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Vigorous activity briefly raised bleeding risk in youth with hemophilia
In children and adolescents with hemophilia, energetic physical activity was briefly associated with a moderate relative increase in risk for bleeding, according to study results in the Oct. 10 issue of The Journal of the American Medical Association.
However, because the increased RR is temporary, the absolute increase in risk for bleeding associated with physical activity is expected to be minute.
In previous studies, prophylactic injections of recombinant Factor VIII have been shown to reduce the risk for bleeds in children with hemophilia, but the clinical effects of lower doses have not been strictly tested.
“The reduction in risk of bleeds conferred by prophylaxis may be such that the benefits of physical activity outweigh the risk of bleeds,” Carolyn R. Broderick, MBBS, of the University of Sydney, Australia, and colleagues wrote. “However, the degree to which risk of bleeds is elevated by physical activity has not been determined. Information about risks associated with physical activity is needed to inform decisions about participation in physical activity and to optimize prophylactic schedules.”
To calculate the temporary increase in risk of bleeding associated with vigorous physical activity in children with hemophilia, Broderick and colleagues conducted a study of 104 children and adolescent boys aged 4 to 18 years, with moderate or severe hemophilia A or B who were monitored for bleeds for up to 1 year.
After each bleed, the child or parent was interviewed to establish exposures to physical activity before the bleed. Physical activity was classified according to expected frequency and severity of collisions.
The risk for bleeds connected with physical activity was calculated by contrasting exposure to physical activity in the 8 hours preceding the bleed with exposures in two 8-hour control (non-bleed) windows, controlling for levels of clotting factor in the blood.
During the study, there were 436 reported bleeds, 336 of which were study bleeds, such as bleeding episodes without another bleeding episode in the preceding 2 weeks. Eighty-eight participants (84%) reported at least one bleed, with the most frequent sites of bleeding located on the knee (15%), ankle (14%) and elbow (10%).
According to study results, compared with inactivity and activities with a low risk for collision, activities with an increased risk for collision were associated with a brief increase in the risk for bleeding (30.6% of bleed windows vs. 24.8% of first control windows; OR, 2.7; 95% CI, 1.7-4.8). In addition, close contact and collision-prone activities were associated with a greater transient increase in risk (7% of bleed windows vs. 3.4% of first control windows; OR, 3.7; 95% CI, 2.3-7.3).
To illustrate absolute risk increase, for a child who bleeds five times annually and is exposed on average to category 2 activities (eg, basketball) twice weekly and to category 3 activities (eg, wrestling) once weekly, exposure to these activities was associated with only one of the five annual bleeds. For every 1% increase in clotting factor level, bleeding incidence was lower by 2% (P=.004).
“The risk of bleeding is mitigated by prophylaxis to the extent that clotting factor levels of around 50% reduce risk of bleeds to below the risk experienced during periods of inactivity with no exogenous clotting factor,” Broderick and colleagues wrote. “With typical prophylaxis regimens, peak factor concentrations of 70% to 100% are achieved which, given a factor VIII half-life of 10.7 hours, is sufficient to maintain levels greater than 50% for between approximately 6 and 12 hours.
“In contrast, factor supplementation reduces risk for long periods yielding sustained reductions in relative risk,” the researchers wrote. “Consequently prophylactic clotting factor is likely to have a larger absolute effect on bleeding risk than physical activity.”
Disclosure: The researchers reported receipts of research grants, speaker fees, consulting fees, travel support and honorarium from Baxter Health Care, Bayer, CSL-Behring, Novo Nordisk and Pfizer.
Perspective
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This case-crossover study in 104 Australian children and adolescents with severe or moderately severe hemophilia — 85% of whom were on prophylaxis — found an increase in risk of bleeds in association with physical activity, with those activities characterized by a greater frequency and severity of collisions associated with greater risk. However, overall the increase in risk in this group of children was very modest. For a child with a moderate level of physical activity, it amounted to only one additional bleed per year. Though there were many limitations to the study, the data provide a useful baseline, particularly as new products — including long-acting factor and gene therapy approaches — enter the treatment landscape.
Perspective
Back to TopThis study is an important landmark in the evolving success story of hemophilia over the past 3 decades. The availability of prophylactic therapy — given on a regular basis two to three times per week — in these boys has led to a remarkable improvement in musculo-skeletal health. Indeed, some children with severe or moderate hemophilia do not even know what it is to experience a joint bleed. This success story has been accompanied by an increasing participation of hemophilic boys in sporting activities.
This study tells us that, given some tolerance for rare bleeds that may occur, these boys can safely participate in the majority of sports, even those that involve moderate contact. This study also reminds us that, in the upcoming era of long-acting bioengineered Factor VIII and Factor IX products, an “adequate” plasma level is a somewhat arbitrary concept that will need to be individualized, depending on the patient’s pharmacokinetic profile and desired activity level.
Perspective
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Broderick and colleagues’ study of the risk of bleeding resulting from increased levels of vigorous activity among children and adolescents with moderate to severe hemophilia (A and B) has several implications for general pediatricians. Their well-designed rigorous trial reveals an increased rate of bleeding requiring acute factor replacement immediately following at-risk activity, with an odds ratio of 2.7 for category 2 activities (eg, basketball) and 3.7 for category 3 activities (eg, wrestling) as compared with inactivity and category 1 activities ( eg, swimming). Most participants (89%) in this Australian trial were receiving standard prophylactic factor replacement therapy. In absolute terms, because high level activity is limited to several episodes per week, the contribution of vigorous activity to the overall number of bleeds is small. On an annual basis, it is estimated to account for one of the five average experienced bleeds per year requiring acute factor infusion in this population. Importantly, the authors also found that for every 1% increase in factor clotting level, bleeding incidence was lower by 2%.
Most of us in office practice do not see very many patients with hemophilia, if at all. However, the importance of an appropriately powered and insightful study to investigate a clinical assumption of unknown magnitude, in this case the risk of bleeding in hemophiliacs from sports participation, should not go unnoticed. Putting limits on an area of clear importance to the well-being of our patients without adequate data is, and always has been, troubling. Socially, emotionally and physically, exercise is an important aspect of a child’s life. For one who already has a chronic disease that in many small and not so small ways separates one from one’s peers, a “diffability” at the very least, even further ostracization is indeed harmful. If we haven’t measured the true risk, we make poor judgments in their care.
How are we doing with guidance for exercise limitation for those with multiple concussions, loss of paired organs, enlarged hearts (or aortic roots) or, for that matter, driving and ADHD? I applaud the authors on their attempt to answer such an important question for our patients and their families. In so doing, their carefully acquired data also bring up the interesting potential of more frequent or targeted factor infusion programs to both decrease the incidence of bleeding episodes but to more safely allow vigorous participation in physical activities in the hemophilia population. There is no end to interesting questions in clinical pediatrics.