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. 2024 Apr 4;143(14):1414-1424.
doi: 10.1182/blood.2023022457.

Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies

Ferdows Atiq  1   2 , Robin Blok  2 , Calvin B van Kwawegen  2 , Dearbhla Doherty  1   3 , Michelle Lavin  1   3 , Johanna G van der Bom  4 , Niamh M O'Connell  3 , Joke de Meris  5 , Kevin Ryan  3 , Saskia E M Schols  6 , Mary Byrne  3 , Floor C J I Heubel-Moenen  7 , Karin P M van Galen  8 , Roger J S Preston  1 , Marjon H Cnossen  9 , Karin Fijnvandraat  10 , Ross I Baker  11   12 , Karina Meijer  13 , Paula James  14 , Jorge Di Paola  15 , Jeroen Eikenboom  16 , Frank W G Leebeek  2 , James S O'Donnell  1   3   12
Affiliations

Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies

Ferdows Atiq et al. Blood. .

Abstract

There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (β = 0.00; 95% confidence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.

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Conflict of interest statement

Conflict-of-interest disclosure: F.A. received research support from CSL Behring, Takeda, Octapharma, and Sobi; and also received travel grants from Sobi. F.W.G.L. has received unrestricted grants/research funding from CSL Behring, uniQure, Sobi, and Takeda; consultancy fees from BioMarin, CSL Behring, Takeda, and uniQure (all fees to the institution); and served as a data safety and monitoring board member for a study sponsored by Roche. J.S.O. has served on the speaker’s bureau for Baxter, Bayer, Novo Nordisk, Sobi, Boehringer Ingelheim, Leo Pharma, Takeda, and Octapharma; served on the advisory boards of Baxter, Sobi, Bayer, Octapharma CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, Takeda, and Pfizer; and has also received research grant funding awards from 3M, Baxter, Bayer, Pfizer, Shire, Takeda, 3M, and Novo Nordisk. D.D. has received honoraria from Takeda and educational support sponsorship from NovoNordisk and Amgen. M.L. has received consultancy fees from Sobi, Band Therapeutics, and CSL Behring; honoraria from CSL Behring and Pfizer; and indirect funding for development of educational content from Takeda. J.G.v.d.B. received research funding from Novo Nordisk. N.M.O. served on advisory boards for Sobi, F. Hoffman-La Roche Ltd, uniQure, CSL Behring, AstraZeneca, and Freeline and on the speaker’s bureau for Novo Nordisk, Sobi, CSL Behring, Bayer, and Takeda. S.E.M.S. has received research funding from Bayer. R.I.B.’s institution has received research support/clinical trial funding from Bayer, Takeda, Pfizer, Daiichi Sankyo, CSL Behring, Roche, Amgen, AstraZeneca, AbbVie, Sanofi, Acerta Pharma, Jansen-Cileg, Bristol Myers Squibb, Boehringer Ingelheim, Werfen, and Technoclone, unrelated to this study. K.M. reports speaker fees from Alexion, Bayer, and CSL Behring; participation in trial steering committees for Bayer and AstraZeneca; consulting fees from uniQure and Therini; and participation in data monitoring and end point adjudication committee for Octapharma (all fees paid to the institution). P.J. receives research funding from Bayer and consultancy fees from Band/Guardian Therapeutics, Star/Vega Therapeutics, and Roche. K.F. has received unrestricted grants/research funding from CSL Behring, Sobi, and Takeda for research unrelated to this study and consultancy fees from SOBI, Sanofi, Takeda, Novo Nordisk, and Roche (all fees to the institution). K.P.M.v.G. has received an unrestricted research grant from Octapharma. The remaining authors declare no competing financial interests.

Figures

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Graphical abstract
Figure 1.
Figure 1.
Effects of age on plasma VWF:Ag levels in patients with low VWF compared with those in type 1 VWD subgroups. Plasma VWF:Ag levels were assessed in patients with low VWF and type 1 VWD at the time of first diagnosis and then subsequently repeated at time of enrollment into the national studies. The left dot depicts the mean plasma VWF:Ag and the corresponding mean age at time of original diagnosis and the right dot depicts mean plasma VWF:Ag and the corresponding mean age at trial enrollment. Broken lines with colored areas depict the standard deviations for separate groups. (A) Age-dependent increases in plasma VWF:Ag aligns for LoVIC participants and WiN patients whose plasma VWF levels increased ≥30 IU/dL. (B) Age-dependent increases in plasma VWF:Ag completely overlap for LoVIC patients compared with WiN patients whose plasma VWF levels normalized ≥50 IU/dL.
Figure 2.
Figure 2.
Pathophysiological mechanisms in patients with low VWF compared with type 1 VWD subgroups. FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios were assessed in patients with low VWF and type 1 VWD to assess underlying pathophysiology. (A) Significantly increased plasma FVIII:C/VWF:Ag ratios suggesting marked reductions in VWF synthesis/secretion were observed in the WiN persistent <30 IU/dL subgroup. In contrast, FVIII:C/VWF:Ag ratios were the same in LoVIC and WiN-normalized patients. (B) Similarly, significantly increased plasma VWFpp/VWF:Ag ratios suggesting markedly enhanced VWF clearance were also observed in the WiN persistent <30 IU/dL subgroup. Again, VWFpp/VWF:Ag ratios were not significantly different between LoVIC and WiN-normalized patients. Ns, not significant.
Figure 3.
Figure 3.
Desmopressin responses in low VWF compared with WiN type 1 VWD subgroups. Plasma VWF:Ag were determined prior to desmopressin administration (T0), and at 1 (T + 1), 4 (T + 4), and 24 (T + 24) hours after desmopressin administration. The mean and standard deviations are depicted; n = 226 before desmopressin administration; n = 217 at 1 hour; n = 146 at 4 hours; and n = 126 at 24 hours. Significantly reduced VWF responses were observed at all postdesmopressin time points in the WiN persistent <30 IU/dL subgroup. Plasma VWF:Ag levels at 1, 4, and 24 hours after desmopressin were significantly higher in WiN-normalized than in LoVIC patients. ns, not significant.
Figure 4.
Figure 4.
Effect of aging on desmopressin-induced VWF responses. The effects of increasing age on plasma VWF:Ag levels after desmopressin administration were assessed in combined subgroups of patients with low VWF and type 1 VWD in whom plasma VWF levels increased ≥30 IU/dL. Plasma VWF:Ag were determined prior to desmopressin administration (T0), and at 1 (T + 1), 4 (T + 4), and 24 (T + 24) hours after desmopressin administration. The mean and standard deviations are depicted; n = 171 before desmopressin administration; n = 164 at 1 hour; n = 123 at 4 hours; and n = 98 at 24 hours after desmopressin administration. Significantly increased VWF responses were observed at 1, 4, and 24 hours after desmopressin administration with increasing age at the time of desmopressin trial. P values are outcomes of linear regression analysis with the presented age groups included as independent variable. ns, not significant.
Figure 5.
Figure 5.
Determinants of age-induced VWF level normalization in low VWF and type 1 VWD. Normalization of plasma VWF levels (defined as increase of VWF:Ag, VWF:Act, VWF:CB and FVIII:C >50 IU/dL with aging) was assessed in LoVIC and WiN patients with more than 5 years of retrospective follow-up. Kaplan-Meier curves were used to illustrate determinants of normalization of VWF levels with aging. P values are outcomes of log-rank tests. (A) Normalization in plasma VWF levels during follow-up was significantly higher in LoVIC than in WiN patients. (B) Normalization in plasma VWF levels during follow-up was significantly increased in patients with low VWF and type 1 VWD who demonstrated complete desmopressin responses (defined according to the 2021 ASH/ISTH/WFH/NHF guideline). (C) Age-induced normalization in plasma VWF levels was significantly higher in patients with low VWF and type 1 VWD who did not have a pathological VWF sequence variant. (D) Normalization in plasma VWF levels with aging was markedly reduced in patients with historically lowest levels VWF levels <10 IU/dL. (E) Age-induced normalization in plasma VWF levels was significantly decreased in patients with marked underlying pathophysiological defects (defined as FVIII:C/VWF:Ag ratio ≥1.9 and/or VWFpp/VWF:Ag ratio ≥2.2).
Figure 6.
Figure 6.
Overview of the relationship between low VWF, type 1 VWD, and progressive aging.
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References

    1. Leebeek FW, Eikenboom JC. Von Willebrand's disease. N Engl J Med. 2016;375(21):2067–2080. - PubMed
    1. Nichols WL, Hultin MB, James AH, 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(2):171–232. - PubMed
    1. Sadler JE, Budde U, Eikenboom JC, 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(10):2103–2114. - PubMed
    1. Laffan MA, Lester W, O'Donnell JS, et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014;167(4):453–465. - PMC - PubMed
    1. Castaman G, Goodeve A, Eikenboom J, European Group on von Willebrand Disease Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. 2013;98(5):667–674. - PMC - PubMed

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