How I treat bleeding disorder of unknown cause

Abstract

Recent studies have demonstrated that only 30% of patients referred for assessment of a possible bleeding tendency will eventually be diagnosed with a mild bleeding disorder (MBD) such as von Willebrand disease (VWD) or platelet function defect (PFD). Rather, most of these patients will be diagnosed with bleeding disorder of unknown cause (BDUC). There remains an important unmet need to define consensus regarding the clinical and laboratory criteria necessary for a formal BDUC diagnosis. Accumulating recent data suggest that BDUC is being diagnosed with increasing frequency. Objective assessment of bleeding phenotype using a standardized bleeding assessment tool (BAT) therefore represents a fundamental first step in the diagnosis of BDUC. Because BDUC is a diagnosis by exclusion, accurate quantification of bleeding phenotype is critical because this will be the primary determinant on which a diagnosis of BDUC is reached. Importantly, BAT scores suggest that patients with BDUC display bleeding phenotypes comparable to those seen in patients with VWD or PFD. Despite the prevalence of BDUC, diagnosis and management of these patients commonly pose significant clinical dilemmas. We consider these challenges in the context of a number of typical case studies, discuss the available evidence, and outline our approach to the management of these patients.

Graphical abstract

Figure 1.

Clinical features associated with inherited and acquired causes of mild to moderate mucocutaneous bleeding. HHT, hereditary hemorrhagic telangiectasia.

Figure 2.

Proposed BDUC diagnostic algorithm. *Level 2 laboratory testing performed in patients with abnormal ISTH BAT scores but normal level 1 tests. **Level 3 laboratory testing is reserved for patients with normal level 2 testing but marked bleeding phenotypes (eg, IATH BAT >10 or recurrent anemia or strong family histories or planned procedures associated with major bleeding risks). Ideally, these level 3 tests should be performed in the context of a research study.

Figure 3.

Considerations in developing personalized treatment plans for patients with BDUC. To develop a personalized treatment plan for a patient with BDUC, we first assess patient-related and procedure-related factors. A treatment plan for the specific procedure is then developed based on an ascending hierarchy of therapeutic options. In some patients with minimal objective evidence of previous bleeding, or in younger patients who have not undergone previous significant hemostatic challenges, with patient agreement we advocate an observation policy in the first instance. In these patients, TA and/or DDAVP are available on standby to manage any bleeding complications. For patients with previous procedure-related bleeding complications, we recommend TA alone or in combination with DDAVP before any significant future challenges. Platelet transfusions are used for patients with BDUC who develop bleeding complications despite therapy with TA and DDAVP. Finally, we only consider rFVIIa as a last-ditch option in patients with BDUC with ongoing active bleeding refractory to other treatment options. C/I, contraindication. All figures were created with BioRender.com.