Endometriosis and mild bleeding disorders Endometriosis is a benign inflammatory disease defined by the presence of endometrial glands and stroma in areas outside the uterus. It is estimated to affect 5%–15% of women of reproductive age and is even more prevalent among women with chronic pelvic pain and infertility. Endometriotic implants may be located anywhere within the pelvis, including the ovaries, ovarian fossa, pelvic peritoneum, recto- vaginal septum, uterosacral ligaments, and cul-de sac. In some cases, ovarian endometriotic cysts (endometriomas) may be observed by ultrasound imaging. The pathophysiology of endometriosis still remains unclear. The etiologic mechanism most widely accepted is retrograde menstruation resulting in tubal backflow of endometrial cells into the pelvis during menses. Over time, these cells may adhere to peritoneal surfaces, prolif- erate, and progressively grow. The amount, duration, and frequency of pelvic exposure to refluxed blood may also determine the severity of endometriosis. This mechanism of endometriosis development is supported by several an- imal models, that demonstrated endometriosis could be induced following injection of menstrual endometrium into the pelvis. Most unaffected women have some degree of retrograde menstruation with menstrual blood, including endometrial cells, frequently observed within the pelvis at the time of laparoscopy. As a result, the pres- ence of a physiologic process that clears endometrial cells from the pelvis and prevents endometriosis has been sug- gested. In women with endometriosis, several dysfunc- tional enzymatic and autoimmune factors have been proposed as possible factors increasing the susceptibility to ectopic endometrial implantation. Endometriosis commonly affects members of the same family also sug- gesting a genetic, although likely multifactorial, mode of development. Women with endometriosis report heavier menstrual bleeding compared to controls and it is known that a signif- icant proportion of patients with menorrhagia may have bleeding disorders (1). It was also our clinical impression that many patients with endometriosis reported easy bruising and mucosal bleeding symptoms even in the absence of any trauma. In this article, we present the hy- pothesis that the presence of an unrecognized mild bleeding disorder may be another potential etiologic factor facili- tating the development of endometriosis. We speculate that women with a bleeding disorder may be at higher risk of developing endometriosis secondary to increased retro- grade menstrual blood flow, more bleeding from extra- uterine implants, and a greater possibility of forming endometriomas. Detecting mild bleeding disorders can be challenging for several reasons. Affected individuals may remain asymp- tomatic or express a range of symptoms following trauma or surgery. Such variability is noted even among family members who carry identical bleeding disorders, high- lighting the importance of other associated genetic and environmental factors. In addition, distinguishing between normal and abnormal levels of bleeding can be challenging. Bleeding disorders are caused by inherited or acquired ab- normalities and the most common disorders include Von Willebrand disease (VWD) and platelet function defects. Von Willebrand disease can be diagnosed by measuring the level of Von Willebrand factor in blood, but the biggest challenge is in diagnosing platelet abnormalities as analysis of platelet function often requires the immediate testing of fresh blood using specialized equipment with variable results that are generally not standardized. The role of platelets in hemostasis is complex and involves several stages including adhesion, aggregation, degranulation, receptor activation, and signaling. Integrins expressed on platelet membranes mediate platelet aggregation. Eicosanoids act as signaling molecules produced within the endothelium and platelets. Both integrins (2) and eicosanoids (3) may be abnormal in endometriosis patients and could result in platelet dysfunction. It may be possible to determine if bleeding problems are increased in women with endometriosis by screening with a simple questionnaire. For example, the condensed MCMDM-1VWD (Supplemental Table 1) is a standardized bleeding questionnaire that has been validated for screening women for VWD and has a reported sensitivity, specificity, positive predictive value, and negative predic- tive value for detecting type I VWD of 100%, 87%, 0.20 and 1, respectively (4). This tool can also be used to eval- uate other bleeding disorders, but has not been validated for such purposes. A cumulative score of 4 or more on the questionnaire is suggestive of a bleeding disorder requiring further investigation. In summary, the prevalence of bleeding disorders among women with endometriosis has not been systematically stud- ied, but our clinical observations suggest that bleeding may be increased compared to the general population. Simple screening through the use of a validated bleeding question- naire can be useful in detecting cases of a mild bleeding dis- order. Screening for a bleeding disorder may be particularly relevant to surgeons prior to operating on women with endo- metriosis. Diagnostic coagulation disorder testing should be offered if clinical suspicion is high based on a MCMDM- 1VWD score of 4 or more. A number of women with endome- triosis could have underlying VWD, or platelet defects that still remain uncharacterized, and may be challenging to diag- nose. Although this hypothesis needs to be confirmed in studies of endometriosis patients and control women, we believe mild bleeding disorders may comprise a potential new avenue for research into the pathophysiology of endometriosis. Frederic Mitri, M.D. a,b Robert F. Casper, M.D. a,b a Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Toronto, Lunenfeld- Tanenbaum Research Institute, Mount Sinai Hospital; and b TCART Fertility Partners, Toronto, Ontario, Canada http://dx.doi.org/10.1016/j.fertnstert.2015.02.037 886 VOL. 103 NO. 4 / APRIL 2015 INKLINGS
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