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.     

Successful treatment of urgent bleeding in von Willebrand disease with factor VIII/VWF concentrate (Humate-P®): use of the ristocetin cofactor assay (VWF:RCo) to measure potency and to guide therapy

This prospective, open-label, non-randomized study evaluated the safety and efficacy of factor VIII (FVIII)/von Willebrand Factor (VWF) concentrate (Humate-P) using treatment regimens based on VWF:ristocetin cofactor (VWF:RCo) activity in patients with von Willebrand Disease (VWD) in (i) urgent bleeding episodes, or (ii) in patients undergoing urgent and necessary surgery. This article summarizes the results of treatment for the 33 patients with 53 urgent bleeding events. The median loading dose of FVIII/VWF concentrate was 67.0 international units per kilogram (IU kg(-1)) VWF:RCo (range 25.7-143.2 IU kg(-1)), and the median daily maintenance dose per infusion was 74.0 IU kg(-1) (range 16.4-182.9 IU kg(-1)) for a median duration of 2 days (range 1-34 days). The overall efficacy (achievement of haemostasis) of FVIII/VWF concentrate was rated as excellent/good for 98% of the urgent bleeding events. No unexpected treatment-related adverse events or serious drug-related adverse events (AEs) were observed. This study supports the safety and efficacy of Humate-P administered in doses calculated in VWF:RCo units for the treatment of urgent bleeding episodes in patients with VWD.     

Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD

We have prospectively evaluated the biologic response to desmopressin in 77 patients with type 1 von Willebrand disease (VWD) enrolled within the Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD project. Complete response to desmopressin was defined as an increase of both ristocetin cofactor activity (VWF:RCo) and factor VIII coagulant activity (FVIII:C) to 50 IU/dL or higher and partial response as VWF:RCo or FVIII:C lower than 50 IU/dL after infusion, but at least 3-fold the basal level. Complete response was observed in 83% of patients; partial in 13%; and no response in 4%. Patients with some abnormality of VWF multimeric pattern had significantly lower basal FVIII:C and VWF, lower VWF:RCo/Ag ratio, and less complete responses to desmopressin than patients with a normal multimeric pattern (P=.002). Patients with mutations at codons 1130 and 1205 in the D'-D3 domain had the greatest relative increase, but shortest FVIII and VWF half-lives after infusion. Most partial and nonresponsive patients had mutations in the A1-A3 domains. Response to desmopressin in these VWD patients seemed to be associated with the location of the causative mutation. The presence of subtle multimeric abnormalities did not hamper potential clinically useful responses, as in typical type 1 VWD.     

Correlation between von Willebrand factor antigen,von Willebrand factor ristocetin cofactor activity and factor VIII activity in plasma

Background The laboratory diagnosis of von Willebrand Factor (VWF) deficiencies includes qualitative and quantitative measurements of VWF and clotting factor VIII (FVIII). Since the FVIII activity is frequently normal in patients with mild type 1 or 2 von Willebrand disease (VWD), there is controversy whether FVIII testing should accompany VWF Antigen (VWF:Ag) assay. Methods The aim of this study was to explore the correlation between VWF:Ag, VWF ristocetin cofactor activity (VWF:RCo) and FVIII in 213 consecutive patients undergoing screening for VWD. Results Forty-six patients were identified with VWF:Ag levels lower than the diagnostic threshold (54 IU/dl). A significant correlation was observed between VWF:Ag and VWF:RCo (r = 0.892; p < 0.001), VWF:Ag and FVIII (r = 0.834; p < 0.001), VWF:RCo and FVIII (r = 0.758; p < 0.001). Receiver operating characteristic curve analysis of the VWF:Ag assay revealed an area under the curve of 0.978 and 0.957 for detecting life-threatening values of FVIII (<30 IU/dl) and VWF:RCo (<40 IU/dl), respectively. The negative and positive predictive values at the VWF:Ag threshold value of 54 IU/dl were 100% and 33% for detecting life-threatening FVIII deficiencies, 94% and 80% for identifying abnormal values of VWF:RCo. Conclusions Due to the excellent correlation between VWF:Ag and FVIII and to the diagnostic efficiency of VWF:Ag for identifying abnormal FVIII levels in patients with VWF deficiency, routine measurement of FVIII may not be necessary in the initial screening of patients with suspected VWD. However, the limited negative predictive value of VWF:Ag for identifying type 2 VWD does not allow to eliminate VWF:RCo or VWF:FVIIIB assays from the diagnostic workout.     

Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P®)

von Willebrand disease (VWD) is characterized by insufficient von Willebrand factor (VWF) activity. It has been proposed that VWF:ristocetin cofactor (VWF:RCo) activity may be useful in evaluating the response to VWD treatment in patients who require replacement therapy. This prospective, open-label, non-randomized study evaluated the safety and efficacy of a factor VIII (FVIII)/VWF concentrate (Humate-P) used in treatment regimens based on VWF:RCo activity in subjects with VWD in situations requiring urgent and necessary surgery. This article summarizes the results for 39 subjects with 42 evaluable surgical treatment events, 100% of which were rated as excellent/good for overall efficacy (achievement of haemostasis). The median loading dose based upon VWF:RCo activity was 82.3 international units/kilogram (IU kg(-1); range 32.5-216.8 IU kg(-1)), and the median maintenance dose per infusion was 52.8 IU kg(-1) (range 24.2-196.5 IU kg(-1)) for a median of 3 days (range 1-50 days). The median number of infusions per event was 6 (range 1-67 infusions). Three unanticipated adverse events (peripheral oedema, extremity pain and pseudo-thrombocytopenia) from two surgical treatment events were reported that were potentially treatment-related. No serious drug-related adverse events (AEs) were observed, and no thrombotic events were reported in this study. This study supports the safety and efficacy of the FVIII/VWF concentrate Humate-P for the prevention of surgical haemorrhage in patients with VWD when administered in doses calculated in VWF:RCo units.     

Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study

This study prospectively evaluated the rate of biologic response to desmopressin (DDAVP) in 66 patients with type 1 or 2 von Willebrand disease (VWD), each of whom had, on the basis of available records, a clinically significant bleeding history and at least one of the following laboratory abnormalities: bleeding time (BT) longer than 15 minutes, ristocetin cofactor activity (VWF:RCo) less than 10 IU/dL, factor VIII coagulant activity (FVIII:C) less than 20 IU/dL (severe VWD). Before the study, responsive patients were defined as those who, 2 hours after infusion of 0.3 microg/kg DDAVP, had increased baseline values of VWF:RCo and FVIII:C by at least 3-fold and achieved levels of at least 30 IU/dL for both and a BT of 12 minutes or less. The rate of biologic response varied according to VWD types and was higher in type 1 (7 of 26, 27%) than in type 2 (7 of 40, 18%) (type 2A [1 of 15, 7%], type 2M [3 of 21, 14%], type 2N [3 of 4, 75%]). Mutations in the VWF gene were previously known or newly identified in most patients with types 2A (n = 15 of 15), 2M (n = 15 of 21), and 2N (n = 4 of 4), but in none of those with type 1 VWD. Genotype provided more information than phenotype in predicting individual responses to DDAVP only in patients with 2A and 2N VWD. This prospective study showed that the rate of biologic response to DDAVP is relatively low not only in type 2 but also in type 1 VWD when uniform and stringent criteria for patient selection and responsiveness are applied.     

Outgrowing the laboratory diagnosis of type 1 von Willebrand disease: A two decade study

Von Willebrand Factor (VWF) levels are known to increase with age in the general population, but that effect is unclear in von Willebrand disease (VWD) patients. Thus, it is important to assess the trends of VWF levels with age, and the extent and rate of their normalization in patients with VWD. In a retrospective cohort study, we reviewed the medical records of 126 patients between 1996 and 2016 who met the NHLBI diagnostic criteria for type 1 VWD or “Low VWF” (LVWF). We followed all their historically documented VWF antigen (VWF:Ag), VWF activity (VWF:RCo), and Factor VIII (FVIII) levels longitudinally over time, correlating data with clinical setting at time of testing. The average duration of follow‐up was 10.5 ± 3.7 years (SD). Out of the total study population, 27.8% achieved the primary outcome of complete normalization (CN) of both VWF:Ag and VWF:RCo levels, including 19.6% and 32.5% of those with VWD and LVWF, respectively. Linear regression demonstrated statistically significant positive trends of VWF:Ag, VWF:RCo, FVIII with time, calculated at 2.4, 1.4, and 1.4 U dL‐1/year, respectively (P < .001 each). In the largest study population of VWD patients to date whose levels were followed longitudinally, there is a statistically significant rise in VWF:Ag, VWF:RCo, and FVIII levels observed with time. CN of both VWF:Ag and VWF:RCo levels was observed in almost a third of patients with VWD or LVWF, over an average of 10 years. Whether the bleeding phenotype also improves is unclear and requires further study.     

Development of an ELISA method for testing VWF ristocetin cofactor activity with improved sensitivity and reliability in the diagnosis of von Willebrand disease

Objectives: Current methods in assessing von Willebrand factor (VWF) ristocetin cofactor activity for Von Willebrand’s disease (VWD) diagnosis include platelet agglutination by aggregometer or macroscopic slide examination, which are both time‐consuming with suboptimal interassay and intra‐assay variation. The purpose of this study is to establish a sensitive assay to detect VWF:RCo activity and evaluate its performance in VWD diagnosis. Methods: We have established a sensitive VWF:RCo–ELISA method using a monoclonal antibody, SZ‐151, to immobilize the recombinant fragment of platelet glycoprotein Ib (rfGPIbα). VWF was captured by rfGPIbα in the presence of ristocetin, and then detected by HRP‐conjugated rabbit anti‐human VWF IgG. We tested the VWF:RCo level by this VWF:RCo–ELISA in 25 patients with different types of VWD and 36 healthy donors, and compared this method to a previously reported ELISA using 2D4 coating antibody. Results: The sensitivity of VWF:RCo–ELISA was greatly improved with this assay (0.008 IU/dL compared to 0.031 IU/dL by 2D4 antibody). The interassay and intra‐assay coefficient variation were 8% and 12%, respectively. The mean values (ranges) of VWF:RCo in patients with type 1, type 2A, type 2B, type 2M, and type 3 of VWD and control group are 31.8 (22.3–56.9), 4.8 (0.6–11.8), 8.6 (1.6–19.7), 3.9 (1.0–6.8), 1.0 (0.5–1.6), and 91.5 (47.3–169.2) IU/dL, respectively. The corresponding ratios (ranges) of VWF:RCo / VWF:Ag are 0.83 (0.70–1.16), 0.27 (0.08–0.58), 0.31 (0.15–0.40), 0.18 (0.14–0.21), 0.52 (0.13–1.19), and 0.92 (0.62–1.26). Conclusion: The VWF:RCo–ELISA using monoclonal anti‐rfGPIbα antibody SZ‐151 showed improved sensitivity and reliability in detecting VWF:RCo activity, and its clinical application would facilitate the diagnosis and classification of VWD.     

Characterization of recessive severe type 1 and 3 von Willebrand Disease (VWD), asymptomatic heterozygous carriers versus bloodgroup O-related von Willebrand factor deficiency, and dominant type 1 VWD.

Recessive type 3 von Willebrand disease (VWD) is caused by homozygosity or double heterozygosity for two non-sense mutations (null alleles). Type 3 VWD is easy to diagnose by the combination of a strongly prolonged bleeding time (BT), absence of ristocetine-induced platelet aggregation (RIPA), absence of von Willebrand factor (VWF) protein, and prolonged activated partial thromboplastin time (aPTT) due to factor VIII:coagulant (FVIII:C) deficiency. VWD type 3 is associated with a pronounced tendency to mucocutaneous and musculoskeletal bleedings since early childhood. Carriers of one null allele are usually asymptomatic at VWF levels of 50% of normal. Recessive severe type 1 VWD is caused by homozygosity or double heterozygosity for a missense mutation. Recessive type 1 VWD differs from type 3 VWD by the presence of detectable von Willebrand factor: antigen VWF:Ag and FVIII:C levels between 0.09 and 0.40 U/mL. Patients with recessive type 1 VWD show an abnormal VWF multimeric pattern in plasma and/or platelets consistent with severe type 2 VWD. Carriers of a missense mutation may have mild bleeding and mild VWF deficiency and can be diagnosed by a double VWF peak on cross immunoelectrophoresis (CIE). There will be cases of mild and moderate recessive type 1 VWD due to double heterozygosity of two missense mutations, or with the combination of one missense mutation with a non-sense or bloodgroup O. Mild deficiency of VWF in the range of 0.20 to 0.60 U/mL, with normal ratios of von Willebrand factor: ristocetine cofactor/antigen VWF:RCo/Ag and VWF:collagen binding/antigen (VWF:CB/Ag), normal VWF multimers, and a completely normal response to desmopressin acetate (DDAVP) with VWF level rising from below to above 1.00 U/mL are very likely cases of so-called pseudo-VWF deficiency in individuals with normal VWF protein and gene. Autosomal dominant type 1 VWD variants are in fact type 2 variants caused by a heterozygous missense mutation in the VWF gene that produces a mutant VWF protein that has a dominant effect on normal VWF protein produced by the normal VWF allele with regard to the synthesis, processing, storage, secretion, and/or proteolysis of VWF in endothelial cells. A DDAVP challenge test clearly differentiates between dominant type 1 VWD phenotype and dominant type 2 M VWD.     

Intravenous DDAVP and factor VIII-von Willebrand factor concentrate for the treatment and prophylaxis of bleedings in patients With von Willebrand disease type 1, 2 and 3.

The current standard set of von Willebrand factor (VWF) parameters used to differentiate type 1 from type 2 VWD include bleeding times (BTs), factor VIII coagulant activity (FVIII:C), VWF antigen (VWF:Ag), VWF ristocetine cofactor activity (VWF:RCo), VWF collagen binding activity (VWF:CB), ristocetine induced platelet aggregation (RIPA), and analysis of VWF multimers in low and high resolution agarose gels and the response to DDAVP. The BTs and RIPA are normal in asymptomatic carriers of a mutant VWF allele, in dominant type 1, and in recessive type 2N VWD, and this category has a normal response of VWF parameters to DDAVP. The response of FVIII:C is compromised in type 2N VWD. The BTs and RIPA are usually normal in type Vicenza and mild type 2A VWD, and these two VWD variants show a transiently good response of BT and VWF parameters followed by short in vivo half life times of VWF parameters. The BTS are strongly prolonged and RIPA typically absent in recessive severe type 1 and 3 VWD, in dominant type 2A and in recessive type 2C (very likely also 2D) VWD and consequently associated with low or absent platelet VWF, and no or poor response of VWF parameters to DDAVP. The BTs are prolonged and RIPA increased in dominant type 2B VWD, that is featured by normal platelet VWF and a poor response of BT and functional VWF to DDAVP. The BTs are prolonged and RIPA decreased in dominant type 2A and 2U, that all have low VWF platelet, very low VWF:RCo values as compared to VWF:Ag, and a poor response of functional VWF to DDAVP. VWD type 2M is featured by the presence of all VWF multimers in a low resolution agarose gel, normal or slightly prolonged BT, decreased RIPA, a poor response of VWF:RCo and a good response of FVIII and VWF:CB to DDAVP and therefore clearly in between dominant type 1 and 2U. The existing recommendations for prophylaxis and treatment of bleedings in type 2 VWD patients with FVIII/VWF concentrates are mainly derived from pharmocokinetic studies in type 3 VWD patients. FVIII/VWF concentrates should be characterised by labelling with FVIII:C, VWF:RCo, VWF:CB and VWF multimeric pattern to determine their safety and efficacy in prospective management studies. As the bleeding tendency is moderate in type 2 and severe in type 3 VWD and the FVIII:C levels are near normal in type 2 and very low in type 3 VWD patients. Proper recommendations of FVIII/VWF concentrates using VWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are proposed and has to be stratified for the severity of bleeding, the type of surgery either minor or major and for type 2 and type 3 VWD as well.     

Undetected factor VIII in a patient with type 3 von Willebrands disease mistaken as severe haemophilia A

Summary.  von Willebrand disease (VWD) type 3 is a rare disorder characterized by absent or <0.1 UmL⁻¹ of ristocetin cofactor (VWF:RCo), and a very low level of factor VIII (FVIII:C). A total absence of FVIII:C has never been reported in type 3 VWD. This case illustrates the effect of severe von Willebrand factor (VWF) deficiency on the factor VIII level.     

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.     

von Willebrand disease R1374C: Type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia)

Patients initially diagnosed with type 1 von Willebrand disease (VWD) have been reclassified as type 2 after a more exhaustive analysis in several studies. Our study's objectives were (1) to reanalyze patients that were previously diagnosed as type 1 to achieve a more accurate diagnosis and (2) to compare the von Willebrand factor (VWF) ristocetin cofactor assay (VWF:RCo) and the VWF collagen binding assay (VWF:CB) in order to evaluate the possibility of replacing the former assay with the latter in the diagnosis of VWD. Twenty-one patients from two large unrelated families and 104 normal controls were studied. VWF:Ag, VWF:RCo, FVIII coagulant activity (FVIII:C), bleeding time (BT), PFA(100), and multimeric analysis of VWF were tested. Genetic analysis by sequencing exon 28 on the VWF gene was also carried out. Patients presented lower levels of VWF:Ag and VWF:RCo, a dissociation between VWF:RCo/VWF:Ag, and the presence of all sizes of multimers in plasma VWF. The results for VWF:CB varied depending on the type of collagen used. The genetic analysis showed that the mutation R1374C is responsible for type 2M VWD. A high frequency of the R1374C mutation is observed in northwestern Spain (Galicia). Some types of 2M VWD are misdiagnosed as type 1 VWD. The VWF:CB (with type I collagen) assay was unable to discriminate defective platelet binding of the R1374C VWF. This confirms that VWF:CB cannot substitute for VWF:RCo, and both should be tested when diagnosing VWD.     

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.     

Laboratory diagnostic approach of the parents-children relationship in differentiating low-level von Willebrand factor from mild type 1 von Willebrand disease

The present study aimed to evaluate the parent-child relationship in differentiating between unaffected healthy individuals and those with von Willebrand disease (VWD). This study was performed on 15 children between the ages of 5 and 15 years and parents with personal and familial evidence of bleeding. Diagnosis of VWD as considered 'low von Willebrand factor (VWF) level or mild type 1 VWD' in the following children: those with low VWF levels (VWF:RCo and VWF:Ag between 30 and 50 U/dl), at least one bleeding symptom and a family member with at least one bleeding symptom. Laboratory values in the parents of families 1-7 were VWF:Ag 65-90, VWF:RCo 54-87, and FVIII:C 74-110, versus VWF:Ag 33-47, VWF:RCo 30-42, and FVIII:C 36-67 in their children. The normal laboratory values in the parents of families 1-7 suggested that their children would probably have low VWF levels. Our findings are that VWF levels are increasing with age. Laboratory values in the parents of families 8-15 were VWF:Ag 30-59, VWF:RCo 32-55, and FVIII:C 44-66, versus VWF:Ag 32-48, VWF:RCo 30-54, and FVIII:C 38-55 in their children. The laboratory values in the children from families 8-15 were close to the minimum range of normal or below normal, which suggested that it was possible that the parents and children in families 8-15 could be diagnosed as having mild type 1 VWD. The present study's findings show that comparison of the VWF levels in parents and their children may be helpful in differentiating children with low VWF levels and mild type 1 VWD from children that only have low VWF levels.     

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.     

A comparative in vitro evaluation of six von Willebrand factor concentrates

The efficacy of von Willebrand factor (VWF) concentrates for treatment of von Willebrand disease (VWD) is dependent on their content of VWF and factor VIII (FVIII). STUDY OBJECTIVES: To measure the content and quality of VWF and FVIII in six VWF concentrates: Haemate-P (Aventis Behring), Immunate (Baxter Bioscience), Koate (Bayer Corp.), 8Y (BPL), Innobrand (LFB) and Facteur Willebrand (LFB). METHODS: The VWF antigen content (VWF:Ag), ristocetin cofactor activity (VWF:RCo), collagen-binding activity (VWF:CB), VWF multimers with electrophoresis and densitometry, FVIII activity and total protein content. RESULTS: Specific activity (VWF:RCo/total protein) varied considerably (4.7-129.5 IU mg(-1)). Activity measures, VWF:RCo and VWF:CB, correlated well, but we found no correlation between any of these and VWF:Ag. The content of high-molecular weight multimer (HMWM) was normal or close to normal in Haemate-P, Innobrand and Facteur Willebrand, moderately reduced in Koate and 8Y, and significantly reduced in Immunate. The HMWM content correlated significantly with the VWF:RCo/VWF:Ag ratio. Only Haemate-P, Innobrand and Facteur Willebrand had VWF:RCo/VWF:Ag ratios >0.7. We found large differences in the content of FVIII and in the FVIII/VWF:RCo ratio. Facteur Willebrand had the lowest (0.02) and Immunate the highest (6.00) ratio. CONCLUSION: Treating physicians must be aware of the large differences between different VWF concentrates and the potential clinical implications. Concentrates lacking HMWM are probably less efficient for mucosal bleedings. FVIII is most important for surgical bleedings, but concentrates with high FVIII/VWF-ratio may induce very high FVIII levels with increased risk of thrombosis. A low FVIII content may be preferable except in case of acute surgery.     

Management of inherited von Willebrand disease in 2006

The aim of treatment of von Willebrand disease (VWD) is to correct the dual defect of hemostasis (i.e., the abnormal platelet adhesion due to reduced and/or dysfunctional von Willebrand factor [VWF] and the abnormal coagulation expressed by low levels of factor [F] VIII). Desmopressin acetate (DDAVP) is the treatment of choice for type 1 VWD because it can induce release of normal VWF from cellular compartments. Prospective studies on biological response versus clinical efficacy of DDAVP in VWD types 1 and 2 are in progress to explore its benefits and limits as a therapeutic option. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective, and for these patients plasma virally inactivated concentrates containing VWF and FVIII are the mainstay of treatment. Several intermediate- and high-purity VWF/FVIII concentrates are available and have been shown to be effective in clinical practice (bleeding and surgery). New VWF products almost devoid of FVIII are now under evaluation in clinical practice. Although thrombotic events are rare in VWD patients receiving repeated infusions of concentrates, there is some concern that sustained high FVIII levels may increase risk of postoperative venous thromboembolism. Dosage and timing of VWF/FVIII administrations should be planned to keep the FVIII level between 50 and 150 IU/dL. Appropriate dosage and timing in repeated infusions are also very important in patients exposed to secondary long-term prophylaxis for recurrent bleedings.     

Validation of the first commercial ELISA for type 2N von Willebrand’s disease diagnosis

Summary. Type 2N von Willebrand’s disease (VWD) is characterized by a factor VIII (FVIII) deficiency and a low FVIII/VWF ratio related to a markedly decreased affinity of von Willebrand factor (VWF) to FVIII. Type 2N VWD is diagnosed using assays allowing the measurement of plasma VWF capacity to bind FVIII (VWF:FVIIIB). These assays, crucial in order to distinguish type 2N VWD patients from mild haemophiliacs A and haemophilia A carriers, remain exclusively homemade and limited to laboratories possessing a high level of expertise in VWD. We evaluated the first commercial ELISA (Asserachrom® VWF:FVIIIB; Stago) comparated to a reference method in a multicentric study involving 205 subjects: 60 healthy volunteers, 37 haemophiliacs A, 17 haemophilia A carriers, 37 patients with type 2N VWD, 9 heterozygous carriers for a 2N mutation and 45 patients with miscellaneous other types of VWD (all previously characterized). A diluted plasma sample adjusted to 10 IU dL^?1 of VWF:Ag was incubated with a rabbit antihuman VWF polyclonal antibody. After removing the endogenous FVIII, recombinant FVIII (rFVIII) was added and bound rFVIII was quantified using a peroxydase‐conjugated mouse antihuman FVIII monoclonal antibody. The intra‐assay and inter‐assay reproducibility was satisfactory. In all subgroups, both methods were well correlated. All type 2N VWD patients exhibited a markedly decreased VWF:FVIIIB (lower than 15%) and all heterozygous 2N carriers had a moderately decreased VWF:FVIIIB (between 30% and 65%). All controls (healthy subjects, haemophiliacs A and haemophilia A carriers) had a normal VWF:FVIIIB (higher than 80%) except one healthy volunteer and three haemophiliacs who exhibited a moderately decreased VWF:FVIIIB suggesting a heterozygous status for a 2N mutation. In conclusion, the Asserachrom® VWF:FVIIIB is easy to perform, standardized and accurate for type 2N VWD diagnosis with a 100% sensitivity and specificity.