Key Clinical Summary: Prophylaxis Decision-Making in Mild and Moderate Hemophilia A

This is a micro-learning module summary of Dr Guy Young’s session which you can find here. Before participating, please read our CME and disclosure information which can be found here.

Acknowledgment: This program is supported by an independent education grant from Bayer. This online education program has been designed for healthcare professionals in the United States only.

Introduction

Patients with hemophilia are at risk of bleeding anywhere in their body. Something unique about this disease is the recurrent joint bleeding events and if bleeds continue to recur in one same joint, inflammation of the synovium will occur, which can in-turn translate into bleeding-inflammation cycles that can result in long-term musculoskeletal deterioration. Even a handful of hemarthroses can initiate the cycle of synovial hypertrophy, inflammation, recurrent bleeding, and progressive arthropathy and muscular atrophy. Contemporary evidence shows that children with mild and moderate hemophilia A are not exempt from clinically meaningful bleeding risk, particularly those at the lower end of the factor VIII (FVIII) spectrum. Prophylaxis, then, is used in hemophilia A to reduce these bleeding episodes and the risk of joint harm.

Who Gets Prophylaxis?

• Typically, it is patients with severe hemophilia.
• They start prophylaxis early in life as it is proven that without prophylaxis, they can develop permanent joint damage.
• In general, most moderate and all mild patients do not start prophylaxis from a young age.

Understanding the Bleeding Phenotype

Contemporary evidence from three recent studies clearly demonstrates that mild and moderate hemophilia A are associated with meaningful bleeding risk:

The bleeding phenotype in people with nonsevere hemophilia (Dutch cohort, Kloosterman et al, 2022): This study assessed age at first bleed and first joint bleed in moderate and mild hemophilia A.

• First bleed: The study showed that ~50% of children with moderate hemophilia had their first bleed before age 5 and 1/3 of children with mild hemophilia had their first bleed before age 10. Additionally, it demonstrated that mild hemophilia is heterogeneous (FVIII 5-40%). Those at 5–15% bled significantly earlier than those with higher FVIII levels.
• First joint bleed: The study showed ~50% of children with moderate hemophilia had their first bleed by the age 10. Additionally, within the mild hemophilia group, one out of five of those in the group of 5-15% had their first joint bleed by the age 6.
• The study also identified an inflection point around 10–15% FVIII where annualized bleeding rates increased sharply. This is also observed for joint bleeds where the inflection point appears at 10%

Bleeding phenotype in nonsevere hemophilia by international Society of Thrombosis and Haemostasis bleeding assessment tool, bleeding frequency, and the joint status (European cohort, Retjo et al, 2023): This study evaluated total and joint bleeds over 5 years based on FVIII levels.

• Patients at ~3% had a ~50% probability of ≥1 bleed and ~30% probability of ≥5 bleeds over 5 years.
• Likewise, a quarter of patients at ~3% had at least one joint bleed and about 15% had at least 5 joint bleeds in the last 5 years.
• Declining FVIII levels correlated with higher hemophilia joint health scores, indicating early structural change. For those patients at 5% (higher end for moderate hemophilia and lower end for mild hemophilia, 60% of patients have joint scores over 1.

Bleeding phenotype according to factor level in 825 children with nonsevere hemophilia: data from the PedNet cohort (European multicenter study, de Kovel et al, 2024): This study provided a refined breakdown of FVIII categories (1–2%, 3–5%, 6–10%, 11–15%, 16–20%, 21–25%).

• Showed progressive earlier bleeding with lower FVIII levels: 1–2% reached 50% cumulative incidence of joint bleeds by age 5; 3–5% by age 7; 6–10% by age 10.
• Highlighted a consistent inflection point for joint bleeds below ~6–10% FVIII.

These three studies collectively reinforce that patients with moderate and mild hemophilia A do develop joint bleeds and that those patients with lower factor levels will develop joint bleeds at a younger age.

Additionally, bleeding that reaches clinical attention likely underestimates the true burden; subclinical microbleeding is believed to contribute meaningfully to early cartilage and synovial injury. Joint health scores worsen proportionally as FVIII levels decrease, demonstrating that conventional “severity” categories do not reliably predict risk.

All children with mild and moderate hemophilia A should be evaluated regularly, at least every 6 months, to identify early signs of joint vulnerability.

When to Initiate Prophylaxis

Evidence supports initiating prophylaxis no later than after the first joint bleed for all patients with mild or moderate hemophilia A.

• FVIII 1–2%: Prophylaxis can be considered before the first bleed due to early-onset risk. Families should be counselled about expected bleeding trajectory and treatment burden.
• FVIII >2%: It is reasonable to wait for the first joint bleed, as onset may occur later (ages 5–10 for moderate; closer to age 10 for milder phenotypes). Clinical judgment should account for lifestyle, activities, early subclinical findings, and parental preferences.

Shared decision-making is essential, particularly when weighing the benefits of early prophylaxis against treatment logistics and adherence considerations.

Conclusion

Modern data challenge historic assumptions about bleeding risk in non-severe hemophilia A. A proactive, phenotype-based approach, grounded in early monitoring and timely prophylaxis, can prevent irreversible joint damage and support long-term musculoskeletal health. Clinicians should integrate factor level, bleeding history, and early joint findings to guide prophylaxis decisions that align with each child's risk profile and developmental stage.