von Willebrand s Disease and Menorrhagia: Prevalence, Diagnosis, and Management

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1 American Journal of Hematology 79: (2005) von Willebrand s Disease and Menorrhagia: Prevalence, Diagnosis, and Management Jody L. Kujovich* Division of Hematology/Medical Oncology, Oregon Health and Science University, Portland, Oregon The reported prevalence of von Willebrand s disease (vwd) is increased in women with menorrhagia, with current estimates ranging from 5% to 20%. The consistent results of multiple studies suggest testing should be included in the evaluation of patients with menorrhagia, especially in unexplained cases and prior to surgical intervention. Although a cyclic variation in von Willebrand s factor levels has not been confirmed, several studies suggest lower levels during menses and the early follicular phase. Menorrhagia is one of the most common bleeding manifestations of von Willebrand s disease, reported by 60 95% of women afflicted with this bleeding disorder. Menorrhagia is typically severe, often resulting in anemia and interfering with quality of life. Despite the frequency of menorrhagia, there is no consensus on optimal management. Although oral contraceptives are frequently prescribed, there are no studies confirming their efficacy using objective measures of response. Desmopressin was associated with an 80 92% response rate in several uncontrolled studies relying on patient assessment of efficacy. However, a small, randomized trial found no significant reduction in menstrual blood flow compared with placebo. There are anecdotal reports of the successful use of antifibrinolytic agents alone and in combination with other therapies. There are no studies comparing the relative efficacy and safety of the available medical therapies for von Willebrand s disease associated menorrhagia. Until these studies are completed, treatment should be individualized based on von Willebrand s disease subtype, patient age, contraceptive needs, and personal preference. Am. J. Hematol. 79: , ª 2005 Wiley-Liss, Inc. Key words: von Willebrand s disease; menorrhagia; bleeding disorder; desmopressin von Willebrand s disease (vwd) is the most common inherited bleeding disorder, found in approximately 1% of the general population, without ethnic differences [1,2]. It was first described by Dr. Erik von Willebrand in 1926 after studying a large kindred on Åland, an island off the coast of Sweden. vwd results from a deficiency or defect in von Willebrand s factor (vwf), the large multimeric protein that mediates platelet adhesion and serves as a carrier protein for FVIII. There are three major types: type 1 is due to a partial quantitative deficiency of a normal vwf and accounts for 70 80% of all vwd; type 2 (20% of vwd) includes several qualitative defects in vwf which affect its multimeric structure or function; and patients with type 3 vwd (5 10% of vwd) are homozygous or doubly heterozygous for two mutant vwf alleles, with a resulting complete deficiency of vwf and a secondary severe deficiency of FVIII. ª 2005 Wiley-Liss, Inc. Although the autosomal inheritance pattern predicts that both sexes should be equally affected, there is a higher frequency of symptomatic vwd in women due to the hemostatic challenges of menses and childbirth [3 5]. Menorrhagia was a common bleeding manifestation in affected female members of the kindred described by Dr. von Willebrand. The proband exsanguinated at age 13 during her fourth menstrual *Correspondence to: Jody L. Kujovich, M.D., Division of Hematology/Medical Oncology, Mail Code: L-586, Oregon Health and Science University, 3181 Sam Jackson Park Road, Portland, OR kujovich@ohsu.edu Received for publication 23 August 2004; Accepted 7 December 2004 Published online in Wiley InterScience ( DOI: /ajh.20372

2 Concise Review: von Willebrand s Disease and Menorrhagia 221 period, underscoring the importance of this bleeding complication [6,7]. This review focuses on menorrhagia and other gynecological bleeding experienced by women with vwd and summarizes the data evaluating the efficacy of available therapies. FREQUENCY OF vwd IN WOMEN WITH MENORRHAGIA Menorrhagia is a common gynecologic problem in women of reproductive age, accounting for a considerable proportion of gynecology referrals [8]. Although a variety of gynecologic, endocrine, or other systemic causes may be responsible, an underlying etiology is identified in only 50% of cases [9]. Menorrhagia is a valuable predictor of a bleeding disorder in women. The frequency of vwd in women with menorrhagia ranges from 5% to 20% in different studies [10 15] (Table I). The different prevalences reported may reflect the different study populations (population based or referral), variable definitions of menorrhagia and vwd, timing, types of laboratory tests, and requirements for retesting. The inaccuracy of subjective assessment of menstrual blood loss is well documented [16]. Studies requiring objective confirmation by either spectrophotometric measurement or a pictorial blood loss assessment chart identified vwd in 13 20% of women with menorrhagia [10,12,15]. Two studies including a contemporaneous control population found a higher frequency of vwd in women with menorrhagia. The difference was statistically significant only in the larger study, which identified vwd in 6.6% of women with menorrhagia, compared to 0.8% of controls (odds ratio 8.6) [14]. In a separate analysis by race, vwd was significantly more frequent in white than African American women with menorrhagia (15.9% vs. 1.4%, respectively) [14,17]. The reason for the racial difference is unclear because population screening suggests a similar prevalence of vwd among different racial groups [1]. The observation that African Americans have significantly higher vwf levels than whites could account for a lower frequency of the disorder [17,18]. However, the racial difference in prevalence persisted when a raceadjusted reference range was used for diagnosis [17]. Von Willebrand s disease-associated menorrhagia may be most severe during the first few years after menarche [4]. The frequency of vwd in adolescents with menorrhagia is not well defined, because most studies evaluating prevalence did not include adolescent women [10,13 15]. Several small retrospective reviews identified vwd in 2.8 5% of adolescent women requiring urgent evaluation or hospitalization for menorrhagia [19,20]. However, in one study, specific testing for vwd was limited to the 20% of TABLE I. Prevalence of von Willebrand s Disease in Women With Menorrhagia a Reference Study population Definition of menorrhagia Diagnosis of vwd Prevalence of vwd Edlund et al. [10] Kadir et al. [12] Dilley et al. [14] Woo et al. [15] Goodman-Gruen et al. [13] Philipp et al. [11] Gynecology referral (n ¼ 30) Gynecology referral (n ¼ 150) Population-based (case-control) (n ¼ 121) Gynecology referral (case-control) (n ¼ 38) Population based (n ¼ 19) Gynecology clinic (n ¼ 74) MBL > 80 ml/cycle (alkaline hematin analysis) vwf Ag low or low normal 20% PBAC score > 100 vwf Act < 0.5 IU/mL on 2 13% occasions Physician diagnosis code MBL > 80 ml/cycle (alkaline hematin analysis) Patient report of bleeding 8 days/month for 2mo Physician diagnosis (confirmed by PBAC score > 100 in 86%) 2 tests (vwf Ag, vwf Act, RIPA) 2 SD below control range NA b 6.6% (0.8% of controls) 13% (2.5% of controls) (1) RCof lowor (2) post-op or 5% post-traumatic bleeding AND decrease in vwf Ag OR decrease in RCof/vWF Ag (<0.5) OR (3) low normal FVIII:C, vwf Ag, and RCof with prolonged aptt RCof < 0.6 IU/mL 13.5% a Abbreviations: vwd, von Willebrand s disease; MBL, menstrual blood loss; vwf Ag, von Willebrand s factor antigen; RCof, ristocetin cofactor activity; RIPA, ristocetin-induced platelet aggregation; PBAC, pictorial blood loss assessment chart; FVIII:C, factor VIII coagulant activity; aptt, activated partial thromboplastin time; SD, standard deviation. b vwf Ag, vwf Activity; FVIII:C measured, but criteria for diagnosis not available.

3 222 Concise Review: Kujovich women with abnormal hemostasis screening tests [19]. Larger studies with systematic testing of all women with menorrhagia are required to accurately estimate the prevalence in the adolescent population. The criteria for diagnosis and frequency and timing of testing varied among the published studies (Table I). Studies requiring testing on only one occasion may underestimate the prevalence of vwd due to the normal fluctuation in vwf levels [11,13,14]. The three studies of women with objectively confirmed menorrhagia required testing on multiple occasions [10,12,15]. However, one study required only a low or low normal vwf antigen level for a diagnosis of probable mild vwd, suggesting that the reported prevalence of 20% may overestimate the frequency [10]. In several studies, the majority of vwf antigen and activity values in affected women were in the range of 50 60% of normal [10,13,15]. Because of the broad range of vwf levels in normal individuals, a proportion of type 1 vwd diagnoses may be false positives and reflect a coincidental association of bleeding with lower vwf levels [21]. However, the largest study of 150 women with objectively confirmed menorrhagia required a vwf activity <50% on two of 3 occasions of testing, suggesting that the diagnosis of vwd in 13% of cases accurately reflects the frequency in this population. A systematic review of 11 studies including 988 women with menorrhagia found a similar overall prevalence of 13% [22]. Thus, the consistent data from multiple studies strongly suggests vwd is more prevalent in women with menorrhagia than in the general population [23]. Several clinical features suggest the possibility of a bleeding disorder contributing to menorrhagia. Women with vwd are more likely to have a history of menorrhagia beginning at menarche and other bleeding problems [12]. In one study of women with objectively confirmed menorrhagia, 65% of women with vwd reported an onset at menarche compared to only 9% of those without a bleeding disorder [12]. Several other series found that menorrhagia began at menarche in the majority of women with vwd [18,24]. Affected women are also more likely to have a history of post-partum or post-operative bleeding [12,25]. Other suggestive clinical features include younger age, anemia, history of dental work-related bleeding, and impaired quality of life during menses [25]. However, there are no prospective studies validating these characteristics as predictors of vwd. Moreover, menorrhagia is often the only bleeding manifestation, especially in women with mild type 1 disease. DIAGNOSIS The frequency of undiagnosed vwd in women with menorrhagia suggests testing should be included in the evaluation, especially in the absence of pelvic pathology and prior to surgical intervention. Testing for other hemostatic disorders should also be considered, because a significant proportion of women with unexplained menorrhagia have multiple hemostatic defects [11]. Laboratory testing is complicated by the considerable variation in vwf levels, which are affected by a variety of genetic, physiologic, and pharmacologic factors including age, blood group, and hormonal status. vwf and FVIII levels are increased by strenuous exercise, inflammation, hyperthyroidism, and high levels of estrogen during pregnancy or use of oral contraceptives. Because vwf levels vary over time in an individual, repeated testing is often necessary to confirm or exclude the diagnosis. Because of the considerable overlap with the normal range of values, vwf levels often do not reliably distinguish between carriers of a vwf mutation and normal individuals. Sadler has proposed that vwf may be a continuously variable modest risk factor for bleeding, analogous to cholesterol or blood pressure [21]. In one study, women with menorrhagia had a significantly lower mean vwf activity level than those with normal menstrual blood loss, even after excluding women with vwd [15]. Analysis of the combined data from the three studies of women with objectively confirmed menorrhagia suggests a low vwf level confers a nearly 4-fold increased risk of menorrhagia [21]. It is unknown whether women with menorrhagia and lower vwf levels may benefit from specific therapies for vwd. vwf LEVELS DURING THE MENSTRUAL CYCLE The variation in vwf levels during the normal menstrual cycle is not well defined, with conflicting results in both longitudinal and cross-sectional studies [26 32]. In studies showing a cyclic variation, the lowest vwf and FVIII levels occurred at variable times during the first half of the cycle [29,31,32]. A study of 19 healthy women tested on 4 occasions showed strong cyclic variation, with the lowest vwf antigen and activity levels during the early follicular phase (days 9 and 10) [31]. In another study, three women with probable vwd had their lowest vwf levels during the first half of the menstrual cycle (days 6 13) [27]. However, in 12 other normal women, there was no significant difference between mean vwf antigen levels obtained early (days 6 10) and later (days 22 28) in the cycle [27]. Similarly, there was no significant difference in mean vwf and FVIII levels obtained during the early, middle, and late phases of a single cycle in 95 healthy women [28]. These inconsistent results may reflect differences in study size and design, timing and frequency of testing,

4 Concise Review: von Willebrand s Disease and Menorrhagia 223 and statistical methodology. A few measurements during a single cycle may not detect nadir and peak levels occurring between the times of testing [27,28,32]. Because of the marked inter- and intraindividual variation in vwf levels, larger study populations may be required to detect significant differences between different phases of the menstrual cycle. The cyclical variation in vwf and FVIII levels is thought to reflect the physiologic fluctuation in estradiol, although the intra-individual variation observed in normal males suggests other contributing factors [30]. The few studies that measured hormone levels found no correlation with estradiol or progesterone levels but did not adjust for a possible delayed change in clotting factor levels [28,30]. Peak vwf antigen levels occurred 2 7 days after the estradiol peak in two women tested 10 times during a single cycle [30]. Women undergoing in vitro fertilization had a significant increase in vwf and FVIII levels at supraphysiologic estradiol levels after ovarian stimulation [33]. Although larger studies are required to confirm a cyclic variation, the preliminary evidence suggesting lower vwf levels during menses and the early follicular phase supports testing at least once during this period. FREQUENCY OF MENORRHAGIA IN WOMEN WITH vwd Menorrhagia is the most common bleeding manifestation in women with vwd, and often it is the only symptom in mild type 1 disease. Menorrhagia was reported by 60 95% of women with vwd, compared to 14 61% of controls, with an onset at menarche in the majority of affected women [4,18,24,25,34,35]. Most studies did not include quantitative measurement of menstrual blood loss to confirm the subjective impression. However, one study using a pictorial blood assessment chart reported menorrhagia in 74% of women with vwd, compared to 24% of controls, confirming the high frequency of this bleeding manifestation [18]. The prevalence of menorrhagia in the different types of vwd is not well defined. Several studies included only women with type 1 disease, 79 93% of whom reported a history of excessive menstrual bleeding [24,25,34]. Menorrhagia severe enough to require blood-product replacement occurred in 86% of women with type 2 and 3 vwd unresponsive to DDAVP [36]. Another study reported menorrhagia resulting in iron deficiency or requiring oral contraceptives in 69% of Iranian women with type 3 vwd [37]. Women with vwd have a higher frequency of bleeding through protection and anemia compared to controls [18,24,25]. Severe menorrhagia resulting in anemia or requiring transfusion was reported by 48 64% and 7 22% of women with type 1 vwd, respectively [18,24,25]. Women with vwd reported a significantly longer duration of bleeding and used a greater number of pads or tampons per cycle, compared to controls [18,25]. Ten to 26% of women underwent a hysterectomy to control excessive menstrual bleeding, prior to diagnosis in a substantial number of cases [4,18,24,25]. Menses had a significantly greater adverse impact on various measures of quality of life in women with known vwd in several studies [25,35,38]. Several studies of the prevalence of vwd in women with menorrhagia excluded women with pelvic pathology [11,12,15]. The prevalence of uterine abnormalities in women with vwd and menorrhagia is unknown. In one survey, nearly half of women with type 1 vwd who underwent hysterectomy for menorrhagia had additional uterine pathology [25]. Another study found that ovarian cysts, endometriosis, fibroids, and endometrial hyperplasia were significantly more common in women with vwd than in controls [35]. Because of the high prevalence of menorrhagia, women with vwd may be more likely to undergo gynecological evaluation. However, vwd may unmask uterine abnormalities, accounting for the higher frequency reported in affected women. Conversely, because anatomic abnormalities may also unmask a bleeding tendency, testing for vwd should still be considered in these cases. OTHER GYNECOLOGICAL BLEEDING Women with vwd may have excessive bleeding after gynecological procedures such as hysterectomy, dilation and curettage, endometrial ablation, tubal ligation, and cone biopsy [4,18,24,25]. The risk of post-operative bleeding is not well defined, with the evidence limited to anecdotal reports and small case series. In three recent series summarizing the surgical outcomes of 29 hysterectomies, the rate of bleeding complications ranged from 0% to 60% [14,18,24]. The risk is likely higher in women with severe disease and in those who do not receive adequate prophylactic therapy. However, there are reports of bleeding complications after hysterectomy despite prophylaxis with desmopressin or vwf concentrates [18]. In several studies, the diagnosis of vwd was unknown preoperatively in a substantial number of women [46 85%] who underwent hysterectomy, despite a prior bleeding history in the majority of cases [24,25]. Several surgeries were complicated by hemorrhage, underscoring the recommendation for pre-operative testing. Midcycle pain ( Mittelschmerz ) due to bleeding into the corpus luteum after ovulation may be severe in women with vwd. In one series, 49% of women

5 224 Concise Review: Kujovich with type 1 vwd reported midcycle pain similar in severity to menstrual pain [25]. Bleeding into the corpus luteum may extend into the broad ligament, resulting in a hematoma large enough to require surgical drainage [39]. A large Swedish series reported ovarian bleeding in 7% of women with vwd. Bleeding often recurred and required transfusion in the majority of cases [4]. Massive hemoperitoneum due to rupture of a hemorrhagic corpus luteum is an uncommon but serious complication of vwd [40 45]. Patients present with severe midcycle abdominal pain, hypotension, and profound anemia, often requiring surgical exploration and aggressive bloodproduct replacement. Hemoperitoneum preceded the diagnosis of vwd in several cases and often recurred during subsequent cycles [40 42,44]. TREATMENT Medical therapies for menorrhagia include oral contraceptives, desmopressin, and antifibrinolytic agents, alone or in combination. However, there is very little data defining their relative efficacy in women with vwd. Oral Contraceptives Combination estrogen progesterone oral contraceptives reduce menstrual blood flow and are often prescribed for menorrhagia, although there are no randomized placebo-controlled trials confirming their benefit. Low- and higher-dose oral contraceptives reduced menstrual blood loss by 43% and 53%, respectively, compared to baseline pretreatment losses in two studies [46,47]. The data on their efficacy for vwd-associated menorrhagia is limited to case reports and surveys of patient report of response, with conflicting results [25,36,39]. In one series, 76% of women with type 1 vwd and menorrhagia treated with oral contraceptives reported a poor response [25]. In contrast, another study found a good response (defined as a subjective decrease in severity or frequency of menorrhagia) in 88% of all treated women and in 74% of those with type 2 and type 3 disease [36]. However, there are no studies evaluating their efficacy for vwd-associated menorrhagia using objective measures of response. The beneficial effect of oral contraceptives is thought to reflect an estrogeninduced increase in vwf and FVIII levels. There are anecdotal reports of the disappearance of bleeding symptoms during treatment, with normalization of vwf and FVIII levels in several cases [48]. A significant increase in FVIII and vwf levels in normal women on oral contraception has been shown in some but not all studies [31,49 51]. However, the hemostatic effects are variable with markedly elevated clotting factor levels in some individuals [50]. Estrogens also inhibit endometrial proliferation, which explains their benefit in women with type 3 disease, in whom FVIII and vwf levels are unchanged. It is unknown whether the particular composition and estrogen dose affect their efficacy for vwd-associated menorrhagia. Oral contraceptives are also used to suppress ovulation and prevent recurrent hemoperitoneum in women with vwd [40 42,44]. Desmopressin Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) a synthetic analogue of vasopressin, increases plasma vwf and FVIII levels transiently in normal individuals and patients with vwd. It is most effective in patients with type 1 disease, who have normal vwf available for release from storage sites. DDAVP can be administered intravenously, subcutaneously, or as a nasal spray, convenient for outpatient treatment of minor bleeding episodes. In one survey, 86% of hematologists reported using intranasal DDAVP for menorrhagia in women with type 1 vwd [52]. Despite the increasing use of DDAVP for this problem, there is limited evidence supporting its efficacy (Table II). Interpretation of the data is limited by the small study populations, varying dosing regimens and definitions of response. Most studies reporting a beneficial effect relied on patient assessment of efficacy. A small prospective study found that selfadministered subcutaneous DDAVP was effective (defined as reduction in pad consumption) in 86% of episodes of menorrhagia. All women had a prior good hemostatic response to DDAVP, and 6 also received tranexamic acid [53]. In another larger prospective study, 90 women with type 1 vwd reported an excellent or good response to intranasal DDAVP (defined as a subjective impression of reduced menstrual flow) during 92% of treatment episodes [54]. Intranasal DDAVP reduced the mean duration of menstrual bleeding in 15 women with vwd surveyed by questionnaire [55]. Multiple other case reports suggest intranasal DDAVP is effective for vwd-associated menorrhagia [25,56]. In contrast, the only randomized controlled trial of intranasal DDAVP found no significant reduction in menstrual blood flow (assessed by pictorial blood assessment chart), compared with placebo [57]. Mean pictorial blood assessment chart scores were significantly lower than pretreatment baseline scores after both DDAVP and placebo, illustrating the importance of the placebo effect in this setting. DDAVP has also been shown to

6 TABLE II. Desmopressin for Menorrhagia in Women With von Willebrand s Disease a Concise Review: von Willebrand s Disease and Menorrhagia 225 Study Study population Dose schedule Measure of response Results Prospective multicenter [53] Prospective multicenter [54] Retrospective [55] Prospective, randomized, placebo-controlled crossover (57) 14 women with vwd b 90 women with type 1 vwd or FVIII deficiency 15 women with vwd b 25 women with Type 1vWD c 0.3 mg/kg SQ (1 3 doses) Intranasal 300 mg/ day (avg. 1.7 days/cycle) Intranasal 300 mg (1 3 doses) Intranasal 300 mg bid days 2 and 3 of menses Subjective decrease in pad consumption Subjective decrease in menstrual blood flow Subjective assessment Decrease in PBAC score Effective in 86% of episodes Good response with 92% of daily uses Good response in 80% of women No significant difference vs. placebo; Significant decrease vs. pretreatment score a Abbreviations: vwd, von Willebrand s disease; PBAC, pictorial blood loss assessment chart; SQ, subcutaneously. b Participants had demonstrated hemostatic response to desmopressin. c Three women also had FXI deficiency. reduce menstrual blood loss in women with menorrhagia due to other causes [58,59]. DDAVP releases tissue plasminogen activator from storage sites, suggesting the possibility of increased endometrial fibrinolytic activity and a paradoxical increase in bleeding. However, intranasal DDAVP had no effect on menstrual fluid fibrinolytic activity in a small study of women with menorrhagia [60]. Intranasal DDAVP is generally well tolerated, but adverse effects have occurred in 25 70% of patients in different studies [54,57,58]. In two small, randomized studies, adverse effects were not significantly more frequent with DDAVP than placebo [57,59]. Side effects are usually mild, with facial flushing and transient headache among the most commonly reported. Severe adverse reactions such as hyponatremia are rare but have occurred in women using intranasal DDAVP for menorrhagia [54,61]. In a review of intranasal DDAVP for vwd or FVIII deficiency, all serious adverse reactions occurred in women, the majority during treatment for menorrhagia [61]. It is unknown whether women are more susceptible to hyponatremia as a result of hormonal fluctuations and water retention during a normal menstrual period. In several cases, frequent dosing and/or excessive fluid intake were suspected contributing factors, suggesting that unsupervised outpatient use may result in more frequent adverse effects [54,61]. Antifibrinolytic Therapy Women with menorrhagia have higher levels of fibrinolytic activity in the endometrium and menstrual fluid than those with normal menstrual blood loss [60]. Antifibrinolytic agents inhibit lysis of newly formed clots by preventing plasminogen binding to fibrin and its subsequent activation to plasmin. The demonstration of high levels of endometrial fibrinolytic activity in women with menorrhagia provides a rationale for their use in this setting [62,63]. Several studies reported that tranexamic acid reduced objectively confirmed menstrual blood loss by 34 59% compared to baseline or placebo in women with idiopathic menorrhagia not due to bleeding disorders [47,64 67]. A recent meta-analysis found a similar 47% reduction in mean menstrual blood loss [68]. Tranexamic acid was also significantly more effective than nonsteroidal anti-inflammatory drugs, etamsylate, and an oral progesterone [62,64,67]. Treatment during menses resulted in a marked improvement in all quality-of-life parameters, with a high level of patient satisfaction [64,69]. E-Aminocaproic acid also reduced menstrual blood loss in several studies [47,70,71]. The efficacy of antifibrinolytic therapy for vwd-associated menorrhagia has not been systematically studied. Antifibrinolytic agents have also been used in combination with other therapies [53,59]. There are no studies comparing antifibrinolytic therapy with DDAVP or oral contraceptives in women with vwd and menorrhagia. Antifibrinolytic agents are well tolerated, with nausea, vomiting, diarrhea the most commonly reported side effects in most studies. However, there are rare anecdotal reports of thrombotic complications, including cerebral arterial and venous thrombosis during antifibrinolytic therapy for menorrhagia [74 76]. Several case reports describe successful treatment of menorrhagia with correction of iron-deficiency anemia [72,73]. CONCLUSIONS The reported prevalence of vwd is increased in women with menorrhagia, with current estimates ranging from 5% to 20%. To what extent the prevalence varies among different populations, such as adoles-

7 226 Concise Review: Kujovich cents or women with uterine pathology, is unknown and deserves further study. The indications for screening are still controversial, with two recent systematic reviews reaching different conclusions [22,23]. In the absence of defined guidelines, testing should be considered, especially in women with a history of unexplained menorrhagia since menarche. Failure to diagnose vwd may impair quality of life during menses, and result in anemia and unnecessary surgical procedures. A recent survey found that only 4% of gynecologists routinely considered vwd in the differential diagnosis in women of reproductive age [77]. In contrast, 91% of hematologists with expertise in hemostasis identified menorrhagia as an indication for vwd testing [52]. The American College of Obstetricians and Gynecologists recommends testing for adolescents with severe menorrhagia and adult women without other identifiable cause and prior to hysterectomy [78]. 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