Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism, is the third most common cause of vascular death [1–3]. According to recent guidelines, the use of direct oral anticoagulants (DOACs) is recommended over vitamin K antagonists (VKAs) to prevent VTE recurrence . Yet, as extended anticoagulation may increase the risk of bleeding, reluctance exists as to whether anticoagulants should be continued beyond 6–12 months [5–9]. One critical setting is that of women of reproductive age, as 10–30% of cases suffer from abnormal uterine bleeding (AUB)  including heavy menstrual bleeding (HMB). The frequency of menorrhagia as well as the mean duration and volume of menstrual bleeding were reported to be increased upon VKA and DOAC therapy . Moreover, HMB was observed in 20–41% of VTE women of reproductive age while on anticoagulant therapy [12–15]. In post-hoc analyses of randomized clinical trials, DOACs seemed to be associated with an increased risk of HMB compared with enoxaparin/VKAs, but the prevalence of major bleeding was low [16–18]. Current real-life data on AUB occurring during DOAC therapy are mostly limited to women on treatment with rivaroxaban [12,15,19] and are insufficient to identify a specific drug effect or to suggest any specific drug choice in women.
In clinical practice, the management of HMB in VTE women on long-term anticoagulant therapy remains to be defined, and decision-making needs to balance the risk of recurrent VTE against the risk of bleeding.
Here we describe the management of a woman treated with rivaroxaban for recurrent VTE, who experienced HMB during the extended therapy.
In August 2014, a 48-year-old white women, smoker, with a history of migraine with aura and gastritis was hospitalized for oedema and pain at the left lower limb, which was localized at the popliteal fossa and leg. Since 2011, she had suffered from endometriosis and episodes of menometrorrhagia, which had been successfully managed with progestin-only pill. At the time of admission, she was receiving no therapy; the following values were recorded: blood pressure (BP) 120/80 mmHg, heart rate (HR) 85 bpm R and SpO2 97% on room air. Lower extremity venous ultrasound showed the presence of proximal DVT (femoral–popliteal–distal) at the left lower limb (Fig. 1). Therefore, rivaroxaban at the dosage of 15 mg twice daily was started and, after 3 weeks, it was decreased to 20 mg/die. After 6 months, during which neither complication nor further episodes of menometrorrhagia had occurred, the oral anticoagulant therapy was discontinued . Notably, mutational screening unveiled the presence of heterozygous Factor V Leiden.
In November 2015, the patient was hospitalized for the occurrence of sudden pleuritic chest pain. During the previous week, she had been partly immobilized because of right sciatica. BP was 95/50 mmHg, HR 120 bpm R and SpO2 96% on room air. Moreover, the following values were recorded: haemoglobin (Hb) 14.7 g/dl, platelets 235 000/μl, creatinine 0.63 mg/dl, troponin 0.07 ng/ml, prothrombin time 0.99 s and activated partial thromboplastin time 0.98 s. Echocardiography showed no dilatation of the right sections and ECG was within the normal range. Chest computed tomography scan with contrast unveiled the presence of massive bilateral pulmonary embolism (right proximal and left segmental pulmonary arteries, Fig. 2). Therefore, the patient started oral anticoagulant therapy with apixaban. Yet, due to intense itching, the treatment was discontinued after 2 days, and the patient was switched to rivaroxaban 15 mg twice daily for 3 weeks and then 20 mg daily, with the indication to continue it as long-term therapy.
Oral anticoagulation was well tolerated until April 2016, when she reported episodes of menometrorrhagia with a drop of Hb down to 10.6 g/dl. At the gynaecological visit, a new large 8 × 6 cm uterine fibroid was found, for which she was advised to take tranexamic acid during the menstrual period.
On 6 May 2016, during an outpatient visit, the woman reported persistence of menometrorrhagia, and Hb was stable at 10.9 g/dl. As a consequence, the decision was made to start hormonal therapy with the gonadotropin-releasing hormone agonist leuprorelide acetate at the dosage of 3.75 mg monthly for up to 3 months. During hormonal treatment, uterine bleeding decreased but did not stop completely, and Hb value was 9.3 g/dl on June 2016. Thus, a progestin intrauterine device was placed, and chronic oral progestin treatment was started.
In January 2017, at the last visit, the patient's clinical conditions were good and menometrorrhagia was under control. On 4 May 2017, Hb was 12.4 g/dl.
At the time of article writing, more than 20 months after the starting of rivaroxaban, the patient was still on 20 mg/die rivaroxaban and progestin hormonal treatment. Importantly, no transfusions or other medical interventions including discontinuation or dose reduction of rivaroxaban were required; HMB was adequately managed and no VTE recurrence occurred.
In clinical practice, the common use of DOACs in different settings has led to the emergence of new scenarios that require novel approaches, such as in the case of VTE women experiencing HMB during anticoagulation [12–15].
The case presented here demonstrates that in women at high risk of VTE recurrence requiring extended anticoagulation, it is possible to effectively and safely control HMB by using hormonal therapy. Indeed, upon hormonal therapy, no transfusions or other medical interventions, including discontinuation or dose reduction of rivaroxaban, were required and, during more than 20 months on rivaroxaban, neither thrombotic episodes nor other complications occurred. We did not perform pictograms to assess menstrual blood loss, as it is not routinely carried out in our institution. Moreover, despite the pictorial blood assessment chart has been validated for the diagnosis of HMB, its sensitivity and specificity vary widely .
Currently, in women at high VTE risk requiring long-term anticoagulation, the optimal approach to control HMB as well as the most adequate anticoagulation duration remain controversial. The possible options are limited by the very delicate balance between bleeding and thromboembolism. Few strategies have been reported [12,15,19], including temporary or permanent discontinuation and dose reduction of the anticoagulant. Yet, temporary discontinuation of anticoagulation therapy is not always feasible as it may increase the risk of VTE recurrence. With regard to dose reduction, results from the AMPLIFY-EXT trial and, more recently, from the EINSTEIN CHOICE trial support the use of low dose of oral anticoagulant, such as 2.5 mg of apixaban twice daily and 10-mg rivaroxaban once daily, to manage VTE patients requiring extended treatment [9,21]. From 353 women enrolled in the EINSTEIN-CHOICE trial, 10-mg rivaroxaban seemed to be associated with a decrease of HMB, without an increased risk of thrombosis, when compared with 20-mg rivaroxaban (Boonyawat K, Lensing AW, Prins MH, Prandoni P, Weitz JI, Crowther M. Menstrual Bleeding Patterns in Women Treated with Rivaroxaban: Data from the EINSTEIN CHOICE Trial. Poster 1191, presented at the XXVI Congress of the International Society on Thrombosis and Haemostasis, Berlin, Germany; 2017). Similarly, low-dose apixaban may attenuate HMB, but definitive evidence supporting the recommendation of this regimen is lacking. Sulodexide, which is an oral glycosaminoglycan, could be considered as an alternative in high-risk patients who are candidates for extended anticoagulation . Given after discontinuation of anticoagulant treatment in patients with previous unprovoked VTE, sulodexide seems to reduce the risk of recurrence, with no apparent increase of bleeding risk. However, whether prevention of recurrence could be performed with sulodexide requires further investigations. Alternatively, oestrogen or progestin hormonal therapy may be employed, but they are not always effective in controlling HMB and are also associated with increased risk of VTE [16,23]. Another option is tranexamic acid, an antifibrinolytic agent shown to be effective in the treatment of HMB in nonanticoagulated women . Notably, despite a label warning by the Food and Drug Administration, the association of tranexamic acid and thrombotic risk in patients with VTE has not been definitively confirmed, and current evidence does not support the hypothesis that tranexamic acid is associated with an unacceptable risk of thrombosis in anticoagulated women [25–27].
As, currently, the available evidence from randomized controlled trials does not allow to draw any definitive conclusion, case reports are paramount to collect data on the use of DOACs in patients experiencing HMB. In a critical setting such as that of VTE women experiencing HMB during extended anticoagulation, the use of hormonal therapy warrants further investigations. Women of reproductive age should be advised on the risk of HMB and on the possible strategies to prevent it.
The authors would like to thank Clara Ricci, PhD (Primula Multimedia SRL, Pisa, Italy) who provided skilful editorial assistance.
Financial support for editorial services was provided by Bayer HealthCare, Italy. Bayer HealthCare was not involved in the collection, analysis and interpretation of data.
Conflicts of interest
There are no conflicts of interest.
Consent: Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
1. ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Thromb Res
2. Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost
3. Centers for Disease Control and Prevention (CDC). Venous thromboembolism in adult hospitalizations – United States, 2007–2009. MMWR Morb Mortal Wkly Rep
4. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest
5. Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med
6. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism
. N Engl J Med
7. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. EINSTEIN Investigators. Oral rivaroxaban
for symptomatic venous thromboembolism. N Engl J Med
8. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med
9. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med
10. Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health J Int Soc Pharmacoeconomics Outcomes Res
11. Själander A, Friberg B, Svensson P, Stigendal L, Lethagen S. Menorrhagia and minor bleeding symptoms in women on oral anticoagulation
. J Thromb Thrombolysis
12. Beyer-Westendorf J, Michalski F, Tittl L, Hauswald-Dörschel S, Marten S. Management and outcomes of vaginal bleeding and heavy menstrual bleeding
in women of reproductive age on direct oral antifactor Xa inhibitor therapy: a case series. Lancet Haematol
13. Ferreira M, Barsam S, Patel JP, Czuprynska J, Roberts LN, Patel RK, et al. Heavy menstrual bleeding
. Br J Haematol
14. Myers B, Webster A. Heavy menstrual bleeding
– comparison with apixaban. Br J Haematol
15. Bryk AH, Piróg M, Plens K, Undas A. Heavy menstrual bleeding
in women treated with rivaroxaban
and vitamin K antagonists and the risk of recurrent venous thromboembolism
. Vascul Pharmacol
16. Martinelli I, Lensing AWA, Middeldorp S, Levi M, Beyer-Westendorf J, van Bellen B, et al. Recurrent venous thromboembolism
and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood
17. Bleker SM, Cohen AT, Büller HR, Agnelli G, Gallus AS, Raskob GE, et al. Clinical presentation and course of bleeding events in patients with venous thromboembolism, treated with apixaban or enoxaparin and warfarin. Results from the AMPLIFY trial. Thromb Haemost
18. Brekelmans MPA, Scheres LJJ, Bleker SM, Hutten BA, Timmermans A, Büller HR, et al. Abnormal vaginal bleeding in women with venous thromboembolism treated with apixaban or warfarin. Thromb Haemost
19. De Crem N, Peerlinck K, Vanassche T, Vanheule K, Debaveye B, Middeldorp S, et al. Abnormal uterine bleeding in VTE patients treated with rivaroxaban
compared to vitamin K antagonists. Thromb Res
20. Boonyawat K, O’Brien SH, Bates SM. How I treat heavy menstrual bleeding
associated with anticoagulants. Blood
21. Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, et al. Rivaroxaban
or aspirin for extended treatment of venous thromboembolism. N Engl J Med
22. Andreozzi GM, Bignamini AA, Davì G, Palareti G, Matuška J, Holý M, et al. Sulodexide for the prevention of recurrent venous thromboembolism
: the Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation
23. Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med
24. Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding
. Cochrane Database Syst Rev
25. Berntorp E, Follrud C, Lethagen S. No increased risk of venous thrombosis in women taking tranexamic acid. Thromb Haemost
26. Sundström A, Seaman H, Kieler H, Alfredsson L. The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case–control study using the General Practice Research Database. BJOG
27. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with postpartum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet