Drugs Ther Perspect (2016) 32:456–462 DOI 10.1007/s40267-016-0350-1
ADIS DRUG Q&A
Recombinant von Willebrand factor (vonicog alfa) in von Willebrand disease: a guide to its use Katherine A. Lyseng-Williamson1
Published online: 20 September 2016 Springer International Publishing Switzerland 2016
Abstract Vonicog alfa (VONVENDI), a human recombinant form of von Willebrand factor (rVWF), is a valuable addition to the treatments available to treat bleeding episodes in adults with von Willebrand disease (VWD). It is a highly purified and homogenous concentrate that contains all sizes of VWF multimers, including high-molecular weight and ultra-large multimers. In patients with VWD, intravenous rVWF provides bleeding control and sustained stabilization of endogenous factor VIII activity, is well tolerated and overcomes some of the inherent limitations associated with the use of plasma-derived VWF concentrates. Adis evaluation of recombinant von Willebrand factor in controlling bleeding in adults with von Willebrand disease Effectively controls bleeding episodes, often with one infusion Provides sustained stabilization of factor VIII activity Well tolerated May be used with or without recombinant factor VIII, with dosages titrated separately based on the individual’s needs Highly purified and homogenous concentrate containing highmolecular weight and ultra-large von Willebrand factor multimers, which are vital in providing primary haemostasis Does not rely on donor plasma during the manufacturing process, which eliminates the risk of pathogen transmission
& Katherine A. Lyseng-Williamson
[email protected] 1
Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand
What is the rationale for developing recombinant von Willebrand factor (rVWF)? Patients with congenital von Willebrand disease (VWD) have a deficiency and/or abnormality in von Willebrand factor (VWF), a large multimeric adhesive glycoprotein that is encoded for by the VWF gene on the short arm of chromosome 12 [1–5]. VWD is usually inherited in an autosomal dominant manner, with a prevalence of &1 % [6, 7], making it the most commonly inherited bleeding disorder. However, the disorder has a wide heterogeneity of laboratory and clinical phenotypes and is clinically relevant in only &10 % of patients [3] and severe in &1 % of patients [8]. Acquired abnormalities and/or deficiencies of VWF may also occur in association with several causes, also with wide laboratory phenotypes and bleeding tendencies [2]. Based on genotypic, clinical and laboratory phenotypic characteristics, VWD may be classified as a partial quantitative deficiency of VWF (Type 1; accounts for &65–75 % of VWD patients); a virtually complete quantitative deficiency (Type 3; accounts for &1–6 % of VWD patients); or a qualitative deficiency of VWF (Type 2; further divided into subtype 2A, 2B, 2 M and 2 N based on the type of abnormality; accounts for &25–30 % of VWD patients) [9]. Bleeding episodes associated with VWD range from mucocutaneous bleeding (the most common presentation) to potentially life-threatening bleeding, especially in patients with type 3 and some type 2 variants [2, 3, 5]. VWF mediates platelet adhesion and aggregation (primary haemostasis role), and also stabilizes procoagulant factor VIII (FVIII) in the circulation (secondary haemostasis role) [2, 3, 10]. Therefore, treatment for bleeding episodes should address both of the haemostasis
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defects associated with VWD, with the choice of treatment depending on the type and severity of VWD, and the severity of the bleeding episode [3, 4]. In patients with less severe VWD deficiencies (i.e. type 1 and some patients with type 2A, 2 M and 2 N), desmopressin (DDAVP), which elicits the release of endogenous VWF from endothelial cells, may be used to correct haemostasis [2–5]. In patients with type 3 VWD, with severe or non-responsive type 1 or 2, and those who have contraindications to the use of DDAVP, including most patients with type 2B VWD, the treatment of choice is replacement therapy with plasma-derived (pd) VWF ± recombinant FVIII (rFVIII) or pdFVIII concentrates. Antifibrinolytic agents, such as tranexamic acid, may be used as an adjunct to DDAVP or pdVWF concentrates [2–5]. The underlying condition in patients with acquired VWD should also be treated, whenever possible. [2]. A number of pdVWF concentrates, most of which also contain pdFVIII, are currently available [3, 11]. The properties and methods of manufacture vary between products. In patients with VWD, repeated use of combination pdVWF/pdFVIII may lead to the significant accumulation of FVIII, which, in turn, can increase the risk of deep vein thrombosis, pulmonary embolism and cardiovascular problems [3]. Careful monitoring is required to provide haemostatic efficacy and reduce the risk of adverse effects. Moreover, as pdVWF and pdFVIII concentrates are derived from human plasma, their manufacture requires a supply of blood and the concentrates have an inherent theoretical risk of blood-borne pathogen transmission [12], although virucidal methods are applied to the concentrates. A human recombinant form of VWF (rVWF), therefore, would be a welcome addition to the options available to treat bleeding episodes in patients with VWD [9, 13]. Vonicog alfa (VONVENDI) [14] is a rVWF concentrate developed to meet this need. It promotes haemostasis during bleeding episodes by providing exogenous VWF in patients in whom endogenous VWF is deficient in quantity or quality, and by stabilizing FVIII in the circulation. In keeping with the nomenclature used in the key published clinical trials [15, 16] and the US prescribing information [14], vonicog alfa is hereafter referred to as rVWF.
How is rVWF manufactured? rVWF is synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line that co-expresses the VWF and FVIII genes, and is purified by immune-affinity chromatography, resulting in a rVWF molecule with [99 % purity [8]. As the glycoprotein molecule is manufactured in the absence of any animal or other human plasma proteins,
it is not exposed to degradation by endogenous ADAMTS13, a metalloprotease which naturally cleaves the large VWF multimers in blood [17]. As a result, the rVWF concentrate is homogenous and contains all sizes of VWF multimers, including high-molecular weight and ultra-large multimers, which are absent from pd products [18]. Ultra-large multimers are the most active form of VWF, are similar to endogenous VWF immediately after their secretion from their storage sites on endothelial cells and megakaryocytes (i.e. before they are rapidly degraded by ADAMTS13), and are vital for primary haemostasis [8, 10, 18].
How does rVWF work? Treatment with rVWF addresses both of the haemostasis defects associated with VWD by [8, 10, 14]: •
•
Promoting haemostasis rVWF mediates platelet adhesion to exposed vascular sub-endothelial matrices, such as collagen, and platelet aggregation (primary haemostasis role). With regard to supporting adhesive interactions with collagen and platelet receptors, the larger the VWF multimers, the more effective they are. Stabilizing FVIII in the circulation rVWF acts as a carrier protein for FVIII to protect it from rapid proteolysis, thereby reducing its clearance (secondary haemostasis role). In plasma, rVWF and endogenous VWF have comparable binding capacity to, and affinity for, FVIII.
For whom is rVWF indicated? In the USA, intravenous rVWF is indicated for the ondemand treatment and control of bleeding episodes in adults with VWD (Table 1) [14]. Treatment with rVWF requires physician supervision; doses of rVWF should be within the designated ranges (Table 1), be based on clinical judgment, taking into account the severity and site of bleeding and the patients’ medical history, and be adjusted when required. Subsequent doses should be administered as long as clinically required, and appropriate clinical and laboratory measures should be monitored (Table 1). The concomitant use of rFVIII is required only when a rapid increase in FVIII is needed and baseline FVIII values are \40 % of normal activity or unknown. When concomitant treatment with rFVIII is required, it should be administered within 10 min of infusing the complete dose of rVWF (Table 1) [14]. It is important that patients and/or their caregivers are advised on [14]:
458 Table 1 Prescribing summary of intravenous recombinant von Willebrand factor (VONVENDI) in adults with von Willebrand disease in the USA [14]. Consult prescribing information for further details What is its approved indication? On-demand treatment and control of bleeding in adults (aged C18 years) diagnosed with von Willebrand disease How is it available and how should it be stored? Availability (contents of carton)
Single-use vial containing nominally either 650 (range 450–850) or 1300 (range 900–1700) IU VWF:RCo as lyophilized powder for solution (actual rVWF activity is printed on the label of each vial and carton) Sterile water for injection, a reconstitution device and physician and patient inserts
Storage of carton
Refrigerate at 2–8 C (36–46 F) in the original box; protect from extreme light exposure May store at room temperature up to 30 C (86 F) for up to 12 months; do not refrigerate after storing at room temperature
Before reconstitution
Allow powder and diluent to reach room temperature
Storage of reconstituted solution
Keep at room temperature [B27 C (81 F)] for up to 3 h; discard after 3 h
What dose should be administered intravenously? Minor haemorrhage (e.g. readily managed epistaxis, oral bleeding, menorrhagia)
Initial dose: 40–50 IU/kg (adjust dose based on the extent and location of bleeding; should achieve VWF levels [60 %, based on VWF:RCo [0.6 IU/mL)
Major haemorrhage (e.g. severe or refractory epistasis, menorrhagia, GI bleeding, CNS trauma, haemarthrosis, traumatic haemorrhage)
Initial dose: 50–80 IU/kg (adjust dose based on the extent and location of bleeding; should achieve VWF levels [60 %, based on VWF:RCo [0.6 IU/mL)
Subsequent doses: 40–50 IU/kg every 8–24 h (as clinically required)
Subsequent doses: 40–60 IU/kg every 8–24 h for &2–3 days (as clinically required; maintain trough VWF:RCo levels [50 % as long as deemed necessary) When a rapid increase in FVIII is needed and baseline FVIII values are \40 % of normal activity or unknown
Administer the first dose of rVWF with an approved rFVIII (one that does not contain VWF) within 10 min of completing rVWF infusion at a ratio of 1.3:1 (i.e. 30 % more rVWF than rFVIII; calculate by dividing rVWF dose by 1.3)
What are the contraindications to its use? Patients who have a life-threatening hypersensitivity reaction to rVWF or its components (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and hamster or mice proteins) How should it be used in special populations? Pregnant women
Use only if clearly needed (lack of data)
Women who are breast-feeding
Consider the benefits of breastfeeding, the mother’s clinical need for rVWF and the potential adverse effects on the breastfed infant from rVWF or the underlying maternal condition (lack of data)
What special warnings and precautions pertain to its use? Embolism and thrombosis
Monitor for early signs/symptoms of thrombosis, such as pain, swelling, discolouration, dyspnoea, cough, haemoptysis and syncope (thromboembolic reactions may occur, particularly in patients with known risk factors) Patients requiring frequent doses of rVWF ? rFVIII: monitor plasma levels of FVIII:C activity (excessive increase in FVIII levels can increase the risk of thromboembolic complications)
Hypersensitivity reactions s
Discontinue rVWF therapy immediately and provide supportive care if signs/ symptoms of severe allergic reactions occur Patients with anaphylactic reactions: evaluate for the presence of inhibitors Patients may develop hypersensitivity reactions to non-human mammalian proteins (rVWF contains trace amounts of mouse and hamster proteins)
Neutralizing antibodies (inhibitors)
Perform appropriate inhibitor assays if bleeding is not controlled as expected (neutralizing antibodies to VWF ± FVIII may develop)
Consider other therapeutic options in patients with high levels of VWF ± FVIII inhibitors (rVWF may not be effective and may cause severe hypersensitivity reactions) FVIII factor VIII, FVIII:C FVIII coagulation activity, rFVIII recombinant FVIII, rVWF recombinant VWF, VWF von Willebrand factor, VWF:RCo VWF activity as measured with the Ristocetin cofactor assay
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• •
•
•
how to reconstitute and administer rVWF (i.e. read patient information and instructions for use); how to recognize the early symptoms of hypersensitivity reactions and what to do if such symptoms occur (i.e. discontinue treatment and seek immediate emergency treatment); what to do if they experience a lack of response to rVWF therapy (i.e. contact their physician or treatment centre for further treatment ± assessment), as this may indicate the manifestation of an inhibitor; what to do prior to travelling (i.e. consult with physician or healthcare provider, and ensure that they have an adequate supply for rVWF, based on their current regimen of treatment).
multicentre, phase 3 trial in 37 adults (age C18–65 years) with severe VWD [16]. Patients were enrolled in one of the following four treatment arms [16]: •
•
What is the clinical efficacy of rVWF? Phase 1 trial The potential value of using rVWF in the treatment of VWD was initially shown in a prospective, randomized, multicentre phase 1 clinical trial in 32 patients with type 3 or severe type 1 VWD [15]. Replacement therapy with rVWF provided rapid normalization of VWF levels, with most patients achieving maximum levels of VWF activity as measured with the Ristocetin cofactor assay (VWF:RCo) within 1 h post infusion [15]. Treatment with rVWF ? a marketed rFVIII concentrate (hereafter referred to as ADVATE, to distinguish it from other commercially available rFVIII concentrates that may have different pharmacological properties) stabilized endogenous FVIII coagulation activity (FVIII:C) to a greater extent than a marketed pdVWF/pdFVIII concentrate (hereafter Humate-P/Haemate P), as shown the significant (p \ 0.01) between-group difference in the area under the plasma concentration–time curve [15]. The overall PK profiles of rVWF ? ADVATE and Humate-P/ Haemate P were similar, with a tendency for rVWF ? ADVATE to have a longer mean VWF:RCo terminal half-life than Humate-P/Haemate P (16.3 vs. 14.4 h), as well as a longer mean VWF antigen terminal half-life (25.5 vs. 17.9 h). These findings support the idea that, once patients with VWD who are experiencing a bleeding episode achieve a therapeutic level of endogenous FVIII, rVWF may be administered alone [15]. Phase 3 trial The haemostatic efficacy of rVWF ± rFVIII (hereafter ADVATE) for the on-demand treatment of bleeding episodes was subsequently evaluated in a pivotal open-label,
•
•
Crossover pharmacokinetic rVWF (50 IU/kg VWF:RCo) Patients received randomized treatment with a dose of rVWF (50 IU/kg VWF:RCo) ? either ADVATE or placebo followed by a washout period of 18 ± 10 days, and finally by crossover treatment with the alternate regimen (pharmacokinetic evaluation n = 8). Crossover pharmacokinetic rVWF (50 IU/kg VWF:RCo) ? on-demand treatment Patients received randomized treatment with a dose of rVWF (50 IU/kg VWF:RCo) ? either ADVATE or placebo, followed by a washout period of 18 ± 10 days, then by crossover treatment with the alternate regimen (pharmacokinetic evaluation n = 8), and finally by on-demand treatment for bleeding for 12 months (efficacy evaluation n = 6). Repeat pharmacokinetic rVWF (80 IU/kg VWF:RCo) ? on-demand treatment Patients received a dose of rVWF (80 IU/kg VWF:RCo) [pharmacokinetic evaluation n = 15], followed by on-demand treatment for 6 months, then by a second pharmacokinetic evaluation of rVWF (80 IU/kg VWF:RCo), and finally by on-demand treatment for 6 months (efficacy evaluation n = 12). On-demand treatment with rVWF Patients received ondemand treatment for bleeding episodes for 12 months (allocated n = 6; efficacy evaluation n = 4).
Bleeding episodes were initially treated on-demand with a 1.3:1 ratio of rVWF and ADVATE to ensure an immediate haemostatic level of FVIII:C. Patients received an initial infusion of rVWF (40–60 IU/kg VWF:RCo) for minor to moderate bleeds (e.g. epistaxis, oral bleeding, menorrhagia), and rVWF (80 IU/kg VWF:RCo) for major bleeds (e.g. severe or refractory epistaxis or menorrhagia, gastrointestinal bleeding, CNS trauma, haemarthrosis, post-traumatic haemorrhage) [16]. Subsequent doses of rVWF were administered ± ADVATE, based on whether or not therapeutic levels of FVIII:C were being maintained. Patients with a major bleeding episode received subsequent doses every 8–12 h for 3 days to maintain trough levels of VWF:RCo [50 IU/dL, and then as necessary for up to 7 days [16]. In the crossover pharmacokinetic studies, physiological saline was used as placebo. Patients exposed to rVWF had a median age of 37 (range 18–65) years, a median weight of 73.0 (range 44–143) kg, and a median of 0.7 (range 0.0–6.0) annual bleeding episodes prior to the trial. The majority of patients had VWD type 3 (78.4 %), with the remaining patients having VWD type 1, 2A and 2N (5.4, 13.5 and 2.7 % of patients, respectively). Prior to the trial, 73.0 % of patients
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had been receiving on-demand treatment for bleeding, 8.1 % had been receiving prophylactic treatment, and 18.9 % had been receiving a combination of on-demand and prophylactic treatment [16]. Haemostatic efficacy The efficacy of rVWF was analysed in a total of 192 bleeding episodes in 22 patients across the three treatment groups receiving on-demand treatment in the phase 3 trial [16]. Most bleeding episodes were of minor (63.5 %) or moderate (31.8 %) severity, with few major/severe episodes (3.6 %); the severity of two episodes was unknown. The site of bleeding episodes included the mucosa (55.2 %), joints (30.7 %), gastrointestinal tract (3.1 %) and other sites (19.3 %); as several bleeding episodes occurred in multiple locations, the total proportion of sites is [100 %. During 45 bleeding episodes in seven patients, antifibrinolytic treatment (e.g. tranexamic acid) was administered [16]. Treatment success (defined as the number of patients with a mean bleeding control score of \2.5) was 100 % [16]. Bleeding control was rated on the following 4-point scale, where rVWFAct indicates the actual number of rVWF infusions received, VWFEst indicates the treating physician’s estimated number of infusions required to treat that bleeding episode, and VWFPlus indicates the use of additional VWF coagulation factor-containing products [16]: •
•
•
•
1 (excellent) Defined as rVWFAct B VWFEst, and VWFPlus = 0 (for both minor and moderate bleeding events and major bleeding events). 2 (good) Defined as rVWFAct [ 1–2 ? VWFEst, and VWFPlus = 0 (for minor and moderate bleeding events), and rVWFAct \ 1.5 9 VWFEst, and VWFPlus = 0 (for major bleeding events). 3 (moderate) Defined as rVWFAct [ 3 ? VWFEst, and VWFPlus = 0 (for minor and moderate bleeding events), and rVWFAct C 1.5 9 VWFEst, and VWFPlus = 0 (for major bleeding events). 4 (none) Defined as severe uncontrolled bleeding or intensity of bleeding not changed and VWFPlus [ 0 (for both minor and moderate bleeding events and major bleeding events).
Bleeding control was rated as excellent in 96.9 % of bleeding episodes (186/192 episodes, including 119/122 minor, 59/61 moderate, 6/7 major and 2/2 severity unknown episodes), and as good in the remaining 3.1 % of episodes (6/192 episodes, including 3/122 minor, 2/61 moderate and 1/7 major bleeds) [16]. Per bleeding episode treated with VWF ± ADVATE, the median cumulative dose of rVWF was 48.2 IU/kg
VWF:RCo (43.3, 52.7 and 100.0 IU/kg VWF:RCo for minor, moderate and major bleeding episodes, respectively) [14]. Most (81.8 %; 157/192) bleeding episodes were treated with one infusion of rVWF. For minor and moderate bleeds, a median of one infusion was required (ranged from one to three infusions for minor bleeds and one to four for moderate bleeds); for major/severe bleeds, a median of two infusions was required (ranged from one to three infusions). Only one bleeding episode (a simultaneous mucosal bleed in the genital tract and oral cavity of moderate severity) required treatment with four rVWF infusions, which was the maximum permitted number of rVWF infusions per episode. Of note, inadvertent administration of the first infusion of rVWF alone (instead of with ADVATE) provided excellent bleeding control in 10 bleeding episodes in three patients [16]. The efficacy of rVWF in controlling bleeding was not affected by the site or cause of the bleeding episode, or the type of VWD [16]. Bleeding control was rated as excellent in: 97.2 % (103/106) of mucosal bleeds, 96.6 % (57/59) of joint bleeds and 95.3 % (41/43) of gastrointestinal and other site bleeds; 97.5 % (160/165) of spontaneous bleeds and 100 % of bleeds due to trauma (26/26); and 99.4 % (171/175) of bleeds in patients with type 3 VWD and 88.2 % (15/17) bleeds in patients with type 2A or 2 N. Control was rated as good in all of the remaining bleeding episodes [16]. Pharmacokinetic parameters Treatment with rVWF provides a proportion of VWF in the form of ultra-large multimers, which undergo subsequent rapid degradation [16]. According to an analysis of the proportion of VWF multimers in a patient with type 3 VWD, large multimers were absent prior to the infusion of rVWF, increased to a peak of 30 % 15 min post-infusion, decreased substantially between 12 and 24 h post-infusion, and were at almost baseline levels by 96 h post-infusion [16]. Across treatment groups in the phase 3 trial, the pharmacokinetics of rVWF at a dose of 50 IU/kg VWF:RCo were analysed in 16 patients with VWD in a nonbleeding state [16]. Plasma samples were obtained at baseline (1 h before infusion) and 11 times after infusion (up to 96 h post-infusion) [16]. After a single infusion of rVWF (50 IU/kg VWF:RCo), the PK profile of rVWF was consistent regardless of whether or not it was administered alone or with ADVATE [16]. Both regimens were associated with a rapid increase from baseline in plasma levels of VWF:RCo. The mean terminal half-life for VWF:RCo was 21.9 and 19.6 h for rVWF and rVWF ? ADVATE, respectively [16]. Moreover, treatment with rVWF (50 IU/kg VWF:RCo) alone induced a substantial stabilization of endogenous
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FVIII; relative to baseline, median FVIII:C increased by [40 % 6 h post-infusion, with peak levels being reported 24 h post-infusion and sustained levels being shown up to 72 h post-infusion [16]. As expected, treatment with rVWF ? ADVATE produced haemostatic FVIII:C levels immediately, with stable levels being sustained for 72 h post-infusion [16].
What is the tolerability profile of rVWF? General tolerability rVWF was well tolerated in 66 patients with VWD receiving a total of 355 infusions of rVWF ± concomitant rFVIII (ADVATE) in two prospective clinical trials [15, 16] (pooled results reported in the US prescribing information [14]). Generalized pruritus, the most common treatment-emergent adverse event (TEAE), was reported in two patients (3.03 %) and with two infusions (0.56 %). All other TEAEs (tachycardia, nausea, mild infusion site paraesthesia, hot flush, hypertension, dizziness, dysgeusia, tremor, electrocardiogram t-wave inversions, chest discomfort and increased heart rate) were each reported in one patient (1.52 %) and with one infusion (0.28 %), with the exception of hypertension, which was reported in one patient and with two infusions [14]. All TEAEs were considered to be of mild [15] or mildto-moderate severity [16]. Moderate chest discomfort and increased heart rate, which occurred simultaneously in one patient in the phase 3 trial, were considered to be serious TEAEs, as hospitalization for observation was required [16]. The patient, who had a history of allergic responses to cryoprecipitate and pdVWF concentrate, fully recovered within 3 h and did not display any clinical cardiac symptoms [16]. Thromboembolic and hypersensitivity reactions Treatment with rVWF is associated with a potential risk of thromboembolic reactions (e.g. venous thrombosis, pulmonary embolism, myocardial infarction and stroke) and hypersensitivity reactions (e.g. anaphylactic shock, generalized urticaria, angioedema, chest tightness, hypotension, shock lethargy, nausea, vomiting, paresthesia, pruritus, restlessness, wheezing and/or acute respiratory distress) [14]. Appropriate precautions and monitoring recommendations (Table 1) should be followed to mitigate the risk of such events [14]. In the clinical trials, no patients displayed clinical signs of a thrombotic event, clinically significant abnormal values of D-dimer or a severe hypersensitivity reaction [15, 16].
Immunogenicity Neutralizing antibodies to VWF and/or FVIII may develop in patients with VWD receiving treatment for bleeding episodes [14]. When high levels of these antibodies develop, treatment with rVWF may not be effective and severe hypersensitivity reactions may occur [14]. Therefore, appropriate monitoring of antibody levels and other precautions should be followed (Table 1) [14]. Anti-VWF neutralizing or binding antibodies did not develop in any of the patients in the clinical trials [14–16]. In addition, no patients in the phase 3 trial developed FVIII neutralizing antibodies, or binding antibodies against potential impurities, such as rFurin, CHO host cell proteins or murine IgG [16]. As the detection of antibodies depends on several factors, the incidence of antibodies in these studies should not be compared with the incidence in other studies or with other products [14].
What is the current clinical positioning of rVWF? rVWF is a valuable addition to the treatments available to treat bleeding episodes in patients with VWD, as it provides bleeding control and sustained stabilization of endogenous FVIII:C. In the clinical trial in patients with severe VWD, all bleeding episodes were successfully treated with rVWF ± ADVATE, with most being controlled with a single infusion (which may reflect the high proportion of ultra-large multimers and long VWF:RCo half-life of rVWF relative to Humate-P/Haemate P). Treatment with rVWF was well tolerated, and was not associated with the development of any neutralizing or binding antibodies, or with the occurrence of any thrombotic event. Nevertheless, appropriate precautions and monitoring recommendations (Table 1) should be followed to reduce the risk of such events. The use of rVWF overcomes some of the inherent limitations associated with the use of pdVWF. Unlike pdVWF, the production of rVWF is not limited by the availability of donor plasma and its use is not associated with a risk of pathogen transmission. Moreover, rVWF is not exposed to proteolysis by endogenous ADAMTS13 during the manufacturing process. As a result, rVWF contains high-molecular weight and ultra-large VWF multimers, which play an important role mediating platelet adhesion and aggregation and stabilizing endogenous FVIII. After infusion, the multimers undergo degradation by endogenous ADAMTS13, thereby ultimately providing a molecule with low thrombogenicity. Furthermore, many products that contain pdVWF also contain pdFVIII, whereas rVWF may be used either alone or, when required, concomitantly with rFVIII (Table 1), thereby better
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meeting the needs of the individual patient. In patients who do not require treatment with exogenous FVIII, treatment with rVWF alone normalizes levels of VWF and also stabilizes endogenous FVIII without exposing the patient to an excess of FVIII:C and its associated prothrombotic risk. The sustained stabilization of FVIII:C may reduce the need for subsequent infusions of rFVIII in patients who require initial treatment with both rVWF and rFVIII. Acknowledgments The manuscript was reviewed by: G. Castaman, Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy; P. M. Mannucci, ‘‘Angelo Bianchi Bonomi’’ Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico and University of Milan, Milan, Italy; M. V. Ragni, Division of Hematology/Oncology, University of Pittsburgh and Hemophilia Centre of Western Pennsylvania, Pittsburgh, PA, USA. During the peer review process, the manufacturer of rVWF (VONVENDI) was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit. Compliance with Ethical Standards Funding The preparation of this review was not supported by any external funding. Conflict of interest K. A. Lyseng-Williamson is a salaried employee of Adis/Springer, is responsible for the article content and declares no conflicts of interest.
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