxis of bleeding in children with VWD.     

Elective surgery in patients with congenital coagulopathies and inhibitors: experience of the National Haemophilia Centre of Venezuela

Summary. Elective surgery in patients with congenital haemophilia with inhibitors carries a high risk of bleeding. However, inhibitor patients also have a high risk of haemarthroses and other orthopaedic complications, and surgery could improve their quality of life. Successful elective surgery has been reported in inhibitor patients under haemostatic cover with plasma‐derived activated prothrombin complex concentrate (pd‐aPCC) or recombinant activated factor VII (rFVIIa). Recombinant FVIIa has recently become available in Venezuela and, unlike pd‐aPCC, has not been associated with an anamnestic response. The aim of this study was to assess our experience using rFVIIa as a first‐line and sustained treatment in elective invasive surgical procedures at the National Haemophilia Centre in Venezuela. Surgical procedures were classified as major or minor, under haemostatic cover with rFVIIa. A total of 13 patients (12 with haemophilia A with high‐responding inhibitors and one with von Willebrand’s disease type 3) underwent a total of 19 surgical procedures under rFVIIa cover. Thirteen procedures were classified as major surgeries. Intraoperative haemostasis was achieved in the majority of patients. Only two patients required an additional dose of rFVIIa, at 30 min and 75 min, respectively, with good results. Postoperative haemostasis was considered effective in 16 of 18 (89%) of the procedures in haemophilia A patients. Treatment was considered to be ineffective in two patients because of excessive postoperative bleeding. Data from the study provide no safety concerns, and demonstrate that rFVIIa provides effective haemostatic cover in elective surgery in patients with inhibitors; research is ongoing to determine the optimal dose for such procedures.     

Clinical efficacy,safety and pharmacokinetic properties of the plasma‐derived factor IX concentrate Haemonine® in previously treated patients with severe haemophilia B

Summary. Plasma‐derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine ^® is a high purity double‐virus inactivated human plasma‐derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open‐label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long‐term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on‐demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half‐life. Mean terminal elimination half‐life was 27.6 h and 25.0 h, mean incremental recovery (IU dL^?1/IU kg^?1) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as ‘excellent’ or ‘good’. Moreover, ‘excellent’ haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long‐term prophylaxis, TOD and when applied after minor and major surgeries.     

Pharmacokinetics and ex vivo whole blood clot formation of a new recombinant FVIII (N8) in haemophilia A dogs

Summary. N8, a new recombinant factor VIII (rFVIII) compound developed for the treatment of haemophilia A, is produced in Chinese hamster ovary (CHO) cells and formulated without human‐ or animal‐derived materials. The aim of the present study was to compare the pharmacokinetics (PK) and the procoagulant effect, measured by ex vivo whole blood clot formation, of N8 and a commercial rFVIII in a cross‐over study in haemophilia A dogs. N8 and Advate^® (100 IU kg^?1) were administered intravenously to three haemophilia A dogs. Blood was sampled between 0 and 120 h postdose and FVIII:C analysed. PK parameters maximum plasma concentration, area under the curve, half‐life (t_½), clearance, mean residence time (MRT) and volume of distribution and incremental recovery were calculated. Whole blood clotting time (WBCT) and thromboelastography (TEG^®) were used to determine the haemostatic potential. No adverse reactions were observed with N8 or Advate^®. N8 and Advate^® exhibited similar PK parameters, with t_½ 7.7–11 h and MRT 11–14 h. Both rFVIII compounds corrected the prolonged WBCT (>48 min) to the range of normal dogs (8–12 min), i.e. N8 to 7.5–10.5 min and Advate^® to 7.5–11.5 min. N8 and Advate^® also normalized the whole blood clot formation according to TEG^®. The native whole blood clotting assays (WBCT, TEG^®) appeared to be more sensitive to low concentrations of FVIII than assays in citrated plasma samples. In conclusion, comparison of N8 and Advate^® in haemophilia A dogs revealed similar safety, similar PK and similar effects in whole blood clot formation assays.     

Major orthopaedic surgeries for haemophilia with inhibitors using rFVIIa

Summary. Between 2000 and 2008, 11 major orthopaedic surgeries for 7 congenital haemophilia patients with inhibitors were performed by the first author as the primary doctor using recombinant activated factor VII (rFVIIa). Orthopaedic surgical treatments were performed for six surgeries for four high‐responder haemophilia A patients, three surgeries for two high‐responder haemophilia B patients and two surgeries for one low‐responder haemophilia B patient. This low‐responder patient is allergic to factor IX products, so he usually uses rFVIIa as a haemostatic agent. All of the surgeries were major, such as joint arthroplasty, arthroscopic synovectomy, and a combination of both, and excellent surgical results were achieved. Seven cases were controlled by bolus infusion of rFVIIa, and the other four cases were controlled by combined bolus and continuous infusion of rFVIIa. An anti‐fibrolytic agent was used for all cases. There were no thrombogenic adverse effects, only two bleeding episodes. As for haemostatic control, nine surgeries were excellent, one was good and one was fair. This report is the largest clinical report on major orthopaedic surgeries at a single institute. We have concluded that the combination of bolus and continuous infusion of rFVIIa is safe and effective, and more convenient to administer than simple bolus infusion therapy to achieve haemostasis at peri‐operative periods. In addition, our data also concurs with the data of several previous reports which showed that orthopaedic surgery for haemophilia patients with inhibitors by means of rFVIIa is safe and effective.