80 and informed consent was obtained from each participant. Exclusion criteria were: medication that could interfere with haemostasis, including bisphosphonates 15. The Medical Ethics Committee of the Isala Hospital, Zwolle, The Netherlands, approved the study. Data collection Patients with OI were seen by the multidisciplinary OI team and the information retrieved was assessed and patient notes were reviewed, with specific attention to comorbidities, medication and diet. The Karnofsky index questionnaire was used to determine the general health of the patients 16. Evaluation of bleeding tendency The history of bleeding in OI patients was assessed using a validated bleeding assessment tool (BAT) created by the International Society on Thrombosis and Haemostasis (ISTH) 17, resulting in a bleeding score with different reference ranges for gender and age. This BAT is a merged version of 4 previous, validated BATs 18 that was primarily designed for identification of congenital disorders of haemostasis. It is mostly used for von Willebrand disease (VWD) type 1 19, but can also be used for the diagnosis of platelet function disorders 20. Data on epistaxis, cutaneous bleeding, minor wounds, haematuria, gastrointestinal bleeds, oral cavity bleeds, prolonged bleeding after trauma, surgeries or tooth extraction, menorrhagia, postpartum haemorrhage, muscle, joint and central nervous system bleeds were collected using an online questionnaire. Our group translated the Self-BAT version of the ISTH-BAT questionnaire 21 into Dutch so that the patients were able to complete it. Blood sampling, laboratory methods and molecular analyses Blood was collected by venepuncture of the cubital vein in Vacutainer blood collection tubes (Becton Dickinson; Vianen, the Netherlands) containing 3.8% sodium citrate or dipotassium ethylene diamine tetraacetic acid (K2EDTA) as anticoagulant. All tests have been standardized with defined reference ranges as criteria for pathological results. The laboratory is subject to national and international external quality assessment in the field of haemostasis and thrombosis. A full blood count was performed on an automated modular haematology system (Sysmex XN9000; Sysmex Europe, Etten-Leur, the Netherlands) for determination of haematocrit, and platelet count. Activated partial thromboplastin time (aPTT), prothrombin time (PT; reported as an International Normalised Ratio), fibrinogen, FVIII activity and von Willebrand factor (VWF) antigen were determined on a Sysmex CA-1500 automated analyser based on turbidimetry. VWF activity was determined by the Sanquin Diagnostic Laboratory (Amsterdam, The Netherlands) using an agglutination method.
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