Reproductive Tract Bleeding in Adolescent and Young Adult Females with Inherited Bleeding Disorders: An Underappreciated Problem.

AYA females with IBDs experience a wide spectrum of bleeding manifestations including mucosal bleeding, musculoskeletal bleeding, surgical/trauma-related bleeding, and gynecologic and obstetric bleeding. Notably, adolescents can have anovulatory bleeding concurrent with an IBD. Table 1 lists the types of bleeding symptoms that have been reported in AYA females with IBDs, indicating the study design.

The pediatrician, adolescent medicine specialist, hospitalist, emergency medicine physician, or gynecologist could be the first point of contact for AYA presenting with reproductive tract bleeding. A systematic approach is recommended to identify patients with IBDs and facilitate timely referrals to tertiary centers. Table 2 enumerates the symptoms to elicit within the personal and family history of bleeding including obstetric and gynecologic bleeding. Red flag signs are listed to help clinicians determine if the bleeding history aligns with a disorder of primary (muco-cutaneous bleeding) or secondary hemostasis (bleeding in muscles, joints). Clinicians must elicit symptoms pertaining to systemic causes of HMB such as obesity, liver and renal disease, hypothyroidism, hyperprolactinemia, and connective tissue disorders. The family history provides clues toward diagnosis of the specific IBD. For example, hemophilia is an X-linked recessive disorder for which females are carriers, whereas most rare factor deficiencies (RFDs) are inherited as autosomal recessive traits. Sometimes, FXI deficiency and dysfibrinogenemia are inherited in an autosomal-dominant manner. Heterozygotes of IBDs pose a clinical challenge due to their variable bleeding phenotype as factor levels do not always correlate with bleeding. 18 – 20 A focused exam with attention to vital signs, body mass index (BMI), and Tanner staging is key in evaluating AYA with a suspected IBD. It should include examination of the skin (petechiae, pallor, bruising, acne, hirsutism, acanthosis nigricans), abdomen (distension, tenderness, striae, masses), and joint mobility. Joint hypermobility is frequently seen among patients with unexplained bleeding. 21 A study showed that about 53% of females with joint hypermobility syndromes, such as Ehlers-Danlos syndrome, experienced HMB. 22 The Beighton score, a 9-point evaluation of joint hypermobility, is validated in children 23 , 24 and is recommended as part of an IBD evaluation. Clinicians are advised to use the International Society of Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) to assess the bleeding phenotype. A positive ISTH-BAT score (≥6 for adult females and ≥3 for children) is associated with an IBD. 25 , 26 Notably, an ISTH-BAT score of less than or equal to 3 has a high negative predictive value (99.2%) for IBD. 27 The Philipp screening tool has a sensitivity of about 90% for hemostatic defects and is more practical for a busy clinic setting. 28 HMB is defined as the loss of more than 80 ml of blood during a single cycle; however, this definition is not clinically useful. Due to variability with subjective assessment, we recommend using the Pictorial Blood Assessment Chart (PBAC) to assess HMB severity. 29 , 30 PBAC is validated in adults but not in adolescents. 31 A score of greater than 100 has a specificity and sensitivity of greater than 80%. 32

A three-tiered testing approach is recommended by experts to rule out IBDs. 33 – 35 Initial investigation should include evaluation for anemia, iron deficiency, screening tests for coagulation factor deficiencies, and in-vivo bleeding time ( Fig. 3 ). 36 We recommend obtaining a FVIII assay and VWD panel (von Willebrand factor [VWF] antigen and VWF activity using ristocetin cofactor). Although FVIII and VWF levels are lowest at the onset of menses, testing is generally not delayed until menstruation. 37 High-dose estrogens can increase VWF levels; hence, testing is repeated when the patient is on low-dose estrogen (30–35 μ g) or off high-dose estrogen for about 3 months. 31 Platelet function analyzer (PFA) is a sensitive test to detect von Willebrand disease (VWD) 38 and severe platelet function defects (PFDs) but does not detect mild PFDs. 39 Its applicability as a tier-1 test remains controversial. Discussion with a hematologist is often helpful in deciding hemostatic evaluation. Since VWF levels are elevated during stress, inflammation, estrogen therapy, and severe HMB, VWD testing is repeated for confirmation. Platelet aggregometry, the gold standard test to diagnose PFDs, should be performed after correcting anemia because results can be altered with Hb less than 10 g/dL. 40 Tier-2 testing should include thrombin time, reptilase time (dysfibrinogenemia workup), and specific factor levels as enumerated in Fig. 3 if prothrombin time (PT) and/or partial thromboplastin time (PTT) is prolonged. 37 Factor XIII deficiency does not prolong the PT or PTT and is included with first or second-tier testing. If the above workup is inconclusive and the patient continues to bleed, tests of fibrinolysis can be considered. Platelet glycoprotein expression by flow cytometry and electron microscopy to evaluate platelet granules is considered on the basis of platelet aggregometry findings. Currently, whole blood assays such as thrombo-elastography (TEG) and thrombin generation assay (TGA) are not standardized for clinical use. Nonstructural causes of HMB, such as anovulation, polycystic ovarian syndrome (PCOS), thyroid dysfunction, pregnancy, and sexually transmitted infections, should be excluded. Routine pelvic ultrasound is not considered as first-line testing because the incidence of uterine pathology is low in adolescents. 33 , 41

Management of gynecologic bleeding depends on the chronicity of bleeding and hemodynamic status. Patients with acute hemorrhage and hemodynamic instability should receive fluid resuscitation and blood products. Coagulation assays should preferably be sent before administering blood products. We often collect an extra tube (with acid citrate dextrose as anticoagulant) prior to therapeutic intervention for additional hemostatic evaluation. Concurrent treatment of iron deficiency in patients with HMB is crucial because it improves quality of life. 42 To treat iron deficiency, we recommend oral iron at a dose of 4–6 mg of elemental iron/kg/day, every other day. 31 , 43 , 44 Intravenous iron is considered if oral iron is not tolerated or a faster response is desired. 31 Surgical methods such as balloon tamponade and arterial ablation are considered for AYA with severe medically refractory bleeding. 45 A two-step approach is recommended for managing HMB. 46 Combined oral contraceptives (COCs) or intravenous conjugated estrogens, and progestins including progestin tapers if estrogen is contraindicated, are the key to controlling acute HMB. 47 The general recommendation is to start with 30 mcg or 35 mcg of estrogen, escalating up to higher doses (50 mcg) as needed. Multiple regimens are available to transition from high-dose estrogens to lower dose maintenance treatment. 47 , 48 Antifibrinolytics are also highly effective in managing acute HMB. 49 , 50 Table 3 lists the various regimens that are available to manage acute HMB 47 , 51 , 52 . Combined hormonal contraceptives (CHCs) are considered first-line therapy for HMB and are available as a pill, patch, or vaginal ring. In adolescents, COCs with 30–35 mcg of estrogen are used to promote bone health. 53 , 54 Monophasic pills with 30–35 mcg of estrogen cause less breakthrough bleeding compared with triphasic pills. 55 Extended cycling regimens are considered in the setting of anemia to decrease continuing menstrual bleeding. Progestin-only agents (levonorgestrel-intrauterine devices [IUDs], progestin-only pills, depot medroxy progesterone acetate [DMPA) injections, and etonorgestrel implants) are considered in patients with personal and/or family history of thrombosis. IUDs are an effective long-term treatment for HMB in IBDs 56 – 58 and are preferred in adolescents due to better compliance 59 and amenorrhea rates of up to 62%. 60 Although studies have shown variable IUD expulsion rates, it is not particularly higher (2%–10%) in adolescents as compared with adults. 61 , 62 Numerous options are available to treat persistent breakthrough bleeding, 1 of which is 5 mg of norethindrone acetate once daily. 31 , 63 Due to the conversion of norethindrone to ethinyl estradiol, there is a concern for venous thromboembolism (VTE); however, data evaluating VTE risk with higher doses (2.5–15 mg) remain limited and inconclusive. 64 – 66 For patients with recurrent hemorrhagic ovarian cysts or hemoperitoneum, ovulation suppression using CHCs is recommended when pregnancy is not desired. 67 , 68 Antifibrinolytics (tranexamic acid or TXA and amino-caproic acid) and intranasal desmopressin (DDAVP; l-desamino-8-D-arginine-vasopressin) are equally effective in reducing menstrual bleeding, according to a crossover study. 69 TXA reduces menstrual bleeding by about 50% 70 , 71 and is used as standalone or adjuvant therapy. Intranasal DDAVP has about 77% efficacy in patients with type 1 VWD 72 and decreases menstrual bleeding in women with hemophilia carriership and PFDs. 73 Intranasal DDAVP has been unavailable since 2020 due to a nation-wide recall; however, intravenous and subcutaneous DDAVP preparations remain available. Recommended dosing regimens for hormonal and nonhormonal therapies are given in Table 4 . For patients with refractory HMB and established diagnosis, disease-specific therapies are used in consultation with a hematologist. There are data supporting the use of VWF concentrates in VWD, 69 , 74 factor VIII and IX concentrates in hemophilia carriers, and rFVIIa in FVII deficiency and PFDs. 75 , 76 Platelet transfusions are generally avoided in patients with platelet disorders due to risk of alloimmunization. In patients with severe ovulation bleeding desiring pregnancy, serial ultrasound has been used to track ovulation, and hemostatic agents have been administered to prevent hemoperitoneum. 77 , 78 VWF levels start to rise in the first and second trimester, reaching 50%–60% above baseline in the third trimester and peaking at about 50% higher at delivery. Levels start to decrease around postpartum day 3 and fall 1–3 weeks after delivery. 79 Significant PPH can occur even in women with normal VWF levels at delivery. 80 It is recommended to monitor VWF and FVIII levels once per trimester and within 2 weeks of anticipated delivery, more frequently if complications arise in IBD patients. Fibrinogen activity increases during pregnancy 81 ; however, AYA with afibrinogenemia and hypofibrinogenemia are at risk of pregnancy losses, APH, and PPH 82 . Factor II, Factor V, and Factor IX levels do not change in pregnancy. Factor VII activity increases in women with FVII deficiency after the first trimester but does not increase in severely deficient patients. FVIII levels increase in hemophilia A carriers from a median of 0.42 to 1.2 IU/ml. 83 Factor X activity increases during pregnancy, but levels remain below the hemostatic range at delivery in AYA with severe FX deficiency. 84 It is unclear if FXI changes during pregnancy. 82 FXIII activity decreases during pregnancy, and prophylaxis is indicated to prevent abortion 85 in FXIII deficiency. Oral or intravenous TXA has been used in most IBDs after delivery to prevent PPH. 86 – 88 Although TXA use is supported by high-quality evidence in patients without IBDs, 89 , 90 data in IBD patients is mostly observational. Disease-specific concentrates are available for all factors except Factor V and Factor II, for which fresh frozen plasma (FFP) and prothrombin complex concentrates (PCCs) are used, respectively. For pregnancy and childbirth, many experts endorse the use of specific recombinant or virally inactivated plasma-derived concentrates over FFP or cryoprecipitate. If possible, IBD patients should receive pathogen-reduced products. Disease-specific concentrates are recommended whenever available for prophylaxis during pregnancy, prior to invasive procedures, and at delivery. 86 , 91 , 92 The role of prophylaxis in maintaining pregnancy is well established in women with fibrinogen disorders and Factor XIII deficiency. 86 For other IBDs, clear guidelines are lacking. It is a clinical decision on the basis of the factor level at delivery and the bleeding phenotype. The use of forceps and fetal scalp electrodes is generally avoided during deliveries in patients with IBDs. Early diagnosis of IBDs will help develop an individualized plan to manage pregnancy and delivery, involving crucial decisions such as obstetric analgesia, mode of delivery, and neonatal care. Minor procedures such as IUD placement and cervical biopsy might need hemostatic coverage in AYA with IBDs. For a review summarizing recommendations for prophylaxis in women with RFDs and platelet disorders, the reader is referred to the paper by Dr Shapiro. 91

Studies are needed to better characterize reproductive tract bleeding in AYA with IBDs. Increasing clinician awareness of the full spectrum of bleeding in AYA females with IBDs is vital. Although HMB or miscarriages are common in the general population, the task is to identify red flag signs that would warrant further hemostatic workup. The goal is to diagnose these patients before menarche, which will help provide appropriate counseling and allow for implementation of optimal prophylactic and therapeutic strategies. A multidisciplinary approach involving hematologists and obstetricians-gynecologists, preferably at an HTC, is critical to improve outcomes of AYA females with IBDs and help them navigate their reproductive challenges

Over the last 3 decades, studies from national registries and hemophilia treatment centers (HTCs) 9 , 10 have led to increased diagnoses of IBDs in AYA with HMB and other bleeding symptoms. In a study of 115 women with HMB, about 47% were found to have a hemostatic defect. 11 In another study of 85 women with PPH, about 23% had an IBD. 12 Data about the disease-specific prevalence of IBDs are limited, 13 and population-based studies are lacking.

Reproductive tract bleeding is an underappreciated problem among adolescent and young adult (AYA) females with inherited bleeding disorders (IBDs). 1 – 3 In addition to heavy menstrual bleeding (HMB), AYA with IBDs experience bleeding complications as a result of ovulation bleeding, miscarriages, and surgical management of fibroids and endometriosis. 4 These bleeding diatheses cause substantial morbidity and mortality due to complications such as anemia, hypovolemic shock, disseminated intravascular coagulation (DIC), therapeutic hysterectomies, and death. 5 – 7 AYA with IBDs are at risk of ante-partum and postpartum hemorrhage (PPH), leading to adverse maternal and fetal outcomes. 8 Early diagnosis and timely intervention are key to preventing the consequences of bleeding in AYA with IBDs. Our review highlights the clinical spectrum of bleeding and outlines a systematic approach to the evaluation and management of reproductive tract bleeding in AYA with IBDs.

Hemostasis is a physiological process that controls bleeding from the vessel wall following vascular injury through interaction between the endothelium, platelets, and coagulation cascade. 14 Uterine hemostasis has been well studied and understood over the last several decades and is regulated by tissue factor- (TF) and sex hormone-dependent fluctuations in coagulation and fibrinolytic proteins. 15 Fig. 1 shows the interplay between TF-mediated coagulation and other pathways required for uterine hemostasis. Fig. 2 shows a graphical representation of hemostatic, angiogenic, and fibrinolytic factors in relation to the menstrual cycle. TF expression on the surface of human endometrial stromal cells (HESCs) is augmented by progesterone during the early and mid-luteal phases ( Fig. 2C ). TF exerts its hemostatic function through the TF/FVIIa complex, resulting in thrombin generation. Progesterone induces plasminogen activator inhibitor (PAI-1) in the endometrium, which inhibits conversion of plasminogen to plasmin, preventing clot lysis. 16 In fertile cycles, TF and PAI-1 help to achieve endometrial hemostasis during trophoblast invasion, thereby preventing hemorrhage. 17 In non-fertile cycles, progesterone withdrawal leads to reduced TF and PAI-1 expression, resulting in increased endometrial plasmin concentrations and menstruation. Studies have shown that the endometrium is highly fibrinolytic, and tissue plasminogen activator (t-PA) levels increase in response to estrogen during the proliferative phase ( Fig. 2C ). Therefore, the sex hormones directly influence the endometrial concentrations of coagulation proteins and angiogenic factors, creating either a hemostatic milieu (if implantation occurs) or a pro-hemorrhagic environment (if menstruation ensues).