Menstrual cycle distribution of uterine natural killer cells is altered in heavy menstrual bleeding.

Heavy menstrual bleeding (HMB) affects 30% of women of reproductive age and significantly interferes with quality of life. Altered endometrial vascular maturation has been reported in HMB and recurrent miscarriage, the latter associated with increased uterine natural killer (uNK) cell numbers. This study compared endometrial leukocyte populations in controls and women with HMB. Formalin-fixed paraffin-embedded endometrial biopsies from controls (without endometrial pathology) and HMB were immunostained for CD14 (macrophages), CD56 (uNK cells), CD83 (dendritic cells), FOXP3 (regulatory T cells/Tregs), CD3 and CD8 (T cells). Leukocyte numbers were analysed as a percentage of total stromal cells in five randomly selected fields of view in the stratum functionalis of each sample. In control women across the menstrual cycle, 2-8% of total stromal cells were CD3(+) cells, 2-4% were CD8(+) T cells and 6-8% were CD14(+) macrophages. Compared with controls, CD3(+) cells were reduced during the mid-secretory phase (4%, P<0.01) and increased in the late secretory phase (12%, P=0.01) in HMB. CD83(+) dendritic cells and FOXP3(+) Tregs were scarce throughout the menstrual cycle in both groups. In controls, 2% of stromal cells in proliferative endometrium were CD56(+) uNK cells, increasing to 17% during the late secretory phase. In HMB, CD56(+) uNK cells were increased in the proliferative (5%, P<0.01) and early secretory (4%, P<0.02) phases, but reduced (10%, P<0.01) in the late secretory phase. This study demonstrates dysregulation of uNK cells in HMB, the functional consequence of which may have an impact on endometrial vascular development and/or endometrial preparation for menstruation.

[Von Willebrand disease in women with menorrhagia]. / Choroba von Willebranda u kobiet z krwotocznymi miesiaczkami.

Excessive menstrual bleeding is a common clinical problem in women of reproductive age. Hereditary bleeding disorders, such as von Willebrand disease, may be one of the causes of menorrhagia. The aim of our study was to assess the frequency of von Willebrand disease and other hemostatic defects in women with unexplained menorrhagia and without uterine pathology. Sixty-five women (mean age 31 +/- 8.7, range 18-48 years) presenting with menorrhagia were screened. An inherited bleeding disorder was diagnosed 9 (13.8%) patients; the disorders were von Willebrand disease of mild severity (type 1) in 8 cases (12.3%) and a platelet dysfunction (storage pool disease) in 1. The frequency of bleeding symptoms was higher in patients with an inherited hemostatic defect than in women without bleeding disorder. The results of this study underscore the need for hemostatic evaluation in women with excessive menstrual bleeding and without obvious pelvic abnormality.

Immunology of normal and abnormal menstruation.

Normal menstruation is an inflammatory process, where the endometrial concentrations and functions of several leukocyte types can change greatly through the menstrual cycle, especially during the premenstrual and menstrual phases. These leukocytes probably have a range of functions related to mucosal protection, decidualization, embryo implantation, and the process of menstrual tissue breakdown, repair and remodeling. Some of these leukocyte changes are apparently linked to changes in the pattern of circulating leukocytes. Many immune cells have been identified in the endometrium, and those with most relevance to the processes of menstruation include uterine natural killer cells, macrophages, mast cells, neutrophils, dendritic cells and Tregs. A range of disturbances in endometrial immune cell numbers, distributions and functions, and in a range of different inflammatory and other mediators, have been identified in women with heavy menstrual bleeding or endometriosis. Sufficient evidence exists to implicate these immune changes in some of the functional disturbances and symptoms identified in these women. This field is greatly under-researched, and ripe for the wider application of modern molecular and cellular techniques in human and animal model studies.

Phase II prospective open-label trial of recombinant interleukin-11 in women with mild von Willebrand disease and refractory menorrhagia.

Lack of effective treatment for menorrhagia is the greatest unmet healthcare need in women with von Willebrand disease (VWD). We conducted a single-centre phase II clinical trial to determine efficacy and safety of recombinant IL-11 (rhIL-11, Neumega®) given subcutaneously for up to seven days during six consecutive menstrual cycles each in seven women with mild VWD and menorrhagia refractory to haemostatic or hormonal agents. rhIL-11 reduced menstrual bleeding severity as measured by pictorial blood assessment chart (PBAC) ≥ 50% (to <100) in 71% of subjects, cycle severity ≥ 50% in 71%, and bleeding duration ≥ 2 days in 85%, all p ≤ 0.01. After rhIL-11, plasma VWF:RCo increased 1.1-fold, but did not correlate with PBAC, r=0.116, bleeding duration, r=0.318, or cycle severity, r=-0.295, or hsCRP, r=-0.003, all p>0.05. Platelet VWF mRNA expression by quantitative PCR increased mean four-fold (1.0-13.5). rhIL-11 was well tolerated with grade 1 or less fluid retention, flushing, conjunctival erythema, and local bruising. In summary, rhIL-11 reduces menorrhagia safely and warrants further study.

[Serious bleeding in systemic lupus erythematosus complicated by lupus anticoagulant-hypoprothrombinaemia syndrome]. / Alvorlig blødning ved systemisk lupus erythematosus kompliceret med lupusantikoagulans-hypoprotrombinaemisyndromet.

Severe hemorrhagic diathesis due to lupus anticoagulant complicated by hypoprothrombinaemia resulting from prothrombin autoantibodies is a rare disorder and is often associated with systemic lupus erythematosus (SLE). We report a case in which a 15-year-old girl with SLE developed marked haemorrhagic manifestations due to menorrhagia and nosebleeds. The acute bleeding episode was treated with SAGM, tranexamic acid and recombinant factor VIIa. Lupus anticoagulant, cardiolipin antibodies and antiprothrombin antibodies were successfully depressed within weeks after corticosteroid therapy was begun.