Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.
Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.1
In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.2 Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:
- What are the most effective treatments for HMB?
- What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
- What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?3
Evidence on management strategies for HMB in women with VWD
The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.3 However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.
The systematic review authors3 identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.4 All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.4
In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.5 Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.5
In addition, the systematic review authors3 identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.6
The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.10
Evidence on management of pregnancy, delivery, and the postpartum period
Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.11 Women are at an increased risk of primary PPH12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,11 they are at increased risk of secondary or delayed PPH.
Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:
- What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
- What is the impact of postpartum administration of TxA on PPH?
The second systematic review the authors performed3 focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).
Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.3 Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.
The third systematic review that the authors performed3 was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:
- severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
- primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
- secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).
Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.3
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