Donna DiMichele, MD

2010-11-01

Deputy Director, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute 

The Question (developed by Zora Rogers, MD)

A healthy 14-year-old female presented with a hemoglobin of 2.9 g/dl, MCV 61fl, and reticulocyte count of 0.9 percent. Pregnancy test was negative. Menarche began at age 11; periods were somewhat irregular and lasted five to seven days with clots. A diagnosis of severe iron deficiency due to menorrhagia was made and appropriately managed with transfusion and iron. Should an evaluation be done for an underlying bleeding disorder? What tests? What about such an evaluation if the anemia due to menorrhagia recurs three years later?

The patient is now interested in contraception. A paternal aunt and maternal grandmother have a vague history of thrombosis requiring treatment. What thrombophilia testing should be undertaken in this patient before contraception is prescribed? Indeed, should thrombophilia testing be recommended for all women before oral contraceptives (OCs) are prescribed? What form of contraception and medication for regularization of periods should be advised?

My Response

This case represents a clinical situation encountered frequently by pediatric hematologists. Unfortunately, clinical management decisions for adolescent females must still be largely extrapolated from published data and recommendations on and for adult women. However, a recent guide to diagnosis and management of adolescent menorrhagia has provided a useful basis for discussion.¹ In 2006, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics defined normal menstruation in girls and adolescents as: 1) beginning between ages 11 and 14; 2) cycle duration of 21 to 45 days; 3) duration of menses of ≤ seven days; and 4) use of ≤ three to six pads or tampons per day.² Heavy menstrual flow can be predicted on the basis of clots of ≥ 1 inch diameter, low ferritin, and “flooding,” defined as a change of pad or tampon more frequently than hourly.^1,3 Based on this definition, menorrhagia in this case was likely diagnosed on the basis of large clots and extremely heavy flow resulting in severe iron-deficiency anemia in the absence of any other source of bleeding.

The causes of menorrhagia in adolescent females include congenital or acquired bleeding disorders, although pre-existing hemorrhagic diatheses can also exacerbate heavy menstrual bleeding due to underlying endocrine, anatomic, or oncologic conditions. Consequently, an adolescent first presenting with menorrhagia requires a thorough evaluation. Although pregnancy and chronic medical disease, including hypothyroidism, were excluded in this patient, pelvic clinical and radiologic examination for ovarian, uterine, and mullerian sources of bleeding would likely have been performed. Importantly, endometriosis is found more commonly in women with bleeding disorders, but whether endometriosis can become more clinically symptomatic due to an underlying hemorrhagic diathesis is unclear. Menstrual irregularity three years after menarche should also prompt a hormonal assessment.

Among adults, not only is heavy menstrual bleeding more prevalent among women with bleeding disorders, but bleeding disorders are more prevalent among women with that symptom.¹ Among adolescents with menorrhagia, the prevalence of von Willebrand disease (VWD), platelet dysfunction, clotting factor deficiency (including hemophilia carrier state), and thrombocytopenia have been reported.⁴ A bleeding evaluation must therefore be strongly considered in this situation.

Not surprisingly, the medical, gynecologic, and family history can be an important screening tool in the decision-making process. Excessive bleeding with tooth extraction, delivery, miscarriage, or surgery can be important clues. In one study, a positive history alone had a sensitivity of 82 percent in the detection of VWD, platelet dysfunction, and clotting factor deficiency, as well as a negative predictive value of 93 percent for VWD; 45 percent for platelet dysfunction; and 38 percent for any bleeding disorder.⁴ Although this young woman had neither a positive personal nor family bleeding history, the severity of her presenting anemia alone would provide sufficient rationale for an immediate evaluation for an underlying bleeding diathesis. The laboratory evaluation would include a platelet count, mean platelet volume (MPV), and review of the blood smear to rule out thrombocytopenia and platelet morphologic disorders; prothrombin (PT), partial thromboplastin (aPTT), and thrombin times along with fibrinogen activity to screen for clotting factor deficiency; and a von Willebrand factor profile and platelet function studies. Additionally, specific factor activity levels would be performed if dictated by a prolonged PT or aPTT or otherwise suggested by high ethnic prevalence or an X-linked family history of a hemorrhagic diathesis. Any history or physical signs of connective tissue laxity should also prompt some consideration of collagen evaluation. If the bleeding is severe and the initial evaluation is negative, evaluation of the fibrinolytic system should be performed. Should menorrhagia persist or recur following a thorough diagnostic workup and appropriate therapeutic intervention, further consideration should be given to anatomic and hormonal evaluations. Recently, a sessile polyp detected on hysteroscopy was reported to be a rare but definitive cause of persistent severe bleeding in an early menarchal female.⁵

Hormonal therapy is a frequent and usually effective approach to treating menorrhagia in women and adolescents.¹ That this adolescent is asking for contraception makes this an ideal first-line therapy. The choice of hormonal therapy is made more complicated by the family history of thrombosis and raises the question of thrombophilia screening prior to prescribing contraceptives. The substantially increased risk of venous thromboembolism (VTE) with either thrombophilic risk factor(s) or OCs is synergistically amplified when underlying thrombophilia and OCs are combined.⁶ Nevertheless, with a low-baseline VTE risk in young women of < 0.8 per 10,000 women years, even a 30-fold risk increase in women with Factor V Leiden on OCs would translate into a very low overall event rate, limiting the cost effectiveness of routine screening prior to initiating OCs.⁶ Furthermore, the psychosocial consequences in adolescents of positive screening for thrombophilia or denied access to OCs remains unexplored but probably significant.

In the absence of an effective predictive screening strategy, alternative approaches include counseling for risk-factor avoidance (especially smoking), intermittent thromboprophylaxis during periods of high thrombosis risk (immobilization, lower extremity injury, surgery), and minimization of risk through the prescription of less thrombogenic OCs. These conservative measures would be warranted for this patient. OC preparations containing low-dose estrogen and second-generation progestin levonorgestrel would be preferred. Although there are limited data on their use in adolescents and women with bleeding disorders, combined hormonal contraception in the form of a ring or patch would likely be equally useful.¹ An alternative given this patient’s family thrombosis history would be a levonorgestrel-containing intrauterine device (IUD), which has been demonstrated to effectively decrease heavy menstrual flow.⁷ Although this patient is quite young, there are anecdotal reports of their successful use in controlling blood flow in adolescents.¹ Hemostasis prophylaxis prior to IUD insertion should be considered in adolescents with severe bleeding disorders. Finally, for those adolescents with a specific bleeding diagnosis who fail gynecologic management of menorrhagia, hemostatic therapy at the time of menses would be the next step. Oral tranexamic acid is FDA-approved for this indication. However, given this patient’s family history, thrombophilia testing should be strongly considered prior to exercising this therapeutic option.

1. James AH. Bleeding disorders in adolescents. Obstet Gynecol Clin North Am. 2009;36:153-162.
2. ACOG Committee on Adolescent Health Care. ACOG Committee Opinion No. 349: Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2006;108:1323-1328.
3. Warner PE, Critchley HO, Lumsden MA, et al. Menorrhagia I: measured blood loss, clinical features, and outcome in women with heavy periods: a survey with follow-up data. Am J Obstet Gynecol. 2004;190:1216-1223.
4. Philipp CS, Faiz A, Dowling N, et al. Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol. 2005;105:61-66.
5. Noorhasan DJ, Weiss G. Perimenarchal menorrhagia: evaluation and management. J Pediatr. 2010;156:162.
6. Wu O, Greer IA. Is screening for thrombophilia cost-effective? Curr Opin Hematol. 2007;14:500-503.
7. Kingman CE, Kadir RA, Lee CA, et al. The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG. 2004;111:1425-1428. 

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