Recommendations for Thrombophilia Testing for Women before Oral Contraceptives are Prescribed

A healthy 14-year-old girl presented with a hemoglobin of 2.9 g/lL, MCV 61 lL, 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?

This case represents a clinical situation encountered frequently by pediatric hematologists. Unfortunately, clinical management decisions for adolescents must still be largely extrapolated from published data and recommendations on and for women.¹  However, in a 2015 Committee Opinion endorsed by the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists revised and updated their guidance on menstruation in girls and adolescents: menstrual cycle duration is typically 21 to 45 days; menstrual flow is seven days or less; and menstrual product use is three to six pads or tampons per day.²  Menorrhagia or heavy menstrual bleeding is defined as greater than 80 mL of blood per cycle and can be predicted on the basis of clots ≥ 1 inch diameter or greater, low ferritin, and "flooding," defined as a change of pad or tampon more frequently than hourly.³  In the case of the 14-year-old girl, heavy menstrual bleeding could be inferred on the basis of clots, cycles of up to seven days and severe iron-deficiency anemia in the absence of any other source of bleeding.

The causes of heavy menstrual bleeding include acquired abnormalities of the uterine cavity (polyps, adenomyosis; leiomyoma; malignancy and hyperplasia; other endometrial abnormality) ovulatory dysfunction; iatrogenic causes (usually hormonal); causes not yet classified; and coagulopathy.⁴  However, in an adolescent, the cause is less likely to be an abnormality of the uterus and more likely to be ovulatory dysfunction, a hormonal cause, or possibly, an underlying bleeding disorder. A bleeding disorder may be the sole cause of heavy menstrual bleeding, or it may be a contributing cause. Consequently, an adolescent presenting with heavy menstrual bleeding requires a thorough evaluation that includes a thorough history and physical examination, an assessment of the uterus, an endocrine evaluation if there is anovulation or hypo-ovulation, and possibly, an evaluation for an underlying bleeding disorder.⁴  If anemia due to menorrhagia recurs three years later, a re-evaluation would be indicated.

Not only is heavy menstrual bleeding more prevalent among women and girls with bleeding disorders, but bleeding disorders are more prevalent among those with heavy menstrual bleeding. In adolescents who present with heavy menstrual bleeding, the prevalence of von Willebrand disease (vWD) has been reported to be 5 to 36 percent; the prevalence of platelet dysfunction (depending on how it was defined) was 2 to 44 percent; the prevalence of factor VIII deficiency was 8 percent; and the prevalence of thrombocytopenia 13 to 20 percent. Dr. Claire S. Philipp and colleagues⁵  reported on the importance of various signs and symptoms as predictors of a bleeding disorder in women with heavy menstrual bleeding. After administering a 12-page questionnaire of bleeding symptoms, the investigators were able to develop a screening tool that was considered to be positive if one of the following four criteria was met:

• Duration of menses greater than or equal to seven days and flooding or impairment of daily activities with most periods

• History of treatment of anemia

• Family history of a diagnosed bleeding disorder

• History of excessive bleeding with tooth extraction, delivery or miscarriage, or surgery

The screening tool alone had a sensitivity of 82 percent for bleeding disorders. Although the results would not be available at an initial visit, adding a pictorial blood assessment chart score > 100 increased the sensitivity of the screening tool to 95 percent. The patient in this case was positive for two of the criteria (7-day periods and anemia). Therefore, an evaluation for an underlying bleeding disorder would be indicated.

The laboratory evaluation for an underlying bleeding disorder 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.

Hormonal therapy is a frequent and usually effective approach to treating heavy menstrual bleeding 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 denial of access to OCs remain unexplored, but are 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 a 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 effective in managing heavy menstrual bleeding, but both the ring and the patch are associated with an increased risk of VTE compared to OCs.⁷  An alternative given this patient’s family thrombosis history would be a levonorgestrel-containing intrauterine device (IUD), which has been demonstrated to decrease menstrual blood loss in women with bleeding disorders,⁸  but does not increase the risk of VTE.⁷  Although this patient is quite young, there are reports of the levonorgestrel IUD’s successful use in controlling menstrual blood flow in adolescents.^1,9  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/hormonal management of heavy menstrual bleeding, hemostatic therapy at the time of menses would be the next step. Oral tranexamic acid is FDA-approved for this indicaton in adults, but has been used in adolescents as well.¹⁰