Fundamentals for a Systematic Approach to Mild and Moderate Inherited Bleeding Disorders: An EHA Consensus Report

Abstract

Healthy subjects frequently report minor bleedings that are frequently 'background noise' of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non-severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus-based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild-to-moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient-centered initial diagnostic approach that will result in classification of MBD into distinct clinical-pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence-based, disease-specific guidelines under development by the IWG.

FIGURE 1

A proposed diagnostic approach for patients referred for investigation of bleeding symptoms. Standard screening is performed in all referred subjects to confirm negative results of previous tests or to clarify any abnormalities detected. Patients with a qualifying bleeding phenotype should undergo 1st stage investigations and, on the basis of the results, be directed to 2nd stage investigations, distinct for VWD, other coagulation and fibrinolytic disorders and platelet number/function disorders. Vascular disorders should be considered based on physical examination. Some tests could be anticipated and a full investigation postponed under particular circumstances requiring a tailored approach. Patients with a doubtful history should undergo standard screening including, in particular circumstances, measurement of VWF activity. A further stage including innovative and/or research investigations can be considered for BUC. All BD are considered together in the diagnostic process, as it is intended to be appropriate as a general approach to patients at risk of bleeding. BP, bleeding phenotype; BD, bleeding disorder; BUC, bleeding of unknown cause. Broken arrows indicate an alternative approach tailored for specific circumstances, as discussed in the text. ^$Includes: umbilical stump bleeding, cephalohematoma, cheek hematoma caused by sucking during breast/bottle feeding, conjunctival hemorrhage, or excessive bleeding following circumcision or venipuncture and post-menarche menorrhagia. ^§If not sure that APTT is sensitive to FVIII and FIX < 40-50%, specific assays for FVIII and FIX are required. ^∗Thrombin time can be used if fibrinogen activity assay is not available or is not being used in the clinical laboratory. ^{^}Low VWF level may be a risk factor for bleeding in subjects not meeting the criteria for a bleeding phenotype qualifying for a MBD. In specific circumstances, in case of doubtful bleeding history in young people undergoing surgery (e.g., tonsillectomy) or other hemostatic challenges, the presence of low VWF may guide specific replacement therapy. Standard platelet aggregometry (LTA) is imperfect and technically challenging but remains the best screen available for a mild/moderate inherited platelet disorder. Quality assurance testing and use of a standardized battery of agonists are critical. Where available, lumi-aggregometry may be preferred because rare platelet disorders may have normal platelet aggregation, but abnormal granule release, like the Hermansky Pudlak syndrome; however the disease can be suspected by physical examination.