Clinical efficacy and safety of the factor VIII/von Willebrand factor concentrate BIOSTATE® in patients with von Willebrand’s disease: a prospective multi‐centre study

Summary. von Willebrand’s disease (VWD) is an inherited bleeding disorder characterized by deficient levels of or dysfunctional von Willebrand factor (VWF). This phase II/III open‐label, multicentre study evaluated the efficacy and safety of BIOSTATE^®, a high purity plasma‐derived double‐virus inactivated FVIII/VWF concentrate, when used in non‐surgical bleeds, surgical procedures and prophylactic therapy in VWD patients for whom desmopressin treatment was deemed ineffective, inadequate or contraindicated. Twenty three patients (7 type 1, 9 type 2 and 7 type 3; 12 male, 11 female), who received FVIII/VWF concentrate as part of their VWD management, were recruited prospectively between December 2004 and May 2007 from eight centres in Australia and New Zealand. BIOSTATE dosing was based on pre‐treatment FVIII:C and/or VWF:RCo plasma levels and a predetermined dosing guide. Haemostatic efficacy of BIOSTATE was rated as excellent or good for all major and minor surgery events, long‐term prophylaxis, and for four of the six assessable non‐surgical bleeding events. Blood transfusions were required by two major surgery patients as well as one patient with a non‐surgical bleed. The median overall exposure to BIOSTATE across all groups was 8 days, greater in the prophylactic group (range 53–197) compared with major surgery (3–24), minor surgery (1–8) and non‐surgical bleeds (1–10). BIOSTATE was shown to be efficacious and well tolerated when treating patients with VWD. This study also provides important insights into dosing regimens with BIOSTATE and the role of monitoring therapy with FVIII:C and VWF:RCo.     

Clinical efficacy in bleeding and surgery in von Willebrand patients treated with Fanhdi® a highly purified,doubly inactivated FVIII/VWF concentrate

Summary. Therapy with factor VIII/von Willebrand factor (FVIII/VWF) concentrate is the mainstay therapy in patients with von Willebrand disease (VWD) unresponsive to desmopressin. There are several commercially available FVIII/VWF concentrates that have been tested in VWD patients. We retrospectively analized the clinical efficacy in bleeding episodes and surgery of a highly purified FVIII/VWF complex with two inactivation steps (Fanhdi^®) in VWD patients. Sixty patients were included in the study. Treatment schedule consisted of one or more doses (standard dose 40 IU/kg body weight of FVIII) of Fanhdi^®. One hundred and fifty bleeding episodes were treated. These were: 28 serious bleedings; 92 moderate and 30 mild. An excellent clinical efficacy in almost 95% of cases was observed. Fanhdi^® was administered during 66 surgical procedures (38 major and 28 minor) with an overall efficacy of 98%. Fanhdi^® a highly purified, doubly virus‐inactivated FVIII/VWF concentrate, with a high content of active VWF and an excellent record of clinical safety, is a valid choice in treating VWD.     

Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi®) in the treatment of von Willebrand disease: a retrospective clinical study

The goal of therapy in patients with von Willebrand disease (vWD) is to correct the dual defect of primary haemostasis and intrinsic coagulation reflected by low levels of von Willebrand factor (vWF) and factor VIII coagulant activity (FVIII:C). Factor VIII/von Willebrand factor (FVIII/vWF) concentrates are currently the treatment of choice in vWD patients unresponsive to desmopressin (DDAVP). However, only few studies on their clinical use are available so far. The main objective of this study was to retrospectively evaluate the clinical efficacy of a highly purified, doubly virus-inactivated FVIII/vWF concentrate with a high content of FVIII/vWF (Fanhdi). Twenty-two patients with congenital vWD have been treated from 1999 to 2001 at eight specialized centres belonging to the Italian Association of Hemophilia Centers (AICE). Ten males and 12 females, median age 28.5 years, range 5-70 years) had type 3 vWD (six cases), DDAVP-unresponsive type 1 (nine cases) and type 2B (seven cases). The study drug was given to stop or prevent 12 bleeding episodes or to prevent excessive bleeding during 14 surgical or invasive procedures. Overall, replacement therapy with the concentrate showed an excellent to good clinical efficacy in 92% of bleeding episodes and in 93% of surgical procedures. No adverse events occurred during 1,601 infusions, accounting for a total of 304,500 IU of FVIII:C administered. These results confirm the efficacy and safety of this concentrate in the management of bleeding episodes and in the prevention of excessive bleeding during major and minor surgery.     

Efficacy and safety of a high purity, double virus inactivated factor VIII/von Willebrand factor concentrate (Biostate®) in patients with von Willebrand disorder requiring invasive or surgical procedures

Biostate is a double virally inactivated, plasma derived coagulation factor VIII (FVIII)/von Willebrand factor (VWF) concentrate registered and used in Australia, New Zealand and Asia for the treatment of patients with haemophilia A. Although Biostate has been well characterized for FVIII and VWF (ratio 1:2 respectively) and shows a similar VWF multimeric pattern to normal plasma, limited published data is available on its clinical efficacy and safety in patients with von Willebrand disorder (VWD) who require surgical procedures. We retrospectively assessed the efficacy and safety of Biostate in all VWD patients treated at three Australian haemophilia treatment centres undergoing invasive procedures or surgery over a 29-month period between April 2003 and September 2005. A chart review of 43 VWD patients (26 VWD type 1, 12 VWD type 2, 5 VWD type 3; 21 male, 22 female; mean age 52 years, range 19-80 years) undergoing 58 surgical procedures (24 major, 34 minor) was performed. For each procedure, data were collected on Biostate dosage and administration, adverse reactions, haemostatic efficacy and bleeding events. Haemostatic efficacy of Biostate was assessed as excellent in 78% or good in 22% of procedures. There were no bleeding events attributable to lack of efficacy in any patients. No adverse reactions related to the administration of Biostate were observed. These results suggest that Biostate is both safe and efficacious for the prevention of excessive bleeding in VWD patients undergoing surgery or invasive procedures.     

Treatment and prevention of acute bleedings in von Willebrand disease – efficacy and safety of Wilate®, a new generation von Willebrand factor/factor VIII concentrate

Summary.  For many patients with von Willebrand disease (VWD), the replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is the treatment of choice. To evaluate clinical efficacy, safety and tolerability of Wilate^®, an albumin-free VWF/FVIII concentrate with a ratio of the two haemostatic moieties of approximately 1 to 1, a prospective clinical programme has been designed. The dataset on the treatment and prevention of bleedings is derived from 44 patients (20 males and 24 females) of all VWD types. Thousand and ninety five bleeding episodes were treated with an overall efficacy rating of excellent or good in 96%. The median dose per treatment day was 26 IU FVIII:C per kg. Eighty-one per cent of bleeds were stopped within 1 or 2 days. Gastrointestinal (GI) bleeds needed higher doses (mean 44 IU kg⁻¹) and longer treatment (mean 4 days). Efficacy and dosing data from eight children of 12 or less years of age did not differ significantly from the overall study population. Nineteen patients, including six children, were treated prophylactically for more than 3 months (mean 14.8, range 3–46) with a mean prophylactic dose of 27.4 IU kg⁻¹ and a mean frequency of 1.9 infusions per week. A drop of bleeding frequency from a mean of 4.5 to 1.4 bleeds per month was observed. The overall tolerability was very good. Adverse drug reactions were rare and were mild or moderate in their intensity. The large prospective clinical dataset shows that Wilate^® is efficacious and safe in the treatment and prevention of haemorrhages in all VWD types in both adult and paediatric patients.     

von Willebrand disease: an update in the Åland islandsSummary of a Nordic Symposium on von Willebrand disease, 24–25 September 1998, Mariehamn, Åland

In the past decades von Willebrand disease (vWD) has, in several respects, fallen into the shadow of classical haemophilia due to all problems that have faced those dealing with congenital bleeding disorders, not least regarding blood-borne diseases. The time has come to revisit and refocus on vWD, probably the most common bleeding disorder. Accordingly, a number of Nordic physicians and scientists working in this field organized a meeting on the ferry boat from Stockholm to Mariehamn, in the Åland islands, the home of the index families with this disease, as described by Erik von Willebrand in 1926. The objective of the meeting was to make a comprehensive survey of vWD as seen from the situation in the Nordic countries. In order to achieve all goals some scientists of note from countries outside the Nordic area were invited as well.
This paper gives a summary of the symposium, mainly based on the separate papers published in this issue.     

Wilate use in 47 children with von Willebrand disease: the North London paediatric haemophilia network experience

Children with von Willebrand disease (VWD) in whom DDAVP is ineffective or contraindicated require treatment with a coagulation factor concentrate containing von Willebrand factor (VWF) and factor VIII (FVIII). The aim of this study was to monitor the safety, efficacy and tolerability of Wilate^® (a VWF:FVIII concentrate with a 1:1 ratio) used across the North London Paediatric Haemophilia Network since May 2010. In total, 47 children (aged 0.0–17.0 years) with type 1 (n = 28), type 2 (n = 7), type 3 (n = 10) and acquired VWS (n = 2) have been treated for bleeds, surgery and/or prophylaxis using 260 000 IU Wilate^®. Analysis of dose and frequency of treatment show expected responses to treatment with mean doses of 55, 50 and 50 IU kg^?1 for bleeds, surgery and prophylaxis respectively. Most bleeds responded to a single treatment. Surgical procedures were covered with clinician approved dosing schedules with 95% (39/41) reported as having excellent or good efficacy. There was no accumulation of FVIII or VWF and no thromboembolic events. This case series confirms the efficacy, safety and tolerability of Wilate^® in neonates, children and adolescents when used on‐demand, prophylactically and in the surgical setting.     

von Willebrand disease: an update in the Åland islandsSummary of a Nordic Symposium on von Willebrand disease, 24–25 September 1998, Mariehamn, Åland

In the past decades von Willebrand disease (vWD) has, in several respects, fallen into the shadow of classical haemophilia due to all problems that have faced those dealing with congenital bleeding disorders, not least regarding blood-borne diseases. The time has come to revisit and refocus on vWD, probably the most common bleeding disorder. Accordingly, a number of Nordic physicians and scientists working in this field organized a meeting on the ferry boat from Stockholm to Mariehamn, in the Åland islands, the home of the index families with this disease, as described by Erik von Willebrand in 1926. The objective of the meeting was to make a comprehensive survey of vWD as seen from the situation in the Nordic countries. In order to achieve all goals some scientists of note from countries outside the Nordic area were invited as well. This paper gives a summary of the symposium, mainly based on the separate papers published in this issue.     

Efficacy of factor VIII/von Willebrand factor concentrate Alphanate® in preventing excessive bleeding during surgery in subjects with von Willebrand disease

Summary.  The adequacy of perioperative haemostasis with a high-purity, plasma-derived factor VIII product containing von Willebrand factor was retrospectively evaluated in 39 patients with type 1, 2 or 3 von Willebrand disease who underwent 61 major or minor surgical or invasive procedures. Overall, 93.5% of the responses to treatment were rated as excellent or good by the physician investigators. These ratings were confirmed by an independent panel of physician referees.     

Application of UKHCDO 2004 guidelines in type 1 von Willebrand Disease ‐ a single centre paediatric experience of the implications of altered or removed diagnosis

Summary. Diagnosis of type I von Willebrand Disease (VWD) can be challenging. In 2004, the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) proposed more stringent diagnostic criteria to replace the 1995 guidelines. To determine the true number of cases of type 1 VWD in a single paediatric centre, the 2004 UKHCDO Guideline for the diagnosis of VWD was used to evaluate 114 patients on our type 1 VWD register. Clinical and laboratory data were collected and analysed to see whether they met the criteria for type 1 VWD. Only 8% remained on the type 1 VWD register. 18% have been classified as ‘possible type 1 VWD’. Twenty five surgical procedures have since been performed on patients from the group in which the diagnosis was removed without any haemostatic support or bleeding complications. Reaction to the removal of the VWD diagnosis or delivery of an alternative diagnosis was positive for most patients and families. This study is the first to assess the impact of the 2004 UKHCDO Guidelines on the diagnosis of VWD. It provides evidence that the prevalence of type 1 VWD may actually be closer to that of haemophilia instead of the previously reported 1–3% of the general population. We propose that all centres should review their patients with a diagnosis of VWD to revalidate this disease that claims to be our most common inherited bleeding disorder.     

Repeated infusions of VWF/FVIII concentrate: impact of VWF:FVIII ratio on FVIII trough and peak levels in a rabbit model

Summary. The ratio of von Willebrand factor (VWF) to FVIII differs among available VWF/FVIII concentrates. Repeated infusions of concentrates with a low VWF:FVIII ratio may expose patients with von Willebrand disease to supranormal FVIII levels. The aim of this study was to determine the effects of repeated infusions with two VWF/FVIII concentrates differing in VWF:FVIII ratio on attained FVIII trough and peak levels as well as other pharmacokinetic parameters. Rabbits were randomized to receive multiple 150 IU kg⁻¹ VWF:RCo infusions at 4 h intervals with VWF/FVIII concentrates of a high (Haemate^® P/Humate‐P^®) or low (Wilate^®) VWF:FVIII ratio. Trough plasma FVIII and VWF levels were measured after each infusion. Pharmacokinetic analysis was performed using samples collected frequently after infusion. Mean FVIII trough level after the first Wilate infusion was 50.6 IU dL⁻¹ with a 95% confidence interval (CI) of 43.1–58.2 IU dL⁻¹, compared with 31.8 IU dL⁻¹ (CI, 24.4–39.1 IU dL⁻¹) for Haemate P (P < 0.001). Trough levels progressively increased over the 24 h treatment period in both groups. After the final infusion, mean trough FVIII remained significantly higher (P = 0.002) in recipients of Wilate. Mean peak FVIII concentration after infusion was 67% higher in the Wilate group (167 vs. 100 IU dL⁻¹, respectively; P = 0.002). Mean cumulative exposure to FVIII, as measured by area under the curve, was 84% greater in Wilate‐treated animals. Half‐life did not differ between the two concentrates. Animal model data suggest that exposure to elevated FVIII levels can be reduced through use of VWF/FVIII concentrates with higher VWF:FVIII ratios.     

von Willebrand factor/factor VIII concentrate (Humate‐P) for management of elective surgery in adults and children with von Willebrand disease

Summary. von Willebrand disease (VWD) is the most common inherited bleeding disorder. Treatment guidelines recommend the use of von Willebrand factor/factor VIII (VWF/FVIII) concentrate for VWD patients with type 2 or 3 VWD undergoing surgery, and type 1 patients undergoing surgery who are unresponsive, or for whom desmopressin acetate is contraindicated. This prospective, open‐label, multinational study evaluated the safety, efficacy and optimal dosing of a VWF/FVIII concentrate (Humate‐P) in subjects with VWD undergoing elective surgery. Dosing was based on VWF ristocetin cofactor (VWF:RCo) and FVIII pharmacokinetic assessments performed before surgery. Pharmacokinetic assessments were completed in 33 adults and 9 children. Haemostatic efficacy was assessed on a 4‐point scale (excellent, good, moderate/poor or none). Overall effective haemostasis was achieved in 32/35 subjects. Median terminal VWF:RCo half‐life was 11.7 h, and median incremental in vivo recovery was 2.4 IU dL^?1 per IU kg^?1 infused. Major haemorrhage occurred after surgery in 3/35 cases despite achieving target VWF and FVIII levels. Median VWF/FVIII concentrate loading doses ranged from 42.6 IU VWF:RCo kg^?1 (oral surgery) to 61.2 IU VWF:RCo kg^?1 (major surgery), with a median of 10 (range, 2–55) doses administered per subject. Adverse events considered possibly treatment‐related (n = 6) were generally mild and of short duration. The results indicate that this VWF/FVIII concentrate is safe and effective in the prevention of excessive bleeding during and after surgery in individuals with VWD.     

von Willebrand disease: still an intriguing disorder in the era of molecular medicine

von Willebrand disease (vWD) is a single-locus disorder resulting from a deficiency of von Willebrand factor (vWF): a multimeric multifunctional protein involved in platelet adhesion and platelet-to-platelet cohesion in high shear stress vessels, and in protecting from proteolysis and directing circulating factor VIII (FVIII) to the site of injury. vWD is the most frequent bleeding disorder, with an estimated prevalence in the general population of 1%. Almost all these cases are represented by a partial quantitative deficiency of von Willebrand factor (vWF) (type 1 vWD). Type 1 is transmitted as an autosomal dominant trait with an extremely variable penetrance and expressivity. A consensus figure for the prevalence of cases with significant bleeding symptoms, requiring some form of treatment, is approximately 100 cases million-1. Among these cases, more than 70-80% are represented by type 1 and respond to deamino-D-arginine vasopressin (DDAVP; desmopressin) administration. The remaining cases are represented by type 2 vWD (qualitative), some of which require substitutive treatment. Only 3-5 cases million-1 result from a total deficiency of vWF in plasma and platelets because of the recessive inheritance of two defective alleles. These cases may have severe bleeding episodes and may require frequent substitutive treatment. The molecular basis of type 2 (missense mutation in the functional domains of the vWF subunit) and type 3 (nonsense or large deletions) is quite well understood. On the contrary the molecular basis for most type 1 cases remains largely unknown, and many genetic factors (e.g. ABO blood group) and environmental or circumstantial factors (e.g. age, stress, drugs, pregnancy, and inflammation) are superimposed on to the genetic background determined by the vWF gene to produce a continuous spectrum from normality to mild type 1 cases. It is extremely difficult to make a clear distinction between mild type 1 cases and normal people because of the wide 'normal' range of laboratory measurements (e.g. length of bleeding time, and levels of vWF and FVIII) and of bleeding symptoms. Molecular testing is useless in this situation, and only good history-taking and repeated laboratory testing of vWF-related measurements in the propositus and his/her family members can help in clinical diagnosis, albeit imprecisely. This difficult task is the main focus of this review which is aimed at alerting the physician toward a balanced approach that should take into consideration both the risk of over- and under-diagnosis of this frequent disorder and the unavoidable production of a number of false positive and false negative cases.     

Optimizing therapy with factor VIII/von Willebrand factor concentrates in von Willebrand disease

In von Willebrand disease, the main goals of treatment are to correct the dual defect of haemostasis caused by a reduced or abnormal von Willebrand factor (vWF), i.e. the prolonged bleeding time (BT) and the deficiency of factor VIII coagulant activity (FVIII:C). The synthetic vasopressin analogue, desmopressin (DDAVP), has reduced the need for transfusions in most of the mild forms of von Willebrand disease but DDAVP is ineffective in type 3 and in other severe cases of types 1 and 2 von Willebrand disease. For many years cryoprecipitate has been the mainstay of replacement therapy but, after the introduction of virucidal methods, concentrates containing FVIII/vWF have been considered much safer than cryoprecipitate and proposed in von Willebrand disease management. FVIII/vWF concentrates have been produced and tested by many authors but there is only one report describing four virus-inactivated FVIII/vWF concentrates evaluated in a cross-over randomized trial. According to these in vitro and pharmacokinetic data, the following information can be derived: (a) no FVIII/vWF concentrate had an intact multimeric structure similar to that of normal plasma or of cryoprecipitate; (b) all FVIII/vWF concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed in the concentrate devoid of FVIII:C; (c) no FVIII/vWF concentrate consistently normalized the BT in a sustained fashion. On the other hand, clinical haemostasis can be achieved in the management of bleeding episodes and of surgery for most of von Willebrand disease cases regardless of whether the BT is corrected; in the few rare cases with mucosal bleeding not controlled by FVIII/vWF concentrates, infusion of DDAVP or platelet concentrates can be administered in addition.