Page 228 - 2020_07-Haematologica-web

A. Zia et al.
Our study aimed to describe the frequency, predictors, and time from bleeding onset to BD diagnosis in a prospective cohort of adolescents with HMB, using a well- defined and rigorous protocol of hemostasis testing and platelet function analysis. We hypothesized that the fre- quency of undiagnosed BD in adolescents with HMB would be similar to adults, and that the menstrual bleed- ing pattern will not predict a BD.
Methods
Postmenarchal adolescents up to 18 years of age referred for HMB without a diagnosis of BD were eligible to participate (Figure 1). Participants were enrolled prospectively from the Young Women’s Blood Disorders Program at The University of Texas Southwestern (UTSW), Dallas, TX (primary site), USA, and the Children’s Hospital of Buffalo (CHOB), NY, USA (external site) between July 2014 and December 2017, after informed consent and/or assent.7 The institutional review board at both UTSW and CHOB (Institutional Review Board numbers: STU 102014-001 and 00003126, respectively) approved the study. Participants were excluded if they did not complete: 1) a minimum of two visits and 2) the minimum BD evaluation, decided a priori.
Definitions
Heavy menstrual bleeding was defined by menstrual duration ≥7 days with a sensation of “gushing” or “flooding” or bleeding through a pad or tampon for ≤2 hours.8,9 Based on the pattern of HMB in the entire cohort, participants were classified and com- pared among two groups: the anovulatory HMB group was defined as having menstrual duration <21 or >45 days; the ovula- tory HMB group was defined when this menstrual pattern was not present.10
Laboratory testing
All participants underwent testing that included complete blood count, serum ferritin, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, von Willebrand Factor (vWF) analysis (repeated at least twice for every participant), platelet aggregation (repeated if abnormal), Factor (F) XI, FXIII fac- tor assays and systemic hyperfibrinolysis assessment using rota- tional thromboelastometry (ROTEM).11 This comprised the mini- mum BD evaluation for retention into the final analysis.
Iron deficiency/iron deficiency anemia
We defined anemia as hemoglobin <110 g/L and iron deficiency as serum ferritin levels ≤ 20 μg/L.
Bleeding assessment tools
Pictorial Blood Assessment Chart (PBAC) - a PBAC score was com-
puted for all participants, and an average score of three cycles was taken as the final score.12 Standardized pads and tampons were not provided.
Outcomes
The primary outcome of the study was the diagnosis of BD defined as low von Willebrand disease (vWD), qualitative platelet dysfunction (QPD), clotting factor deficiencies or hyperfibrinoly- sis.
Statistical analysis
Sample size - based on adult data,4,5 we assumed that 20% of adolescents with HMB, irrespective of menstrual bleeding pattern, will be diagnosed with BD within six months from study entry; with a total of 180 patients, we estimated the rate of BD in this group with such precision that the 95% confidence interval has a half-length smaller than 8%.14
A multivariable logistic regression model was built following the technique described by Hosmer, Lemeshow, and Sturdivant.15 Variable selection was performed using the stepwise procedure.
Kaplan-Meier curves were constructed from the first bleed to BD diagnosis for the entire cohort and the main two groups and compared using the log-rank test.
Further information on the methods used is available in the
Online Supplementary Appendix.
Results
Demographic and clinical characteristics
Two hundred and thirty-five consecutive adolescents were enrolled during the study period, of which 200 par- ticipants met eligibility criteria, and had complete out- come data: 185 from UTSW and 15 from CHOB. The median age of participants was 15 years (y) (Table 1), and 28% were Hispanic. Fifty-five percent had normal body mass index (BMI) as determined by Center for Disease Control (CDC) growth charts. The median age at menar- che was 12 years, and BD evaluation occurred at a median of three years from menarche. Thirty-three percent pre- sented to the Emergency Department (ED) for evaluation and management of HMB; 25% needed to be hospital- ized, of which 19% received packed red blood cells (pRBC). The mean PBAC score was 386 [standard devia- tion (SD), 243] and the ISTH score was 3.5 (SD 1.3). A
Main outcome
The frequency of BD was compared among groups using χ2 test.
Figure 1. Study design. Prospective, multicenter, observational study of adolescents presenting with heavy menstrual bleeding.
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haematologica | 2020; 105(7)