Impaired thrombin generation as a reproducible feature of bleeding disorder of unknown cause

Introduction The diagnosis of a bleeding disorder of unknown cause (BDUC) reflects normal results on in-depth hemostatic investigations, excluding known disorders such as von Willebrand disease, coagulation factor deficiencies and platelet function defects, despite a clinically relevant bleeding tendency. The pathomechanisms underlying the bleeding tendency in BDUC have remained elusive despite increased scientific interest and growing research efforts. To address this gap, global assays of hemostasis, such as the thrombin generation assay (TG) have been measured in cohorts of BDUC patients, however with discrepant results. Method In this case-control cohort study we sought to replicate our previously published results 1 in an independent BDUC cohort using an alternative TG method. TG was measured in BDUC patients and age- and sex-matched healthy controls (HC) using the fully automated Ceveron S100 analyzer with two trigger reagents: RB (very low tissue factor (TF) concentration) and RC-low (low TF concentration). The bleeding tendency was quantified using the International Society of Thrombosis and Hemostasis bleeding assessment tool (ISTH-BAT). Results In total, 62 BDUC patients and 22 HC were analyzed. As outlined in [ Fig. 1 ], patients and controls were similar in age, sex and blood group distribution, activated partial thromboplastin time, prothrombin time, fibrinogen and factor VIII activity. The total ISTH-BAT score was significantly higher in patients (median 5, interquartile range [IQR] 3-8) than in HC (0 [0-0], p