Page 232 - 2020_07-Haematologica-web

A. Zia et al.
Hispanic
Non-Hispanic
ED evaluation for HMB
Yes
2·48 1.13, 5.05
0.021
No
ISTH BAT score
0·14 0.05, 0.38
1·57 0.54, 4.13 8.27 2.60, 26.44
C-statistic: 0.78
<0.0001
0.435 0.0004
≥3 ≥4 ≤2
BMI: body mass index; ED: emergency department; HMB: heavy menstrual bleeding; ISTH-BAT: International Society of Thrombosis Haemostasis-Bleeding Assessment Tool; pRBC: packed red blood cells; PBAC: pictorial blood assessment chart; TSH: thyroid-stimulating hormone; y: years.
those with BD had a diagnosis of either low vWF or vWD. Our findings suggest that BD are equally prevalent in the anovulatory or ovulatory pattern of menstrual bleeding. Identification of adolescents with BD is the first step in preventing delays in diagnosis and, by extension, long- term untoward complications of BD. HMB soon after menarche is traditionally deemed as “hormonal,” and anovulation is the default etiology. These findings have implications for clinicians who routinely manage adoles- cents with HMB: screening or referral for screening for BD is appropriate, irrespective of the pattern of menstrual bleeding.
Seravalli et al. investigated the frequency of BD in ado- lescents, dividing participants into two groups based on whether abnormal uterine bleeding started in the first two years from menarche or later. Overall, 48% of adolescents were diagnosed with a hemostatic defect (18% with QPD, 14% with vWD, 13% with clotting factor deficiencies, and 7% with an increase in bleeding time), but there were no differences in the prevalence of BD between the groups (44% vs. 59%; P=0.17).16 Philipp et al. also reported that adolescents and peri-menopausal women were just as likely to have hemostatic defects as were women aged 20- 44 years;17 the former age brackets representing periods of anovulatory menstrual bleeding. Furthermore, Vo et al. reported that adolescents with BD were more likely to perceive and report their menstrual cycles as irregular.18 These studies had certain limitations, such as retrospec- tive data collection, and a lack of uniform and comprehen- sive laboratory investigation.
In our cohort, younger age at first bleeding event, Hispanic ethnicity, non-presentation to the ED for HMB, and ISTH BAT score of ≥4 were identified as predictors of BD. Younger age at first bleeding event is known to be associated with hemostatic evaluation and BD diagnosis, representing those with an earlier phenotypic expression or more severe bleeding phenotype. Hispanic girls in our cohort were more likely to have a BD, even though non- Hispanics made up the majority. Previous studies have included mostly non-Hispanics; more specifically, women of eastern European ancestry and a lower prevalence of vWD and higher levels of VWF antigen, vWF activity, and FVIII have been reported in black women,19,20 which can explain these findings. Adolescents who presented to ED for evaluation and management of HMB in our cohort were less likely to have a BD, which is similar to results from another multicenter analysis.21 This may be further explained by: a) negative family history of HMB (60% of adolescents did not have a first-degree relative with HMB
and the caregivers of these adolescents were likely unpre- pared to manage HMB at home); and b) 55% presenting to the ED had anovulatory bleeding (generally deemed diffi- cult to manage with conventional route and doses of hor- mones).22 Moreover, 67% of those with anovulatory bleeding were overweight or obese, the latter being asso- ciated with gonadal steroid hormone changes that result in disruption of ovulation and menstrual irregularities including HMB.23,24 Previous studies show that adolescents who present acute symptoms and require hospitalization are more likely to have an underlying BD that was report- ed only in descriptive analyses, showing 19% and 33% of patients with abnormal uterine bleeding and coagulation disorders when compared with 74% and 67% without, respectively.25-27
When objectively assessing bleeding in patients with BD, consensus guidelines recommend the use of BAT.28 The ISTH BAT has been shown to optimally identify BD in both adults and children; the pediatric cut-off able to optimally discriminate between no BD and a possible BD is a score of ≥3.13 Instead, we identified a score of ≥4 to be predictive of BD. Recently, using identical data, ISTH-BAT was shown to be more sensitive for assessment of HMB in women with low vWF levels compared with other BAT, supporting a need to investigate and validate a higher “adolescent” specific cut-off.29 The ISTH BAT score of ≥4 in those with BD was driven mostly by the presence of additional bleeding symptoms with HMB; 57% of adoles- cents with BD had other bleeding symptoms compared to 12% in those without BD. Previous data clearly show that the number of hemorrhagic symptoms is higher in the young when a more severe bleeding phenotype or disor- der is present.30,31 The presence of at least three bleeding symptoms, irrespective of severity, result in 99.5% speci- ficity for the most common bleeding disorder, vWD, a finding that has been confirmed in the pediatric age group.32
The median time from onset of the first bleeding symp- tom to BD diagnosis was four years in the entire cohort, two years in the anovulatory, and six years in the ovulato- ry group. Adolescents with anovulatory HMB had heavier (mean PBAC score 427 vs. 345) or difficult to manage menses, resulting in an earlier referral and diagnosis, accounting for an earlier diagnosis. Lavin et al., on the other hand, have reported no differences in age at diagno- sis for women with low vWF levels who reported HMB to physicians compared to those who did not go to the doc- tor (age 34.2 vs. 33.4 years; P=0.7).29 Even though the time to diagnosis in our cohort is a significant improvement
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haematologica | 2020; 105(7)