Mild or Moderate Hemophilia Is Not Always a Mild or Moderate Bleeding Disorder: Back to the Clinical Phenotype

Authors: Rodeghiero, F; Ghiotto, L; Pontalto, L; Casini, A; Castaman, G; Abdul-Kadir, R; Berntorp, E; Bodó, I; Degenaar-Dujardin, M; Fijnvandraat, K; Gresele, P; Key, NS; Lassila, R; Leebeek, FW; Lillicrap, D; Makris, M; Meijer, S; Mezzano, D; Noris, P; Pabinger, I; Ragni, MV; Silva, D; Srivastava, A; Tosetto, A; Windyga, J; Zieger, B

Affiliations: Hematology Project Foundation, Affiliated to the Department of Hematology San Bortolo Hospital Vicenza Italy. Division of Angiology and Hemostasis, Department of Medicine, University Hospitals of Geneva University of Geneva Geneva Switzerland. Department of Oncology, Center for Bleeding Disorders and Coagulation Careggi University Hospital Florence Italy. The Royal Free NHS Foundation Hospital, Institute for Women’s Health University College London London UK. Department of Translational Medicine Lund University Malmö Sweden. Department of Internal Medicine and Hematology Semmelweis University Budapest Hungary. European Haemophilia Consortium Brussels Belgium. Department of Pediatric Hematology, Emma Children’s Hospital, Amsterdam University Medical Center University of Amsterdam Amsterdam The Netherlands. Department of Molecular Cellular Hemostasis Sanquin Research and Landsteiner Laboratory Amsterdam The Netherlands. Department of Medicine and Surgery, Section of Internal and Cardiovascular Medicine University of Perugia Perugia Italy. Division of Hematology, Department of Medicine, UNC Blood Research Center University of North Carolina School of Medicine Chapel Hill North Carolina USA. Coagulation Disorders Unit, Division of Hematology, Department of Medicine Helsinki University Central Hospital, Finland Wihuri Research Institute Helsinki Finland.

Publication: HemaSphere ; 2025 ; 9. e70111

ABSTRACT: 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 the 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.