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Abstract

Background

Prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in von Willebrand disease (VWD) patients with a history of frequent and severe bleeds. Despite nosebleeds being a frequent manifestation of VWD, few studies have investigated the efficacy of factor prophylaxis in preventing nosebleeds in patients with severe VWD.

Methods

This post-hoc analysis of a prospective, 12-month, phase 3 study assessed the efficacy of wilate in the prevention of nosebleeds in 33 patients aged ≥6 years with severe type 1, type 2 or type 3 VWD. All patients previously participated in a 6-month prospective study of on-demand treatment with any VWF concentrate. Prophylactic efficacy was assessed by comparing total and spontaneous annualized bleeding rates for nosebleeds (TABR and SABR, respectively) during prophylaxis with rates during on-demand treatment.

Results

The mean TABR and SABR for nosebleeds were reduced by 76% and 81% respectively during prophylaxis versus on-demand treatment (2.7 vs 11.0 and 2.1 vs 10.9). During the second 6 months of prophylaxis, mean TABR was 49% lower and mean SABR 57% lower versus the first 6 months. The percentage of patients with zero nosebleeds was 19% during 6 months of on-demand treatment, 55% during the first 6 months of prophylaxis, and 68% during the second 6 months of prophylaxis. The efficacy of wilate in the treatment of breakthrough nosebleeds was rated excellent in 99% of cases.

Conclusion

This post-hoc analysis demonstrated the efficacy of wilate prophylaxis in the prevention and treatment of nosebleeds in children and adults with severe VWD.

Keywords

epistaxis factor VIII prophylaxis von Willebrand disease von Willebrand factor

Introduction

von Willebrand disease (VWD) is an inherited autosomal bleeding disorder caused by a deficiency in von Willebrand factor (VWF), a plasma glycoprotein that mediates platelet adhesion/aggregation and stabilizes coagulation factor VIII (FVIII).^1–3 The estimated prevalence of reported VWD is 26 per million people⁴ although it is thought that up to 90% of people with VWD are undiagnosed.⁵

VWD is categorized into three main subtypes based on quantitative or qualitative defects in VWF activity.⁶ The bleeding phenotype varies between and within VWD subtypes.^7,8 VWD is characterized by easy bruising, excessive mucocutaneous bleeding, such as nosebleeds, oral bleeds, gastrointestinal bleeding, and heavy menstrual bleeding,^1,9,10 which are associated with reduced quality of life and high healthcare costs.^9,11 Nosebleeds are a frequent manifestation of VWD, occurring in 55% to 86% of patients with VWD and across subtypes.⁹ Nosebleeds are a frequent cause of outpatient visits,¹² emergency room visits¹³ and hospitalizations¹² in patients with VWD, and can be life-threatening in some cases.^14,15

Over the past 20 years, a large body of evidence has accumulated to support the use of prophylaxis in patients with severe VWD.^16–19 The 2021 international VWD guidelines suggested the use of prophylaxis with a VWF concentrate in VWD patients with a history of frequent and severe bleeds.¹³ In studies evaluating prophylaxis in VWD, nosebleeds were often a frequent^20,21 or primary^22–24 indication for prophylaxis or accounted for a considerable proportion of prior bleeds.^19,25,26 However, few studies have specifically evaluated the efficacy of prophylaxis in preventing nosebleeds in patients with severe VWD.^22,24,25

The largest prospective study of prophylaxis in patients with severe VWD to date is the phase 3 WIL-31 study of 33 patients treated with wilate,¹⁹ a plasma-derived VWF/FVIII concentrate with a 1:1 activity ratio that is indicated for the prevention and treatment of bleeds in patients with VWD.^27,28 During 12 months of wilate prophylaxis in the WIL-31 study, the mean annualized bleeding rate (ABR) was reduced by 84% compared with prior on-demand treatment with any VWF concentrate, with reductions observed in children and adults and across VWD types.¹⁹ Here we report on a post-hoc analysis of data from this study¹⁹ that assessed the efficacy of wilate in the prevention and treatment of nosebleeds.

Methods

Study Design

WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years with VWD type 1 (VWF:RCo <30 IU/dL), type 2 or type 3.¹⁹ Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29; NCT04053699). Patients who experienced at least 6 bleeding episodes (BEs) during WIL-29, excluding menstrual bleeds, of which ≥2 were treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular prophylaxis with wilate 2–3 times per week at a dose of 20–40 international units (IU)/kg for 12 months. In case of unacceptably frequent spontaneous breakthrough BEs (ie more than 2 spontaneous BEs or 1 major spontaneous BE within a 30-day period), the dose of wilate was to be increased by approximately 5 IU/kg. If, after a dose increase, patients still experienced more than 2 spontaneous bleeding episodes, the dosing interval was to be shortened from 2 times per week to 3 times per week. Concomitant therapies were permitted at the discretion of the treating physician.

The study was performed in accordance with the Declaration of Helsinki and the respective local regulations. Voluntarily given, fully informed written and signed consent was obtained from patients (or their legal guardians) before any study-related procedures were conducted.

Further information on the overall study design and methodology has been published previously.¹⁹

Analyses

The primary aim of this post-hoc analysis was to assess the efficacy of prophylaxis in preventing nosebleeds by comparing ABRs for nosebleeds during prophylaxis in WIL-31 with ABRs during on-demand treatment in WIL-29. ABRs were calculated based on the number of nosebleeds occurring within the on-demand or prophylaxis period relative to the time under treatment, which was transformed to an annualized rate. Any BEs occurring within surgery periods were excluded. ABRs were calculated for the total number of nosebleeds (TABR) and the number of spontaneous nosebleeds (SABR) in all patients, and according to age group (6-11, 12-16, ≥ 17 years), VWD type (type 1, 2A, or 3), and sex (male, female).

Nosebleeds requiring hospitalization or causing incapacity or significant pain were classified as major. All other nosebleeds were considered minor. The efficacy of wilate in the treatment of breakthrough nosebleeds was assessed using a 4-point scale – excellent: bleeding was completely stopped within 3 days in case of minor bleeds, within 7 days in case of major bleeds; good: bleeding was completely stopped, but time and/or dose slightly exceeded expectations; moderate: bleeding could be stopped only by significantly exceeding time and/or dose expectations; none: bleeding could be stopped only by using other VWF-containing products. Nosebleeds with efficacy ratings assessed as either ‘excellent’ or ‘good’ were considered ‘successfully treated’.

Results

Study Population

The study population included 33 VWD patients who received wilate prophylaxis during the 12-month WIL-31 study. Nine (27%) patients were aged 6–11 years, 6 (18%) were 12–16 years, and 18 (55%) were ≥17 years (median [range]: 31 [17-61] years). Six (18%) patients had severe type 1 VWD, 5 (15%) had type 2A and 22 (67%) had type 3. Nineteen (58%) patients were male and 14 (42%) were females. The median (range) weekly prophylactic dose of wilate was 58 (28-114) IU/kg. At study start, 91% of patients were on twice-weekly dosing and 9% on a three times per week dosing regimen. At study end, 70% of patients received twice-weekly dosing and 30% three times per week dosing. During the course of the study, dosing frequency was increased from twice weekly to three times weekly in 7 (21%) patients after a median (range) of 4.3 (2.1-10.0) months; 26 (79%) patients did not require a change in dosing frequency. Three patients prematurely discontinued from the study: 2 due to adverse events (after 0.5 and 1.4 months) and 1 due to permanently leaving their country after 10.6 months. Further details on the study population have been reported previously.¹⁹

Characteristics of Nosebleeds

Details of the nosebleeds are shown in Table 1.

Table 1.

Characteristics of Nosebleeds During on-Demand Treatment and During Prophylaxis (N = 33).

Characteristic	WIL-29On-Demand	WIL-31Prophylaxis
Treatment duration, months, mean (SD)	6.4 (0.6)	11.4 (2.8)
Patients with nosebleeds, n (%)[total number of nosebleeds]	26 (79) [194]	16 (48) [89]
6–11 years (N = 9)	9 (100) [60]	5 (56) [25]
12–16 years (N = 6)	6 (100) [28]	3 (50) [12]
≥17 years (N = 18)	11 (61) [106]	8 (44) [52]
Type 1 (N = 6)	5 (83) [48]	3 (50) [39]
Type 2A (N = 5)	5 (100) [24]	1 (20) [4]
Type 3 (N = 22)	16 (73) [122]	12 (55) [46]
Males (N = 19)	13 (68) [95]	10 (53) [57]
Females (N = 14)	13 (93) [99]	6 (43) [32]
Type of nosebleed, n (% of total)
Spontaneous	192 (99)	69 (78)
Traumatic	2 (1)	17 (19)
Other	—	3 (3)
Severity of nosebleed, n (% of total)
Minor	176 (91)	82 (92)
Major	18 (9)	7 (8)
Duration of nosebleeds, h, mean (SD)
All nosebleeds	6.5 (13.4)	6.0 (14.4)
Treated nosebleeds	7.6 (14.7)	7.2 (15.9)
Patients with treated nosebleeds, n (%) [total number of nosebleeds]	24 (73) [157]	13 (39) [72]
Treatment, n (% of total treated bleeds)
wilate	95 (60.5)	72 (100)
Haemate P	47 (29.9)	—
Haemate P/wilate	1 (0.6)	—
Cryoprecipitate	14 (8.9)	—

Nosebleeds were the most common BEs during wilate prophylaxis in WIL-31 (89/173; 51%) and occurred in 16 of the 33 (48%) patients. These 16 patients included 3 of 6 (50%) type 1 patients, 1 of 5 (20%) type 2A patients, and 12 of 22 (55%) type 3 patients. Nosebleeds were also the most common BEs during WIL-29 (194/593; 33%) and occurred in 26 of the 33 (79%) patients. These 26 patients included 5 of 6 (83%) with type 1 VWD, 5 of 5 (100%) with type 2A, and 16 of 22 (73%) with type 3.

Of the 89 nosebleeds in WIL-31, 69 (78%) were spontaneous, 17 (19%) traumatic and 3 (3%) were due to allergic rhinitis and classified as other. The severity of nosebleeds in WIL-31 was classified as minor in 82 (92%) cases and as major in 7 (8%) cases. The 7 major bleeds occurred in 2 male patients (6 in a 52-year-old patient with type 1 VWD and 1 in a 15-year-old patient with type 3 VWD). Of the 194 nosebleeds in WIL-29, 192 (99%) were spontaneous and 2 (1%) were traumatic. The severity of nosebleeds in WIL-29 was classified as minor in 176 (91%) cases and as major in 18 (9%) cases. Of the 18 major bleeds, 13 occurred in a 52-year-old male patient with type 3 VWD, 3 in a 9-year-old male patient with type 1 VWD, and 2 in a 55-year-old female patient with type 3 VWD. The percentage of nosebleeds that were treated with a VWF concentrate was 81% in both WIL-31 (72/89) and WIL-29 (157/194); all untreated bleeds were minor.

Annualized Bleeding Rates for Nosebleeds

The mean TABR for nosebleeds was 2.7 during prophylaxis compared with 11.0 during on-demand treatment, corresponding to a reduction of 76% (Table 2, Figure 1a). Among those patients with at least one nosebleed during WIL-29 (N = 26), the TABR was reduced by 76% from 14.0 to 3.4. Reductions in the mean TABR were seen during prophylaxis compared with during on-demand treatment across all age groups (77%, 76%, and 74% in the 6-11, 12-16, and ≥17 years age groups, respectively) and all VWD types (55%, 91% and 81% in types 1, 2 and 3, respectively), and in males and females (67% and 83%, respectively) (Table 2, Figure 1a). The mean SABR for nosebleeds was 2.1 during prophylaxis compared with 10.9 during on-demand treatment, corresponding to a reduction of 81% (Table 2, Figure 1b). The reductions in SABRs by age, VWD type and sex followed similar patterns to those for TABRs (Table 2).

Figure 1.

Mean ABR for nosebleeds during on-demand treatment with any pdVWF/FVIII concentrate and during prophylaxis with wilate by age, VWD type and sex. (A) TABR and (B) SABR.

Table 2.

Mean (SD) TABRs and SABRs for Nosebleeds by Age Group, VWD Type and Sex.

	TABR		Change (%)	SABR		Change (%)
Patient Group	WIL-29	WIL-31	Change (%)	WIL-29	WIL-31	Change (%)
All patients (N = 33)	11.0 (15.3)	2.7 (4.7)	−76	10.9 (15.2)	2.1 (3.8)	−81
Age group
6–11 years (N = 9)	12.2 (9.3)	2.7 (4.5)	−77	11.8 (8.4)	2.3 (4.1)	−80
12–16 years (N = 6)	8.3 (5.6)	2.0 (2.4)	−76	8.3 (5.6)	1.2 (2.0)	−86
≥17 years (N = 18)	11.3 (19.7)	2.9 (5.5)	−74	11.3 (19.7)	2.3 (4.2)	−80
VWD type
Type 1 (N = 6)	14.4 (11.8)	6.6 (8.7)	−55	13.9 (10.9)	5.0 (6.2)	−64
Type 2A (N = 5)	8.5 (4.8)	0.8 (1.8)	−91	8.5 (4.8)	0.4 (0.9)	−95
Type 3 (N = 22)	10.6 (17.8)	2.0 (3.2)	−81	10.6 (17.8)	1.6 (3.1)	−84
Sex
Male (N = 19)	9.2 (13.1)	3.0 (5.4)	−67	9.1 (12.9)	2.3 (4.2)	−75
Female (N = 14)	13.3 (18.1)	2.2 (3.8)	−83	13.3 (18.1)	1.8 (3.8)	−86

During prophylaxis, 17 (52%) patients had zero nosebleeds and 19 (58%) patients had zero spontaneous nosebleeds. During 6 months of on-demand treatment, 7 (21%) patients had zero nosebleeds and zero spontaneous nosebleeds.

Individual TABRs and SABRs for nosebleeds are shown in Figure 2. TABR and SABR were reduced during prophylaxis in 31 of the 33 patients. A 32-year-old male with type 3 VWD, who had zero nosebleeds during on-demand treatment in WIL-29, had a spontaneous nosebleed during prophylaxis in WIL-31. A 52-year-old male with type 1 VWD, who had 1 spontaneous nosebleed in WIL-29, had 12 spontaneous and 8 traumatic nosebleeds during prophylaxis in WIL-31 of which 6 were classified as major. Due to the increased rate of nosebleeds and other bleeds observed in this patient, an inhibitor test was performed, which was negative. In this patient, the mean in vivo recoveries of VWF (VWF:RCo) and FVIII (one-stage assay) during WIL-31 were 1.1 and 1.4 IU/dL per IU/kg, respectively, which were at the lower end of the range of what might be expected. The underlying cause of the increase in nosebleeds could not be ascertained. This patient accounted disproportionately to the subgroup TABRs for type 1 VWD, male patients, and the ≥17 years age group. Without this patient, the percentage reduction in TABR in WIL-31 versus WIL-29 in type 1 patients was more pronounced (78% vs 55%). Similarly, the percentage reduction was more pronounced in male patients (79% vs 67%) and in patients ≥17 years (84% vs 74%).

Figure 2.

Individual nosebleed ABRs during on-demand treatment and during prophylaxis. (A) TABR and (B) SABR. * Denotes zero bleeds.

Considering only the patients who were treated in both the first and second 6-month periods of WIL-31 (N = 31), mean TABRs were 67% and 83% lower in the first 6 months and second 6 months of prophylaxis, respectively, compared with prior on-demand treatment (Figure 3a). The corresponding values for mean SABR were 73% and 88%, respectively (Figure 3a). Mean TABR and SABR were 49% and 57% lower in the second 6 months of prophylaxis compared with the first 6 months. The percentage of patients with zero nosebleeds in the second 6 months of prophylaxis was 68% compared with 55% during the first 6 months of prophylaxis, and 19% during on-demand treatment (Figure 3b).

Figure 3.

Bleeding outcomes for nosebleeds during on-demand treatment in WIL-29 and during the first and second 6 months of prophylaxis in WIL-31 (N = 31). (A) TABR and SABR for nosebleeds and (B) percentage of patients with zero nosebleeds.

The median (range) dose per injection of wilate in the first and second 6 months of prophylaxis was 32 (20-41) and 32 (20-50), and the median weekly dose was 63 (40-113) and 59 (38-127) IU/kg, respectively. The reduction in mean SABR in the second 6 months of prophylaxis was mainly due to two patients who increased their dosing frequency from twice weekly to three times weekly. In one of these patients, who increased dosing frequency after 2.7 months, SABR was reduced from 73 during on-demand treatment in WIL-29 to 24 during the first 6 months of prophylaxis, and to 2 during the second 6 months. In the other patient, who increased dosing frequency after 6.9 months, SABR was reduced from 29 in WIL-29 to 24 during the first 6 months of prophylaxis, and reduced to 2 during the second 6 months.

Treatment of Breakthrough Nosebleeds

During prophylaxis, 81% (72/89) of breakthrough nosebleeds were treated with wilate. The mean (SD) dose per nosebleed was 47.2 (31.5) IU/kg via 1.2 (0.6) infusions. A single infusion was sufficient to treat 86% of nosebleeds and 92% of nosebleeds only required treatment for 1 day. The efficacy of wilate was rated as excellent for 99% (71/72) of treated nosebleeds and moderate for 1%. None of the nosebleeds required to hospitalization.

The one treated nosebleed with a moderate efficacy rating was a major nosebleed that occurred in a 15-year-old male patient with type 3 VWD. Oral tranexamic acid (1 g 3 times daily) was initiated 15 min after the start of the nosebleed. wilate (42 IU/kg) was administered 3 h after the start of the nosebleed and a second dose of 64 IU/kg administered after 13.5 h. The nosebleed stopped 10 min after the end of the second wilate infusion.

Concomitant tranexamic acid (500 mg) was also used to treat a minor spontaneous nosebleed in an 11-year-old male patient with type 3 VWD. Tranexamic acid was administered 1 h after the onset of the nosebleed and a single dose of wilate (32 IU/kg) was administered after 9 h 40 min. The bleeding stopped 15 min after the wilate infusion and efficacy was rated as excellent. All nosebleeds during on-demand treatment in WIL-29 were treated successfully. Information on the products used to treat nosebleeds in WIL-29 is provided in Table 1. The mean (SD) duration of treated nosebleeds of all types was 7.2 (15.9) hours during prophylaxis compared with 7.6 (14.7) hours during on-demand treatment; the corresponding values for all bleeds (treated and untreated) were 6.0 (14.4) and 6.5 (13.4) hours, respectively (Table 1).

Discussion

This post-hoc analysis demonstrated that prophylaxis with wilate reduced the mean TABR and SABR for nosebleeds by 76% and 81%, respectively, compared with prior on-demand treatment. Compared with on-demand treatment, reductions in mean TABRs and SABRs were seen across all age groups and VWD types, and in males and females. These data were consistent with data for all bleeding sites reported previously.¹⁹ Our analysis also demonstrated a reduction in TABR and SABR in the second 6 months versus the first 6 months of prophylaxis. The reduction in SABR was driven by improved bleeding control in 2 patients following an increase in dosing frequency from twice to three times weekly, which highlights that dose adjustment may be needed in some patients to optimize prophylaxis. The efficacy of wilate in the treatment of breakthrough bleeds was rated excellent in 99% of cases.

Nosebleeds are a common manifestation of VWD of all types, particularly in children, and are associated with increased healthcare utilization; severe cases may lead to anemia and the need for blood transfusions or iron replacement therapy.^9,16,17 However, few studies have investigated the efficacy of prophylaxis in preventing nosebleeds in patients with severe VWD.^22,24,25 A retrospective analysis by the VWD Prophylaxis Network reported data on 59 patients aged 2–77 years with clinically severe VWD who received prophylaxis with Humate P or Fanhdi/Alphanate for a median of 2.2 years.²² In 13 patients with a primary indication of epistaxis, the median ABR for nosebleeds was reduced by 75% during prophylaxis compared with prior treatment (24 vs 6).²² The VWD Prophylaxis Network subsequently analyzed data for 105 patients (95 retrospective, 10 prospective) on prophylaxis.²⁴ The median ABR for nosebleeds in 28 patients with a primary indication of epistaxis was reduced by 87% compared with prior treatment (11.1 vs 3.8).²⁴ The PRO.WILL study remains the only randomized controlled trial that has compared on-demand and prophylaxis in patients with severe inherited VWD.²⁵ Compared with the on-demand arm, patients in the prophylaxis group had a 62% lower incidence rate per patient-month for nosebleeds (0.16 vs 0.42).²⁵

Although our analysis, along with other reports,^22,24,25 showed that the very high frequency of nosebleeds in patients with severe VWD can be reduced considerably with prophylaxis, the impact of prophylaxis on quality of life related to nosebleeds was not assessed. On average, patients had 8 fewer nosebleeds per year during prophylaxis in WIL-31 than they had during on-demand in WIL-29. Considering that the mean duration of nosebleeds was 6.5 h during on-demand treatment, this equates to an average reduction of 52 h of nosebleeds per patient per year. Thus, a positive impact on quality of life, and on the overall burden of nosebleeds on patients and their caregivers, would be anticipated. Patient testimonies also allude to the significant burden associated with nosebleeds and to a lack of awareness among healthcare professionals.^29,30

Measuring the impact of nosebleeds on quality of life in patients with VWD, and the effect of prophylaxis, is complicated by the fact that patients with VWD can experience bleeding at multiple sites.^1,9,10 In patients with Hereditary Hemorrhagic Telangiectasia (HHT), a disorder in which nosebleeds are the greatest cause of morbidity, several nosebleed-specific questionnaires have been developed.³¹ These include the Epistaxis Severity Score (ESS),³² the Epistaxis Questionnaire Quality of Life (EQQoL)³³ and the Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE HHT),³¹ which could be considered as the basis for measuring the nosebleed-specific burden, and the effect of prophylaxis, in patients with severe VWD.

Limitations of this analysis include that it was a post-hoc analysis, the relatively small sample size, the differences in the number of patients in subgroups, and the absence of data for children <6 years of age. An ongoing phase 3 study (WIL-33; NCT04953884) is investigating wilate prophylaxis in children with severe VWD <6 years of age and will provide information on the efficacy of prophylaxis in this age group.

In conclusion, this post-hoc analysis demonstrated the efficacy of wilate prophylaxis in the prevention and treatment of nosebleeds in patients with severe VWD. These results add to the growing body of evidence supporting the use of prophylaxis in people with severe VWD^16–19 and suggest that greater utilization of prophylaxis could improve patient care.

Footnotes

Acknowledgements

This analysis was supported by research funding from Octapharma AG. Natascha Blaudeck (Ergomed GmbH,Frankfurt am Main,Germany) provided support with programming and data analysis,which was funded by Octapharma AG. nspm ltd (Meggen,Switzerland) provided medical writing assistance,which was funded by Octapharma AG.

Author Contributions

All authors contributed to the collection of data and had access to the primary clinical trial data. All authors contributed to the writing of the manuscript,provided critical revision and approved the final version for publication.

Consent

Voluntarily given,fully informed written and signed consent was obtained from patients (or their legal guardians) before any study-related procedures were conducted.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research,authorship,and/or publication of this article: Ana Boban has received research funding from Octapharma,honoraria from Amgen,Astra Zeneca,Bayer,CSL Behring,Novo Nordisk,Octapharma,Pfizer,Roche,Swedish Orphan Biovitrum,Swixx,and Takeda,and travel support from Swedish Orphan Biovitrum,Novo Nordisk and Takeda. She has participated on a Data Safety Monitoring Board or Advisory Board for Swedish Orphan Biovitrum,Takeda,Bayer,Swixx,Astra Zeneca,and has had roles with the European Association for Haemophilia and Allied Disorders and the International Society on Thrombosis and Haemostasis.

Leonid Dubey has participated as a clinical trial investigator for Octapharma.

Kateryna V. Vilchevska has nothing to disclose.

Adlette Inati has received consultancy and speaker fees from Novartis,Global Blood Therapeutic/Pfizer,Roche,Novo Nordisk,and research funding from Agios,Octapharma,Novartis,Global Blood Therapeutic /Pfizer,Roche,Forma/Novo Nordisk,Pharmacosmos and Vifor.

Claudia Djambas Khayat has received presentation and speaker fees from Octapharma,CSL Behring,and LFB,and support for travel and attending meetings from Octapharma,CSL Behring,and LFB.

Robert F. Sidonio Jr has received research funding from Octapharma,LFB/Hema Biologics and Takeda,honoraria for consulting and advisory boards from Octapharma,Takeda,LFB,Sanofi,Swedish Orphan Biovitrum,Novo Nordisk,Bayer,Biomarin,Pfizer,Vega,and Guardian Therapeutics,and payment for expert testimony from Sanofi. He has participated on a Data Safety Monitoring Board or Advisory Board for Uniqure and has had a role with the American Thrombosis and Hemostasis Network (board member),the International Society on Thrombosis and Haemostasis (chair),the Hemophilia Federation of America (medical advisor),and the Medical and Scientific Advisory Council of the National Hemophilia Foundation.

Ethics

The study was performed in accordance with the Declaration of Helsinki and the respective local regulations.

Funding

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

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Efficacy of Wilate Prophylaxis in Reducing Nosebleeds in Patients with Severe VWD – A Post-hoc Analysis of the WIL-31 Study

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Study Design

Analyses

Results

Study Population

Characteristics of Nosebleeds

Annualized Bleeding Rates for Nosebleeds

Treatment of Breakthrough Nosebleeds

Discussion

Footnotes

Acknowledgements

Author Contributions

Consent

Declaration of Conflicting Interests

Ethics

Funding

References