- Top of page
Summary. Menorrhagia is a common clinical problem and is unexplained in more than 50% of women. Although studies suggest that von Willebrand's Disease (VWD) is found in a substantial number of women with unexplained menorrhagia, the prevalence of platelet defects in women with menorrhagia is unknown. To determine the prevalence of platelet and other hemostatic defects, we evaluated women ages 17–55 diagnosed with unexplained menorrhagia. Seventy-four women (52 white, 16 black, six other) were studied. Bleeding time was prolonged in 23 women (31.5%). Maximal percent platelet aggregation was decreased with one or more agonists in 35 (47.3%) women. The most commonly found platelet function defects were reduced aggregation responses to ristocetin in 22 women and to epinephrine in 16 women. Sixteen of 22 women with reduced ristocetin aggregation had von Willebrand ristocetin cofactor (VWF:RCo) and von Willebrand factor antigen (VWF:Ag) > 60%. Platelet ATP release was decreased with one or more agonists in 43 (58.1%) women. Of the black women studied, 11/16 (69%) had abnormal platelet aggregation studies compared with 20/52 white women (39%) (P = 0.06). Black women with menorrhagia had a higher prevalence of decreased platelet aggregation in response to ristocetin and epinephrine than did white women (P = 0.0075, P = 0.02). Ten women (13.5%) had VWF:RCo and/or VWF:Ag < 60%. Using race and blood group specific ranges, 5 (6.8%) women had decreased VWF:RCo, VWF:Ag and/or collagen binding (VWF:CB). Mild factor XI deficiency was found in two women and one woman with mild factor V deficiency and one hemophilia A carrier were identified. We conclude that the prevalence of platelet function defects and other inherited bleeding disorders is substantial in a multiracial US population of women with unexplained menorrhagia.
Unexplained menorrhagia is a common clinical problem among women of reproductive age, frequently resulting in anemia, impairing women's daily activities, and often managed by surgery. Menorrhagia is the presenting symptom for the majority of the over 500 000 women who undergo hysterectomy yearly in the USA . More than a quarter of the USA female population undergo hysterectomy by age 60 . Approximately 20% of hysterectomies are performed for ‘dysfunctional’ uterine bleeding not attributable to uterine leiomyomas, polyps, endometrial or cervical cancer, prolapse, pregnancy, or endometriosis .
Despite the potential for excessive bleeding in women undergoing major surgical procedures, hysterectomy mortality rates ranging from six to 11 per 10 000 , and the availability of potential alternative management approaches, women in the USA with unexplained menorrhagia are currently rarely evaluated for inherited bleeding disorders. Recent reports from the USA and Europe have suggested that the prevalence of von Willebrand's disease (VWD) in white women with menorrhagia ranges from 13% to 20% [5–7], with a much lower prevalence reported in black women studied . The frequency and characteristics of qualitative platelet disorders in women with menorrhagia are unknown. Based on results of previous studies which did not systematically include evaluations for platelet disorders, the commonly held presumption has been that VWD is the major bleeding disorder in women with menorrhagia [5–7]. In this study, we evaluated women who had been diagnosed by their gynecologists with unexplained menorrhagia for underlying bleeding disorders. Our data demonstrate that the frequency of undiagnosed qualitative platelet disorders is substantial among women with menorrhagia in a USA multiracial population.
- Top of page
Our results demonstrate that underlying hemostatic defects, in particular qualitative platelet abnormalities, occur in the majority of women with unexplained menorrhagia. We found that 49% of women we studied with menorrhagia had two or more hemostatic defects as previously defined. Our results are consistent with prior studies which have also found that a substantial number of women with unexplained menorrhagia have bleeding disorders [5–7]. However, in contrast to previous studies, we found that in this multiracial group platelet dysfunction was more prevalent than VWD. The most likely explanation is that none of the prior studies included systematic examination of platelet function in their study population [5–7]. Interestingly, Edlund et al.  performed bleeding times and found that 5/30 had prolonged bleeding times without evidence of VWD, suggesting that these women may have had platelet defects. Based on these results one might surmise that platelet dysfunction may have been at least as prevalent as VWD in this population. In addition, our study population was composed of approximately 20% African-American women who have recently been reported to have a lower prevalence of VWD [7,10]. The present data suggests that, compared with white women, black women are more likely to have platelet dysfunction associated with menorrhagia.
Bleeding time, a measure of the platelet–microvascular interaction , has been described as a screening test for platelet function for nearly a century , provided it is performed in a standardized manner. A substantial portion (43%) of the women with abnormal platelet aggregation studies in our study had a prolonged bleeding time, but significant numbers of women (57%) with abnormal platelet aggregation studies would have been missed if the bleeding time was used to screen for further tests of platelet function. Our data does not support earlier literature suggesting a relationship between prolonged bleeding time and anemia [15,16].
The most commonly found platelet function defect was a reduced aggregation response to ristocetin in 30% women. Most of the women with decreased ristocetin induced platelet aggregation had normal VWF:RCo and VWF:Ag, and normal VWF:CB suggesting the possibility of differences in the glycoprotein IB–IX–V receptor complex or its interaction with VWF. This defect was particularly common in black women with menorrhagia, occurring in 56% of black women tested. We also found low ristocetin induced aggregation in 20% of black controls, but this was significantly less prevalent than in black women with menorrhagia. Decreased ristocetin-induced platelet aggregation in black controls compared with white controls has been previously reported [9,10,17,18], but the mechanism of this defect is not known. One author  has postulated a plasma inhibitor to ristocetin aggregation based on an inhibition of normal ristocetin aggregation by their plasma.
We found 16 women with impaired platelet aggregation with epinephrine, including 11 who had either subnormal collagen and/or ristocetin induced aggregation. The five women with isolated impaired epinephrine aggregation also had subnormal ATP release and 3/5 had a prolonged bleeding time in addition. Thus abnormal epinephrine aggregation, in addition to being significantly more prevalent in women with menorrhagia, was not found as an isolated defect in this population but rather was uniformly found to be associated with other aggregation or release defects. Epinephrine aggregates human platelets and also potentiates the aggregation of platelets with other agonists . Familial decreases in epinephrine responsiveness have been reported by several investigators in apparently normal individuals [20,21] as well as in individuals with mild bleeding diathesis [22,23]. Decreased epinephrine responsiveness has been associated with decreases in α2-adrenergic receptors [21–23] and to defects in activation of the fibrinogen receptor [24,25]. The prevalence of epinephrine aggregation abnormalities in individuals with mild bleeding diathesis has not been previously reported in the literature. Similar to our findings with ristocetin induced aggregation, black women with menorrhagia had a higher prevalence of defective epinephrine aggregation than did white women with menorrhagia.
The diagnosis of VWD is complex and, in the absence of genetic analysis, considerable variability in prevalence exists between studies. Such variability can be explained in part based on whether blood type and/or race specific ranges were used, the racial composition of the cohort, whether borderline concentrations were included, and if menstrual cycle specific testing was utilized. In our study, the prevalence of VWD varied from 6.7% to 13% depending on whether race and blood type-specific ranges were used. Using race and blood type specific ranges, Dilley et al. and Miller et al.[7,10] reported a VWD prevalence of 6.6%, whereas Edlund et al. and Kadir et al. using VWF levels of < 55% and 50%, respectively, reported prevalences of 20% and 13%. Differences in the racial composition of the cohorts studied further confound comparison of the prevalence rates between the studies. When white cases were analyzed separately, Dilley et al.  found a prevalence of VWD of 15% compared with an overall prevalence of 6.6%.
A number of authors [26–30] have suggested that fluctuations in VWF levels occur with the menstrual cycle. Although data on the optimal days for testing vary [26–28], it has been suggested that restricting sampling to specific days of the cycle reduces interindividual variation [6,24]. Cycle specific blood draws were obtained in the present study and by Edlund et al. but not in other reported studies examining the prevalence of bleeding disorders in women with menorrhagia [5,7,10]. The effects of menstrual cycle, if any, on platelet function have not been reported to date.
Our findings extend the results of earlier studies and emphasize the importance of comprehensive hemostatic testing, including platelet function testing, in the evaluation of women with unexplained menorrhagia. Studies elucidating specific platelet defects have largely been limited to individual family studies. Our results demonstrate that mild platelet defects are common in women with unexplained menorrhagia. Since approximately 5% of women are estimated to have menorrhagia  and half of them have no organic explanation , an extrapolation of our data to the general menstruating female population suggests a high prevalence of platelet dysfunction in the general population. Further elucidating their specific platelet abnormalities and developing targeted medical treatment options should have a profound impact on the health and quality of life of large numbers of women.