Comprehensive Evaluation of Bleeding Disorders in Adolescents with Heavy Menstrual Bleeding
Authors: Zia Ayesha , Journeycake Janna M. , Jain Shilpa , Sarode Ravi 
Published: October 2019

Introduction: Unpredictable, prolonged or heavy menstrual bleeding (HMB) is not unusual in many adolescents soon after menarche. Anovulation, owing to immaturity of the hypothalamic-pituitary-ovarian axis, is often the cause of HMB; however, it may coexist and mask an underlying bleeding disorder (BD). Retrospective data in adolescents with HMB suggest a prevalence of BDs from 10 to 62%. Prospective studies with uniform hemostatic evaluation and concurrent quality of life (QoL) assessments have not been performed. The incidence of BDs in adolescents, especially those with anovulatory bleeding, remains unknown.
Methods: In this ongoing prospective cohort study (targeted n=200), 130 adolescents referred for HMB to multidisciplinary Young Women's Blood Disorders Clinics were enrolled. An assessment of menstrual loss using pictorial blood assessment chart (PBAC) and bleeding symptoms using ISTH-bleeding assessment tool (BAT) was undertaken. Participants underwent a comprehensive evaluation determined a priori, including assessment of hypermobility, standardized laboratory evaluation (prothrombin time, activated partial thromboplastin time, fibrinogen, thrombin time, von Willebrand disease (VWD) panel, whole blood platelet aggregation with ATP secretion, factor assays (FIX and FXIII), global hemostasis and hyperfibrinolysis using ROTEM, and a pelvic ultrasound (US). Patient reported outcomes for health related QoL(HR-QoL) was completed.
Results: The mean age of participants was 14 (range 11-18) and mean age at menarche was 11.7 yrs. (range: 9-16). The mean PBAC score, before contraceptive initiation, was 504 (range: 100- 1200) and the mean ISTH BAT score was 3.8 (range: 1-8) in all participants. 62% had anovulatory menstrual bleeding. An inherited BD and/or bleeding risk was diagnosed in 24.6% (n=32); 9% (n=12) were diagnosed with VWD, 5% (n=6) with qualitative platelet dysfunction and 2 subjects were found to be hemophilia A (HA) carriers. Low VWF levels (VWF:Rco 30-50%) were detected in 9% (n=12). 15% had evidence of mild systemic hyperfibrinolysis (lysis 3-8% on ROTEM) but none met the criteria for further investigation for an inherited disorder of hyperfibrinolysis . Of those without BD, 2 were diagnosed to have VWF exon 28 polymorphism, and 3 were referred and ultimately diagnosed with hypermobility syndrome by Genetics. One was found to have endometriosis by laparoscopy and 3 were diagnosed with PCOS. Of those with BDs (all with low VWF), 3 were diagnosed with hypermobility syndrome (total 6) and 4 with PCOS (total 7). US was normal in all subjects. The PBAC scores were higher in BDs (634 vs. 410; SD ± 275 p=0.002), irrespective of the pattern of bleeding. No differences were found in the ISTH BAT scores (after excluding HA carriers) (3.6 vs. 4.8; SD ± 1.19, p=0.06), initial hbg or ferritin levels between the two groups. Only 6% (n=8) with BDs required ED visit and/or hospitalization for HMB vs. 14% (n=18) without a BD, of which majority had anovulatory bleeding. On multivariate logistic regression, no predictors of BDs were found. Adolescents with BDs had a decreased HR-QoL compared to those without a BD (QoL score 58 vs.87; SD± 12.5, p=<0.001) even after control of HMB and correction of anemia.
Conclusions: Inherited BDs are common in adolescents with HMB, confer a decreased HR-QoL and can be associated with anovulatory bleeding. A comprehensive evaluation is required to unravel disorders causing HMB. In this ongoing study, at this time, no predictor of an inherited BD was found in adolescents with HMB. Data accrual from the fully powered, ongoing, prospective study may offer further data to develop an ideal tool with a scoring system to take into account all prevalent causes of HMB to accurately predict a BD in adolescents.

Disclosures
Zia: NHLBI K23: Research Funding. Journeycake:CSL: Consultancy; Biogen: Consultancy; Baxalta/Shire: Consultancy. Jain:Novo Nordisk: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees; Biogen: Speakers Bureau. Sarode:CSL Behring: Consultancy, Honoraria.