Diagnosis of bleeding disorder of unknown cause: how many tests are enough to diagnose BDUC?

Abstract

The challenges associated with achieving a clear diagnosis in patients with a suspected bleeding disorder are evident in those who end up categorized as bleeding disorder of unknown cause (BDUC), which can contribute to uncertainty in management and suboptimal care. BDUC is a diagnosis of exclusion, with nondiagnostic first-line hemostatic laboratory testing not meeting the criteria of an inherited mild bleeding disorder, despite the patient having a positive bleeding phenotype and/or positive family history. An abnormal bleeding phenotype, an important diagnostic criterion for BDUC, should be assessed through the use of standardized bleeding assessment tools, allowing for the quantification of bleeding symptoms as well as through clinical gestalt and judgment. The first-line laboratory workup must include a minimum set of hemostasis assays with normal results, including complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, von Willebrand disease testing, factor VIII, platelet aggregation testing, and, if available, platelet-dense granule assessment. Following normal results of initial laboratory testing, specialized tests may be ordered based on examination in addition to the patient's clinical history, including measurement of individual clotting factor assays to identify other rare bleeding causes, and in rarer cases, additional platelet assays and fibrinolysis assays may be performed. Genetic testing involving targeted genomic sequencing of known genes associated with bleeding and platelet dysfunction is not currently part of the standard line of care, primarily due to the cost and low diagnostic yield.