Age and sex influence bleeding score in mild VWF deficiency Open Access

Type 1 von Willebrand disease (VWD) is the most frequent type of the disease and is characterized by variable quantitative reduction of von Willebrand factor (VWF), a bleeding tendency, and typically, a positive family history for bleeding.¹ Although VWF levels <30 U/dL prompt the diagnosis of VWD,¹ a significant proportion of subjects present VWF levels consistently between 30 to 50 U/dL, with heterogeneous clinical phenotypes. The use of standardized bleeding assessment tools has been recommended to support or rule out a definitive diagnosis of VWD in these patients.¹ The International Society on Thrombosis and Haemostasis endorsed Bleeding Assessment Tool (ISTH-BAT) has been developed and recommended for this purpose and normal reference ranges for healthy adult males (0-3), adult females (0-5), and children (0-2) have been defined.² Hence, a definite diagnosis of type 1 VWD (or low VWF in previous guidelines) has been proposed if subjects with VWF levels between 30 to 50 U/dL present a positive bleeding history. Thus, the demonstration of the presence of a significant bleeding history, remains fundamental in the diagnostic workup of VWD.

Is the ISTH-BAT homogeneously applicable to these broad categories of patients, even with a mild VWF deficiency? An association with increasing ages, particularly in women, has been already well established in type 1 VWD with variable VWF deficiencies.³ Interestingly, it has been shown that even small decreases in VWF levels may increase the risk of bleeding, even when VWF levels are not substantially reduced.³ However, BAT scores accumulate symptoms over a lifetime and thus are inherently age-dependent. Thus, at variance with the originally established reference ranges, recent studies have shown that 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.⁴ Furthermore, it has been suggested that an ISTH-BAT score >4 should be considered abnormal in adolescent girls rather than the threshold of >2.⁵ Thus, it could be argued that age-adjusted normal ranges for the ISTH-BAT could be useful for improving diagnostic sensitivity and specificity. However, the effect of aging and sex has not been specifically examined for children and adults with mild-to-moderate reduced plasma VWF levels.

In this issue of Blood Advances, Atiq et al⁶ report the effect of age and sex on ISTH-BAT score in a large population of 325 patients with VWF levels consistently between 30 to 50 U/dL, enrolled into the Zimmerman Program. Overall, the results underline that ISTH-BAT results should be interpreted in this patient population dynamically according to age and sex. The likelihood of a low VWF/type 1 VWD diagnosis is influenced by the age at which ISTH-BAT is first assessed in these individuals. Abnormal ISTH-BAT scores were seen in 84.4% of children aged 15 to 17 years compared to only 27.3% of children aged 0 to 4 years and the frequency of ISTH-BAT scores ≥8 were >3 times higher in children aged 12 to 17 years at the time of diagnosis (22.4%) compared to children aged <12 years (6.9%, P = .033). Children ≤4 years had significantly lower ISTH-BAT score (mean, 2.7 ± 3.1) compared to the group of 15 to 17 years (5.2 ± 2.9, P = .004). Importantly, specific bleeding domains also gave different results. Average epistaxis scores were significantly greater in boys aged 12 to 17 years as well as heavy menstrual bleeding in girls of the same age range. Overall, children first assessed at ≥10 years were twice as likely to have an abnormal ISTH-BAT compared to those first investigated <10 years (P < .001).

In the adult cohort, older age was significantly associated with higher ISTH-BAT scores in women, but not in men. In the adult female cohort, aging was associated with an ∼1.5 unit increase in ISTH-BAT scores per decade. 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 to those aged 18 to 28 years (66.7%, P = .004). Again, significantly higher ISTH-BAT scores were observed in the oldest quartile (≥44 years) compared to the youngest quartile (18-28 years): 11.3 ± 5.0 vs 6.9 ± 3.7; P < .001. Overall, the change in abnormal ISTH-BAT threshold at the age of 18 critically impacts low VWF diagnosis, due to lower rates of abnormal ISTH-BAT scores in young adults (P = .006). Finally, women with VWF levels of 30 to 50 U/dL, who were older at diagnosis were significantly more likely to be assigned a severe bleeding phenotype (ISTH-BAT scores ≥10), in keeping with previous evidence.³ This age-related effect on ISTH-BAT in women with VWF levels in 30 to 50 U/dL range was attributable to accumulating scores in both the intervention (surgery and dental extraction), sex-specific (heavy menstrual bleeding and postpartum hemorrhage), and spontaneous bleeding domains (gastrointestinal bleeding and minor wounds) between the oldest and youngest quartiles.

Based on this data, the utility of ISTH-BAT scores in diagnosis of mild VWD should be considered in a broader context, with appropriate consideration of additional contributing factors including age at assessment and sex. In addition, previous studies have also shown the importance of factor VIII levels, which were not considered in the study of Atiq et al, platelet function analyser-100 closure times and ITGA2 haplotypes of platelet integrin α₂β₁ in determining the severity of scores in type 1 VWD.^3,7,8 

It should be borne in mind however, that BAT tools were initially developed to screen at the diagnosis of a possible bleeding disorder. When at least 3 different symptoms are present, the history is considered suggestive of the presence of a bleeding disorder and particularly of VWD, but again age at assessment could influence this assessment.⁹ Finally, an important aspect is related to the demonstration of family history of bleeding associated with a VWF deficiency. Type 1 VWD is defined as an autosomal dominant inherited bleeding disorder with partial quantitative deficiency of VWF. The identification of other family members with these characteristics greatly increases the likelihood of a type 1 VWD diagnosis, even in presence of mild VWF deficiencies.¹⁰ These aspects require validation also in the cohort of patients with levels of VWF between 30 to 50 U/dL.

The study by Atiq et al shows that age at assessment and sex critically influence 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. Further studies are warranted to determine how the ISTH-BAT might be adapted, and which additional variables should be included to further improve its clinical utility for VWD diagnosis in mild quantitative VWF deficiency.

Conflict-of-interest disclosure: The author declares no competing financial interests.