Plasma Factor Levels, Bleeding History, Physical Activity Could Inform Hemophilia Bleeding Risk Assessments

Federico Germini, MD, MSc

An ideal risk assessment model for bleeding risk in patients with hemophilia should include factors including plasma factor levels, history of bleeds, and physical activity, according to results from a systematic literature review of patients on prophylactic treatment.

In new study data, a team of Canadian investigators were unable to find an established bleeding risk assessment model for patients with hemophilia among already existing literature. However, their assessment of outcomes data pointed to a series of relevant clinical factors that should constitute the foundation of such guidance for physicians and caregivers.

Led by Federico Germini, MD, MSc, of the Department of Health Research Methods, Evidence and Impact at McMaster University, investigators sought to identify the risk factors associated with bleeding among patients treating hemophilia with regular prophylaxis, as well as to observe available risk assessment model guidance.

As they noted, patients with hemophilia can have varied bleeding patterns, even when treated with similar regular prophylaxis regimens.

“This is at least in part explained by the fact that prophylactic treatment is usually dosed by weight but, due to high inter-patient variability in the drug pharmacokinetics, this can translate in either under- or over-dosing,” they wrote. “Other factors can have a role in determining the individual risk for bleeding, like physical activity levels, bleeding history, or treatment adherence.”

Germini and colleagues assessed the MEDLINE, EMBASE, and multiple Cochrane registries to derive literature on risk assessment models and bleeding risk factors among treated patients. The assessment took place through August 2019; a qualitative synthesis of results was not performed due to a high heterogeneity of observed risk factors, outcomes definitions and measurements, and statistical analyses of trial results.

Of 1843 search results, 152 full texts were assessed. From there, 11 articles from 10 trials met investigators’ inclusion criteria. Five studies included patients with hemophilia A, 1 included patients with hemophilia B, and 4 studies included patients with either type. A majority of the trials were conducted in North America and/or Europe; severe hemophilia cases were included in all 10 trials, study sample populations ranged from 32 – 286 patients, and follow-up duration ranged from 6 – 72 months.

None of the observed studies developed nor validated a risk assessment model, leading investigators to instead only report studies reviewing hemophilia bleeding risk factors.

Among the identified prognostic bleeding risk factors were the following:

• 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
• Seasonal variability

“Only one of the studies reporting on risk factors for bleeding was at low risk of bias in all the domains, and the remaining studies were at high risk of bias in at least two domains,” investigators wrote. “All the studies but one agreed that higher plasma factor levels are associated with lower risk for bleeding, with variability in the risk estimates.”

Acknowledging the lack of risk assessment models available for clinicians, investigators stressed that such a guidance—including key factors such as plasma factor levels, physical activity, and bleeding history—would be significantly valuable for managing hemophilia bleeding risks.

“Lastly, efforts are needed to reduce the heterogeneity in the measurement and reporting in the field of risk for bleeding in hemophilia,” they wrote. “Important sources of heterogeneity were the definitions of and methods for measuring the risk factors, the way these were handled in the statistical analysis, and the model used for the statistical analysis, yielding to heterogenous risk measures. A harmonized approach to measurement, handling, and reporting of these data is needed.”

The study, “Risk factors for bleeding in people living with Hemophilia A and B treated with regular prophylaxis: a systematic review of the literature,” was published online in Journal of Thrombosis and Hemostasis.