Acquired Von Willebrand Disease: The Real Explanation for “Explained” Menorrhagia?.

5% of women seek treatment for menorrhagia and 500,000 undergo hystererctomy in the US each year. CDC advocates screening for von Willebrand disease (vWD) in the ~50% of menorrhagia patients whose menorrhagia is unexplained. Inherited vWD is found in 10–37% of such women but vWD has not been investigated in “explained” menorrhagia (e.g. uterine fibroids, etc.). A 44 year old African American woman with severe menorrhagia and multiple 2 cm uterine fibroids was referred to us for iron deficiency anemia (Hb 7.9 g/dl; MCV 68.5 FL; ferritin 1 ng/ml) and intolerance to oral iron. Weekly injections of iron sucrose improved her blood count (Hb 11.2 gm/dl; MCV 83.4 FL; ferritin 13 ng/ml) but with change to a monthly schedule (because of her new job) anemia recurred (Hb 8.6 gm/dl; MCV 75.3 FL). Despite her negative family history and the absence of other bleeding symptoms, the severity of her menstrual bleeding led us to screen her for vWD. She was blood group O Rh+, aPTT 31 sec, PT 12.3 sec, bleeding time 6 minutes, platelets 345x10⁹/liter. Seven days before menses: FVIII activity 61% (55–205), von Willebrand factor (vWf) antigen 54% (55–200), ristocetin co-factor 42% (55–200). During menses: FVIII activity 37%, vWf antigen 48%, ristocetin co-factor 23%. Agarose gel electrophoretic analysis of her plasma vWf multimers revealed absence of normal higher molecular weight multimers, consistent with Type II vWD or acquired vWD. The patient elected to undergo hysterectomy (ovaries left in). DDAVP (0.3 μg/kg) was injected IV 1 hour prior to surgery. A blood specimen obtained 30 minutes after injection revealed a normal multimer pattern. Four months post-op FVIII activity 53%, vWf antigen 52%, ristocetin co-factor 50%. Multimer analysis normal. Immunohistochemical staining of the leiomyomata (fibroids) for vWf revealed strong staining using either polyclonal rabbit anti-human vWf or monoclonal mouse anti-human vWf but no staining for carcinoembryonic antigen (CEA). The normal myometrium stained neither for vWf nor CEA. These findings are consistent with an acquired von Willebrand disease syndrome resulting from binding of our patient’s plasma vWf to her fibroids. Although her phenotype was mild (e.g. normal coagulation tests and bleeding time), she was susceptible to the hemostatic challenge of menstruation which coincides with a fall in estradiol and thus a nadir in release of vWf to the circulation. DDAVP injection presumably increased release of vWf sufficiently to saturate the uterine vWf binding sites thus rendering her plasma vWf multimers structurally normal and permitting normal hemostasis at hysterectomy. After removal of the uterus her multimer pattern was normal without injection of DDAVP. Uterine fibroids (leiomyomata) are hitherto unidentified as a cause of acquired vWD and “explained” menorrhagia. The prevalance of the association is unknown, however preliminary retrospective staining of tissue from other hysterectomies performed in our institution because of menorrhagia indicate that it is not unique to the patient described herein. Further studies are needed before treatments such as intranasal DDAVP can be recommended as alternatives to hysterectomy for selected patients with “explained” menorrhagia.