Editor's Note: At the 2025 European Hematology Association (EHA) Annual Congress, a dedicated guideline session was grandly held, bringing together top experts in the global hematology field. One of the core topics of this meeting was the new "Recommendations for the Management of Mild-to-Moderate Hemophilia A and B," promoted by the EHA Guidelines Committee. These guidelines challenge the long-standing classification system based on coagulation factor levels, innovatively proposing a dynamic classification standard centered on clinical bleeding phenotype. Based on the on-site reports by meeting chairs Professor Francesco Rodeghiero and Professor Alessandro Casini, as well as Dr. Michael Yarussi, this article systematically outlines the background, core methodology, and clinical significance of these upcoming landmark guidelines, aiming to provide a cutting-edge reference for clinical and research colleagues.Introduction: Challenging Traditional Cognition, The Systematic Layout of the EHA Guidelines Committee
At the beginning of the meeting, Professor Steffen Koschmieder from Aachen, Germany, a member of the EHA Guidelines Committee, first introduced the committee’s background and mission. Since its formal establishment in 2019, the EHA Guidelines Committee has published 19 guidelines, with over 20 new guidelines currently in development, dedicated to providing high-quality, accessible, evidence-based medical evidence for clinical practice. He emphasized, “We have established a standardized proposal and review process for new guidelines and ensure that colleagues worldwide can easily access and apply these results through various channels, including the official website and the EHA Guidelines App.”
Subsequently, Professor Francesco Rodeghiero, one of the leaders of this guideline project, formally introduced the core topic—”New EHA Recommendations for Mild-to-Moderate Hemophilia A and B.” He stated at the outset that although these guidelines have not yet been officially published, the research behind them has brought disruptive thinking to the hematology field. The project not only gathered 22 clinical experts from Europe, North America, South America, and Asia but also included 3 patient representatives, ensuring both the scientific rigor and patient-centricity of the recommendations.
Redefining “Mild-to-Moderate”: The Key Shift from Laboratory Metrics to Clinical Phenotype
For a long time, the severity of hemophilia has been primarily classified based on the residual activity level of coagulation factors in the patient’s body. However, clinical practice has repeatedly shown that many patients classified as “mild” or “moderate” may also experience life-threatening severe bleeding events during their lifetime. Professor Rodeghiero reviewed the EHA consensus report published by his team in 2019, which laid the theoretical foundation for the subsequent guideline development. The research team proposed an important principle-based definition: “We preliminarily define a mild-to-moderate bleeding disorder as one in which there is a measurable activity of the affected component in laboratory tests; whereas a severe bleeding disorder refers to those conditions where no residual functional activity can be detected.”
However, this preliminary definition was soon challenged by clinical reality. Professor Rodeghiero cited a recent study conducted in collaboration with the European Association for Haemophilia and Allied Disorders (EAHAD), whose title is highly impactful—”Mild or moderate haemophilia is not always a mild or moderate bleeding disorder.” The study used strict inclusion criteria to analyze the complete medical history of patients from birth to the time of publication and found astonishing facts. Professor Rodeghiero pointed out: “We found that among the 1970 patients with mild-to-moderate hemophilia who met the strict inclusion criteria, over 20% should be reclassified as having a ‘severe bleeding disorder’ because they had experienced at least one severe bleeding event.”
Based on this, the guideline working group proposed a revolutionary concept: when a patient’s clinical phenotype shifts from mild-to-moderate to severe, they should be managed under the severe bleeding disorder category, regardless of their baseline coagulation factor level. This dynamic classification standard means that patient assessment is no longer a static diagnosis based on a single laboratory test result, but a continuous evaluation throughout their life cycle.
The Rigorous Methodology of Guideline Development: Systematic Review and Focus on Core Clinical Questions
The scientific integrity and authority of the guidelines depend on a rigorous development method. Professor Alessandro Casini from Geneva detailed the systematic process followed in developing these guidelines. First, the expert panel identified key clinical questions across four core areas: women-related issues, surgery and dental extractions, treatment strategies, and comprehensive management. For example, in women-related issues, the panel focused on specific scenarios such as postpartum hemorrhage prevention, choice of anesthesia, and management of menorrhagia.
Second, the research team conducted a large-scale literature search following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Professor Casini presented a detailed search flowchart, which started with an initial 2875 articles. After a dual screening process based on title, abstract, and the PICO (Population, Intervention, Comparator, Outcome) method, 202 high-quality studies were ultimately included for final analysis. He emphasized, “We only selected non-selective cohort studies with follow-up from birth to the time of reporting and a sample size greater than 10 to ensure data reliability.”
Finally, for evidence assessment and grading the strength of recommendations, the working group used the internationally recognized GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. This series of rigorous methodologies ensures that the forthcoming guideline recommendations are built on a solid foundation of evidence-based medicine.
In-depth Analysis of a Clinical Case: The Application and Significance of Dynamic Classification in Practice
To help attendees more intuitively understand the clinical value of the new classification system, Dr. Michael Yarussi from Geneva shared a thought-provoking clinical case. The case involved a 16-year-old boy diagnosed with mild hemophilia A at age 4 after persistent bleeding following a tonsillectomy. His baseline factor VIII level was approximately 15%. Throughout his childhood, he received multiple factor replacement therapies for traumatic hematomas and a complex tooth extraction. Dr. Yarussi initiated the first live poll: “Based on this patient’s history, should he be reclassified?” The vast majority of attendees chose “Yes, he should be adjusted based on clinical phenotype.” Dr. Yarussi agreed, explaining, “This is the core spirit of the new guidelines. A classification based solely on factor levels can be misleading for treatment decisions, preventing patients from receiving adequate protection and negatively impacting their quality of life. This patient was hospitalized for surgery, which fully meets our new criteria for defining him as having a ‘severe bleeding disorder.'”
As his condition progressed, the boy was admitted for a spontaneous hematoma two weeks after his last factor exposure. Tests revealed his factor VIII level was below 1%, and he had developed an inhibitor with a high titer of 13 Bethesda Units. Dr. Yarussi posed a second question: “What is the probability of a patient with mild-to-moderate hemophilia A developing an inhibitor?” The poll results were concentrated between “5-10%.” Dr. Yarussi cited data showing that the overall incidence of inhibitors in this group is about 5.5%, but the risk increases significantly with the number of exposure days, reaching 13% after 100 exposure days. He stressed that specific gene mutation types are significant risk factors, making genotyping crucial for guiding individualized treatment.
Ultimately, the patient successfully underwent Immune Tolerance Induction (ITI) therapy. Dr. Yarussi concluded with a final question: “What factors can change a patient’s clinical phenotype?” The answer was the sum of three factors: “inhibitor development, age and cumulative joint damage, and changes in physical activity and trauma exposure.” This powerfully demonstrates that the severity of the disease is a dynamic process, and clinical management must adapt accordingly.
Expert Perspectives and Future Outlook: Balancing Evidence and Consensus, Leading the Future of Rare Bleeding Disorder Management
In the summary discussion, Professor Rodeghiero profoundly pointed out the unique challenges of developing guidelines in the field of rare diseases. “When we face rare diseases with a scarcity of high-level evidence, relying solely on the GRADE system may prevent us from reaching valuable clinical recommendations.” He believes that in such cases, the value of expert consensus must be re-evaluated and fully respected, combining a rigorous evidence-based system with the collective wisdom of experienced clinicians.
Looking ahead, the EHA Guidelines Committee has planned a series of guidelines for other rare bleeding disorders, including non-type 3 von Willebrand disease, inherited platelet function disorders, fibrinolytic defects, and bleeding disorders of unknown cause.
The new guideline philosophy presented at this meeting marks a major leap in the hemophilia management paradigm. It not only brings more precise and individualized treatment approaches to the clinic but also highlights EHA’s leadership and contribution to the standardization of hematology care globally, promoting the worldwide sharing of more advanced management strategies that better meet the real needs of patients.
