Effect of age on ISTH-BAT scores and low VWF diagnosis in the Zimmerman Program Open Access

By definition, 2.5% of the normal population have plasma von Willebrand factor (VWF) levels below the lower limit of the normal range (typically <50 IU/dL).^1,2 Previous studies have shown that most individuals with mild-to-moderate reductions in plasma VWF levels do not have any significant bleeding phenotype.^1,2 Conversely, a subset of patients with plasma VWF levels in the 30 to 50 IU/dL range may experience increased bleeding.^3-5 Notably, increased heavy menstrual bleeding (HMB) and postpartum hemorrhage (PPH) have been reported in some female patients with mild-to-moderate VWF reductions.^3-5 Previous international consensus guidelines recommended that patients with a bleeding phenotype and plasma VWF levels in the 30 to 50 IU/dL range should be diagnosed as low VWF.^6-9 In contrast, the American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF), and World Federation of Hemophilia (WFH) consensus guidelines published in 2021 recommended that individuals with VWF levels between 30 and 50 IU/dL and an increased bleeding phenotype should instead be classified as type 1 von Willebrand disease (VWD).¹⁰ Therefore, assessment of individual bleeding phenotype constitutes a critical aspect of low VWF/type 1 VWD diagnosis.¹¹ 

The ASH, ISTH, NHF, and WFH guidelines recommend use of the ISTH-bleeding assessment tool (ISTH-BAT) for objective assessment of bleeding phenotype.¹⁰ The ISTH-BAT assigns scores ranging from 0 to 4 points across various bleeding domains, based on the presence and severity of each type of bleeding, and any treatments previously administered.¹² The total ISTH-BAT score is then calculated for each individual at the time of original presentation as the sum of the bleeding domain scores. Normal reference ranges for healthy adult males (0-3), adult females (0-5), and children (0-2) have been defined.¹² A limitation of the ISTH-BAT score is that points are cumulatively accrued based on bleeding episodes over time. Importantly, a recent study demonstrated that ISTH-BAT score increases progressively with aging even in healthy adult females.¹³ This study reported that, in contrast to the originally defined reference ranges, normal ISTH-BAT values range from 0 to 4 in women aged 18 to 30 years, and 0 to 6 in women aged 52 to 88 years.¹³ In addition, Jain et al suggested that in adolescent girls with HMB, an ISTH-BAT score >4 should be considered abnormal, rather than the threshold of >2.¹⁴ Collectively, these data suggest that further age-adjusted normal ranges for the ISTH-BAT may be useful for improving diagnostic sensitivity and specificity.

In addition to their use in VWD diagnosis and classification, previous studies have investigated whether BATs may also be useful in stratifying bleeding severity, thereby defining subgroups of patients at increased risk for future bleeding.^4,15 Federici et al reported that an MCMDM1 score >10 was associated with an increased risk of bleeding that required therapy in patients with VWD.¹⁵ Similarly, Atiq et al found that increasing ISTH-BAT scores were associated with a higher risk of future bleeding requiring treatment in individuals with low VWF.⁴ On this basis, European Hematology Association guidelines suggest stratification of patients with mild-to-moderate inherited bleeding disorders based upon the maximum score achieved in any ISTH-BAT domain.¹⁶ Similarly, the recent ASH, ISTH, NHF, and WFH guidelines suggest that ISTH-BAT scores may be clinically useful to assess and document bleeding severity at the time of VWD diagnosis in the tertiary care setting.¹⁰ Importantly, assignment of bleeding phenotype severity based on ISTH-BAT scores has the potential to impact subsequent treatment choices.

Despite the critical role of the ISTH-BAT in assessing bleeding phenotype, and thus low VWF/type 1 VWD diagnosis, the effect of aging has not been specifically examined for adults with mild-to-moderate reductions in plasma VWF levels. Furthermore, the relationship between aging, ISTH-BAT scores, and VWD classification in children has not been defined. To address these clinically important questions, we have examined the relationship between age and ISTH-BAT scores in a large cohort of deeply phenotyped individuals with plasma VWF levels in the 30 to 50 IU/dL range collected through the Zimmerman Program. Our findings demonstrate that age critically influences ISTH-BAT scores, and thus the likelihood of formal low VWF/type 1 VWD diagnosis in adults and children with plasma VWF levels in the 30 to 50 IU/dL range. Furthermore, our data provide important insights into the bleeding mechanisms underlying age-dependent effects.

This study evaluated patients enrolled into the Zimmerman Program (which incorporated the low VWF in Ireland Cohort [LoVIC, study; Dublin, Ireland]; the Zimmerman Program R01 and PPG cohorts [Milwaukee, Wisconsin], and the Canadian type 1 VWD study).^3,17-19 Previous publications have extensively described the methods for all 3 studies.^3,17-19 In brief, the LoVIC study is a nationwide study in Ireland, enrolling individuals with VWF levels in the 30 to 50 IU/dL range, measured on 2 separate occasions at least 3 months apart. The Zimmerman Program included patients with VWD from 11 primary hematology centers and multiple secondary hematology centers across North America. Patients from the Zimmerman Program were classified as low VWF based on centrally measured VWF levels in the 30 to 50 IU/dL range. The Canadian type 1 VWD study included patients with VWD with VWF levels ranging from 5 to 50 IU/dL, recruited from 13 academic health science centers across Canada. For the current analysis, we included participants from all 3 studies that had VWF antigen (VWF:Ag) and/or VWF activity and/or VWF collagen binding assay in the 30 to 50 IU/dL range. Patients with mild-to-moderate reductions in plasma VWF levels with an increased ISTH-BAT score were in the current study diagnosed as low VWF. All studies received approval from their respective institutional review boards, and informed consent was obtained from all participants. The research was conducted in accordance with the Declaration of Helsinki.

Trained health care professionals, including physicians, nurses, or study coordinators, administered a bleeding questionnaire to participants. The answers to these questions were used to calculate individual ISTH-BAT domain scores and the total ISTH-BAT score. In line with current guidelines, an ISTH-BAT score of ≥3 was considered abnormal in children <18 years old, ≥4 was considered abnormal in men, and ≥6 was considered abnormal in women.^12,20 Subanalyses were performed using ISTH-BAT abnormal thresholds of >4 in adolescent girls with HMB, >5 in women aged 18 to 30 years, >7 in women aged 52 to 88 years, according to recent publications by Jain et al and Doherty et al, respectively.^13,14 ISTH-BAT subgrouped domain scores: Intervention domains score (sum of the surgery and dental extraction domains), Sex-specific domains score (sum of the menorrhagia and PPH domains), and spontaneous domains score (sum of all other domains) were evaluated as previously described.¹³ 

Continuous data are presented as mean ± standard deviation, whereas categorical data are reported as number (percent). Independent t tests were used to compare continuous variables between 2 groups. Categorical variables were compared using the χ² test or the Fisher exact test in case of <5 individuals in a group. The linear associations between age and ISTH-BAT scores were evaluated with linear regression analysis. Outcomes of linear regression analysis are presented as β coefficients (β) and 95% confidence intervals (CIs). Statistical analyses were conducted using IBM SPSS Statistics version 25 (IBM Corp, Armonk, NY), and a P value < .05 was considered statistically significant.

A total of 325 individuals enrolled in the Zimmerman Program with plasma VWF levels in the 30 to 50 IU/dL range were included in this study (Table 1). Of these individuals, 220 patients had an increased ISTH-BAT score, and were diagnosed with low VWF. In contrast, 105 individuals with VWF levels in the 30 to 50 IU/dL range had normal ISTH-BAT scores. Overall, females were significantly (P < .001) more prevalent in the low VWF cohort with abnormal BAT scores (n = 186 [84.5%]) compared with the group with mild-to-moderate reductions in VWF but normal ISTH-BAT scores (n = 71 [67.6%]; Table 1). Conversely, no significant difference (P = .21) was observed in the prevalence of blood group O between the 2 groups (Table 1). The US and Canadian studies recruited both adults and children with mild-to-moderate reductions in plasma VWF levels (n = 174; mean age, 17.1 years [range, 1-65]). In contrast, only adult patients were enrolled in the Irish LoVIC study (n = 151; mean age, 38.7 years [range, 18-72]; Figure 1A). Consistent with their increased age, we observed that ISTH-BAT scores were significantly (P < .001) increased in the Irish subgroup, with VWF levels in the 30 to 50 IU/dL range (Figure 1B). Importantly, however, increasing age was associated with significantly higher ISTH-BAT scores in both the Irish and US/Canadian subgroups (Figure 1C; P < .001). In keeping with previous reports, analysis of individual ISTH-BAT domains in the Zimmerman adult patient cohort highlighted that HMB was a particular problem (Figure 1D). Together, these data demonstrate that age significantly impacts ISTH-BAT scores in patients with mild-to-moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range.

The relationship between aging and ISTH-BAT scores in children with mild-to-moderate reductions in plasma VWF levels has not previously been defined. In total, the Zimmerman Program included 116 children (mean age, 9.9 years [range, 1-17]) with plasma VWF:Ag levels in the 30 to 50 IU/dL range (Figure 2A). This cohort consisted of 73 girls (62.9%) and 43 boys (37.1%). Overall, 75 children (64.7%) had an abnormal ISTH-BAT score >2, and thus were classified as low VWF. Multiple different domains contributed to ISTH-BAT scores in children with mild-to-moderate reductions in VWF levels (Figure 2B). Importantly, even in pediatric patients with VWF levels in the 30 to 50 IU/dL range, we observed a significant effect of age on ISTH-BAT scores. Specifically, the youngest group (first quartile [Q1], ≤4 years) had a mean ISTH-BAT score of 2.7 ± 3.1, which increased to 5.2 ± 2.9 in the oldest group (fourth quartile [Q4], 15-17 years; P = .004; Figure 2C). Consistent with this effect, the prevalence of abnormal ISTH-BAT scores for children with VWF levels in the 30 to 50 IU/dL range also rose significantly with age (P < .001; Figure 2D). Consequently, abnormal ISTH-BAT scores were seen in 84.4% of children aged 12 to 17 years with VWF levels in the 30 to 50 IU/dL range, compared with only 27.3% of children aged 0 to 4 years. The prevalence of ISTH-BAT scores ≥8 was >3 times higher in children aged 12 to 17 years at the time of diagnosis (22.4%) compared with children aged <12 years (6.9%; P = .033; Figure 2E).

Interestingly, we observed that boys were overrepresented in the youngest age group (n = 16; 72.7% vs 27.3% girls; Figure 3A). This sex difference balanced out in the 5 to 11 years age group (50% boys and 50% girls). In contrast, from ≥12 years of age, girls were significantly overrepresented (n = 21 [84.0%]; P < .001; Figure 3A). Accordingly, in the youngest age group (≤4 years), boys more often had an abnormal bleeding score (37.5%) compared with girls (0%; Figure 3B). Again, this sex difference balanced out with increasing age (Figure 3B). Investigation of individual domains demonstrated that in girls, the age-dependent increase in ISTH-BAT scores was mainly driven by HMB (Figure 3C). Average HMB scores were 1.8 ± 1.6 for adolescent girls aged 12 to 14 years (third quartile), and 2.2 ± 1.3 for girls aged 15 to 17 years (Q4; P < .001). For boys, the increase in ISTH-BAT scores with age was primarily due to epistaxis, which rose from an average score of 0.7 ± 1.1 in boys aged ≤4 years to 3.2 ± 0.8 in adolescent boys aged 15 to 17 years (P < .001; Figure 3D). Collectively, these findings show that age has an important effect on ISTH-BAT scores in children with VWF levels in the 30 to 50 IU/dL range, and thus significantly influences type 1 VWD/low VWF diagnosis in the pediatric setting.

At the age of 18 years, the threshold for defining an abnormal ISTH-BAT score shifts from 3 in children, to 6 for women and 4 for men.²⁰ To assess the impact of this change in cutoff, we investigated individuals in the Zimmerman Program with plasma VWF levels in the 30 to 50 IU/dL range aged between 12 and 27 years. Overall, no significant difference in mean ISTH-BAT scores was observed between adolescents aged 15 to 17 years (5.2 ± 2.9) and young adults aged 18 to 20 years (5.5 ± 3.3; P = .787; Figure 4A). However, because the cutoff required for an abnormal ISTH-BAT score increased for patients aged ≥18 years, the proportion of adolescents aged 15 to 17 years with abnormal scores (n = 18 [84.8%]) was significantly (P = .006) higher compared with young adults aged 18 to 20 years (n = 17 [53.1%]; Figure 4B). This decline in abnormal bleeding scores was observed in both sexes, but was particularly noticeable among adolescent boys, with only 28.6% of men aged 18 to 20 years attained an abnormal score (Figure 4C). Applying previously reported age-adjusted ISTH-BAT reference ranges, in which a score of ≥5 is considered abnormal in young women aged 18 to 30 years, still resulted in a significantly lower prevalence of abnormal ISTH-BAT scores (64%) in young women aged 18 to 20 years compared with adolescent girls aged 12 to 17 years (85.7%; P = .032).¹³ Together, these data highlight that age at ISTH-BAT assessment (ie, before or after 18 years) has a significant impact upon whether an individual will have an “abnormal” ISTH-BAT score, and thus be diagnosed with low VWF or type 1 VWD.

In total, the Zimmerman Program included 209 adult patients (mean age 36.9 years [range, 18-72]) with plasma VWF:Ag levels in the 30 to 50 IU/dL range (Table 1). This cohort consisted of 184 women (88%) and 25 men (12%). Overall, 145 (69.4%) adults in the study had abnormal ISTH-BAT scores, and thus were classified as low VWF. In this adult cohort, older age was significantly associated with higher ISTH-BAT scores in women (P < .001; Figure 5A), but not in men (P = .185; supplemental Figure 1). In the adult female cohort, aging was associated with an ∼1.5 unit increase in ISTH-BAT scores per decade (β = 1.5; 95% CI, 1.5-2.1; P < .001). In line, significantly higher ISTH-BAT scores were observed in the oldest quartile (≥44 years) compared with the youngest quartile (18-28 years; 11.3 ± 5.0 vs 6.9 ± 3.7 [P < .001]; Figure 5A). In addition, the prevalence of abnormal ISTH-BAT scores, and consequently the prevalence of low VWF diagnosis, was significantly higher in women aged ≥44 years (91.8%) compared with those aged 18 to 28 years (66.7%; P = .004; Figure 5B). Applying age-adjusted reference ranges for ISTH-BAT scores, as recently recommended, reduced the differences between groups (87.8% abnormal scores in women aged ≥44 years vs 72.9% in women aged 18-28 years), though a statistically significant difference remained (P = .039; supplemental Figure 2).¹³ Finally, women with VWF levels of 30 to 50 IU/dL who were older at diagnosis were significantly more likely to be assigned a severe bleeding phenotype (ISTH-BAT scores ≥10; P = .002; Figure 5C).

Bleeding subdomain analysis demonstrated that the age-related effect on ISTH-BAT in women with VWF levels in the 30 to 50 IU/dL range was attributable to accumulating scores in both the intervention and sex-specific domains (Figure 5D). Specifically, older patients showed elevated scores in the surgical domain (Q4 vs Q1, 1.3 ± 1.6 vs 0.4 ± 1.0; P = .002) and the dental extraction domain (Q4, 1.9 ± 1.3 vs Q1, 0.6 ± 1.2; P < .001; Figure 5D). In sex-specific domains, older patients exhibited significantly higher scores for HMB domain (Q4 vs Q1, 3.0 ± 1.2 vs 2.4 ± 1.3; P = .008) and PPH (Q4 vs Q1, 1.0 ± 1.2 vs 0.1 ± 0.6; P < .001; Figure 5D). Finally, significant differences were also observed in the spontaneous bleeding domains of gastrointestinal bleeding and minor wounds between the oldest and youngest quartiles (P = .010 and P = .011, respectively; Figure 5D). Conversely, no age-related increase was seen in the other spontaneous bleeding domains.

Diagnosis and management of individuals with mild-to-moderate reductions in plasma VWF levels (30-50 IU/dL) remains a topic of ongoing debate.^21,22 Importantly, from a translational perspective, plasma VWF levels in this range are relatively common, and not all individuals with such VWF levels exhibit a bleeding phenotype.^1,2,23,24 Consequently, determining whether a given individual has a significant bleeding phenotype constitutes an essential criterion in making a formal diagnosis of low VWF or type 1 VWD in this cohort.¹⁰ In this Zimmerman Program analysis, to our knowledge, we provide the first evidence that age significantly influences ISTH-BAT scores in both children and women with VWF levels in the 30 to 50 IU/dL range. Importantly, the association between age and ISTH-BAT scores remained significant regardless of the timing of ISTH-BAT assessment (supplemental Figure 3; P < .03), the reason for referral (supplemental Figure 4; P < .001), or the presence or absence of VWF variants (P < .001). This observation is consistent with our recent report demonstrating that increasing age is also associated with a progressive increase in ISTH-BAT in normal adult females.¹³ Our findings have direct clinical implications for treating physicians. Critically, we demonstrate that the likelihood of a low VWF (or type 1 VWD) diagnosis is influenced by the age at which ISTH-BAT is first objectively assessed in any person with mild-to-moderate reduced VWF levels in the 30 to 50 IU/dL range.

In addition to the relationship between age and ISTH-BAT scores, previous studies have shown that plasma VWF levels progressively increase with aging in normal individuals.^25,26 More recent reports have further shown an age-related increase in VWF levels in many patients with type 1 VWD and low VWF.^27-29 for example, in the Willibrand in the Netherlands (WiN) cohort study of patients with initial VWF levels <30 IU/dL, plasma VWF levels increased into the normal range (>50 IU/dL) in ∼23% of patients with progressive aging.²⁸ Moreover, VWF levels increased into the low VWF range (30-50 IU/dL) in a further 30% of the WiN type 1 VWD cohort.²⁸ These data highlight that VWF levels measured at the time of initial diagnostic workup only represent a single snapshot of an age-dependent incline in plasma VWF levels.²⁸ Overall, it is therefore clear that age significantly affects both ISTH-BAT score and plasma VWF:Ag levels, and thus constitutes a major confounding factor that must be considered in any patient undergoing diagnostic assessment for VWD. Notably, the significant effects of age on ISTH-BAT and VWF levels likely explain why ISTH-BAT scores do not correlate with plasma VWF:Ag levels in patients with low VWF.^3,4,19 

The marked heterogeneity in bleeding seen among patients with plasma VWF levels in the 30 to 50 IU/dL range presents a greater clinical issue in pediatric practice, where objective assessment of bleeding phenotype is even more challenging.^2,30 Our analysis of the Zimmerman pediatric cohort demonstrates that age critically influences the likelihood of attaining an abnormal ISTH-BAT score, and thus being registered with a formal diagnosis of low VWF or type 1 VWD. For example, if children are first assessed and have an ISTH-BAT performed at ≥10 years, they are twice as likely to have an abnormal ISTH-BAT compared with those first investigated at <10 years. In keeping with Jain et al, we observed that applying a threshold of ≥5 as abnormal in girls with HMB meant that the probability of an abnormal ISTH-BAT score was consistent across all pediatric age groups (data not shown).¹⁴ In addition, based on our data, it seems likely that early clinical assessment of children (<4 years) with VWF levels in the 30 to 50 IU/dL range may be of limited diagnostic value. Because they have not yet encountered enough hemostatic challenges, a normal ISTH-BAT score cannot be used to exclude a diagnosis of low VWF or type 1 VWD in younger children. Overall, our findings would suggest that younger children with VWF levels in this range, and specifically those who have not undergone enough hemostatic challenges, need to be followed up prospectively to ascertain whether they may have a bleeding tendency.²¹ However, it is also important to appreciate that many of these children will not experience significant bleeding during future invasive procedures.³⁰ Thus, for future hemostatic challenges, there is no evidence to support the routine use of prohemostatic treatments in children with VWF levels in the 30 to 50 IU/dL range who do not have a personal or family bleeding history.^1,2,21,30 Indeed, the use of prophylactic hemostatic treatment before procedures in this cohort may make it difficult to ever determine whether an individual child has a true constitutional bleeding disorder, or whether they are instead normal children who simply have plasma VWF levels falling below the lower limit of the normal range.

Interestingly, significant sex differences in low VWF diagnosis were observed in our pediatric cohort. Perhaps unsurprisingly, there was a female predominance in the 12 to 17 years group. Examination of the ISTH-BAT subdomains demonstrated that this was driven primarily by significant HMB occurring after menarche. In contrast, boys were significantly overrepresented in the low VWF cohort diagnosed in the 0 to 4 years group. Abnormal ISTH-BAT scores in these young boys were mainly attributable to epistaxis. Further studies will be necessary to determine whether epistaxis is actually increased in young boys compared with girls, or whether this may reflect a sex bias in referral for specialized hemostasis laboratory testing.³¹ Given that delays of up to 16 years have been reported in young women from the onset of bleeding symptoms through to final VWD diagnosis, these differential effects of age and sex on ISTH-BAT scores in young people with VWF levels in the 30 to 50 IU/dL range have direct clinical relevance.^32-34 

The threshold for an abnormal ISTH-BAT score shifts from 3 in children, to 6 for women and 4 for men.²⁰ Our findings highlight that this transition in what constitutes an abnormal BAT score at 18 years significantly affects VWD diagnosis and classification in young adults. Even though ISTH-BAT scores are similar between adolescents (15-17 years) and young adults (18-20 years), a much smaller proportion of young adults are classified as having an abnormal bleeding score. This discrepancy leads to fewer diagnoses of low VWF/type 1 VWD in young adults, despite comparable bleeding phenotypes. Thus, if a young person is first assessed and has an ISTH-BAT performed between 12 and 17 years, they are significantly more likely to achieve an “abnormal” ISTH-BAT and be diagnosed with low VWF/type 1 VWD compared with those aged 18 to 20 years. Together, these data further support the concept that a more progressive age-dependent normal range for ISTH-BAT should be considered through both childhood and adulthood.

Our findings demonstrate that beyond adolescence, age continues to markedly affect ISTH-BAT scores among adult females with low VWF levels. Rather than a true difference in bleeding phenotype, these findings reflect implicit weighting within the ISTH-BAT scoring system toward older women. In particular, we show that hemostatic challenges remain a dominant modifier of overall ISTH-BAT scores in female patients through adulthood. Importantly, however, the age-related increase in ISTH-BAT scores seen in adult females with VWF levels in the 30 to 50 IU/dL range is not solely attributable to intervention-related bleeding. Weighting toward older women also occurs within the ISTH-BAT menorrhagia domain. Maximal menorrhagia domain scores among women with low VWF levels most frequently occur due to surgical management, such as hysterectomy or endometrial ablation.²⁰ However, these treatments are rarely offered to younger women, leaving many essentially capped at a maximum menorrhagia domain score of 3. Importantly, our novel data further highlight that simply by being diagnosed at an older age, older women are significantly more likely to be deemed to have a more “severe” bleeding phenotype.

In conclusion, this comprehensive analysis of the Zimmerman Program demonstrates that age has a significant impact on ISTH-BAT scores in children and women with VWF levels of 30 to 50 IU/dL. This critical effect of age on ISTH-BAT scores directly affects the likelihood of formal low VWF or VWD diagnosis. Furthermore, our data provide important insights into the mechanisms underlying age-dependent effects on the ISTH-BAT. Collectively, our findings suggest that a more nuanced approach to the use of ISTH-BAT scores in the clinical diagnosis of VWD may be indicated. Rather than serving as a strict dichotomous classification tool to label an individual’s bleeding phenotype as normal or abnormal, the utility of BAT scores in VWD diagnosis should instead be considered in a broader context, with due consideration of additional factors, including age, sex, previous hemostatic challenges, family history of bleeding, and repeated bleeding episodes within 1 BAT domain. Further studies will be required to determine how the ISTH-BAT might be adapted to further improve its clinical utility for VWD diagnosis.

F.A. is supported by a Rubicon grant (452022310) from the Netherlands Organisation for Health Research and Development. J.S.O. is supported by a Science Foundation Ireland Frontiers for the Future Award (20/FFP-A/8952) and the National Institutes of Health for the Zimmerman Program (HL081588).

The graphical abstract was created with BioRender.com.

Contributions: F.A. and J.S.O. designed the research and wrote the manuscript; F.A. performed statistical analysis; and all authors contributed to patient enrollment, literature review, data interpretation, drafting of the final manuscript, and critical revision, participated sufficiently in this work, took public responsibility for the content, and gave consent to the final version of the manuscript.

Conflict-of-interest disclosure: J.S.O. has served on speakers’ bureaua for Baxter, Bayer, Novo Nordisk, Sobi, Boehringer Ingelheim, Leo Pharma, Takeda, and Octapharma; has served on the advisory boards of Baxter, Sobi, Bayer, Octapharma CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, Takeda, and Pfizer; and reports research grant funding awards from 3M, Baxter, Bayer, Pfizer, Shire, Takeda, and Novo Nordisk. D.D. reports honoraria from Takeda; and educational support sponsorship from Novo Nordisk and Amgen. M.L. reports 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. N.M.O. served on the advisory boards of Sobi, F. Hoffman-La Roche Ltd, uniQure, and Freeline; and served on the speaker’s bureau for Novo Nordisk. M.B. reports consultancy fees from Sobi. P.D.J. reports research funding from Bayer; and consultancy fees from Band/Guardian Therapeutics, Star/Vega Therapeutics, and Roche. V.H.F. has been a consultant for Octapharma. The remaining authors declare no competing financial interests.

Correspondence: James S. O’Donnell, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Ardilaun House, 111 St Stephen’s Green, Dublin 2, D02 YN77, Ireland; email: jamesodonnell@rcsi.ie.