Received: 18 January 2024

- -
Revised: 21 March 2024

https://doi.org/10.1016/j.jtha.2024.04.002

REVIEW ARTICLE
Accepted: 4 April 2024

Management of abnormal uterine bleeding on anticoagulation:

the patient–clinician perspective

Bethany T. Samuelson Bannow

The Hemostasis and Thrombosis Center at

Oregon Health & Science University, Abstract
Portland, Oregon, USA
Bleeding is a well-recognized side effect of anticoagulant therapy, which is used to treat
Division of Hematology & Medical
venous thromboembolism (VTE) in individuals of all ages, including those of female sex,
Oncology, Department of Medicine, Oregon
Health & Science University, Portland, who commonly experience VTE as a complication of hormonal therapies and/or preg-
Oregon, USA
nancy. Heavy menstrual bleeding (HMB) is also extremely common in reproductive-
Correspondence aged individuals of female sex. Despite these overlapping situations, relatively little
Bethany T. Samuelson Bannow, The
attention has been paid to the impact of anticoagulant-associated HMB on treatment
Hemostasis and Thrombosis Center,
Oregon Health & Science University, 3181 strategies and the patient experience. In this review, we summarize incidence and
SW Sam Jackson Park Road, OC14HO,
complications of HMB in anticoagulated individuals as well as management strategies
Portland, OR 97239, USA.
Email: samuelsb@ohsu.edu for HMB in this population. We also address the patient experience, including the
impact of HMB on quality of life and the impact of discontinuing hormonal therapies at
the time of VTE diagnosis and anticoagulant initiation. We conclude by highlighting
specific gaps related to the patient experience of anticoagulant-associated HMB in both
the research and clinical settings.

KEYWORDS
abnormal uterine bleeding, anticoagulants, menorrhagia, menstruation, venous thromboembolism

1 | INTRODUCTION pregnancy. Menstruation is expected to occur roughly every 28 days

in virtually all individuals of female sex for an average of 40 years. This
Venous thromboembolism (VTE) affects up to 900 000 individuals in equates to up to 500 individual cycles over a lifetime. Twenty percent
the United States annually [1]. An estimated 46% of these individuals to 30% of the general population of menstruating individuals will
are female [2]. While risk of VTE increases with age, female individuals experience heavy menstrual bleeding (HMB) during this time period,
experience unique risks during their reproductive years, including use the current definition of which is “excessive menstrual losses which
of hormonal therapies such as combined hormonal contraceptives interferes with the [individual’s] physical, emotional, social and ma-
(CHCs) and pregnancy. As a result, a disproportionate number of VTE terial quality of life” [4].
events affecting reproductive-aged (15-45 years) individuals occur in The combination of increased risk of VTE and the recurrent cyclic
females [3]. bleeding event known as menstruation requires additional consider-
In addition to experiencing increased risk of VTE compared with ation and attention when balancing risks and benefits of therapies for
male counterparts, reproductive-age females experience unique risks both VTE and HMB. In this review, we discuss the incidence and
with regard to bleeding complications, specifically menstruation and impact of HMB in anticoagulated individuals as well as management

-
Manuscript handled by: Saskia Middeldorp

Final decision: Saskia Middeldorp, 04 April 2024

© 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.

J Thromb Haemost. 2024;22:1819–1825 jthjournal.org 1819

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strategies from both the clinician’s perspective and the patient’s general practitioner about it [10]. While more research is needed to
perspective. Accordingly, discussion will be centered around a case, fully understand the reasons for this, there can be little doubt that the
highlighting patient experience in addition to data supporting diag- stigma associated with menstruation, treating it as something “dirty”
nostic and management strategies. or shameful instead of a totally normal bodily process, contributes to
this hesitancy.
Studies that do address HMB are most often observational,
2 | CASE without the benefit of randomization or, in many cases, prospective
data collection. Post hoc analyses of registry trials, while offering
A 27-year-old woman reports to the emergency department with a improved oversight and comparators, are limited by criteria that
report of bilateral pleuritic chest pain for several hours. She also notes grossly underestimate occurrence of HMB. Despite this recognized
a 2-week history of ongoing left-sided leg pain. Her medical history is limitation, there is no true “gold standard” measure of HMB for
notable for mild asthma and iron deficiency. Her only current medi- studies that do address it. The most objective approach, the alkaline
cation is ethinyl estradiol 0.03 mg/drospirenone 3 mg, which she takes hematin method, can accurately quantify menstrual blood loss (MBL)
continuously. This was initiated approximately 3 months ago for but is prohibitively demanding and costly as it requires collection and
treatment of HMB resulting in iron deficiency anemia. She is mildly processing of all menstrual hygiene products for an entire cycle [11].
tachycardic with shallow respirations. Current hemoglobin concen- Other methods, such as the Pictorial Blood Loss Assessment Chart,
tration is 12.1 g/dL, mean corpuscular volume is 80 fL, plasma D-dimer are easier to administer but not universally used or adaptable to
concentration is >3000 ng/mL, and imaging is significant for bilateral methods other than standard disposable pads and tampons [12].
segmental and subsegmental pulmonary emboli. Her CHCs are dis- Ideally, pads and tampons should also be consistent (requiring the
continued; she is prescribed rivaroxaban for a planned 3-month study to provide them) for a fully accurate comparison. For this
course and discharged home. reason, a variety of other subjective methods are often used, with
inconsistent findings. While the clinical definition of HMB, based on
the perspective of the patient, has come a long way, research defini-
2.1 | Anticoagulation and HMB tions lag behind.
A number of available reviews have summarized and attempted to
As discussed above, HMB affects up to a third of the general combine the available data on rates of HMB with various anticoagu-
menstruating population [5]. This clearly increases in anticoagulated lants. Incidence estimates are highly variable, but most available data
individuals, with an estimated prevalence of 60% to 70% [6]. However, strongly suggest an increased rate of HMB with rivaroxaban (a nearly
estimates remain rough and highly variable due to a number of limi- 2-fold increase compared with low-molecular-weight heparin/
tations in how HMB is addressed, or in many cases not addressed, in warfarin) and perhaps a decreased rate with dabigatran (slightly more
clinical studies. Virtually all registry trials of anticoagulants, including than half the rate compared with low-molecular-weight heparin/
direct oral anticoagulants such as rivaroxaban, rely on International warfarin), with apixaban appearing roughly equivalent to warfarin for
Society on Thrombosis and Haemostasis definitions of major bleeding this outcome [6,13–16]. The increased rate with rivaroxaban is pre-
(MB) and clinically relevant nonmajor bleeding (CRNMB) [7,8]. These sumed to be due to higher circulating doses of anticoagulant in order
measures are inadequate to detect HMB for 2 primary reasons. to facilitate daily vs twice daily dosing. Based on previous estimates
The first reason MB and CRNMB criteria fail to detect HMB is with warfarin, it seems very likely that more than three-quarters of
that they are designed for discrete bleeding events, not recurrent menstruating individuals treated with rivaroxaban, such as our case
ones. Many patients with HMB do develop anemia, and the majority study, are likely to develop HMB while on anticoagulation [6]. This risk
have iron deficiency with or without anemia [9], but due to the fact is higher if the patient has a history of HMB [15], as our patient does,
that blood loss is slower, occurring over days each month, criteria such and must be balanced against the convenience of daily vs twice daily
as a 2-g/dL decrease in hemoglobin concentration and/or need for dosing of anticoagulation, which can have a meaningful impact on
blood transfusion are rarely met, even though annual blood loss may adherence [17].
very well exceed that seen in a single MB event [9].
The second limitation of MB and CRNMB criteria for detecting
HMB is the fact that 1) researchers rarely ask about it specifically in 2.2 | Impact of HMB
study questionnaires and 2) patients/research subjects are often
reticent to volunteer this information. A survey of 1000 women in the As previously mentioned, a definition of HMB based solely on quality
United Kingdom not on hormonal birth control or hormone replace- of life, which conveniently bypasses the need for painstaking counting
ment therapy reported that 55% had to take time off work for men- and measuring of menstrual products, has come into favor in clinical
strual symptoms, 60% of whom had a disciplinary hearing for amount practice. Most importantly, this addresses the fact that HMB can
of time off work and 51% of whom subsequently lost their jobs. severely negatively affect quality of life. Patients with HMB and
Despite this, less than 50% and as few as 23% of women in some related health complications including iron deficiency experience fa-
regions of England had talked to or were willing to talk to their tigue, missed school/work, isolation, and generally negatively
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experience upon initiating an anticoagulant. They report that their

healthcare providers rarely, if ever, discuss the potential impact of an
anticoagulant on their periods, and many find the increase in bleeding
with their first period to be frightening, adding, in some cases, to the
already difficult experience of a VTE diagnosis [25].
In addition to this dramatic impact on quality of life, available data
demonstrate an increased risk, as high as 5-fold, of recurrent VTE in
individuals with vs without HMB on rivaroxaban [13]. While the
precise mechanism of this increase remains unproven, decreased
adherence to anticoagulation must be considered as a possible cause,
particularly given the combination of stigma around and potentially
devastating impact of HMB for patients who may not feel that they
have other good options.

F I G U R E 1 Impact of heavy menstrual bleeding on physical,

social, emotional, and material domains of quality of life. 2.3 | Case continued

impacted health-related quality of life [18]. A survey study of 2000 As could be anticipated, our patient experienced withdrawal bleeding
women in the United Kingdom revealed that 69% of individuals with shortly after discontinuing CHCs; this was compounded by her
symptoms from menstruation reported it had a negative impact at rivaroxaban use, and despite using maximally absorptive products, she
work. Fifty-three percent reported they were unable to go to work at found herself having to change protection every hour for the first
some point, and 4% missed work on a monthly basis. Six percent re- 2 days. Even doubling up on protection (wearing a pad and tampon
ported that their menstrual symptoms had an impact leading to formal together) only allowed her to go 3 to 4 hours between changes. As a
action, and 12% reported that menstrual symptoms had a negative result, and due to the fact that her work as a teacher offered infre-
impact on career progression [19]. Additionally, menstrual hygiene quent bathroom breaks, she found herself having to miss multiple days
products are expensive, and period poverty, defined as lack of access of work.
to adequate menstrual hygiene products, education, and sanitation At her 3-month follow-up to determine the final duration of
facilities, is a common problem internationally and is only worsened by anticoagulation, she was found to have iron deficiency anemia, with a
HMB [20,21]. Other aspects of quality of life which may be adversely hemoglobin concentration of 9.8 g/dL, a mean corpuscular volume of
impacted by HMB are listed in Figure 1. 73.2 fL, and a ferritin concentration of 7 ng/mL. She reported fatigue,
Individuals with HMB frequently find themselves having to decreased exercise tolerance, hair loss, and symptoms of depression.
change a menstrual hygiene product more often than every 2 hours
[9], which can be incredibly disruptive to school, work, and social ac-
tivities. Individuals in professions that do not allow frequent bathroom 2.4 | Impact of discontinuing hormonal therapy
breaks, such as teachers and nurses, may struggle to attend work at all
during their periods. “Normal” menses should last approximately 2 to As our case demonstrates, due to the fact that estrogen-containing
7 days, but individuals with HMB frequently have periods lasting 7 to therapies such as CHCs are a common provoking factor for VTE in
10 days or even longer, equating to ≥25% of days each cycle. As reproductive-age females, such therapies are often discontinued upon
referenced above, a survey study of menstruating individuals found diagnosis. The impact of such a decision, while rarely considered by
that, despite some reporting even losing their jobs due to missing providers, can be enormous for the patient.
work for menstruation-related symptoms, fewer than half of women Discontinuation of CHCs almost universally results in withdrawal
felt comfortable talking to their doctor about their periods [10]. This bleeding, something that individuals who use such therapies contin-
serves to emphasize the heavy impact of shame and stigma on in- uously or regularly and are subsequently accustomed to regular or no
dividuals suffering from HMB and other menstruation-related symp- menstrual bleeding are rarely counseled to expect. As discussed
toms. In addition to frequent changes of protection and prolonged above, this can have a dramatic, negative impact on quality of life. As
days of bleeding, a defining feature of HMB is iron deficiency [9], CHCs are a highly effective treatment for HMB, discontinuation can
which can be associated with a wide variety of symptoms, including be expected to result in increased MBL in many, something which may
fatigue, brain fog, restless legs, dizziness, hair loss, muscle weakness/ be compounded by initiation of anticoagulation therapy.
soreness, and pica, all of which can be profoundly disturbing to quality Additionally, CHCs, while associated primarily with pregnancy
of life [22–24]. prevention in most providers’ minds, are effective therapies for a
Anecdotally, in this author’s clinical practice and experience multitude of symptoms and conditions, including but not limited to
working with patients and advocates, many menstruating individuals dysmenorrhea, endometriosis, premenstrual dysphoric disorder, acne,
feel unprepared for the increase in menstrual bleeding they and hirsutism (Figure 2). Use of CHCs can also reduce future incidence
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T A B L E Opportunities for intervention to reduce the impact of

abnormal uterine bleeding in anticoagulated individuals.
At VTE diagnosis

Assess for history of HMB

Assess for and treat iron deficiency

Defer discontinuation of CHCs until an alternative strategy for HMB

management and/or contraception can be implemented (so long as
patient is on anticoagulation)

Discuss anticipated impact of anticoagulation on uterine bleeding

• High likelihood of increased menstrual bleeding
• Discuss indications for urgent/emergent evaluation of HMB
• Provide education on “normal” parameters of menses (no longer than
7-10 d, changing a pad/tampon less often than every 2 h, clots no
larger than 1 in)

On follow-up

F I G U R E 2 Noncontraceptive benefits of combined hormonal Assess for and treat HMB, if indicated, at every visit
contraceptives (CHCs). Assess for iron deficiency and treat and reassess regularly if identified

Discuss importance of and options for safe and effective contraception

of ectopic pregnancy, benign breast disease, ovarian cysts, ovarian to prevent undesired pregnancy, with potential dual benefit of
cancer, endometrial cancer, and colorectal cancer. menstrual management

The importance of effective contraception is paramount, partic- CHC, combined hormonal contraceptive; HMB, heavy menstrual
ularly in patients experiencing or at risk for VTE. Experts commonly bleeding; VTE, venous thromboembolism.
recommend that individuals wait until at least 3 months after a VTE
event to become pregnant, similar to recommendations around
who require long-term anticoagulation and desire one or more of the
delaying elective surgeries. Furthermore, many anticoagulants can
benefits of CHCs outlined in Figure 2. Individualized and informed
lead to adverse pregnancy outcomes. Warfarin has known teratogenic
risk/benefit analysis should be offered to all patients.
effects, and while data on risk of direct oral anticoagulants in preg-
Given the inevitability of withdrawal bleeding and high likelihood
nancy are not available, use is not recommended in pregnancy [26].
of return of or development of new HMB, many patients may prefer to
Patients who subsequently suffer from pregnancy complications such
continue on CHCs while anticoagulated if given the option. Occa-
as spontaneous abortion and/or ectopic pregnancy may suffer from
sionally, patients on long-term anticoagulation may even need to start
increased risk of bleeding complications due to anticoagulant use.
a new therapy with CHCs, particularly in circumstances such as the
development of endometriosis, for which CHCs are a major compo-
nent of therapy. It is, however, important to note that the increased
2.5 | Management of HMB risk of VTE continues for 2 to 4 weeks past discontinuation of
estrogen-containing therapies [28]; therefore, transition to an alter-
Strategies of HMB management are largely the same, regardless of native method of menstrual management should be initiated at least a
whether or not the HMB is associated with anticoagulation. CHCs, month before discontinuation of anticoagulation.
along with tranexamic acid, are first-line therapies for HMB in the A preferred alternative for patients with history of VTE planning
general population [27]. CHCs can be used to regulate, increase, or to discontinue anticoagulation is the levonorgestrel (LNG) intrauterine
decrease frequency of menstrual bleeding, reduce MBL, or even device (IUD), which has dual benefit for HMB management and highly
induce amenorrhea. Additionally, as outlined in Figure 2, they can be effective contraception. In addition to reducing overall MBL, the LNG-
used to reduce and/or ameliorate other symptoms associated with IUD is associated with an amenorrhea rate of 20% within the first
menstruation. While the increased risk of VTE with CHCs is generally year, increasing to 40% between years 3 and 8, and a <1% con-
considered to outweigh the benefits in individuals with a personal traceptive failure rate [29,30]. Establishing care with a practitioner
history of VTE who are not on anticoagulation, post hoc data on in- who is able to insert IUDs may take some time, however, and
dividuals involved in registry trials of apixaban and rivaroxaban sug- continuing CHCs (so long as anticoagulation is also continued) until
gest that hormonal therapies, including CHCs, can be safely used in placement is a very reasonable approach. The etonogestrel implant is
individuals on therapeutic anticoagulation [14]. This is of particular another long-acting, reversible contraceptive method that can reduce
importance in disease states such as endometriosis, which may only be overall MBL but can commonly be associated with irregular and
responsive to estrogen-based therapies, and the risk and impact of intermenstrual bleeding that some patients find troublesome [31].
anticoagulation on quality of life may be outweighed by benefits of Depomedroxyprogesterone acetate injections boast the highest
disease management. However, it may be relevant even in individuals rate of amenorrhea (>55%) but have a number of side effects,
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including being the only progesterone-only option, which is associated anticoagulation and reports much decreased menstrual bleeding as
with increased risk of VTE and therefore is not recommended in this well as decreased fatigue and increased exercise tolerance.
population outside of ongoing therapeutic anticoagulation [32].
Progesterone-only pills can also be used but may also result in
irregular bleeding and are less effective as contraception.
3 | CONCLUSION
Antifibrinolytics, such as tranexamic acid, are considered first-line
therapy for HMB outside the setting of acute thrombosis [27]. While
While the initial focus of VTE therapy is, appropriately, prevention of
many express theoretical concerns about the risk of new thrombosis,
progression and recurrence, it is essential also to consider the impact
this theory has been disproven by large volumes of data from a variety
of treatment on uterine bleeding, particularly in menstruating in-
of randomized controlled trials, including in high-risk populations such
dividuals. This impact has been grossly underestimated thus far largely
as trauma victims and postpartum patients, demonstrating no
due to inadequate and inconsistent use of appropriate outcome
increased risk of VTE [33]. It is important to note, however, that
measures in prospective studies. However, it is clear that HMB is very
fibrinolysis is a key process to VTE resolution, and therefore, initiation
common among menstruating individuals on anticoagulation; that
of antifibrinolytics is best delayed at least until initial symptoms
rates are increased with some anticoagulants, such as rivaroxaban,
improve and likely for as long as 1 to 3 months. Data on the use of
compared with others; and that HMB can have an enormous impact
antifibrinolytics in anticoagulated patients are lacking; however, tra-
on a patient’s quality of life.
nexamic acid was one of the treatment strategies employed for HMB
Opportunities for improvement in the care of these individuals
associated with anti-Xa use in the Heavy MEnstrual bleeding in pre-
abound in both clinical and research settings. In the research
menopausal women treated with DirEct oral Anticoagulants (MEDEA)
setting, standardization and consistent use of clinically meaningful
study, data from which are not yet available at the time of this review
measures of HMB and other forms of abnormal bleeding must be
[34].
routinely used in studies of medications that may increase HMB. In
In addition to the above-mentioned methods, which may be useful
the clinical setting, there are many points of contact at which to
in patients with HMB due to any cause, in individuals on anti-
improve care for these patients (Table). Firstly, an up-front dis-
coagulation, consideration may be given to switching from an anti-
cussion about the increased risk of HMB on anticoagulation, taking
coagulant with a higher rate of HMB, such as rivaroxaban, to one with
into consideration the individual’s own menstrual history, and the
a slightly lower rate of HMB, such as apixaban. However, this
risks associated with the anticoagulant of choice and potential
approach has not been studied, and in patients such as the one
discontinuation of any therapies that may have impacted menstrual
described here, who already suffered from HMB prior to anticoagu-
bleeding, either as a primary goal or side effect, is essential. In-
lant initiation, this is unlikely to be adequate as a sole approach.
dividuals who do experience VTE in the setting of exogenous es-
Alternative modifications, such as interrupting or reducing the dose of
trogen, such as CHCs, must be counseled on the risks and benefits
anticoagulant on days of bleeding, have not been studied for safety
of continuing or discontinuing these therapies and should be
and, given the aforementioned data regarding increased rates of VTE
included in shared decision making around how to manage these
in individuals with HMB while on anticoagulation, may pose a serious
important therapies. Finally, at each point of follow-up, both vol-
risk [13].
ume and impact of menstrual losses must be considered, extending
Importantly, individuals who develop new HMB outside the
beyond evaluation for anemia and iron deficiency to include impact
setting of a recent initiation of anticoagulation should be evaluated by
on quality of life and daily functioning.
a gynecologist for potential structural causes. Menstruating in-
In conclusion, HMB and other forms of abnormal bleeding are far
dividuals with heavy bleeding, and even those without, would ideally
more common and impactful in patients on anticoagulant therapy than
be screened for iron deficiency at the time of anticoagulation initia-
previously recognized. Stigma can be a major barrier to a full and open
tion. Iron supplementation can be a key component of the manage-
discussion about risks and concerns for both patient and provider.
ment of HMB and may, theoretically, even impact heaviness of
Risks associated with missing and failing to manage this treatment
bleeding itself due to impact on platelet function [35].
complication range from inconvenience to missed work or school, lost
jobs, and even increased rates of recurrent VTE. Both clinicians and
patients will benefit from increased open and nonjudgmental
2.6 | Case concluded communication about risks associated with anticoagulants and treat-
ment strategies for HMB. Questions about uterine bleeding must be
Our patient’s HMB was initially treated with oral progesterone until included in follow-up assessments for all patients at risk, particularly
she was able to establish care with a gynecologist who evaluated her as patients may be less likely to report these symptoms than other,
for potential structural causes of HMB and placed an LNG-IUD for less stigmatized ones such as epistaxis or bruising. A variety of man-
long-term management. She also received iron supplementation in the agement strategies are available, and appropriate management can
form of intravenous iron dextran. Three months later, she was eval- provide great satisfaction to both patient and provider and must be an
uated by her primary care physician as she is no longer on essential component of the care of anticoagulated patients.
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AUTH OR CONT RIBUTIONS [13] Bryk AH, Piróg M, Plens K, Undas A. Heavy menstrual bleeding in
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risk of recurrent venous thromboembolism. Vascul Pharmacol.
manuscript.
2016;87:242–7.
[14] Martinelli I, Lensing AWA, Middeldorp S, Levi M, Beyer-
Westendorf J, van Bellen B, Bounameaux H, Brighton TA, Cohen AT,
DECL AR ATION OF COMPETING INT ERES TS
Trajanovic M, Gebel M, Lam P, Wells PS, Prins MH. Recurrent
B.T.S.B. receives research funding from the Office of Research on venous thromboembolism and abnormal uterine bleeding
Women’s Health of the National Institutes for Health (Grant with anticoagulant and hormone therapy use. Blood. 2016;127:
K12HD043488) and the Foundation for Women and Girls with Blood 1417–25.
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