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Mild or moderate hemophilia is not always a mild or moderate bleeding disorder: Back to the clinical phenotype

Groups and Associations Francesco Rodeghiero 1,✉, Lisanna Ghiotto 1, Luca Pontalto 1, Alessandro Casini 2, Giancarlo Castaman 3, Rezan Abdul‐Kadir 4, Erik Berntorp 5, Imre Bodó 6, Manon Degenaar‐Dujardin 7, Karin Fijnvandraat 8,9, Paolo Gresele 10, Nigel S Key 11, Riitta Lassila 12, Frank W G Leebeek 13, David Lillicrap 14, Mike Makris 15, Stephan Meijer 16, Diego Mezzano 17, Patrizia Noris 18, Ingrid Pabinger 19, Margaret V Ragni 20, David Silva 21, Alok Srivastava 22, Alberto Tosetto 23, Jerzy Windyga 24, Barbara Zieger 25
Hemasphere. 2025

In a previous paper, a comprehensive clinicopathologic approach to mild and moderate bleeding disorders (MBD) was proposed by an international working group (IWG) as a part of a project promoted by the European Hematology Association (EHA) on the development of guidelines on the various MBDs. A single pre‐diagnosis grade 4 bleeding event according to the ISTH‐BAT scale or a comparable event after diagnosis was considered sufficient to classify a patient as affected by a severe bleeding disorder (SBD). In this article, the original IWG integrated by experts and patients' representatives proposed by the European Haemophilia Consortium (EHC) and European Association of Haemophilia and Allied Disorders (EAHAD) applied these criteria to mild and moderate hemophilia A and B to establish the proportion of cases that would be reclassified as SBD taking into account bleeding phenotype, thus improving over the current classification based exclusively on basal factor VIII or IX level. To this aim, publications of unselected cases with bleeding history available from birth to the time of publication were considered to estimate the incidence of a first severe bleeding event. More than 20% of cases with mild or moderate hemophilia met the criteria for SBD by experiencing joint or non‐joint severe bleeding events. Furthermore, a significant proportion of patients developed an inhibitor against factor VIII or IX. These results, based on a rigorous methodologic approach, substantiate the criticism of the current classification of hemophilia and argue for the adoption of a new classification that takes into account bleeding phenotype in addition to basal clotting activity.