Call to action: identifying an underlying bleeding disorder in adolescents with heavy menstrual bleeding

As per ACOG, the menstrual cycle is a vital sign; abnormal menses are concerning for an underlying pathology requiring diagnosis and treatment [ 53 ]. The diagnostic evaluation of HMB in adolescence requires a structured and age-appropriate approach by GYNs and hematologists. The PALM–COEIN classification system, developed by the International Federation of Gynecology and Obstetrics, provides a useful framework for categorizing etiologies of abnormal uterine bleeding in adolescents when interpreted in the context of pubertal physiology and developmental considerations [ 53 , 54 ]. This mnemonic distinguishes structural causes (P-polyps, A-adenomyosis, L-leiomyomas, M-malignancy/hyperplasia) from nonstructural etiologies (C-coagulopathy, O-ovulatory dysfunction, E-endometrial, I-iatrogenic, and N-not otherwise classified). Anovulatory cycles related to the immaturity of the hypothalamic–pituitary–ovarian axis are often considered the default explanation for HMB [ 55 ] and are the most common cause of HMB in adolescents, followed by BDs, with the caveat that both conditions can coexist [ 53 , 54 ]. In a systematic review and meta-analysis of HMB etiology in 2770 adolescent females, ∼50% of cases were of indeterminate etiology, with the rest equally divided between ovarian-uterine disorders (24%; majority with anovulatory bleeding) and BDs (25%; coagulation disorders 19%, platelet function defects 6%) [ 36 ]. In adolescents, structural causes are less frequent but should be considered, particularly in cases refractory to first-line management of HMB or if associated with pelvic symptoms. Several factors including lifestyle, age, environment, family history of uterine fibroids, and vitamin D deficiency contribute to a higher incidence of uterine fibroids in African American women compared with Caucasian women (>80% vs ∼70%) [ 56 ]; comparative numbers are not known in adolescents and could be a potential cause for HMB. In adolescents with HMB, the PALM–COEIN framework should be applied dynamically rather than sequentially. Overreliance on anovulation as an explanation may delay diagnosis of a BD, with implications for acute management, future surgical risk, and reproductive health. Hallmarks for an underlying BD based on a clinical history include onset of HMB at menarche; longer, more frequent menstrual cycles, with failure of several trials of standard hormonal therapy due to reported breakthrough bleeding, warranting addition of other treatment strategies; need for blood transfusions due to severe anemia; hospitalizations in first year of menarche; continued HMB beyond the first 2 years of menarche; a positive personal and/or family history of abnormal bleeding or a BD; and/or concomitant IDA [ 30 , 37 , 57 , 58 ]. Other symptoms of BDs include mucocutaneous, postsurgical, posttraumatic, postpartum bleeding and in some cases, hemorrhagic ovarian cysts [ 59 , 60 ]. A higher number and severity of bleeding symptoms translate into a higher likelihood of a BD. Several versions of bleeding assessment tools (BATs) based on this rationale have been developed to provide objective assessment of a bleeding tendency, some of which are complemented with additional questions on anemia. These include the Phillip tool [ 61 ], the widely accepted and standardized International Society of Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT) [ 62 ], and self-BAT score [ 63 ]. The ISTH-BAT, commonly administered by hematologists in evaluating a diverse set of bleeding symptoms, incorporates menstrual bleeding with higher points being awarded for the level of medical intervention required with 1 point for consultation only to 4 points for HMB necessitating transfusion [ 62 ]. The self-BAT can be accessed online and completed prior to a clinical encounter, saving time in busy clinical settings, with the caveat that overestimation of score is a possibility in young adolescents[ 64 , 65 ]. The Phillip tool has the drawback of a low sensitivity of 62% in girls aged 13 to 19 years [ 57 ], and there are limitations to the ISTH-BAT score, including a blanket normal range of 0 to 5 for those aged >18 years, which was recently age adjusted as older women bleed more with surgeries and are more likely to have undergone hysterectomies for HMB. Adolescents are grouped under the pediatric age group where a score >2 is considered abnormal, which is often misleading as menarche impacts the score [ 66 ]. An in-depth family history of bleeding symptoms is an important component of deciphering the possibility of an inherited BD, specifically for autosomal dominant disorders like VWD. Perceived normalization of menstrual flow across generations of undiagnosed affected women results in delayed HMB care and BD diagnosis for their adolescent daughters. Females with HMB who have used different versions of hormonal therapies with poor control of menstrual flow, have been affected with IDA, received intravenous iron and/or blood transfusions, undergone early-age hysterectomies, or who may/may not report a gynecologic etiology as a cause for HMB should be evaluated for a BD. Alternatively, mothers of adolescent females may not endorse bleeding symptoms if an autosomal recessive disorder is present; similarly, incomplete penetrance and variable expression of disorders such as VWD may mask expression of other family members’ symptoms, with the adolescent female with HMB presenting as the index case. After the diagnosis of HMB by providers, laboratory evaluation should be initiated for an underlying BD. Basic evaluation includes a complete blood count (CBC), iron studies and coagulation assays including activated partial thromboplastin time (aPTT), prothrombin time/International Normalized Ratio/thrombin clotting time, PFA-100, and VWD panel, which can be performed prior to referral to a hematologist. Extended testing should be ordered by classical hematologists, optimally at a Hemophilia Treatment Center (HTC), and ideally done in real time on-site at the time of the patient’s visit, as shown in the detailed laboratory approach in Figure 2 . To avoid preanalytical variables that confound coagulation analysis, standardized sample collection and proper handling and transport to the laboratory is critical. Hematologists should be well trained in the interpretation of coagulation tests as there are several nuances. Some of the coagulation tests (aPTT, factor VIII [FVIII], VWF, fibrinogen, and platelet counts) might be in the “normal to high” range in a state of excessive bleeding, stress, inflammation, and ID/IDA [ 67 ]. Repeated evaluation is warranted, especially with a family history or impressive personal bleeding phenotype; however, initial values of VWF ≥100 IU/dL are unlikely to identify VWD [ 68 , 69 ] unless the patient has ID and/or anemia [ 70 ]. Fewer than 40% of menstruating females referred with abnormal VWF results from offsite laboratories were confirmed to have VWD when repeated at onsite specialized coagulation laboratory testing [ 71 ]. Estrogen in high doses (>35 μg) elevates VWF, but with present estrogen doses in combined hormonal therapy pills, discontinuation of medication is not needed prior to VWF testing [ 72 ]. Although lowest values of VWF are detected on days 1 to 4 of the menstrual cycle, there is no uniform consensus regarding the precise timing for VWF testing specifically in adolescents with irregular and unpredictable cycles [ 73 ]. International guidelines for the stepwise diagnosis of VWD have been published to guide hematologists [ 74 ]. The PFA-100 has poor sensitivity and specificity but is often used as a screening tool, especially in the pediatric population, as minimal blood volume is required. Detailed platelet function analysis is complex, with limited availability of specialized laboratories to perform and interpret results, and includes PLTA, platelet electron microscopy, and flow cytometric fluorescence for glycoprotein expression analysis; of note PLTA cannot be a shipped sample to an outside laboratory. The PFA-100 and PLTA should be performed in a steady state once bleeding is under control, and anemia [ 75 ] and thrombocytopenia have been corrected. Use of medications including nonsteroidal anti-inflammatory agents, selective serotonin receptor inhibitors, antiplatelet agents, antiepileptics, and other medications/supplements might impact platelet function assays by varying degrees and should be avoided, if feasible, prior to testing [ 76 ]. Figure 2 Laboratory work-up for suspected bleeding disorder in an adolescent with HMB. ADP, adenosine diphosphate; Ag, Antigen; aPTT, activated partial thromboplastin time; BDUC, bleeding disorder of unknown cause; CBA, collagen binding assay; CBC, complete blood count; EDS, Ehlers Danlos syndrome; F, factor; GPIbM, glycoprotein Ib receptor with gain-of-function mutations; HA/HB, hemophilia A/B; HHT, hereditary hemorrhagic telangiectasia; HMB, heavy menstrual bleeding; INR, International Normalized Ratio; MPV, mean platelet volume; PAI-1, plasminogen activator inhibitor; PLTA, platelet light transmission aggregometry, PT, prothrombin time; PTEM, platelet electron microscopy; RCo, Ristocetin; TCT, thrombin clotting time; TIBC, total iron binding capacity; TSAT, transferrin saturation; TxA2, thromboxane A2; VWD, von Willebrand disease; VWF, von Willebrand factor. ∗Prolonged aPTT/PT: perform mixing studies. ∗∗Repeated testing might be warranted based on high index of clinical suspicion. Laboratory work-up for suspected bleeding disorder in an adolescent with HMB. ADP, adenosine diphosphate; Ag, Antigen; aPTT, activated partial thromboplastin time; BDUC, bleeding disorder of unknown cause; CBA, collagen binding assay; CBC, complete blood count; EDS, Ehlers Danlos syndrome; F, factor; GPIbM, glycoprotein Ib receptor with gain-of-function mutations; HA/HB, hemophilia A/B; HHT, hereditary hemorrhagic telangiectasia; HMB, heavy menstrual bleeding; INR, International Normalized Ratio; MPV, mean platelet volume; PAI-1, plasminogen activator inhibitor; PLTA, platelet light transmission aggregometry, PT, prothrombin time; PTEM, platelet electron microscopy; RCo, Ristocetin; TCT, thrombin clotting time; TIBC, total iron binding capacity; TSAT, transferrin saturation; TxA2, thromboxane A2; VWD, von Willebrand disease; VWF, von Willebrand factor. ∗Prolonged aPTT/PT: perform mixing studies. ∗∗Repeated testing might be warranted based on high index of clinical suspicion. Further evaluation for hemostatic disorders includes assessment of individual coagulation factors and evaluation for rare BDs. For example, mild FVIII or FIX deficiency and combined FV and FVIII deficiency can be missed with a normal aPTT. Other rare BDs necessitating specialized assays include deficiencies of FXIII and fibrinogen disorders (hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia); some conditions warrant genetic testing for accurate diagnosis such as deficiency of alpha-2-antiplasmin, plasminogen activator inhibitor, FV short, and heterozygous tissue factor deficiency [ [77] , [78] , [79] ]. In Ehlers Danlos syndrome, there is no discrete coagulation test to capture the hemostatic defect, although it is known that it could be associated with platelet function abnormalities [ 80 ]. Hereditary hemorrhagic telangiectasia is the second most common BD after VWD, with a high prevalence of HMB compared with the general population. Uterine arteriovenous malformations and endometrial telangiectasias have been implicated as possible etiologies, with further research needed. A clinical diagnosis is made using the Curacao criteria, and genetic testing should be considered in suspected cases [ [81] , [82] , [83] ]. Adolescents with HMB and impressive bleeding symptoms who have undergone extensive laboratory and comprehensive genetic testing without an identified etiology may represent a BD of unknown cause (BDUC) [ 84 ]. These patients require close follow-up and optimally, participation in an institutional review board-approved, consented sample biorepository for future analysis and/or research as available, which would support further understanding of these disorders and advance patient care.

A national survey reported that 24.7% of pediatricians do not provide anticipatory guidance, 33.1% do not discuss menstruation with patients premenarche, and 28.4% do not ask the date of the last menstrual period [ 88 ]; these figures underscore the importance of educating providers. In a single-center survey of OB/GYN residents, ∼67.7% reported sufficient training regarding HMB and BD, with 9 to 11 hours per year dedicated to HMB education during different years of residency [ 104 ]. In a national survey of OB/GYN residents, didactics on HMB and BD evaluation were reported by ∼42% and those on treatment by 28%, with low resident confidence; this survey resulted in creation of an OB/GYN curriculum to address knowledge gaps in this area [ 105 ]. The United States Partners Physician Academy program initiated in 2022 represents a practical approach to mitigate the gap in the training of classical hematologists. This program is delivered by national hematology experts to enhance education of hematology fellows/early career hematologists, and ∼96% of participants agreed that the program increased their knowledge and confidence in treating patients with BDs [ 106 ]. Professional organizations and experts can also promote education of medical students and residents through webinars, conferences, and continuing medical education to diagnose HMB, ID/IDA, and BDs so that future providers are better informed. In the United States, the Foundation of Women and Girls with Blood Disorders (FWGBD), guided by the principle “Educating Providers. Changing Lives” [ 107 ], has educated more than 13,000 healthcare professionals, built a collaborative network of 300+ members with the Women and Girls with BD (WGBD) Learning Action Network, and supports over 60 and counting WGBD Clinics of Excellence. FWGBD holds workshops/convenings at national/international conferences, webinars/journal clubs, online toolkits, and a podcast: “7-2-1: All you need to know about periods” [ 24 ]. The National Bleeding Disorders Foundation, World Federation of Hemophilia, and European Association for Haemophilia and Allied Disorders Women and Bleeding Disorders Working Group are focused on provider education, training, investigation of new therapies, and global collaboration in the field of HMB and BDs to improve outcomes [ [108] , [109] , [110] , [111] , [112] ]. An international expert panel established by the joint effort of 2 Scientific and Standardization Committees of the ISTH emphasized the hemostatic and nonhemostatic management of HMB as appropriate care consideration in adolescents with BD [ 113 ]. HMB is flagged as concerning by parents, school nurses, teachers, and coaches due to its consequences—frequent school absenteeism, repeated requests for menstrual supplies at school or home, declining academic and athletic performance, and symptoms of fatigue and dizziness, and mood and sleep disorders. These indicators should prompt timely conversations with adolescents and their families to seek timely medical attention. Educational initiatives targeting school nurses include presentations at the National Association of School Nurses that highlight their dual role as gatekeepers in early recognition of HMB/IDA and educators for adolescents. Additional strategies include displaying key signs and symptoms of HMB and IDA in school restrooms and including content in middle school health curricula to encourage adolescents to self-advocate, recognize abnormal bleeding, ask informed questions, share their stories on social media to spread awareness among peers, and overcome inhibitions of having menstrual conversations at home, school and with healthcare providers. Figure 5 presents artwork by adolescent girls reflecting their perceptions on menses. Figure 5 Adolescent girls sharing their perceptions on menses through their artwork. Site: Girls Only (GO) Clinic (WGBD Clinics of Excellence) at Innovative Hematology, Indiana Hemophilia and Thrombosis Center. Adolescent girls sharing their perceptions on menses through their artwork. Site: Girls Only (GO) Clinic (WGBD Clinics of Excellence) at Innovative Hematology, Indiana Hemophilia and Thrombosis Center. HMB and bleeding symptoms should be captured through PBAC and self-BAT assessments that are incorporated into the electronic medical records and sent through patient portals prior to clinic visits. Modified versions of PBAC are needed to document variability in absorbency of menstrual hygiene products to include menstrual cups and period underwear. Smart phone user-friendly applications are in development to capture menstrual blood loss [ 114 ], associated symptoms, side effects of medications, and adherence to prescribed regimens. A pivotal need is the availability of well-equipped, easily accessible, specialized coagulation testing laboratories in all countries that are willing to work in partnership with HTCs to perform complex testing to avoid missing the diagnosis of a BD. Despite widespread prevalence of VWD, the laboratory panel is not uniform across institutions and countries. This is particularly relevant for the use of VWF multimers vs VWF collagen binding assay/VWF antigen, VWF ristocetin cofactor vs glycoprotein Ib receptor with gain-of-function mutation assay, and scarce availability of VWF propeptide antigen to subclassify Type1C VWD. For fibrinolytic disorders, a shortened euglobulin clot lysis time is a screening test but is not consistently standardized/reliable; plasminogen activator inhibitor antigen and activity levels are difficult to interpret due to diurnal variation and the normal activity range including “0” or <15 U/mL, resulting in overdiagnosis [ 77 ]. Tissue factor pathway inhibitor levels can help diagnose FV-short abnormalities, but this test is not commercially available [ 79 ]. In an effort to standardize the laboratory approach among hematologists, guidance for a standardized laboratory algorithm for BDUCs and for diagnostic testing for inherited platelet disorders has been recommended by ISTH Scientific and Standardization Committee [ 115 , 116 ]. Genetic screening tools may provide more accurate information (genome-wide association studies and whole exome sequencing) on genetic variants and/or genetic modifier(s) in hemostatic proteins, the partial deficiency/abnormality of which may be potentially responsible for HMB [ 117 ]. Prophylaxis with clotting factor concentrates is not widely utilized in women with BDs, and data is scarce regarding its use in HMB. One study in women with VWD showed that VWF concentrate was considered as third-line treatment for HMB after hormonal therapy, TXA, and DDAVP [ 118 ]. Recombinant VWF was recently approved in 2025 for on-demand use in pediatrics; approval for prophylaxis in adolescents with VWD and HMB is awaited. DDAVP has potential to be used in HMB but has been underutilized in mild and moderate hemophilia A and type 1 VWD, even though it has the potential globally to treat more than 220,000 bleeding episodes successfully [ 119 ]. There is an ongoing effort to expand access to a new intranasal formulation of DDAVP, which was shown to be noninferior to the discontinued intranasal or subcutaneous DDAVP in type 1 VWD [ 120 ]. Several novel nonfactor agents are in preclinical development that may have potential in preventing HMB with BD; promising among these is subcutaneous prophylaxis with HMB-002, a monoclonal antibody that has been shown to bind and elevate endogenous VWF in women with partial VWF deficiency [ [121] , [122] , [123] ].

Prior to understanding the association of HMB with BD, a universally applicable and practical definition for HMB is warranted. Quantitative definition of heavy flow as menstrual blood loss >80 mL per cycle using the alkaline hematin method, a resource-intensive procedure requiring specialized laboratory resources, is expensive, burdensome, and impractical in research as well as clinical settings [ 23 ]. The mnemonic 7-2-1 highlighting menses lasting >7 days or requiring sanitary product changes more frequently than every 2 hours, or the appearance of clots larger than 1 inch should prompt consideration of HMB [ 24 ]. Although it is simple, inexpensive, and validated, the Pictorial Bleeding Assessment Chart (PBAC), a semiquantitative method comprised of a visual scoring system that defines HMB by a controversial score cutoff of ≥ 100 vs >150 vs >185, is subject to recall bias and does not account for varying absorbency of sanitary products [ [25] , [26] , [27] , [28] ]. More recently, a more inclusive, pragmatic, and patient-centered definition of HMB, agreed upon by both the National Institute for Health and Care Excellence in the UK and the American College of Obstetrics and Gynecology (ACOG), is any excessive menstrual blood loss that interferes with a woman’s physical, social, emotional, or material QoL [ 29 , 30 ]. HMB identification by adolescents and family members is challenging. Providers should be encouraged to use directed questions capturing menstrual flow details focusing on the severity and the pattern of bleeding, as listed in Table 1 . Table 1 Key elements of a menstrual history. • Age at menarche • Time since menarche • Cycle regularity • Duration of flow • Number of heavy days in each cycle • Objective or semiobjective proxies of blood loss • Number of pads/tampons per day • Size and absorbency of pads/tampons • Need for double protection • Capacity and overflow of menstrual cups • Frequency of change of period underwear • Flooding • Passage and size of blood clots • Soaking through clothes, bedsheets • Nighttime changes • History of “sentinel events”; acute heavy menstrual bleeding warranting • Emergency room access • Hospitalization • Transfusion • Intravenous iron • Impact on daily activities • School • Work attendance • Participation in sports • Participation in school life Key elements of a menstrual history. Age at menarche Time since menarche Cycle regularity Duration of flow Number of heavy days in each cycle Objective or semiobjective proxies of blood loss • Number of pads/tampons per day • Size and absorbency of pads/tampons • Need for double protection • Capacity and overflow of menstrual cups • Frequency of change of period underwear • Flooding • Passage and size of blood clots • Soaking through clothes, bedsheets • Nighttime changes Number of pads/tampons per day Size and absorbency of pads/tampons Need for double protection Capacity and overflow of menstrual cups Frequency of change of period underwear Flooding Passage and size of blood clots Soaking through clothes, bedsheets Nighttime changes History of “sentinel events”; acute heavy menstrual bleeding warranting • Emergency room access • Hospitalization • Transfusion • Intravenous iron Emergency room access Hospitalization Transfusion Intravenous iron Impact on daily activities • School • Work attendance • Participation in sports • Participation in school life School Work attendance Participation in sports Participation in school life It is crucial to be cognizant that HMB is more prevalent in adolescents with an underlying BD [ 8 ]. Importantly, providers need to be aware that HMB might be the only or the presenting symptom in females with an underlying BD. Per an international survey of 183 OB/GYNs across 22 countries, only 13% of the responders would consider a BD in their differential diagnosis of HMB during initial consultation [ 31 ]. In a US survey of OB/GYN fellows of ACOG, 82% of the responders had seen patients with HMB due to a BD, and a higher percentage of responders would consider BDs in adolescents with HMB than in women with HMB (77% vs 36.4%) [ 17 ]. Several studies in adolescents with HMB report variable prevalence of BDs, as listed in Table 2 [ [7] , [8] , [9] , 11 , [32] , [33] , [34] , [35] , [36] ]. Variability is due to lack of a standardized definition of HMB (self-report, variable PBAC score thresholds, or institutional criteria), diagnostic criteria used for VWD vs low von Willebrand factor (VWF), and differences in laboratory testing for platelet function defects (platelet function assay [PFA-100] or platelet light transmission aggregometry [PLTA]). Additional contributors include limited and aggregated data on clotting factor deficiencies and institutional differences in evaluation of fibrinolytic disorders. In a meta-analysis of 45 studies ( n = 41,541), BDs were more prevalent in adolescents than in adult women with HMB (39% vs 16%); rates of VWD were 9% vs 6%, platelet function defects 6% vs 16%, polycystic ovarian syndrome 6% vs 10%, and thyroid disease 1% vs 16%. Presumed immaturity of the hypothalamic–pituitary–ovarian axis was reported in 78% of adolescents, while ∼52% of adult women were found to have structural causes [ 8 ]. In a prospective study of 200 adolescents, BD prevalence did not differ between anovulatory and ovulatory groups; however, there was significant delay in the diagnosis of BDs in ovulatory vs anovulatory cohorts (6 vs 2 years from menarche) [ 11 ]. In a single-center study of adolescents with BDs, nearly half reported HMB at menarche, only 28% had a treatment plan for HMB discussed premenarche. Although hormonal therapy was commonly used as initial treatment, half failed initial treatment requiring escalated regimens of hormonal and nonhormonal therapy, the latter including antifibrinolytics alone or in combination with desmopressin acetate (DDAVP) [ 37 ]. Table 2 Prevalence of bleeding disorders in adolescents presenting with heavy menstrual bleeding. Identified bleeding disorder Reported prevalence References VWD/low VWF 3%-36% Diaz R et al. J Pediatr Adolesc Gynecol. 2014 [ 7 ] Comishen KJ et al. J Thromb Haemost. 2025 [ 8 ] Alaqzam TS et al. J Pediatr Adolesc Gynecol. 2018 [ 9 ] Zia A et al. Haematologica. 2020 [ 11 ] Bevan JA et al. J Pediatr. 2001 [ 32 ] Mikhail S et al. Haemophilia 2007 [ 33 ] Hutspardol S et al. J Med Assoc Thai. 2010 [ 34 ] Vo, KT et al. Haemophilia 2013 [ 35 ] Hall EM et al. BMC Womens Health. 2024 [ 36 ] Platelet function disorders 4.5%-44% Clotting factor deficiency 2% Diaz R et al. J Pediatr Adolesc Gynecol. 2014 [ 7 ] Zia A et al. Haematologica. 2020 [ 11 ] Fibrinolytic disorders 1% Diaz R et al. J Pediatr Adolesc Gynecol. 2014 [ 7 ] VWD, von Willebrand disease; VWF, von Willebrand factor. Prevalence of bleeding disorders in adolescents presenting with heavy menstrual bleeding. VWD, von Willebrand disease; VWF, von Willebrand factor. The problem of HMB is compounded by its association with widely prevalent ID and IDA. Overall, ID with or without anemia affects 2 billion people worldwide, with 40% of affected females aged between 12 and 21 years [ 38 ]. The prevalence of ID in females with HMB has been reported to be as high as 73% [ 39 ]. In BD patients, HMB along with other mucocutaneous bleeding symptoms can exacerbate anemia severity [ 40 ], and pre-existing anemia can increase bleeding tendency, setting up a vicious cycle [ 41 ] ( Figure 1 ). The prevalence of ID in females with BDs from single institution studies ranges from 22% to 61% [ 20 , 42 ]. A large multicenter study found ID in 72% of females with BD, although laboratory evaluations were only checked in 3.6% [ 43 ]. Prevalence rates vary between studies as a ferritin cutoff for identification of ID is not universally agreed upon. Relying on the standard laboratory cutoff of 12 ng/mL for diagnosing ID is outdated and was a result of including ID individuals as “normal” while ascertaining this range. The World Health Organization defines ID using a ferritin cutoff of 15 ng/mL in adolescents and adults without inflammation [ 44 ]; many experts consider ≥30 ng/mL as normal [ 45 ], with recent recommendations to support ferritin level <50 ng/mL as ID for BD patients of all ages regardless of sex [ 46 ]. Lower ferritin levels likely miss many females affected by ID, as differential absorption of iron, symptom correlation, and changes in sensitive iron biomarkers all occur at a ferritin threshold of 50 ng/mL [ 47 ]. ID is more prevalent in menstruating adolescent athletes, ranging from 9% to 60%, due to higher iron demand, increased loss of iron in menses, urine, and sweat, and foot-strike hemolysis. These teens might benefit from higher ferritin values, although this needs to be determined [ 48 ]. Among other symptoms, ID can cause pica/pagophagia, hair loss, headache, fatigue, exercise intolerance [ 19 ], sleep disorders, and restless leg syndrome, impacting QoL [ 49 , 50 ]. Figure 1 Interaction of heavy menstrual bleeding (HMB), bleeding disorder (BD), iron deficiency/iron deficiency anemia (ID/IDA), and quality of life (QoL). Red flags denote screening alerts for providers. Interaction of heavy menstrual bleeding (HMB), bleeding disorder (BD), iron deficiency/iron deficiency anemia (ID/IDA), and quality of life (QoL). Red flags denote screening alerts for providers. All providers should initiate early and prompt treatment for ID/IDA, and if needed, consult a hematologist who is well-versed in the identification and treatment of an underlying cause, the nuances of iron study interpretations, prescribing oral iron replacement therapy, assessing the ideal candidate for ordering and administering iron intravenously and ensuring close follow-up until complete ID/IDA resolution. Dietary inadequacy, sports participation, and nonadherence or intolerance to prescribed regimens lead to inadequate iron stores or repletion and are additional risk factors for persistent ID/IDA in adolescents. Oral iron is preferred for individuals who are expected to have normal absorption. Alternate day dosing at 60 to 120 mg once daily increases absorption by 35% to 50% by mitigating the effects of elevated hepcidin, which is noted at 24 hours [ 51 ]. Intravenous iron is preferred for individuals who are oral iron-intolerant, have inflammatory bowel disease or other proinflammatory conditions, are on continued use of antacids, or are status post-gastrectomy or bariatric surgery. A recent study in adult women with HMB and IDA has prompted a press release by American Society of Hematology stating that intravenous iron is a cost-effective treatment for this population with increased quality-adjusted-life-expectancy over first-line oral iron [ 52 ]. Recently, National Bleeding Disorders Foundation Medical and Scientific Advisory Council published practice guidelines for ID/IDA screening, diagnosis, and management considerations in BD patients [ 46 ].

Evidence shows that HMB in adolescents impacts school absenteeism, mood symptoms, reduced productivity, and overall diminished QoL [ 18 ]. QoL scores used in the adolescent population with HMB and BD include the 36-item Short Form Health Survey, Peds QL Teens, Menorrhagia Impact Questionnaire, and the Patient-Reported Outcomes Measurement Information System Fatigue scale, with reported poor QoL scores improving significantly after treatment of HMB [ 85 , 86 ]. VWD is the most common BD, affecting up to 0.1% to 1% of the general population [ 87 ]. However, data demonstrate that only ∼10.6% of adolescents with HMB underwent screening for VWD, 41.2% underwent screening for anemia with CBC, 14.2% underwent iron studies, and 3.3% were referred to a hematologist [ 88 ]. In a Centers for Disease Control and Prevention survey of women with VWD, there was an average of 16 years between the onset of bleeding symptoms and diagnosis of a BD, an average of 6 bleeding symptoms were present before the diagnosis was made, and 38% were diagnosed by an HTC physician. Among women diagnosed by another center/specialty, 42% were diagnosed by a hematologist, 28% by an internist/primary care physician, and 19% by a gynecologist [ 89 ]. In a single-center Canadian HTC study, the median time from the first bleeding event to VWD diagnosis was 14 years [ 90 ]. In assessing HMB in adolescents, the critical role common to PCPs and specialists is to include a detailed menstrual history in every clinical encounter, assess signs and symptoms of ID/IDA, inquire regarding other bleeding symptoms if HMB is diagnosed, perform baseline CBC and complete iron panel with a ferritin to promptly diagnose ID/IDA, initiate treatment, and start with a basic coagulation work-up. The PCP’s responsibility is to initiate appropriate referrals optimally to hematologists at an HTC and GYNs or preferably to combined specialty clinics for a comprehensive HMB diagnostic evaluation and initiation of optimal therapy ( Figure 3 ). Figure 3 Menarche to menopause: diagnostic journey and optimal care of an adolescent with HMB and BD. BD, bleeding disorder; GYN, gynecology; HMB, heavy menstrual bleeding; HTC, Hemophilia Treatment Center; ID/IDA, iron deficiency/iron deficiency anemia; L&D, labor and delivery; MDT, multidisciplinary team. ∗Hematologist optimally at an HTC. ∗∗Gynecology providers include adult obstetricians and gynecologists (OB/GYNs), pediatric and adolescent gynecologists, and adolescent medicine physicians. Menarche to menopause: diagnostic journey and optimal care of an adolescent with HMB and BD. BD, bleeding disorder; GYN, gynecology; HMB, heavy menstrual bleeding; HTC, Hemophilia Treatment Center; ID/IDA, iron deficiency/iron deficiency anemia; L&D, labor and delivery; MDT, multidisciplinary team. ∗Hematologist optimally at an HTC. ∗∗Gynecology providers include adult obstetricians and gynecologists (OB/GYNs), pediatric and adolescent gynecologists, and adolescent medicine physicians. Specific tasks assigned to GYNs are to identify HMB and investigate gynecologic causes through a detailed history, clinical examination, laboratory testing, imaging studies including pelvic ultrasound, and simultaneously ensuring a referral to an HTC hematologist or ideally consult alongside a hematologist at a combined specialty clinic for young girls for an underlying BD ( Figure 3 ). Discussion and treatment of acute HMB using high-dose combined oral hormonal therapy or progestins, and/or tranexamic acid (TXA) followed by maintenance regimens for control of blood loss and improved cycle predictability is best done by GYNs in partnership with hematologists through a shared decision-making process with the adolescent and their family [ 30 , 57 , 91 , 92 ]. There are several delivery modes for hormonal therapy, with adolescents preferring one over the other based on lifestyle, convenience, side effect profile, cost, and insurance coverage [ 93 ] ( Table 3 ). Clear documentation of response to hormonal treatment, persistent flooding despite adequate therapy, or recurrent emergency department visits should be discussed with the combined team as part of a shared-care model [ 30 , 57 , 92 , 94 ]. Females with BDs have an increased incidence of hemorrhagic ovarian cysts; incidence in adolescents is unknown. Per a survey of women conducted by the Centers for Disease Control and Prevention, 52% of patients with VWD compared with 22% of the control group reported ovarian cysts [ 95 ]. Hemoperitoneum can be a life-threatening consequence of ruptured ovarian cysts warranting comanagement by GYNs and hematologists [ 59 , 60 , 95 , 96 ]. At HTCs through a comprehensive care model, GYNs will continue to manage reproductive health of the adolescent with a BD throughout the lifespan by discussing contraceptive needs, preconception counseling, future fertility, antenatal care, pregnancy, and delivery planning. Table 3 Hormonal therapy options for heavy menstrual bleeding. Method of delivery Hormone category Frequency of administration Oral hormonal therapy Combined estrogen + progestin Progestin only: drosperinone, norethindrone Daily Oral progestin Medroxyprogesterone acetate Daily Transdermal patch Combined estrogen + progestin Weekly Vaginal rings Combined estrogen + progestin Insert for 3 of 4 wk Injectable (intramuscular or subcutaneous) Progestin: depo medroxyprogesterone Every 12-15 wk Subdermal arm implant Progestin: etonogestrel 3 y Intrauterine devices Progesterone: levonorgestrel 8 y for contraception 5 y for heavy menses Hormonal therapy options for heavy menstrual bleeding. Referral to a hematologist at an HTC ensures comprehensive investigation for BD as a possible HMB etiology through detailed personal/family history and laboratory evaluation as listed under the above coagulopathy discussion. Both GYNs and hematologists routinely prescribe nonhormonal therapy, TXA for HMB, or an antifibrinolytic that reduces HMB by ∼50% [ 97 , 98 ]. The excellent efficacy and safety of TXA has documented, including in a Cochrane meta-analysis of 2702 women across 35 studies [ 99 ]. TXA use in adolescents with HMB improves health-related QoL [ 100 ]. Other nonhormonal therapy prescriptions for BD patients, including clotting factor concentrates and DDAVP, are the responsibility of a hematologist; however, the decision of adding these medications to standard hormonal therapy or as a first-line treatment strategy is best done in consultation with GYNs. The use of DDAVP via intranasal, subcutaneous, or intravenous administration may be an option for eligible patients (eg, patients with type 1 VWD, mild hemophilia A, platelet function defects, Ehlers Danlos syndrome) [ 101 ]. COX-2 inhibitors (celecoxib) are preferred for dysmenorrhea in BD due to minimal bleeding risk and are routinely prescribed by hematologists [ 102 ]. The hematologist has a central role in deciding safe therapeutic options to avoid or decrease the risk of thrombosis, avoiding estrogen-containing hormonal treatment for adolescents with personal history of thrombosis or known thrombophilia, which can infrequently occur with an underlying BD, or if there is a history of migraines with aura [ 103 ]. In the rare adolescent with a suspected BD who needs surgical intervention for a gynecologic cause for HMB, the hematologist should ensure a complete hemostatic evaluation is performed preoperatively and draft a detailed surgical hemostatic plan, coordinating with GYNs. Another essential role for the hematologist at the HTC is to ensure ongoing comprehensive care services for adolescents with a BD, provide education and testing for the entire family, and offer genetic counseling ( Figures 3 and 4 ). Figure 4 Comprehensive care at Hemophilia Treatment Center for an adolescent with heavy menstrual bleeding and bleeding disorder. APP, Advanced Practice Provider; HTC, Hemophilia Treatment Center; OB/GYN, obstetrics and gynecology. ∗Draft surgical, dental, and pregnancy care plans with hematologists and specialists. ∗∗Gynecology providers include adult obstetricians and gynecologists (OB/GYNs), pediatric and adolescent gynecologists, and adolescent medicine physicians. Comprehensive care at Hemophilia Treatment Center for an adolescent with heavy menstrual bleeding and bleeding disorder. APP, Advanced Practice Provider; HTC, Hemophilia Treatment Center; OB/GYN, obstetrics and gynecology. ∗Draft surgical, dental, and pregnancy care plans with hematologists and specialists. ∗∗Gynecology providers include adult obstetricians and gynecologists (OB/GYNs), pediatric and adolescent gynecologists, and adolescent medicine physicians.

Adolescents typically reach menarche at ∼12 years and experience monthly menses for nearly 4 decades, totaling an estimated ∼480 menstrual cycles over a lifetime, with intermittent respite during pregnancy. With an underlying BD, adolescents experience an increased burden of heavier, prolonged, and more frequent bleeding, leading to substantial iron loss, reduced QoL, delayed diagnosis, and inadequate management, all of which contribute to significant physical and psychosocial morbidity. A stepwise algorithm approach to the evaluation of HMB and BD diagnosis should be followed by PCPs, GYNs, and hematologists in close collaboration to minimize diagnostic delays. Improved outcomes are achievable by focusing on increasing community and clinician awareness, standardizing ferritin thresholds for ID, advancing investigation of new potential disorders of hemostasis in the large BDUC population with HMB, expanding therapeutic range and availability, and implementing outcome measures designed specifically for adolescents with BDs to capture patients’ voices and needs. Greater inclusion of adolescents and women in clinical trials, alongside engagement of Lived Experienced Experts in study protocol design, will further the evidence base and refine clinically meaningful endpoints. Collective efforts of national and international organizations are critical to reframing HMB in BDs from an underrecognized and often normalized symptom of puberty to a clinical priority for providers, ensuring meaningful and actionable health outcomes.

Heavy menstrual bleeding (HMB) resulted in the death of 14-year-old Hjördis after her fourth menstrual cycle because of von Willebrand disease (VWD), the most common bleeding disorder (BD), first described in 1926 [ 1 ]. This historical case and several others demonstrate the strong association between HMB and BDs. Globally, the prevalence of HMB varies between 20% and 51%, with higher numbers reported in low- and middle-income countries [ [2] , [3] , [4] , [5] ]. Approximately 34% to 58% of menstruating adolescents report HMB, and 21% to 46% of these adolescents have an underlying BD [ [6] , [7] , [8] , [9] ]. Of adolescents hospitalized for HMB, ∼33% have a BD [ 10 ]. The most common causes of HMB in adolescence are anovulatory cycles and BDs [ 11 , 12 ]. In females with a BD, ∼75% to 80% have HMB [ 13 , 14 ]. The initial question posed to an adolescent, “ Are your periods heavy? ” often elicits a “ No ,” possibly due to discomfort in discussing menstrual issues with providers or family members and comparison to relatives who may also have an underlying BD, thereby masking the definition of “normal.” The lack of open-ended questions and ready acceptance of this response results in early dismissal of the adolescent without further evaluation. In a European survey, it was noted that 46% of women had never sought medical attention for HMB [ 4 ]. Physician survey data indicate that comprehensive menstrual history intake is performed in <10% of consultations by pediatricians and family practitioners [ 15 ]. HMB and BDs are underestimated in part due to the absence of standardized definitions and limited provider awareness that HMB is a significant hallmark symptom of an underlying BD. Gynecology providers (GYNs), including adult obstetricians and gynecologists (OB/GYNs), pediatric and adolescent gynecologists, and adolescent medicine physicians, frequently encounter HMB yet do not always pursue systematic evaluation for a BD in adolescents [ 16 , 17 ]. Additionally, gaps in knowledge and variability in training among hematologists further contribute to underdiagnosis and delayed referral. Prolonged and recurrent HMB in BD patients is a common cause of iron deficiency (ID) and/or iron deficiency anemia (IDA), resulting in poor quality of life (QoL) [ 18 , 19 ]. Increasing awareness and education among the community and providers about HMB is imperative for early diagnosis, identifying underlying etiologies, and initiating prompt and appropriate treatment. Notably, the past decade has seen a significant shift in both hematologists and GYNs toward greater emphasis on menstrual health, driven by publications, dedicated sessions at national and international conferences, increased research studies, the advancement of new therapeutics for HMB and BDs, and the emergence of combined subspeciality clinics aimed at improving overall health outcomes [ [20] , [21] , [22] ]. This review highlights knowledge gaps among providers related to the intersection of HMB in adolescents and BDs and provides potential pathways to address these gaps.