Risk Factors for Hemophilia-Related Bleeding From Prophylaxis Explored in New Study

Creating and validating effective risk assessment models could help facilitate appropriate prophylaxis for hemophilia, but more research is needed to confirm the prognostic value of various clinical risk factors and biomarkers.

Regular prophylaxis has demonstrated better efficacy than episodic treatment for patients with hemophilia, but even patients undergoing prophylactic treatment still have varied bleeding patterns. A recent review assessed current literature on risk factors and risk assessment models (RAMs) for bleeding in patients with hemophilia being treated with prophylactic clotting factor replacement therapies.

The main therapeutic approach for patients with hemophilia is treatment with the deficient clotting factor, typically dosed by weight. However, variability in each individual patient’s drug pharmacokinetics (PKs) can lead to inadequate dosing or excessive dosing when weight is used to determine dosage. RAMs to clarify patient risk levels could help identify appropriate nonclotting factor therapy approaches and lower the risk of bleeding for patients with hemophilia.

The review, published in Journal of Thrombosis and Haemostasis, included 10 studies that explored risk factors for bleeding in patients with hemophilia on regular prophylaxis. There were no RAMs for bleeding in patients with hemophilia in any of the studies in the analysis, and none aimed to develop or validate a RAM for these patients. All of the studies explored possible risk factors, however. Five of the studies only included patients with hemophilia A, 4 included both hemophilia A and B, and 1 study included only hemophilia B.

Potential prognostic factors explored in the studies included estimated plasma factor levels, treatment adherence and frequency, physical activity, bleeding history, history of sport injuries, age at target joint development, age, obesity, antithrombotic treatment, blood tests, and seasonal variability.

Heterogeneity between studies was also high, although all but one agreed that higher plasma factor levels were associated with a lower risk of bleeding. Only 1 study was considered to have a low risk of bias, while the rest had a high risk for bias in at least 2 of 6 domains that were analyzed.

The sole study that had low bias risk also found that physical activity involving potential collisions was associated with a higher risk of bleeding in hemophilia, while another study’s results were inconclusive in this patient subgroup. In other studies, which notably had a high risk for bias, age, body mass index, antithrombotic therapy, season, and some laboratory tests were risk factors. Bleeding history may also be associated with bleeding risk, 2 studies reported.

The significant heterogeneity of the studies prevented researchers from conducting a meta-analysis, but the review did provide insight into factors that may be useful indicators in RAMs for patients with hemophilia.

“[Plasma] factor levels, physical activity, and bleeding history appear to be the most important risk factors to be included in such a model.,” the authors wrote. “However, these data are not conclusive, and the role of other risk factors should also be explored.”

Overall, the authors conclude that more large, high-quality studies with well-defined predictors and outcomes in patients with hemophilia would help identify clinical risk factors and biomarkers that could be used to create and validate RAMs in this population.


Germini F, Noronha N, Abraham Philip B, et al. Risk factors for bleeding in people living with hemophilia A and B treated with regular prophylaxis: A systematic review of the literature. J Thromb Haemost. Published online April 23, 2022. doi:10.1111/jth.15723

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