Abstract
Introduction:
Concomitant antifibrinolytic agents and combined hormonal contraceptives (CHC) have been anecdotally used to manage refractory heavy menstrual bleeding (HMB). Yet, there remains uncertainty among clinicians regarding the safety of this therapeutic option as concomitant CHC is listed as a contraindication to tranexamic acid use in the United States.
Aim:
To describe current treatment practices and physician-reported safety and effectiveness of concomitant antifibrinolytics and CHCs.
Methods:
We surveyed clinician members of the Hemostasis and Thrombosis Research Society and the Foundation of Women and Girls with Blood Disorders using a web-based survey. We also shared the survey link on Twitter.
Results:
Of the 224 respondents who completed the survey, 214 treated women of reproductive age with HMB. Of the 214 respondents, 138 (64%) had treated at least 1 woman with concomitant antifibrinolytic agents and CHCs in the past 12 months. Over half of these respondents (n=77, 57%) reported that at least 50% of women had resolution of refractory HMB. One respondent reported an arterial or venous thrombotic event that occurred in 1 woman.
Conclusion:
We found that the use of concomitant CHCs and antifibrinolytic agent for refractory HMB is prevalent, appears to be efficacious and is relatively safe. Further research is warranted.
Keywords: antifibrinolytics, heavy menstrual bleeding, thrombosis, hormonal contraceptives
Introduction
Heavy menstrual bleeding (HMB) is a common gynecologic problem, estimated to affect as many as 30% of women at some point in their life [1]. Pharmacological interventions to treat HMB include hormonal therapies and antifibrinolytic agents. Tranexamic acid is an antifibrinolytic agent indicated for the treatment of HMB and was approved by the US Food and Drug Administration in 2009 for this indication [2].
In women with HMB who are not controlled with a single pharmacological agent such as tranexamic acid, combined pharmacological interventions are sometimes prescribed. Specifically, concomitant tranexamic acid and combined hormonal contraceptives (CHCs) have been anecdotally used in refractory HMB [3]. This raises a therapeutic dilemma as per the product labeling in the United States, the use of tranexamic acid is contraindicated in women who are using CHCs [2]. CHCs are known to increase the risk of venous thromboembolism (VTE) and arterial thromboses such as stroke and myocardial infarction. Because tranexamic acid is an antifibrinolytic, hypothetically the risk of VTE, as well as arterial thromboses, may be elevated when CHCs are co-administered with tranexamic acid. This is of particular concern in women who are obese or smoke cigarettes, especially women who smoke and are over 35 years of age [3].
In the clinical trials supporting the safety and efficacy of tranexamic acid, women using hormonal contraception were excluded [4]. Unfortunately, no clinical trial data are available on the risk of thrombotic events with the concomitant use of tranexamic acid and CHC. However, there have been US post-marketing reports of venous and arterial thrombotic events in women who have used tranexamic acid concomitantly with CHC [2]. For this reason, the product label for tranexamic acid in the US lists concomitant use of CHC as a contraindication. Along the same lines, aminocaproic acid, another antifibrinolytic agent that is often used interchangeably with tranexamic acid, is also assumed to be contraindicated in women using CHCs although the product label does not state this.
Against this background, we surveyed clinicians involved in the management of women with HMB with the primary aim of identifying the extent of concomitant antifibrinolytic agent and CHC use in clinical practice. We also assessed clinicians’ experience on the effectiveness and safety of concomitant antifibrinolytic agent and CHC use, and their viewpoints on barriers to use using predefined factors.
Methods
Instrument
The web-based survey consisted of 21 multiple choice-answer items developed by the investigators: Nine practice-pattern items regarding management of HMB; two viewpoint items on factors taken into consideration when prescribing concomitant antifibrinolytic agent and CHC; seven demographics and characteristics of clinical practice items; and three clinical case scenarios. For each scenario (Table 1), respondents were asked, “How comfortable are you in prescribing concomitant antifibrinolytic agents to treat the refractory HMB?” with the following four response options of (i) Extremely comfortable, (ii) Somewhat comfortable, (iii) Somewhat uncomfortable and (iv) Extremely uncomfortable.
Table 1.
Clinical scenario descriptions
| Scenario 1 | A 15-year-old woman witd a normal BMI and active migraines witdout aura on CHCs |
| Scenario 2 | A 38-year-old woman witd a BMI of 38 on CHCs |
| Scenario 3 | A 24-year-old woman witd a BMI of 31 who smokes a pack of cigarettes a day on CHCs |
CHCs, combined hormonal contraceptives; BMI, body mass index
The complete survey is available in the Supplemental Material. Responses on all items were voluntary. Three items allowed for skip logic to guide respondents through the survey, thus avoiding questions not relevant to the respondent. The survey was pilot-tested for clarity with five individuals, including two adult hematologists, two pediatric hematologists, and a survey methodologist, and refined based on their feedback before distribution.
Distribution
Participants for the survey were recruited using convenience sampling. In February and March 2021, the Hemostasis and Thrombosis Research Society sent two emails to all clinician members inviting and reminding members to participate in the anonymous online survey. The Foundation for Women and Girls with Blood Disorders also sent out one email to all clinician members inviting them to participate. The survey was reviewed and approved by the subcommittee/executive director of each society, and the survey link was distributed electronically to its membership. In addition, the survey link was shared on Twitter by 2 of the co-authors (MYL, @heme_fan and ACW, @acweyand). Responses to the survey were automatically recorded via Qualtrics online software (Qualtrics Labs Inc., Provo, UT, USA). All survey participants and responses were anonymized. There were no financial incentives provided for survey participants. This research was approved in the “exempt” category by the University of Utah Institutional Review Board.
Statistical Analyses
Respondents’ demographics, clinical characteristics, experiences and beliefs on concomitant use of CHC and antifibrinolytic were summarized using descriptive statistics. The proportion of respondents who had prescribed concomitant use were compared to the overall survey respondents using chi-square test or Fisher’s exact test. The differences in proportions of respondents by type of specialty and their comfort level for prescribing concomitant use for the three clinical case scenarios were analyzed using Fisher’s exact test. All analyses were performed using Stata version 16 (StataCorp, College Station, Texas, USA).
Data sharing statement
For original data, please contact the corresponding author, Ming Y. Lim.
Results
Survey respondent characteristics
The survey was open from February to March 2021. A total of 224 respondents completed the survey, of which 214 treated women of reproductive age with HMB and were used for data analysis. A survey response rate was not available as the invitation to participate in this survey was also distributed via Twitter. The demographic and clinical characteristics of the 214 survey respondents are shown in Table 2. The majority of respondents were from the US (n=188, 88%) and female (n=156, 73%). Approximately two-thirds of the respondents had been in clinical practice for 10 years or less (n=137, 65%) and worked in a university-based practice (n=133, 62%).
Table 2.
Characteristics of all survey respondents (n=214) and respondents who have prescribed concomitant CHC and antifibrinolytic agent within the past 12 months (n=138)
| Respondent Characteristics | All respondents (n=214) N# (%) |
Prescribed concomitant use (n=138) N# (%) |
p-value |
|---|---|---|---|
|
| |||
| Country of practice | 0.445 | ||
| United States | 188 (88) | 113 (83) | |
| Canada | 15 (7) | 14 (10) | |
| Other | 11 (5) | 9 (7) | |
|
| |||
| US regions | 0.988 | ||
| Northeast | 32 (17) | 18 (16) | |
| Midwest | 44 (24) | 26 (23) | |
| South | 41 (22) | 24 (22) | |
| West | 68 (37) | 43 (39) | |
|
| |||
| Gender | 0.895 | ||
| Female | 156 (73) | 96 (71) | |
| Male | 55 (26) | 38 (28) | |
| Other/Prefer not to say | 3 (1) | 2 (1) | |
|
| |||
| Years in practice | 0.924 | ||
| <5 | 76 (36) | 44 (32) | |
| 5 - 10 | 61 (29) | 37 (27) | |
| 11 - 15 | 26 (12) | 20 (15) | |
| >15 | 50 (23) | 34 (25) | |
| Prefer not to say | 1 (0) | 1 (1) | |
|
| |||
| Type of patients seen | 0.845 | ||
| Adult | 77 (36) | 52 (38) | |
| Pediatric | 62 (29) | 40 (30) | |
| Both | 74 (35) | 43 (32) | |
|
| |||
| Board-certified/eligible specialty* | 0.273 | ||
| Family medicine | 30 (14) | 12 (9) | |
| Internal medicine | 26 (12) | 19 (14) | |
| Hematology | 51 (24) | 41 (30) | |
| Medical oncology | 14 (7) | 9 (7) | |
| Pediatrics | 20 (9) | 6 (4) | |
| Pediatric hematology/oncology | 52 (24) | 47 (34) | |
| Obstetrics/gynecology | 51 (24) | 33 (24) | |
| Maternal-fetal medicine | 4 (2) | 2 (1) | |
| Other | 7 (3) | 2 (1) | |
|
| |||
| Clinical practice setting | 0.549 | ||
| University-based | 133 (62) | 97 (71) | |
| Hospital-based | 34 (16) | 18 (13) | |
| Primary group with >2 physicians | 28 (13) | 11 (8) | |
| Solo or two-provider practice | 5 (2) | 2 (1) | |
| Community health center | 7 (3) | 5 (4) | |
| Other | 7 (3) | 3 (2) | |
|
| |||
| Patient volume per month | 0.444 | ||
| <50 | 37 (17) | 24 (18) | |
| 50 - 99 | 70 (33) | 54 (40) | |
| 100 - 249 | 65 (31) | 40 (30) | |
| 251 - 500 | 32 (15) | 12 (9) | |
| >500 | 9 (4) | 5 (4) | |
|
| |||
| Average number of women of reproductive age with HMB managed annually | 0.857 | ||
| 1 – 5 | 15 (7) | 6 (4) | |
| 6 – 10 | 36 (17) | 20 (15) | |
| 11 – 25 | 47 (22) | 29 (21) | |
| 26 – 50 | 48 (22) | 35 (26) | |
| 51 – 100 | 32 (15) | 24 (18) | |
| >100 | 35 (16) | 23 (17) | |
|
| |||
| Primary age group of women of reproductive age with HMB managed annually | 0.850 | ||
| <18 years | 76 (36) | 53 (39) | |
| 18 – 34 years | 82 (38) | 50 (36) | |
| 35 – 49 years | 55 (26) | 34 (25) | |
| >50 years | 0 (0) | 0 (0) | |
US, United States; HMB, heavy menstrual bleeding
Total may not equal N due to incomplete data
Respondents may have more than one specialty
Clinician experience with prescribing concomitant CHC and antifibrinolytic agent
Of the 214 respondents, 146 (68%) had prescribed concomitant CHC and antifibrinolytic agent for the management of women with refractory HMB. Specifically, in the past 12 months, 138 (64%) respondents had treated at least one woman with concomitant antifibrinolytic agents and CHCs. The demographic and clinical characteristics of these 138 survey respondents are shown in Table 2. Clinicians who had prescribed concomitant CHC and antifibrinolytic agent were similar in characteristics to the overall survey respondents (P>0.05 in all characteristics).
The majority of the 138 respondents treated between 1 – 10 women in the past 12 months with concomitant antifibrinolytic agents and CHCs (n=104, 75%) (Table 3). These women were primarily younger than 35 years of age. Most respondents did not modify the dose or formulation of CHCs when using concomitant antifibrinolytic agents (n=109, 80%). In terms of efficacy, over half of the respondents (n=77, 57%) reported that at least 50% of women had resolution of refractory HMB with concomitant use of antifibrinolytic agents and CHCs (Table 3). As for safety, one respondent reported an arterial or venous thrombotic event that occurred in 1 woman.
Table 3.
Efficacy and safety of concomitant antifibrinolytic agents and CHCs in the management of women with refractory HMB in the past 12 months (n=138)
| Characteristics | N# (%) |
|---|---|
| Number of women treated with concomitant use | |
| 1 – 5 | 75 (54) |
| 6 – 10 | 29 (21) |
| 11 – 25 | 19 (14) |
| 26 – 50 | 12 (9) |
| 51 – 100 | 3 (2) |
| Primary age group of women treated with concomitant use | |
| <18 years | 57 (42) |
| 18 – 34 years | 57 (42) |
| 35 – 49 years | 23 (16) |
| >50 | 0 (0) |
| Modification of dose or formulation of CHCs to reduce the thrombotic risk | |
| No | 109 (80) |
| Resolution of refractory HMB | |
| <25% | 12 (9) |
| 25 – 49% | 46 (34) |
| 50 – 74% | 56 (41) |
| 75 – 100% | 21 (16) |
| Development of an arterial or venous thrombotic event (n=136) | |
| No | 135 (99) |
Total may not equal N due to incomplete data
Clinicians who have never prescribed concomitant CHCs and antifibrinolytic agents
Sixty-eight respondents (32%) had never prescribed concomitant CHCs and antifibrinolytic agents. The most common reason reported was that respondents had not encountered a situation where the use of concomitant CHC and antifibrinolytic agent was indicated (Figure 1). Using the free text in the ‘Other’ option, ten respondents reported a lack of awareness, education, or training on the use of antifibrinolytic agents. Four respondents referred to subspecialties for further management of refractory HMB.
Figure 1. Reasons reported by clinicians who have never prescribed concomitant antifibrinolytic agents and combined hormonal contraceptives (n=68).
* Respondents could respond with more than one reason
Factors in deciding whether to prescribe concomitant CHCs and antifibrinolytic agents
All respondents were asked to indicate which factors were taken into consideration and which factors were absolute contraindication when deciding whether or not to prescribe concomitant CHCs and antifibrinolytic agents to manage refractory HMB (Figure 2). Although all factors were taken into consideration, the most common factors that were considered to be absolute contraindications were the presence of strong inherited thrombophilia (defined as protein C, protein S or antithrombin deficiency, homozygous Factor V Leiden or prothrombin gene mutation, or compound heterozygous for Factor V Leiden and prothrombin gene mutation) (n=103), personal history of thrombosis and currently not on anticoagulant therapy (n=88), presence of positive antiphospholipid antibodies (n=68) and personal history of thrombosis and currently on anticoagulant therapy (n=60). Age greater than 35 years and obesity were considered as absolute contraindications in six respondents each.
Figure 2.
Factors taken into consideration and factors considered to be absolute contraindication on determining concomitant use of CHCs and antifibrinolytic agents
Responses to Clinical Case Scenarios
The responses to the three clinical case scenarios are shown in Figure 3. For scenario 1, over half of all survey respondents (66%) were extremely or somewhat comfortable with prescribing concomitant antifibrinolytic agent. Adult or pediatric hematologists were more comfortable doing so (86%) as compared to pediatricians (35%) (P<0.05). For scenario 2, just under half of all survey respondents (48%) were extremely or somewhat comfortable with prescribing concomitant antifibrinolytic agent. Pediatricians were least comfortable in doing so (15%) as compared to other specialties (P<0.05). For scenario 3, only 38% of all respondents were extremely or somewhat comfortable with prescribing concomitant antifibrinolytic agent. Again, pediatricians were least comfortable in doing so (15%) as compared to other specialties (P<0.05).
Figure 3. Overall responses to the clinical case scenarios and by board-certification.
* Respondents may have more than one specialty
Peds, pediatrics; HO, hematology-oncology; ObGyn, obstetrics & gynecology; MFM, maternal-fetal medicine; IM, internal medicine; FM, family medicine
Discussion
The clinical benefit of antifibrinolytic agents, specifically tranexamic acid, for HMB is well-established [4–7]. Yet, the role of antifibrinolytic agents as an adjunctive treatment for women on CHCs with refractory HMB remains controversial due to the concern for elevated risk of VTE. A systematic review of the literature by Thorne et al found no studies that directly addressed this question [3]. Therefore, we conducted this survey to better understand the extent of concomitant use of antifibrinolytic agents and CHCs in clinical practice, characteristics of clinicians prescribing these drugs, and clinician-reported efficacy and safety of concomitant use. The results of our survey found that despite the US contraindication labeling, approximately 60% (113/188) of US clinicians have prescribed antifibrinolytic agents in addition to CHCs for the management of refractory HMB. Adverse events attributed to concomitant use of antifibrinolytic agents and CHCs were rarely reported by the respondents with only one participant reporting an arterial or venous thrombotic event that occurred in one woman. Further details on this woman were not collected.
In our survey, the majority of respondents that prescribed concomitant CHCs and antifibrinolytic agents for refractory HMB were adult (30%) and pediatric hematologists (34%). Similarly, adult and pediatric hematologists were most comfortable prescribing concomitant use of CHCs and antifibrinolytic agents for all 3 clinical case scenarios provided. This is not surprising given that hematologists are familiar with and frequently use antifibrinolytic agents to reduce bleeding complications in different hemostatic challenges [8]. Furthermore, the American College of Obstetricians and Gynecologists recommends that women with refractory HMB undergo screening for an underlying disorder of hemostasis [9]. Women with a positive screen are then referred to hematologists for further evaluation and subsequent management of their refractory HMB.
For clinicians who have never prescribed concomitant CHCs and antifibrinolytic agents, the most common reason was lack of medical indication to do so. However, there were a number of respondents who reported unfamiliarity with antifibrinolytic agents. Although tranexamic acid has been used to treat HMB for over four decades in Europe, it was only approved in the US for treatment of HMB in 2009 [2]. Additional education and awareness of the clinical benefit of antifibrinolytic agents may alleviate this issue.
Our survey also assessed respondent’s perspectives on contraindications to concomitant antifibrinolytic agent and CHCs use. As expected, clinical situations that were high-risk for VTE (strong thrombophilia, antiphospholipid antibodies, prior history of VTE) were most commonly considered as absolute contraindication for concomitant use. This is hardly surprising since both the World Health Organization (WHO) Guidelines for CHCs lists established VTEs as an unacceptable health risk for the use of CHCs and the product monograph for tranexamic acid indicates that it is contraindicated in patients with active VTEs or with a history of VTEs [2, 10]. Despite the WHO guidelines, recent evidence suggests that CHCs can be safely continued in selected patients with VTE presenting with anticoagulant-associated HMB, as long as therapeutic dose anticoagulants are continued [11, 12].
Unlike CHCs that increase the risk of VTE fourfold, the association of antifibrinolytic agents and thrombotic risk has not been clearly determined [13]. Large randomized controlled trials have demonstrated that the use of tranexamic acid in trauma, postpartum hemorrhage and orthopedic surgeries – all very high-risk thrombotic situations – did not significantly increase the risk of thrombosis [14–16]. Yet, in the past year, two additional randomized studies looking at the use of antifibrinolytic agents vs. placebo in acute gastrointestinal bleeding and as bleeding prophylaxis for hematologic malignancy-induced thrombocytopenia noted an increased rate of VTE and catheter-associated VTE, respectively, in the antifibrinolytic arm [17, 18]. A recent meta-analysis of 22 studies concluded that the use of tranexamic acid in the non-surgical setting was not associated with an increased risk of venous or arterial thrombotic complications, although none of the included studies for HMB evaluated the use of concomitant antifibrinolytic agents and CHCs [19]. The closest resemblance to such a situation is the WOMAN trial which was a randomized double-blind, placebo-controlled trial involving 20,600 women with postpartum hemorrhage who were randomized to either tranexamic acid or placebo [20]. Given that the incidence of VTE is as high as 424 per 100 000 person-years during the postpartum period, much higher than the incidence of VTE from CHC use, it is reassuring that the WOMAN trial found no increased VTE risk observed in women randomized to tranexamic acid as compared to placebo [20, 21].
Given the paucity of evidence to inform clinical decision making, our survey findings provide reassuring data on the safety of concomitant CHCs and antifibrinolytic agent use in most clinical situations, and feasibility data that an international randomized trial, similar to the WOMAN trial, could be conducted [20]. A major restriction in conducting such a trial has been the US labeling where the use of tranexamic acid is contraindicated in women who are using CHCs [2]. The results of this trial would also be applicable to women with bleeding disorders, especially since HMB is the most common bleeding symptom reported in up to 80% of women with inherited bleeding disorders [22]. Intuitively, we would expect women with bleeding disorders on concomitant CHCs and antifibrinolytic agent to have a lower risk of thrombosis, although this has not been studied. Notably, a recent multidisciplinary guideline panel has identified such a study as a research priority for women with von Willebrand disease [23].
Dissemination of the results of this survey is the first step in demonstrating the relatively common off-label use of antifibrinolytic agents with CHCs and may help alleviate the US labeling concerns. If the latter remains a concern, this research question should instead be addressed by conducting an international multicenter, prospective registry-based observational study of women with refractory HMB treated with this combination. Plans for such a registry are underway and have been approved by the International Society on Thrombosis and Haemostasis (A. Weyand, personal communication). By standardizing patient characteristics and assessment of exposures and treatment outcomes, a prospective study of this nature would help address the current knowledge gap and provide more reliable data.
This study has limitations. First, as a survey-based study, it is subject to respondent bias and recall bias. To reduce respondent bias of clinicians who prescribe concomitant use of CHCs and antifibrinolytic agents, the survey was targeted to all clinicians who treat women with HMB. To reduce recall bias related to efficacy and safety of concomitant use of CHCs and antifibrinolytic agents, we limited the timeframe to the past 12 months. Given the safety concerns for thrombotic events, we anticipate that respondents would be able to recall these adverse events, if they had occurred within the past 12 months. Second, our results reflect practice patterns of respondents only, and thus may not be generalizable to nonrespondents. Third, we do not have a response rate of the survey and thus it is unknown if the results are broadly applicable. Fourth, the study only addressed a few clinical scenarios. We restricted the scenarios to common situations where concerns of thrombotic risk have been raised in the literature to describe differences in comfort level in prescribing concomitant CHCs and antifibrinolytic agents. Even though we were not able to determine differences in comfort level for other clinical situations, we were able to expand on this further by asking respondents what risk factors were taken into consideration and were absolute contraindication when prescribing concomitant CHCs and antifibrinolytic agents.
In conclusion, we surveyed clinicians, using a web-based survey, with questions regarding their experience on the effectiveness and safety of concomitant antifibrinolytic agent and CHC use, and their viewpoints on barriers to use. Despite the US contraindication labeling, 60% of US clinicians have prescribed antifibrinolytic agents in addition to CHCs for the management of refractory HMB, with only one reported thrombotic event. Our finding suggests that concomitant CHCs and antifibrinolytic agent use is relatively safe in most clinical situations. Further research is underway to provide more evidence-based data.
Supplementary Material
Acknowledgement
We thank the Hemostasis and Thrombosis Research Society and the Foundation for Women and Girls with Blood Disorders for disseminating the survey to their members. We thank all clinicians who responded to the survey.
Funding sources
The research reported in this publication was supported (in part or in full) by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002538. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations:
- CHCs
combined hormonal contraceptives
- HMB
heavy menstrual bleeding
- TXA
tranexamic acid
- VTE
venous thromboembolism
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