39 Reduced thrombin generation and/or decreased platelet response in women with HMB INTRODUCTION Heavy menstrual bleeding (HMB) is a condition that affects 20-30% of women of reproductive age (1-3). HMB is defined as excessive menstrual blood loss that interferes with the woman’s physical, emotional, social and material quality of life and has detrimental consequences for the economy, because these women have increased absenteeism at work (4). HMB is a common medical reason for referral to hospitals. Clinically it is defined as more than 80 mL blood loss per cycle and/or a menstrual bleeding period of longer than 7 days (5). HMB is a complaint with multiple etiologies and diverse pathophysiology that is incompletely understood (6). In 40% of the women, a clear pathophysiological cause can be diagnosed, including hormonal imbalances, dysfunctions in the ovaries and polyps, fibroids, or adenomyosis in the uterus (6). Another mechanism underlying this complaint could be a bleeding disorder. It is known for a long time that the majority of women with platelet function disorders (PFDs), coagulation defects (eg coagulation factor XI deficiency) and Von Willebrand disease (VWD) have more severe bleeding complications (7-9), including HMB (7, 10, 11). Approximately 83% of women with VWD reported HMB (12). The current diagnostic infrastructure for HMB does not facilitate testing for haemostasis deficiencies, despite consistent evidence that there is a higher prevalence of VWD (5, 12), impaired platelet function in patients with HMB (12-14) and the fact that Von Willebrand factor (VWF) and platelet function testing is recommended by American Academy of Pediatrics Committee on Adolescence and the American College of Obstetricians and Gynecologists Committee on Adolescent Health Care (15, 16). Platelet function testing with light transmission aggregometry (LTA) is routinely used to measure platelet function in patients with bleeding complications (17). Although LTA has shown to be useful for the detection of platelet function disorders in women with HMB (17), it has the disadvantage that many hospitals do not have access to a laboratory, which is using LTA. Furthermore, many laboratories have stopped using LTA, because it is time-consuming; it requires large blood volumes to prepare platelet rich plasma and needs to be performed on freshly collected blood samples (18). In addition, it requires expert laboratory skills, it needs dedicated equipment, and it has a high intra- and interbatch and technician variability within and between tests (17, 18). In this study, we have used agonist-induced platelet activation measured in whole blood (19). Similar to LTA, this test triggers platelet activation with different agonists, but it quantifies platelet activation with sur- face markers (P-selectin expression and αIIbβ3 activation) instead of aggregation. In our hands, platelet function testing with flow cytometry is less laborious than LTA, because the reaction mix is prepared in advance and stored stable as ready to use reaction mix for at least 6 months at −20°C. The test can be done in unprocessed whole blood and is fixed after an incubation period of 20 minutes. Platelet activation state in the fixed reactions can be directly quantified or ana- lysed after maximally 1 week, and if necessary, stably transported to a central laboratory with a flow cytometer. We have compared flow cytometric platelet function testing with LTA and found that the discriminative ability to detect unknown bleeding disorders was slightly better with flow cytometry than with LTA. (20) 3
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