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Abstract

A deficiency and/or dysfunction of von Willebrand factor (VWF) or factor VIII (FVIII) results in the bleeding disorders of von Willebrand disease (VWD) and hemophilia A (HA), respectively. Whereas HA impacts coagulation, VWD primarily impairs hemostasis through defective platelet adhesion and aggregation. In addition, because VWF protects FVIII from proteolytic degradation, a deficiency in VWF can also reduce FVIII levels and affect coagulation. While regular prophylaxis to restore FVIII activity is the standard of care for severe HA, its use to correct the dual VWF/FVIII defect in severe VWD is less well established. Current treatment guidelines suggest the use of long-term prophylaxis rather than no prophylaxis in persons with VWD with a history of severe and frequent bleeds. In this narrative review, we discuss the barriers to the broader adoption of prophylaxis in persons with severe VWD and results of recent clinical studies that provide further evidence to support its use. A growing body of evidence suggests that prophylaxis should be established as the standard care for individuals with severe VWD and recurrent bleeding.

Keywords

coagulation factor replacement therapy factor VIII hemophilia A prophylaxis von Willebrand disease von Willebrand factor

Introduction

Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) circulate in the bloodstream as a complex and both play a crucial role in hemostasis.^1–5 At the site of endothelial injury, VWF and FVIII dissociate to contribute to primary and secondary hemostasis, respectively.^1,2 During primary hemostasis, VWF promotes platelet adhesion, aggregation, and subsequent formation of the initial platelet plug.^3,4 During secondary hemostasis, FVIII promotes the synthesis of insoluble fibrin, thereby strengthening and further stabilizing the blood clot.^1,5 Because FVIII is protected from proteolytic degradation by its natural binding to VWF, a deficiency in VWF can also cause a decrease in FVIII levels, indirectly affecting secondary hemostasis.¹

Deficiency and/or dysfunction of VWF or FVIII results in von Willebrand disease (VWD) and hemophilia A (HA), respectively.^1,6–8 Treatment of VWD and HA shares the common goal of correcting the underlying factor deficiencies,^6–8 which can be achieved through regular replacement therapy with either plasma-derived or recombinant factor concentrates.^6–9 In persons with milder forms of VWD or HA, treatment is usually administered on an as-needed (on-demand) basis to treat acute bleeding events or to provide hemostatic coverage for challenges such as surgery or medical procedures.^6–8

Regular prophylaxis to restore and maintain a minimum FVIII activity and prevent bleeding, particularly into the muscles and joints, is the standard of care in persons with severe HA or a severe bleeding phenotype.⁸ Prophylaxis in HA is supported by many years of clinical experience and robust efficacy and safety data from multiple clinical trials as well as established FVIII trough level targets.^8,10–12 Several plasma-derived FVIII (pdFVIII) and recombinant FVIII (rFVIII) products are currently approved for HA prophylaxis. In the last decade, new rFVIII products have become available, including concentrates derived from human cell lines and extended half-life products.^11,12 Non-factor therapies, administered subcutaneously, such as the FVIII mimetic emicizumab,¹³ anti-tissue factor pathway inhibitors (marstacimab¹⁴ and concizumab¹⁵) and an antithrombin-targeting small interfering RNA (fitusiran¹⁶) have also been approved for prophylaxis in persons with HA. In addition, gene therapy (valoctocogene roxaparvovec) is now licensed for the treatment of adults with severe HA in certain regions of the world.¹⁷ According to the American Thrombosis and Hemostasis Network, 83% of persons with severe HA in the United States receive prophylaxis.¹⁸ Indeed, the HA community has moved beyond debating the need for primary, secondary, or tertiary prophylaxis to focusing on how to best individualize treatment strategies and improve health-related quality of life (HR-QoL).^8,19,20

VWD is associated with a significant health burden due to its increased bleeding risk, negative impact on QoL, and high healthcare resource utilization.^21,22 Current treatment guidelines for VWD suggest the use of long-term prophylaxis rather than no prophylaxis in persons with VWD with a history of severe and frequent bleeds.²³ However, regular prophylaxis to correct the dual VWF/FVIII defect in persons with severe VWD is less widely adopted.^6,9 In contrast to severe HA, VWF replacement treatment options for prophylaxis in severe VWD are currently limited to replacement therapy using VWF-containing products administered by intravenous infusion. International guidelines, published in 2021, recommend the use of long-term prophylaxis in persons with VWD who have a history of severe and frequent bleeds.²³

In this narrative review, we identify some of the potential barriers to the adequate implementation of prophylaxis in severe VWD based on our collective clinical experience and review published clinical data supporting its use,^24–31 with a focus on the results from VWD-specific studies investigating the efficacy of prophylaxis with recombinant VWF (rVWF, Vonvendi)²⁸ and a plasma derived (pd)VWF/FVIII concentrate (wilate),³⁰ conducted after the publication of the international guidelines.²³ This review was guided by the Scale for the Assessment of Narrative Review Articles (SANRA).³²

Barriers to the use of prophylaxis in severe VWD

Defining and identifying severe VWD

The classification of VWD severity is more complex than in HA, where severity is classified according to residual plasma FVIII activity (FVIII:C) levels as mild (>5 to <40 IU/dL), moderate (1–5 IU/dL), or severe (<1 IU/dL).^8,33 Residual FVIII levels closely correlate with the risk of bleeding in men,⁸ although some individuals, including women, with non-severe HA (FVIII:C ⩾1 IU/dL) may also present with severe bleeding phenotypes and require prophylaxis.⁸ In contrast, VWD is classified into three main types according to either quantitative or qualitative VWF deficiencies.^7,34,35 Type 1, the most common form of VWD (~70%–80% of cases), is characterized by a partial quantitative VWF deficiency and is further subdivided into subtype 1C depending upon VWF half-life; type 2 (~20% of cases) is caused by qualitative abnormalities of VWF and is further subdivided into subtypes 2A, 2B, 2M, and 2N depending on the specific VWF functional abnormality. Finally, type 3 (<5% of cases) is characterized by a virtual absence of VWF and consequently very low FVIII levels.^7,34,35

In the United States, 24,508 persons with HA receive treatment at specialized hemophilia treatment centers (HTCs) with 10,046 (41%) of them having severe disease (FVIII:C <1 IU/dL³⁶; Figure 1(a)). The number of persons with VWD treated at the HTCs is 35,466, of whom 27,641 (77.9%) have type 1, 3808 (10.7%) type 2, and 531 (1.5%) type 3³⁶ (Figure 1(b)). However, the true numbers of persons affected by HA and VWD are likely to be considerably higher. The World Federation of Hemophilia (WFH) estimates that >75% of persons with HA and up to 90% of those with VWD are currently undiagnosed, worldwide.^37,38 Based on available data, approximately half of all persons with HA can be expected to have severe disease whereas most persons with VWD are expected to have non-severe disease.

Figure 1.

Disease classification of persons treated at US hemophilia treatment centers between January 1, 2012, through March 31, 2024. (a) Hemophilia A by severity, (b) VWD by VWD type, (c) sex distribution by VWD type, and (d) sex distribution in HA severity.³⁶

Owing to its autosomal inheritance pattern, men and women are equally likely to inherit VWD, although more women are diagnosed with VWD³⁶ (Figure 1(c)). This discrepancy is due to the presence of recurrent female-specific reproductive tract VWD bleeding symptoms such as heavy menstrual bleeding (HMB) and bleeding associated with pregnancy and childbirth.³⁹ In contrast, owing to its X-linked inheritance pattern, HA affects all XY men,^6,8,40 while XX women can be affected by bleeding and/or low FVIII levels.⁴¹ Affected XX women usually have FVIII deficiencies in the mild range (FVIII:C >5 and <40 IU/dL)⁴² and currently account for <1% of persons with severe HA treated at HTCs in the United States (Figure 1(d)).^36,42

Although type 1 VWD is considered to be a milder form of VWD and type 3 is considered the most severe,^7,34 the clinical severity of VWD varies considerably between and within VWD types.⁴³ The difficulty in classifying VWD disease severity is exemplified by the wide range of definitions used in different clinical trials (Table 1).^43–50 A recent Delphi exercise⁵¹ was undertaken with the aim of developing a consensus definition of severe VWD.⁵⁰ The Delphi panel agreed that most (but not all) persons with type 3, many type 2, and some type 1 might have severe VWD. The consensus definition for severe VWD resulting from the Delphi exercise was as follows: (A) anyone meeting the diagnostic classification for VWD and (B) any VWF antigen or activity <20 or <30 IU/dL with excessive bleeding symptoms: (1) bleeding that results in hospitalization, requires a surgical procedure; packed red blood cell blood transfusion, hemoglobin decrease >2 g/dL, or (2) intracranial, intraspinal, intramuscular with compartment syndrome, or (3) persistent or recurrent bleeding that is disruptive of regular functioning.⁵⁰

Table 1.

Definitions of VWD severity.

Study group/reference	Severity classification	VWD subtypes and/or factor levels	Desmopressin response^a	Bleeding history/symptoms
VWD-PN^44–47	Clinically severe	Type 1 (VWF:RCo ⩽20% and/or FVIII:C ⩽20%)Type 2, or Type 3	Unresponsive	Defined patterns of joint bleeding, epistaxis, GI bleeding, or menorrhagiaCriteria for inclusion by bleeding indication were(1) Joint bleeding—documentation of at least two spontaneous BEs in the same joint in the 6 months prior to enrollment; or ⩾3 apparently spontaneous BEs in different joints in the 6 months prior to enrollment(2) GI bleeding—history of ⩾2 severe GI BEs associated with either a drop in hemoglobin of ⩾2 g/dL or required red blood cell transfusion or treatment with VWD concentrate(3) Excessive bleeding during menstruation—a diagnosis of menorrhagia, prospectively completed PBAC score >185, and normal cervical cytology(4) Epistaxis— ⩾3 BEs during a 6-month period that required treatment with VWD concentrates or red blood cell transfusions
WiN study group^43,48	Moderate or severe VWD	Type 1, Type 2, or Type 3Moderate VWD: VWF:Ag 10–30 U/dL and/or VWF:RCo 10–30 U/dL, and/or FVIII:C 20–40 U/dLSevere VWD: VWF:Ag ⩽10 U/dL, and/or VWF:RCo ⩽10 U/dL, and/or FVIII:C ⩽20 U/dL	Not stated	Hemorrhagic symptoms
PRO.WILL study⁴⁹	Severe VWD	Type 1, Type 2, or Type 3	Lack of response, contraindication, or intolerance	Frequent BEs (⩾5 BEs in the last 12 months, or ⩾3 episodes of hemarthrosis at the same joint, or ⩾2 episodes of GI hemorrhage) either unexplained or in association with underlying GI angiodysplasia with requirement of VWF/FVIII therapy
Vonvendi study²⁸	Severe VWD	Type 1, Type 2,^b Type 3VWF:RCo <20 IU/dL and additionally VWF:Ag <3 IU/dL for type 3	Not stated	⩾3 documented spontaneous BEs (not including menorrhagia) requiring VWF treatment during the past 12 months^c
WIL-31 study³⁰	Severe VWD	Type 1 (baseline VWF:RCo <30 IU/dL), Type 2,^b or Type 3	Not stated	⩾6 BEs during the past 6 months of on-demand treatment (excluding menstrual bleeds) of which at least two were treated with a VWF-containing product
VWD Delphi group⁵⁰	Severe VWD	(1) Anyone meeting the diagnostic classification for VWD and (2) Any VWF:Ag or activity <20 or <30 IU/dL with excessive bleeding symptoms	Not stated	Excessive symptoms including(1) Bleeding that results in hospitalization, requires a surgical procedure, PRBC blood transfusion, hemoglobin decrease >2 g/dL, or (2) Intracranial, intraspinal, intramuscular with compartment syndrome, or (3) Persistent or recurrent bleeding that is disruptive of regular functioning

Desmopressin can be used for short-term treatment of many persons with type 1 VWD and some persons with type 2 VWD, except type 2B VWD patients in whom it is generally contraindicated, and it is ineffective in persons with type 3 VWD.^1,6,23

Except type 2N.

In persons on prior on-demand therapy.

BE, bleeding episode; FVIII:C, factor VIII activity; GI, gastrointestinal; PBAC, pictorial blood assessment chart; PRBC, packed red blood cell; VWD-PN, VWD Prophylaxis Network; VWF:Ag, VWF antigen; VWF:RCo, VWF ristocetin cofactor activity; WiN, Willebrand in the Netherlands.

The use of bleeding assessment tools (BATs) is recommended in the diagnosis of VWD⁵² and could play an important role in defining and identifying severe VWD. International Society on Thrombosis and Haemostasis (ISTH) BAT scores have been shown to correlate with the type of VWD; higher ISTH BAT scores have been recorded in type 3 VWD than in type 2 or type 1, and in persons with VWF levels <10 U/dL compared with VWF levels of 10–30 U/dL.⁵³

Delays in the diagnosis of VWD

VWD is often underdiagnosed or misdiagnosed in symptomatic persons, which delays optimal treatment of VWD-associated bleeding symptoms.^54–56 This can be attributed in part to a lack of disease awareness and the complexity of clinical and laboratory assessment of VWD.^55–58 Diagnostic delay is common in VWD and more so in women,⁵⁹ which may reflect the persistent barrier of sexism in the treatment of bleeding disorders.⁶⁰ VWD is diagnosed approximately 6 years later in women than in men (22.5 years vs 16.6 years) and the diagnostic delay is estimated to be approximately 4 years longer in women than in men (11.6 years vs 7.7 years).⁵⁹ In contrast, severe HA is usually diagnosed early in life and regular prophylaxis is recommended from an early age prior to establishment of joint disease.^8,61 Children with severe HA usually gain experience with regular infusions that started in childhood, which is not currently the case in VWD. The diverse bleeding symptoms of VWD may also contribute to diagnostic delays. In contrast to severe HA, which is characterized by muscle and joints bleeds,⁸ VWD is often characterized by excessive and recurrent mucocutaneous bleeding, such as epistaxis, oropharyngeal bleeds, gastrointestinal bleeding, HMB, and postpartum hemorrhage in women,^6,7,56 although joint bleeding can occur with VWD.⁶² In clinical studies of persons with VWD and severe bleeding who received on-demand treatment, bleeding symptoms mainly affected the nose and oral mucosa, and less frequently the joints (Figure 2(a)), whereas joint bleeds predominate in persons with severe HA (Figure 2(b)). As the typical symptoms of VWD (e.g., epistaxis) are common in the general population or are physiological in the case of reproductive tract-specific VWD bleeding symptoms, these symptoms are not specific to VWD and may be normalized in families with VWD and therefore likely contribute to the diagnostic delay.

Figure 2.

Distribution of bleeding sites during on-demand treatment. (a) Studies in persons with severe VWD^30,47,49 and (b) Studies in persons with severe hemophilia A.^79–81

Under recognition of VWD-specific disease burden

Compared with the general population, persons with VWD have poorer HR-QoL and higher resource utilization.^21,22 A population-based case-control study reported a twofold increase in the rate of outpatient visits and hospitalizations in persons with VWD compared with age- and sex-matched controls.⁶³ Epistaxis and HMB were the most common causes of outpatient visits, and gastrointestinal bleeding was the most common cause of hospitalization.⁶³ Frequent and severe nosebleeds can lead to the development of iron deficiency anemia (IDA) and a potential need for blood transfusions or recurrent oral or intravenous iron replacement.⁶⁴ HMB occurs in ⩾80% of women with VWD⁶⁵ and affects women with moderate or severe VWF deficiencies across all VWD types.⁶⁶ The presence of HMB is also associated with a significant increased risk for IDA,⁶⁷ blood transfusion,⁶⁶ hospitalization,⁶³ reduced HR-QoL,⁶⁸ and interference with social, school, and work activities.⁶⁹ Furthermore, women with VWD have an increased risk for bleeding during pregnancy and delivery.^70–74 Additionally, the incidence of anxiety and depression is considerably higher in persons with VWD (54%–64%) compared with the general population (6%–7%).⁷⁵

The burden of VWD-related bleeding symptoms is generally considered to be lower than the burden of joint bleeding associated with severe HA for which prophylaxis is the standard of care.⁸ Although VWD may be clinically mild in many cases, the seriousness of the disease may be under recognized, particularly in persons with a more severe condition⁷⁶ and in women who have bleeding symptoms.^77,78 In studies investigating the use of prophylaxis versus on-demand treatment, the total annualized bleeding rates (ABRs) during on-demand treatment appear to be slightly higher in HA (ABRs of 31–58)^79–81 than in VWD (ABR of 13–33),^25,30 although the ABRs in persons with severe VWD were still significant. It is important to note that there are limitations in comparing ABRs in VWD and HA. For example, defining a bleeding event in the setting of HMB can be more challenging than defining a joint bleed in HA because regular bleeding symptoms related to menstruation are expected but joint bleeds are not.

Data from the Willebrand in the Netherlands (WiN) study showed that HR-QoL is lower in persons with moderate and severe VWD compared to the general population, and this HR-QoL was strongly associated with the observed severity of their bleeding phenotype.⁸² Further data from the WiN study showed that hemophilia-like joint bleeding and arthropathy can also occur in persons with moderate or severe VWD.^62,83 Joint bleeds were reported with 22% of those with type 1, 21% with type 2, and 47% of those with type 3.⁶² A case-control study, analyzing the same cohort, reported that arthropathy was present in 40% of persons with VWD who had a history of joint bleeds.⁸³ This complication was associated with chronic joint pain, radiological abnormalities, functional limitations, and reduced social participation.⁸³ In a separate analysis, joint outcomes were compared for persons with moderate or severe VWD versus persons with moderate or severe HA.⁸⁴ Joint outcomes were similar in persons with moderate or severe VWD and moderate HA, and between persons with type 3 VWD and severe HA.⁸⁴

VWD represents a significant burden for persons with VWD and their families. For example, a nationwide Swedish study of caregivers of children with more severe forms of VWD reported that caregivers’ QoL was significantly affected by their child’s VWD diagnosis.⁸⁵ High rates of school absenteeism, limitations in physical activity, and financial impact were also reported.⁸⁵

Although the burden of VWD is increasingly recognized, a greater awareness and recognition of this burden will undoubtedly facilitate the wider adoption of prophylaxis in VWD.

Efficacy and safety, HR-QoL, hospitalizations, and resource use

Clinical studies investigating the efficacy of prophylaxis in persons with severe VWD

Guidelines of the American Society of Hematology (ASH), the ISTH, the National Hemophilia Foundation (NHF), and the WFH, published in 2021, recommend the use of long-term prophylaxis in persons with VWD who have a history of severe and frequent bleeds.²³ Although the exact definitions of severity or bleeding frequency were not provided, it is important to highlight that this recommendation did not specify whether prophylaxis should be restricted to a particular type of VWD or within a certain range of VWF activity level.²³ The panel also called for further studies to investigate the use of prophylaxis for women with VWD and HMB.²³

Since the cut-off date (October 2019) for the ASH/ISTH/NHF/WFH guidelines,⁸⁶ results of several, prospective, non-randomized observational,^24,26,27,31 and interventional^25,28–30 studies investigating prophylaxis with VWF concentrates have been published (Table 2).

Table 2.

Studies reporting ABRs during long-term prophylaxis in persons with VWD published after the ASH/ISTH/NHF/WFH²³ cut-off date.

Author, year	Study designProduct	N M/F (%)	VWD type (%)			Age, median, range (years)	Duration of prophylaxis (months)^a	Main indication for treatment		Median weekly VWF dose (IU/kg)^b	ABRs
Author, year	Study designProduct	N M/F (%)	1	2	3	Age, median, range (years)	Duration of prophylaxis (months)^a	BE site	%	Median weekly VWF dose (IU/kg)^b	ABRs
Observational studies
Goudemand, 2020²⁴	Prospective, observationalWilfactin	3244/56	3	41	56	33.55–81	351–44	JointGIOther	444116	87^c	Median (range) TABR of 1 (0–11)
Sholzberg, 2021²⁶	Prospective, observationalWilate	2528/72	12	32	56	141–83	145 EDs11–512	NR	NR	69	Median (range) TABR decreased from 12 (0–208) prior to the study to 1.9 (0–27) during prophylaxis
Rugeri, 2022²⁷	Prospective, observationalVoncento	2348/52	0	30	70	161–85	195–48	JointsENTMuscle	433922	96	Median (range) TABR during prophylaxis of 0.3 (0–2) vs 1 (0–6) during prior prophylaxis
Miesbach, 2024³¹	Post-marketing, observationalVoncento	1443/57	0	21	79	36	125–13	MucosalJointMuscleOther	4621826	NR	For treated non-surgical bleeds, the median (range) TABRs and SABRs were 4.4 (0–26) and 3.3 (0–11) respectively, during prophylaxis (n = 14), and 3.0 (0–25) and 1.0 (0–25) during on-demand treatment (n = 11)
Interventional studies
Lissitchkov, 2020²⁵	Prospective, interventionalVoncento	1080/20	10	20	70	376–70	7–28	MucosalJointMuscleOther	88435	81^d	Median (range) TABR of 4.4 (0–26) during prophylaxis (n = 10) vs 12.7 (1–57) in persons treated on-demand (n = 7)
Leebeek, 2022^28,29	Prospective, phase IIIVonvendi	2352/48	13	9	78	41^e 18–77	12	NR	NR	96^f 107^g	46% reduction in model-based mean TABR vs prior on-demand treatment (n = 13; 57% reduction in SABR)^h 25% increase in model-based mean TABR vs the switch group (n = 10; 7% increase in SABR)^h
Sidonio, 2024³⁰	Prospective, phase IIIⁱ wilate	3358/42	18	15	67	187–61	12	NoseJointsOral	332221	58	84% reduction in mean TABR of vs prior on-demand treatment (87% reduction in SABR)

Median or median (range) or range.

Dose refers to IU/kg VWF:RCo.

Estimate from 43.5 IU/kg per infusion twice weekly.

Estimate from 42.8 IU/kg per infusion once (n = 4), 2–3 times (n = 3) or 3 times (n = 2) per week or 1–2 times per month (n = 1).

Mean value; median values were not reported.

In persons on prior on-demand treatment.

In persons on prior prophylaxis.

Data for all bleeds (treated and untreated).

WIL-31 is the only prophylaxis study in VWD with a prospective on-demand run-in study as an intra-individual comparator.

ABR, annualized bleeding rate; ASH, American Society of Hematology; BE, bleeding episode; ED, exposure day; ENT, ear, nose, and throat; GI, gastrointestinal; ISTH, International Society on Thrombosis and Haemostasis; IU, international unit(s); NHF, National Hemophilia Foundation; NR, not reported; SABR, spontaneous annualized bleeding rate; TABR, total annualized bleeding rate; VWD, von Willebrand disease; WFH, World Federation of Hemophilia.

In a prospective, observational, post-marketing study using Wilfactin, a pdVWF almost devoid of FVIII, the median total ABR (TABR) was 1.0 in 20 persons who received prophylaxis for ⩾12 months (prior TABR was not reported).²⁴ In an observational study with Voncento, a 2.4:1 pdVWF/FVIII, the median TABR was reduced from 1 to 0.3 in 19 persons on prior prophylaxis with other concentrates.²⁷ In a different post-marketing study with Voncento in persons with severe VWD, median TABR for treated non-surgical bleeds in 14 persons on prophylaxis was 4.4.³¹ In another study with Voncento, those on prophylaxis (n = 10) experienced a median of 4.4 non-surgical bleeds per year compared with 12.7 in those persons treated on-demand (n = 7).²⁵ In an observational, prospective, phase IV, post-marketing study with wilate, a 1:1 pdVWF/FVIII, median TABR was 1.9 compared with 12 prior to the study in 25 persons on prophylaxis.²⁶ In a case report of a 12-year-old boy with type 3 VWD who experienced frequent bleeding while receiving prophylaxis with Wilfactin and FVIII (Factane), switching to wilate prophylaxis reduced the TABR by 73% (7.5 vs 2) and spontaneous ABR (SABR) by 83% (3 vs 0.5).⁸⁷

Leebeek et al.²⁸ published the first evidence supporting the efficacy of rVWF (Vonvendi) prophylaxis in a prospective, 12-month, phase III study in adults with severe VWD, defined as VWF:RCo <20 IU/dL. Persons with ⩾3 documented spontaneous bleeding episodes (not including menorrhagia) requiring VWF therapy in the past year (prior on-demand group) or persons receiving pdVWF prophylaxis (switch group) were eligible for this study. The study included 13 participants in the “prior on-demand group” and 10 in the “switch group,” 78% of whom had type 3 VWD. The median weekly prophylactic dose of Vonvendi was 96 and 107 IU/kg in the “prior on-demand” and “switch” groups, respectively. All the participants in the “prior on-demand group,” and 8 (80%) of participants in the “switch group,” were on a twice-weekly regimen. ABRs during prophylaxis were compared with historical bleed data derived from medical records. In the “prior on-demand group,” the model-based mean TABR was reduced by 46% from 5.1 to 2.7 and SABR was reduced by 57% from 4.9 to 2.1.²⁹ Despite this trial having some limitations (non-randomized, non-comparative design, collection of historical bleeding data from medical records, small sample size), these results led to US FDA approval of rVWF (Vonvendi) for prophylaxis in adults with VWD.⁸⁸

The WIL-31 study is currently the largest prospective prophylaxis study in VWD with an on-demand run-in study as an intra-individual comparator.³⁰ This was a 12-month, prospective, phase III study that evaluated the efficacy of wilate prophylaxis in 33 participants with severe VWD. It was preceded by a 6-month prospective run-in study (WIL-29) during which participants received on-demand treatment with any available VWF concentrate. Participants with type 3, type 2 (except 2N), or severe type 1 VWD (VWF:RCo <30 IU/dL) were eligible for the study if they had experienced ⩾6 bleeding episodes during WIL-29 (excluding menstrual bleeds), of which ⩾2 were treated with a VWF-containing product. The median weekly prophylactic dose of wilate was 58 IU/kg, with 70% of participants on a twice-weekly regimen at the end of the study. The mean TABR decreased by 84% from 33.4 during on-demand treatment to 5.2 during prophylaxis. Similarly, the mean SABR decreased by 87% from 24.4 during on-demand treatment to 3.2 during prophylaxis. Reductions in ABRs were seen across all age groups, in men and women, and across VWD types (Figure 3).³⁰ Despite this trial having some limitations (non-randomized, non-controlled open-label design, small sample size), the results of this study led to the US FDA approval of wilate for prophylaxis in individuals ⩾6 years with all types of VWD.⁸⁹

Figure 3.

TABRs for wilate during on-demand treatment (WIL-29) and during prophylaxis (WIL-31).³⁰

The WIL-31 study³⁰ is the only prophylaxis study published after the ASH/ISTH/NHF/WFH guidelines^24–30 to separately report data on HMB, although the sample size was small. In five participants, mean intra-individual heavy menstrual ABR was reduced by 74% from 9.7 to 2.4.⁹⁰ All the menstrual bleeds during prophylaxis occurred in two participants with concomitant comorbidities that may have affected their menstrual health (polycystic ovaries in one participant, and hypothyroidism, obesity, anemia, type 2 diabetes, and hypertension in another). In four participants with available pictorial blood loss assessment chart (PBAC) scores, including the two participants with comorbidities, median scores decreased by 43% from 227 during on-demand treatment to 131 during prophylaxis.⁹⁰

The VWDMin study, a phase III, open-label, randomized crossover trial, compared the effect of rVWF (Vonvendi) versus tranexamic acid on HMB in persons with mild or moderate VWD.⁹¹ Participants were randomly assigned (1:1) to Vonvendi, 40 IU/kg on day 1 of the menstrual cycle, or tranexamic acid 1300 mg three times daily on days 1–5 of the menstrual cycle. The primary outcome measure was the amount of blood loss during each cycle, which was determined using PBAC scores. The findings showed significantly lower PBAC scores with tranexamic acid compared with rVWF (146 vs 213; p = 0.039). The authors concluded that rVWF was not superior to tranexamic acid in reducing HMB in this study, and that tranexamic acid was less costly.⁹¹ The VWDMin study had some limitations. The target number for inclusion was not reached, and the study was stopped after inclusion of 36 of the 60 individuals planned. This limited the validity of the study results, especially given the well-known variability in PBAC scores over time in persons with VWD. Other limitations were the inclusion of only persons with mild and moderate VWD, no persons with type 3 VWD were included, the absence of a clear target VWF level, treatment was not given prior to menstruation, and rVWF was only administered on day 1 of the menstrual cycle.⁹¹

Safety of prophylaxis in persons with VWD

Many years of clinical experience with VWF concentrates in on-demand treatment for acute bleeding episodes and short-term surgical prophylaxis in persons with VWD have demonstrated that VWF concentrates are well tolerated.^92–98 Hypersensitivity, immunogenicity, and thromboembolic risk are considered adverse events of special interest in the management of VWD as is the case for HA.

While allergic-type hypersensitivity reactions are possible with VWF concentrates, reported incidence rates of hypersensitivity in post-marketing surveillance were 1 case per 14,788 doses of Voncento⁹⁷ and 1 case per 23,636 doses of Humate-P.⁹⁸

In contrast to FVIII inhibitors,^99,100 development of VWF inhibitors in persons with VWD is less common and it mainly occurs in persons with type 3 VWD.¹⁰¹ VWF genotype is a risk for VWF inhibitors, with genotypes that include a deletion posing the highest risk.¹⁰² The 3WINTERS study reported an anti-VWF inhibitor frequency of 8.4% in a cohort of 213 persons with type 3 VWD and a possible association with anaphylactic reactions.¹⁰³ This finding underscores the importance of careful monitoring for all persons receiving regular VWF treatment. Reported incidence rates of VWF inhibitors for Voncento⁹⁷ and Humate-P⁹⁸ in post-marketing surveillance were 1 case per 916,875 doses and 1 case per 92,857 doses, respectively.

Supraphysiologic levels of both VWF and FVIII are associated with an increased thromboembolic risk.^104–107 When using VWF concentrates there is the potential for thromboembolic events, especially in situations where repeated high doses are required, such as during perioperative prophylaxis. Reported incidences of thromboembolism with VWF concentrates have been rare and mainly in a surgical setting.^108–111 An analysis of two studies of Humate-P found that supraphysiologic levels of VWF and FVIII were recorded in most persons during surgery.¹¹⁰ In one study,¹¹¹ VWF:RCo and/or FVIII activity ⩾150% was observed at least once in 29 of the 35 individuals, yet no venous thromboembolic events occurred. In the other study,¹¹² VWF and/or FVIII activity ⩾150% was observed at least once in 24 of 27 individuals who underwent surgery and 2 individuals had postoperative venous thromboembolic events: a mild thrombophlebitis of the lower leg (FVIII:C not reported) and pulmonary embolism (FVIII:C 450 IU/dL). The reported incidence rates of thromboembolic events for Voncento and Humate-P in post-marketing surveillance were 1 case per 183,375 doses⁹⁷ and 1 case per 78,787 doses,⁹⁸ respectively. In the prophylaxis setting, the doses administered would not be expected to significantly elevate VWF and/or FVIII levels above normal levels. In the WIL-31 study, analysis of FVIII and VWF levels over time during wilate prophylaxis confirmed that there was no accumulation.³⁰

The ASH/ISTH/NHF/WFH analysis of PRO.WILL data concluded that prophylaxis may increase the risk of serious adverse events (SAEs) compared with on-demand treatment^49,86 because of one SAE (intestinal perforation) reported in the prophylaxis arm and none in the on-demand arm.^49,86 However, this SAE was not considered to be treatment-related.⁴⁹ Otherwise, no SAEs were reported during prophylaxis in five observational studies analyzed by the ASH/ISTH/NHF/WFH.⁸⁶ Furthermore, no treatment-related SAEs were reported in studies with VWF concentrates published after the ASH/ISTH/NHF/WFH cut-off date.^24–31 Safety data from these studies indicate that prophylaxis with VWF concentrates is well tolerated and there were no reports of VWF or FVIII inhibitor development.^24–31 There was a single reported case of thromboembolism (purpura) in a participant receiving rVWF prophylaxis,^28,29 but no cases of thromboembolism were reported in studies of prophylaxis using pdVWF/FVIII.^{24–27,30,31}

Prophylaxis effect on HR-QoL, hospitalizations, and resource use

Although the clinical studies of prophylaxis in persons with severe VWD did not report data on HR-QoL changes, the observed reduction in bleeding rates, as well as the potential reduction in the fear of bleeding when on prophylaxis, would be expected to positively impact HR-QoL. It is important to recognize that not only life-threatening bleeds, but all VWD-related bleeds, can significantly impact a person’s life by limiting daily activities, including missed days of school or work, reduced social and physical activity, and increased anxiety and depression.^{75,82,113,114}

Data on hospitalizations and resource use for severe VWD are sparse. One analysis of clinical trial data showed that prophylaxis significantly reduced the incidence of hospitalizations in 105 persons with clinically severe VWD (712 vs 448 events per 1000 person years).⁶³ Two analyses^115,116 have been conducted in persons who were not on prophylaxis, but would be eligible for prophylaxis based on their bleeding history meeting the definition used in the randomized PRO.WILL study.⁴⁹ One was a retrospective analysis of European data that assessed the disease-related burden of VWD in persons on prophylaxis (n = 229) and those potentially eligible persons but not receiving prophylaxis (n = 102). Persons on prophylaxis were less likely to be hospitalized due to acute bleeds or have chronically damaged joints compared with persons not receiving prophylaxis (Figure 4).¹¹⁵ Work productivity and HR-QoL were similar between the two groups, although only approximately 20%–25% of individuals completed these questionnaires.¹¹⁵ The second analysis used data from the integrated US healthcare system for two different cohorts: the overall VWD population (n = 396); and a subset of these (n = 75) who were considered potentially eligible for prophylaxis treatment based on a history of severe and frequent bleeding.¹¹⁶ Resource use was higher in the prophylaxis-eligible subset compared with the overall VWD population in terms of the percentage of persons with ⩾1 VWD-related outpatient (91% vs 81%) or emergency department (39% vs 13%) visit, and the mean number of inpatient stays (2.5 vs 1).¹¹⁶

Figure 4.

Bleeding-related complications in persons with VWD who were receiving prophylaxis compared with persons who were eligible for prophylaxis, based on bleeding history, but were not receiving prophylaxis.¹²⁴

Future directions

In contrast to HA, there are limited data available on prophylaxis in young children with VWD. The efficacy and safety of wilate prophylaxis in children (<6 years) with severe VWD is being investigated in the phase III WIL-33 study (NCT04953884).³⁰ A phase III study (NCT05582993) evaluating the efficacy and safety of Vonvendi in children up to 17 years of age is ongoing.²⁸

Determining the exact clinical indicators for prophylaxis in VWD is an important topic for investigation. Current international guidelines recommend the use of long-term prophylaxis in persons with VWD with a history of severe and frequent bleeding events.²³ However, a consensus on what constitutes “severe and frequent bleeds” would be beneficial to identify those who could benefit from prophylaxis.

Aside from playing an important role in VWD diagnosis and inhibitor risk assessment,^52,117,118 genetic testing could also play a role in identifying persons with VWD who have a severe phenotype and may benefit from prophylaxis. The planned Genetics of VWD in the U.S. (VUS) study will investigate genotype-phenotype relationships in VWD and the potential role of comprehensive VWF genotyping in informing treatment decisions.

Individualized prophylaxis in VWD could help to optimize the dose and/or dosing frequency and provide even better protection against bleeding, in a similar way to what has been achieved with HA where individualized prophylaxis is now recommended as the standard of care.^8,119–121 Factors that could be taken into consideration when individualizing VWD prophylaxis include age, VWD type, residual FVIII and VWF levels, bleeding phenotype (frequency, severity, and location (e.g., gastrointestinal bleeds vs nose/oral bleeds)), desmopressin response, and pharmacokinetics (PK). A population PK model has been developed by the OPTI-CLOT group that may facilitate more accurate targeting of VWF and FVIII levels during perioperative treatment with Humate-P.¹²² Another group has developed a population PK model for type 3 VWD based on PK data in persons treated with rVWF or Humate-P.¹²³ However, the results of PK-guided dosing studies for prophylaxis in persons with VWD have not yet been published. Unlike prophylaxis studies in HA, where a target FVIII trough levels of ⩾1% is usually specified, there are limited data on the optimal VWF trough level target, or whether the same trough would be applicable in persons with different types of VWD, and how to account for the fact that many persons with VWD on prophylaxis may have measurable baseline levels. Studies to determine the appropriate trough levels in persons with VWD during prophylaxis could aid decision-making regarding dosing regimen. Such studies are more difficult in VWD than in HA due to the differences in VWF levels across VWD subtypes and the greater heterogeneity of bleeding sites in VWD than in HA. The predictive performance of population PK models in measuring VWF and FVIII levels and the association between these concentrations and bleeding events in persons with VWD is being evaluated in the OPTI-CLOT:To WiN study (EudraCT 2018-001631-46).¹²⁴ In addition, a population PK study is planned that aims to create and optimize a PK model for wilate.

Short-term prophylaxis with VWF replacement may be indicated to counter the increased risk of bleeding during menstruation, pregnancy, and postpartum in women with VWD.^71,72 Current guidelines for HMB recommend consideration of hormonal therapy in women with VWD who do not wish to conceive and to consider tranexamic acid in those who wish to conceive.²³ There is evidence from clinical practice of the use and effectiveness of combination therapy with tranexamic acid and hormonal therapy for HMB.^125,126 Efficacy and safety studies comparing combination therapy with single therapy are needed.²³ Persons not responding to these treatments or with contraindications should be treated with a VWF-containing product¹²⁷ which may also be used as an alternative to surgical control to mitigate HMB symptoms.¹²⁸ The EMPOWER trial (NCT06205095) will evaluate the effect of prophylaxis with wilate compared with placebo on HMB in women with VWD. The double-blind, randomized controlled trial will evaluate the effect of 2–3 doses of prophylaxis with 40–60 IU/kg wilate when provided on the two heaviest days within the first 4 days of menstruation compared with placebo (normal saline). In the childbirth setting, peripartum wilate was shown to be effective in preventing bleeds in a case series of 10 deliveries.¹²⁹ In addition, a report from a single-institution cohort study concluded that a strategy of targeting higher peak plasma VWF and FVIII:C levels (⩾100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery-associated bleeding complications.¹³⁰ The Von Willebrand Factor in Pregnancy (VIP) study (NCT04146376) is an ongoing investigator-initiated, prospective, open-label, multicenter cohort study in the United States that is assessing the peripartum efficacy and safety of wilate in women with VWD. The primary objective is to observe the rate of primary postpartum hemorrhage in women who deliver with VWF levels >100%. Those with endogenous VWF levels <100% will be treated with wilate and tranexamic acid peripartum, and those with plasma levels ⩾100% will be treated with tranexamic acid. An ongoing, prospective, randomized trial (NCT04344860, VWD-WOMAN trial) is comparing the efficacy of rVWF (Vonvendi) plus tranexamic acid versus Vonvendi alone in reducing postpartum hemorrhage in women with VWD.

Further studies are needed to assess disease-related burden of severe VWD in well-defined populations, and to examine the effectiveness of prophylaxis in reducing this burden, as well as that of their family and caregivers. While the cost-effectiveness of prophylaxis versus on-demand treatment is well documented in persons with HA,¹³¹ economic analyses comparing prophylaxis and on-demand treatment in persons with VWD are certainly needed and will be important to extend the currently limited reimbursement of VWF replacement for prophylaxis.

Several potential treatment strategies for VWD prophylaxis are at various stages of development that offer the prospect of reducing the frequency of intravenous infusion or enabling subcutaneous administration.^132,133 These include therapies currently used for the treatment of HA (ultra-long half-life rFVIII (efanesoctocog alfa) and non-factor therapy (emicizumab)), an aptamer that increases VWF levels (BT200, rondoraptivon pegol), a bispecific antibody that binds and accumulates endogenous activated FVII (HMB-001), a monovalent antibody designed to increase levels of VWF and FVIII (HMB-002), and gene therapy.^132–134

Conclusion

Despite the proven efficacy and safety of prophylaxis use in VWD, its adoption remains less established than FVIII prophylaxis in HA. The 2021 ASH/ISTH/NHF/WFH guidelines represented a step forward for persons with VWD by recommending the use of long-term prophylaxis for those who have a history of severe and frequent bleeds. Results from several studies of VWF prophylaxis have now been published since the guidelines were released,^24–31 including phase III studies leading to the US FDA approval of Vonvendi for VWD prophylaxis in adults^28,88 and for wilate in adults and children at least 6 years of age.^30,89 Updated prophylaxis guidelines are needed and would provide valuable support for both treating physicians and persons with VWD.

Selecting those individuals who could benefit from prophylaxis is more complex than for HA. The FDA approval of prophylaxis for any type of VWD is a major step forward for persons with VWD in the United States because it allows treatment to be based on clinical needs regardless of VWD type. In persons treated on-demand, reasons to switch to prophylaxis might include frequent on-demand treatment in the past 6–12 months, bleeding events requiring hospitalization, failure of other therapeutic options (e.g., for HMB), bleeding interfering with daily activities, bleeding leading to iron deficiency and/or anemia, and bleed prevention for high levels of physical activity. For newly diagnosed individuals, reasons to start prophylaxis might include type 3 VWD, history of bleeds requiring hospitalization, recurrent bleeding episodes, and iron deficiency and/or anemia.

This narrative review was undertaken to identify potential barriers to the adequate implementation of prophylaxis in severe VWD and review the latest clinical evidence on prophylaxis in VWD. As a narrative review, it is acknowledged that there are some limitations. The identification of the barriers to prophylaxis was largely based on the personal experiences of the authors, together with a broad review of available published literature, and was not intended to constitute an exhaustive list. Given the nature of topic explored, a narrative review was selected to enable wider evaluation of the literature rather than the more structured but narrower approach of a systematic review.

After many years of lagging behind HA, barriers to prophylaxis use among individuals with VWD are finally being overcome. In the United States, persons with VWD now have access to effective prophylaxis options that have the potential to position this strategy as the new standard of care for persons with severe VWD and replicate the successful experience observed in HA. The use of personalized therapy in VWD deserves further investigation as it is likely this will also become a central component of VWD prophylaxis in the same way that it has for HA. A consensus on the most effective approach to identify individuals with VWD who would benefit from prophylaxis remains a key research priority.

Footnotes

Acknowledgements

Medical writing assistance was provided by Dominic Hague, PhD, at Cactus Life Sciences AG, Meggen, Switzerland. All the authors have authorized the submission of their manuscript via third party and approved any statements or declarations.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Author contributions

Robert F. Sidonio Jr.: Conceptualization; Writing – original draft; Writing – review & editing.

Fernando F. Corrales-Medina: Conceptualization; Writing – original draft; Writing – review & editing.

Jill M. Johnsen: Conceptualization; Writing – original draft; Writing – review & editing.

Michelle Sholzberg: Conceptualization; Writing – original draft; Writing – review & editing.

Caroline Malcolmson: Conceptualization; Writing – original draft; Writing – review & editing.

Nathan T. Connell: Conceptualization; Writing – original draft; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Medical writing assistance was funded by Octapharma AG.

Competing interests

R.F.S. Jr has received research funding from Octapharma and Takeda, honoraria for consulting and advisory boards from Octapharma, Takeda, LFB, Sanofi, SOBI, Novo Nordisk, Bayer, Pfizer, BioMarin, Vega, and Guardian Therapeutics, and payment for expert testimony from Sanofi; has participated on a data safety monitoring board or advisory board for UniQure; and has had a role as American Thrombosis and Hemostasis Network board member, International Society on Thrombosis and Haemostasis (ISTH) Chair, Hemophilia Federation of America medical adviser, and with the Medical and Scientific Advisory Council of the National Hemophilia Foundation. F.F.C.-M. has a received a research grant from Bayer and educational grants from Octapharma; has received honoraria from Novo Nordisk and Biomarin, and acted as an advisory board member for Bayer, CSL Behring, Genentech, Octapharma, Sanofi, and Takeda. J.M.J. has received research funding from Octapharma to the University of Washington, and consulted for Biomarin, CSL Behring, and Takeda. M.S. reports unrestricted research funding from Octapharma and Pfizer, and honoraria for advisory boards and speaking engagements from Octapharma, SOBI, and Pfizer. C.M. has received research support from Roche, Bayer, Sanofi, Takeda, Pfizer, and Novo Nordisk; honoraria from Sanofi, Bayer, Octapharma, and Novo Nordisk; and participated in advisory boards for Bayer and Takeda. N.T.C. reports serving as a consultant for Takeda; participating in advisory boards for Takeda, Genentech, Sanofi Genzyme, Pfizer, Bayer, and Medzown; and receiving honoraria/travel support from Octapharma AG.

Availability of data and materials

Data sharing not applicable—no new data generated.

ORCID iD

Nathan T. Connell

References

Kiouptsi

Reinhardt

Physiological roles of the von Willebrand factor-factor VIII interaction. Subcell Biochem 2020; 94: 437–464.

Pipe

Montgomery

Pratt

, et al. Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood 2016; 128: 2007–2016.

Swami

Kaur

Von Willebrand disease: a concise review and update for the practicing physician. Clin Appl Thromb Hemost 2017; 23: 900–910.

Gale

AJ.

Continuing education course #2: current understanding of hemostasis. Toxicol Pathol 2011; 39: 273–280.

Samuelson Bannow

Recht

Négrier

, et al. Factor VIII: long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Rev 2019; 35: 43–50.

Miesbach

Berntorp

Translating the success of prophylaxis in haemophilia to von Willebrand disease. Thromb Res 2021; 199: 67–74.

Leebeek

FWG

Eikenboom

JCJ

. Von Willebrand’s disease. N Engl J Med 2016; 375: 2067–2080.

Srivastava

Santagostino

Dougall

, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia 2020; 26: 1–158.

Franchini

Seidizadeh

Mannucci

PM.

Prophylactic management of patients with von Willebrand disease. Ther Adv Hematol 2021; 12: 20406207211064064.

10.

Manco-Johnson

Abshire

Shapiro

, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535–544.

11.

Mancuso

Mahlangu

Pipe

SW.

The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing. Lancet 2021; 397: 630–640.

12.

Mannucci

PM.

Hemophilia therapy: the future has begun. Haematologica 2020; 105: 545–553.

13.

López-Jaime

F-J

Benítez

Díaz Jordán

, et al. Expert opinion paper on the treatment of hemophilia A with emicizumab. Hematology 2023; 28: 2166334.

14.

Mahlangu

Luis Lamas

Cristobal Morales

, et al. Long-term safety and efficacy of the anti-tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: phase II study results. Br J Haematol 2023; 200: 240–248.

15.

Castaman

Jimenez-Yuste

Mahlangu

Concizumab, a non-replacement therapy for persons with hemophilia with inhibitors. J Clin Med 2025; 14: 2961.

16.

Dou

Gao

Fitusiran: the first approved siRNA therapy for hemophilia via reducing plasma antithrombin levels. Drug Discov Ther 2025; 19: 131–132.

17.

Mahlangu

Kaczmarek

von Drygalski

, et al. Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A. New Engl J Med 2023; 388: 694–705.

18.

American Thrombosis and Hemostasis Network (ATHN). Welcome to the ATHNdataset. Improving care—for you and the blood disorders community, www.athn.org (2023, accessed 9 May 2024).

19.

Manco-Johnson

Warren

Buckner

, et al. Outcome measures in haemophilia: beyond ABR (Annualized Bleeding Rate). Haemophilia 2021; 27(Suppl. 3): 87–95.

20.

Thachil

Connors

Mahlangu

, et al. Reclassifying hemophilia to include the definition of outcomes and phenotype as new targets. J Thromb Haemost 2023; 21: 1737–1740.

21.

Bergamasco

Moride

, et al. Von Willebrand disease epidemiology, burden of illness and management: a systematic review. J Blood Med 2023; 14: 189–208.

22.

Castaman

Katsarou

Jansen

, et al. Clinical, economic, and health-related quality of life burden associated with von Willebrand disease in adults and children: systematic and targeted literature reviews. Haemophilia 2023; 29: 411–422.

23.

Connell

Flood

Brignardello-Petersen

, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021; 5: 301–325.

24.

Goudemand

Bridey

Claeyssens

, et al. Management of von Willebrand disease with a factor VIII-poor von Willebrand factor concentrate: results from a prospective observational post-marketing study. J Thromb Haemost 2020; 18: 1922–1933.

25.

Lissitchkov

Klukowska

Buevich

, et al. An open-label extension study to assess the long-term efficacy and safety of a plasma-derived von Willebrand factor (VWF)/Factor VIII (FVIII) concentrate in patients with von Willebrand disease (SWIFT-VWDext Study). J Blood Med 2020; 11: 345–356.

26.

Sholzberg

Khair

Yaish

, et al. Real-world data on the effectiveness and safety of wilate for the treatment of von Willebrand disease. TH Open 2021; 5: e264–e272.

27.

Rugeri

Harroche

Repessé

, et al. Effectiveness of long-term prophylaxis using pdFVIII/VWF concentrate in patients with inherited von Willebrand disease. Eur J Haematol 2022; 109: 109–117.

28.

Leebeek

FWG

Peyvandi

Escobar

, et al. Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results. Blood 2022; 140: 89–98.

29.

Leebeek

FWG

Peyvandi

Tiede

, et al. Prophylaxis with recombinant von Willebrand factor (rVWF) in patients with type 3 von Willebrand disease (VWD): results of a post hoc analysis from a phase 3 trial. Eur J Haematol 2023; 111: 29–40.

30.

Sidonio

Boban

Dubey

, et al. Von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease. Blood Adv 2024; 8: 1405–1414.

31.

Miesbach

Halimeh

Platokouki

, et al. An open-label, multi-centre, post-marketing study to assess the efficacy and safety of a plasma-derived VWF/FVIII concentrate in patients with von Willebrand disease. Haemophilia 2024; 30: 236–240.

32.

Baethge

Goldbeck-Wood

Mertens

SANRA—a scale for the quality assessment of narrative review articles. Res Integr Peer Rev 2019; 4: 5.

33.

Blanchette

Key

Ljung

, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1935–1939.

34.

Sadler

Budde

Eikenboom

, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4: 2103–2114.

35.

Heijdra

Cnossen

Leebeek

FWG

. Current and emerging options for the management of inherited von Willebrand disease. Drugs 2017; 77: 1531–1547.

36.

Centers for Disease Control and Prevention. Community counts, https://www.cdc.gov/ncbddd/hemophilia/communitycounts/data-reports/2023-9/index.html (2023, accessed May 2024).

37.

World Federation of Hemophilia. Identification and diagnosis, https://www.wfh.org/en/our-work-global/vwd-initiative-program (accessed March 2024).

38.

World Federation of Hemophilia. About Bleeding Disorders. https://www.wfh.org/about-bleeding-disorders/#vwd (accessed March 2026).

39.

Eladly

Miesbach

Von Willebrand disease-specific aspects in women. Hämostaseologie 2022; 42: 330–336.

40.

World Federation of Hemophilia. Report on the Annual Global Survey 2022. Montreal, QC: World Federation of Hemophilia, 2023.

41.

van Galen

Lavin

Skouw-Rasmussen

, et al. European principles of care for women and girls with inherited bleeding disorders. Haemophilia 2021; 27: 837–847.

42.

Miller

Soucie

Byams

, et al. Women and girls with haemophilia receiving care at specialized haemophilia treatment centres in the United States. Haemophilia 2021; 27: 1037–1044.

43.

de Wee

Sanders

Mauser-Bunschoten

, et al. Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease. Thromb Haemost 2012; 108: 683–692.

44.

Berntorp

Abshire

The von Willebrand disease prophylaxis network: exploring a treatment concept. J Thromb Haemost 2006; 4: 2511–2512.

45.

Abshire

Federici

Alvarez

, et al. Prophylaxis in severe forms of von Willebrand’s disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN). Haemophilia 2013; 19: 76–81.

46.

Abshire

Cox-Gill

Kempton

, et al. Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network. J Thromb Haemost 2015; 13: 1585–1589.

47.

Holm

Abshire

Bowen

, et al. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network. Blood Coagul Fibrinolysis 2015; 26: 383–388.

48.

Wee

EM de

Leebeek

Eikenboom

JC.

Diagnosis and management of von Willebrand disease in the Netherlands. Semin Thromb Hemost 2011; 37: 480–487.

49.

Peyvandi

Castaman

Gresele

, et al. A phase III study comparing secondary long-term prophylaxis versus on-demand treatment with vWF/FVIII concentrates in severe inherited von Willebrand disease. Blood Transfus 2019; 17: 391–398.

50.

Wynn

Walsh

Cesta

, et al. Development of a working definition of severe von Willebrand disease. Blood 2024; 144(Suppl. 1): 5019.

51.

Nasa

Jain

Juneja

Delphi methodology in healthcare research: how to decide its appropriateness. World J Methodol 2021; 11: 116–129.

52.

James

Connell

Ameer

, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021; 5: 280–300.

53.

Sanders

Fijnvandraat

Boender

, et al. Bleeding spectrum in children with moderate or severe von Willebrand disease: relevance of pediatric-specific bleeding. Am J Hematol 2015; 90: 1142–1148.

54.

Castaman

Linari

Obstacles to early diagnosis and treatment of inherited von Willebrand disease: current perspectives. J Blood Med 2021; 12: 165–175.

55.

Colonne

Reardon

Curnow

, et al. Why is misdiagnosis of von Willebrand disease still prevalent and how can we overcome it? A focus on clinical considerations and recommendations. J Blood Med 2021; 12: 755–768.

56.

Sidonio

Zia

Fallaize

Potential undiagnosed VWD or other mucocutaneous bleeding disorder cases estimated from private medical insurance claims. J Blood Med 2020; 11: 1–11.

57.

Sidonio

Haley

Fallaize

Impact of diagnosis of von Willebrand disease on patient outcomes: analysis of medical insurance claims data. Haemophilia 2017; 23: 743–749.

58.

Noone

Skouw-Rasmussen

Lavin

, et al. Barriers and challenges faced by women with congenital bleeding disorders in Europe: results of a patient survey conducted by the European Haemophilia Consortium. Haemophilia 2019; 25: 468–474.

59.

Atiq

Saes

Punt

, et al. Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders. EClinicalMedicine 2021; 32: 100726.

60.

Weyand

James

PD.

Sexism in the management of bleeding disorders. Res Pract Thromb Haemost 2021; 5: 51–54.

61.

Warren

Thornhill

Stein

, et al. Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study. Blood Adv 2020; 4: 2451–2459.

62.

van Galen

KPM

Sanders

Vojinovic

, et al. Joint bleeds in von Willebrand disease patients have significant impact on quality of life and joint integrity: a cross-sectional study. Haemophilia 2015; 21: e185–e192.

63.

Holm

Carlsson

Lövdahl

, et al. Bleeding-related hospitalization in patients with von Willebrand disease and the impact of prophylaxis: results from national registers in Sweden compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network. Haemophilia 2018; 24: 628–633.

64.

Federici

Prophylaxis of bleeding episodes in patients with von Willebrand’s disease. Blood Transfus 2008; 6: s26–s32.

65.

Ragni

Machin

Malec

, et al. Von Willebrand factor for menorrhagia: a survey and literature review. Haemophilia 2016; 22: 397–402.

66.

Wee

EM de

Knol

Mauser-Bunschoten

, et al. Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease. Thromb Haemost 2011; 106: 885–892.

67.

Munro

MG.

Heavy menstrual bleeding, iron deficiency, and iron deficiency anemia: Framing the issue. Int J Gynaecol Obstet 2023; 162(Suppl. 2): 7–13.

68.

Rae

Furlong

Horsman

, et al. Bleeding disorders, menorrhagia and iron deficiency: impacts on health-related quality of life. Haemophilia 2013; 19: 385–391.

69.

Sanigorska

Chaplin

Holland

, et al. The lived experience of women with a bleeding disorder: a systematic review. Res Pract Thromb Haemost 2022; 6: e12652.

70.

VanderMeulen

Tang

Sholzberg

Tranexamic acid for management of heavy vaginal bleeding: barriers to access and myths surrounding its use. Res Pract Thromb Haemost 2024; 8: 102389.

71.

Castaman

James

PD.

Pregnancy and delivery in women with von Willebrand disease. Eur J Haematol 2019; 103: 73–79.

72.

Kalvehalli Kashinath

Kouides

. The diagnosis, natural history, and management of von Willebrand disease in women in the age of guidelines. Expert Rev Hematol 2023; 16: 435–450.

73.

Corrales-Medina

Federici

Srivastava

, et al. A need to increase von Willebrand disease awareness: vwdtest.com—a global initiative to help address this gap. Blood Rev 2023; 58: 101018.

74.

Johnsen

MacKinnon

HJ.

JTH in Clinic—Obstetric bleeding: VWD and other inherited bleeding disorders. J Thromb Haemost 2022; 20: 1568–1575.

75.

Roberts

Kulkarni

Kouides

, et al. Depression and anxiety in persons with Von Willebrand disease. Haemophilia 2023; 29: 545–554.

76.

Denis

Susen

Lenting

PJ.

Von Willebrand disease: what does the future hold?

Blood 2021; 137: 2299–2306.

77.

Arya

Wilton

Page

, et al. Healthcare provider perspectives on inequities in access to care for patients with inherited bleeding disorders. PLoS One 2020; 15: e0229099.

78.

Arya

Wilton

Page

, et al. “They don’t really take my bleeds seriously”: barriers to care for women with inherited bleeding disorders. J Thromb Haemost 2021; 19: 1506–1514.

79.

Tiede

Oldenburg

Lissitchkov

, et al Prophylaxis vs. on-demand treatment with Nuwiq^® (Human-cl rhFVIII) in adults with severe haemophilia A. Haemophilia 2016; 22: 374–380.

80.

Giangrande

Andreeva

Chowdary

, et al. Clinical evaluation of glycoPEGylated recombinant FVIII: efficacy and safety in severe haemophilia A. Thromb Haemost 2017; 117: 252–261.

81.

Valentino

Mamonov

Hellmann

, et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10: 359–367.

82.

de Wee

Mauser-Bunschoten

van der Bom

, et al. Health-related quality of life among adult patients with moderate and severe von Willebrand disease. J Thromb Haemost 2010; 8: 1492–1499.

83.

van Galen

KPM

de Kleijn

Foppen

, et al. Long-term impact of joint bleeds in von Willebrand disease: a nested case-control study. Haematologica 2017; 102: 1486–1493.

84.

van Galen

KPM

Timmer

de Kleijn

, et al. Long-term outcome after joint bleeds in von Willebrand disease compared to haemophilia A: a post hoc analysis. Thromb Haemost 2018; 118: 1690–1700.

85.

Olsson

Petrini

Engman Grahn

, et al. HRQoL and psychosocial aspects of burden on caregivers to children with moderate or severe von Willebrand disease. Haemophilia 2023; 29: 1056–1062.

86.

El Alayli

Brignardello Petersen

Husainat

, et al. Outcomes of long-term von Willebrand factor prophylaxis use in von Willebrand disease: a systematic literature review. Haemophilia 2022; 28: 373–387.

87.

Berger

Thouvenin

Montmartin

, et al. Switch to pdVWF:pdFVIII concentrate for prophylaxis in a paediatric patient with Type 3 von Willebrand disease: a case report. Hematology 2023; 28: 2186332.

88.

Baxalta US Inc. Vonvendi^® US Prescribing Information, www.fda.gov/media/94863/download (2025, accessed December 2025).

89.

Octapharma AG. wilate^® US Prescribing Information, www.fda.gov/vaccines-blood-biologics/approved-blood-products/wilate (2024, accessed September 2025).

90.

Kiss

Boda

Khayat

, et al. Efficacy of regular prophylaxis with a plasma-derived von Willebrand factor/factor VIII concentrate with a 1:1 activity ratio in reducing heavy menstrual bleeding in girls/women with von Willebrand disease. AJOG Glob Rep 2025; 5: 100501, https://www.sciencedirect.com/science/article/pii/S2666577825000620(2025).

91.

Ragni

Rothenberger

Feldman

, et al. Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial. Lancet Haematol 2023; 10: e612–e623.

92.

Peyvandi

Kouides

Turecek

, et al. Evolution of replacement therapy for von Willebrand disease: from plasma fraction to recombinant von Willebrand factor. Blood Rev 2019; 38: 100572.

93.

Berntorp

Archey

Auerswald

, et al. A systematic overview of the first pasteurised VWF/FVIII medicinal product, Haemate P/Humate-P: history and clinical performance. Eur J Haematol Suppl 2008; 70: 3–35.

94.

Gill

Castaman

Windyga

, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015; 126: 2038–2046.

95.

Srivastava

Serban

Werner

, et al. Efficacy and safety of a VWF/FVIII concentrate (wilate^®) in inherited von Willebrand disease patients undergoing surgical procedures. Haemophilia 2017; 23: 264–272.

96.

Klukowska

Windyga

Batorova

Clinical efficacy of a novel VWF-containing FVIII concentrate, Wilate^®, in the prophylaxis and treatment of bleeding episodes in previously treated haemophilia A patients. Thromb Res 2011; 127: 247–253.

97.

Rugeri

Thomas

Schirner

, et al. A systematic review of efficacy and safety of plasma-derived von Willebrand factor/Factor VIII concentrate (Voncento^®) in von Willebrand disease. Thromb Haemost 2024; 124: 828–841.

98.

Kouides

Wawra-Hehenberger

Sajan

, et al. Safety of a pasteurized plasma-derived Factor VIII and von Willebrand factor concentrate: analysis of 33 years of pharmacovigilance data. Transfusion 2017; 57: 2390–2403.

99.

Garagiola

Palla

Peyvandi

Risk factors for inhibitor development in severe hemophilia A. Thromb Res 2018; 168: 20–27.

100.

Peyvandi

Kavakli

El-Beshlawy

, et al. Management of haemophilia A with inhibitors: a regional cross-talk. Haemophilia 2022; 28: 950–961.

101.

James

Lillicrap

Mannucci

PM.

Alloantibodies in von Willebrand disease. Blood 2013; 122: 636–640.

102.

Johnsen

. Von Willebrand disease. GeneReviews®, https://www.ncbi.nlm.nih.gov/books/NBK7014/ (2024, accessed 19 August 2025).

103.

Pagliari

Budde

Baronciani

, et al. Von Willebrand factor neutralizing and non-neutralizing alloantibodies in 213 subjects with type 3 von Willebrand disease enrolled in 3WINTERS-IPS. J Thromb Haemost 2023; 21: 787–799.

104.

Rietveld

Lijfering

Le Cessie

, et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J Thromb Haemost 2019; 17: 99–109.

105.

Martinelli

Von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis. Semin Hematol 2005; 42: 49–55.

106.

Kyrle

Minar

Hirschl

, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457–462.

107.

Michels

Lillicrap

Yacob

Role of von Willebrand factor in venous thromboembolic disease. JVS Vasc Sci 2022; 3: 17–29.

108.

Makris

Colvin

Gupta

, et al. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost 2002; 88: 387–388.

109.

Mannucci

PM.

Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002; 88: 378–379.

110.

Gill

Mannucci

PM.

Thromboembolic incidence with transiently elevated levels of coagulation factors in patients with von Willebrand disease treated with VWF:FVIII concentrate during surgery. Haemophilia 2014; 20: e404–e406.

111.

Gill

Shapiro

Valentino

, et al. Von Willebrand factor/factor VIII concentrate (Humate-P^®) for management of elective surgery in adults and children with von Willebrand disease. Haemophilia 2011; 17: 895–905.

112.

Lethagen

Kyrle

Castaman

, et al. Von Willebrand factor/factor VIII concentrate (Haemate^® P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery. J Thromb Haemost 2007; 5: 1420–1430.

113.

Atiq

Mauser-Bunschoten

Eikenboom

, et al. Sports participation and physical activity in patients with von Willebrand disease. Haemophilia 2019; 25: 101–108.

114.

Kempers

van Kwawegen

de Meris

, et al. Social participation is reduced in type 3 Von Willebrand disease patients and in patients with a severe bleeding phenotype. Haemophilia 2022; 28: 278–285.

115.

Morgan

Brighton

, et al. Disease burden in patients with von Willebrand disease potentially eligible for prophylaxis: post hoc analysis of a European cross-sectional study. Clin Appl Thromb Hemost 2022; 28: 10760296221130334.

116.

Swallow

Marden

Billmyer

, et al. Burden of illness and treatment patterns among patients with von Willebrand disease in US clinical practice. Clin Appl Thromb Hemost 2023; 29: 10760296231177023.

117.

Laffan

Sathar

Johnsen

JM.

Von Willebrand disease: diagnosis and treatment, treatment of women, and genomic approach to diagnosis. Haemophilia 2021; 27(Suppl. 3): 66–74.

118.

Borràs

Batlle

Pérez-Rodríguez

, et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. Haematologica 2017; 102: 2005–2014.

119.

Lissitchkov

Rusen

Georgiev

, et al. PK-guided personalized prophylaxis with Nuwiq^® (human-cl rhFVIII) in adults with severe haemophilia A. Haemophilia 2017; 23: 697–704.

120.

Mahlangu

Powell

Ragni

, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123: 317–325.

121.

Berntorp

Hermans

Solms

, et al. Optimising prophylaxis in haemophilia A: the ups and downs of treatment. Blood Rev 2021; 50: 100852.

122.

Bukkems

Heijdra

de Jager

NCB

, et al. Population pharmacokinetics of the von Willebrand factor-factor VIII interaction in patients with von Willebrand disease. Blood Adv 2021; 5: 1513–1522.

123.

Bauer

Friberg-Hietala

Smania

, et al. Pharmacokinetic-pharmacodynamic comparison of recombinant and plasma-derived von Willebrand factor in patients with von Willebrand disease type 3. J Blood Med 2023; 14: 399–411.

124.

Heijdra

Al Arashi

de Jager

NCB

, et al. Is pharmacokinetic-guided dosing of desmopressin and von Willebrand factor-containing concentrates in individuals with von Willebrand disease or low von Willebrand factor reliable and feasible? A protocol for a multicentre, non-randomised, open label cohort trial, the OPTI-CLOT: to WiN study. BMJ Open 2022; 12: e049493.

125.

Lim

Olson

Rajpurkar

, et al. Concomitant use of combined hormonal contraceptives and antifibrinolytic agents for the management of heavy menstrual bleeding: a practice pattern survey. Thromb Res 2021; 204: 95–100.

126.

Turan

Gomez

Kadir

RA.

Review of interventions and effectiveness for heavy menstrual bleeding in women with moderate and severe von Willebrand disease. Haemophilia 2024; 30: 1177–1184.

127.

Nichols

Hultin

James

, et al. Von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14: 171–232.

128.

Byams

Kouides

Kulkarni

, et al. Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres. Haemophilia 2011; 17(Suppl. 1): 6–13.

129.

Iorio

James

, et al. Hemostatic management of von Willebrand disease during childbirth with a plasma-derived von Willebrand factor/factor VIII concentrate. J Thromb Haemost 2024; 22: 2739–2744.

130.

Lim

Rodgers

Branch

, et al. Targeting a higher plasma VWF level at time of delivery in pregnant individuals with von Willebrand disease: outcomes at a single-institution cohort study. Haemophilia 2024; 30: 470–477.

131.

Thorat

Neumann

Chambers

JD.

Hemophilia burden of disease: a Systematic review of the cost-utility literature for hemophilia. J Manag Care Spec Pharm 2018; 24: 632–642.

132.

van Kwawegen

Leebeek

FWG

. Prophylaxis in von Willebrand disease with von Willebrand factor concentrate and nonfactor therapies. Res Pract Thromb Haemost 2024; 8: e102599.

133.

James

Leebeek

Casari

, et al. Diagnosis and treatment of von Willebrand disease in 2024 and beyond. Haemophilia 2024; 30(Suppl. 3): 103–111.

134.

Ostergaard

Zivkovic

Ghandi

, et al. Elevating levels of endogenous circulating von Willebrand factor (VWF): the potential of HMB-002 as a prophylactic treatment of von willebrand disease (VWD). Haemophilia 2025; 31: 24.

Prophylaxis for von Willebrand disease: Is it time for parity with established practice in hemophilia A?

Abstract

Keywords

Introduction

Barriers to the use of prophylaxis in severe VWD

Defining and identifying severe VWD

Delays in the diagnosis of VWD

Under recognition of VWD-specific disease burden

Efficacy and safety, HR-QoL, hospitalizations, and resource use

Clinical studies investigating the efficacy of prophylaxis in persons with severe VWD

Safety of prophylaxis in persons with VWD

Prophylaxis effect on HR-QoL, hospitalizations, and resource use

Future directions

Conclusion

Footnotes

Acknowledgements

Declarations

Ethics approval and consent to participate

Consent for publication

Author contributions

Funding

Competing interests

Availability of data and materials

ORCID iD

References