Collision Risk in Active Hemophilia A Patients Tied to Greater Bleed Risk

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by Patricia Inacio PhD |

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Physical activities with a high risk of a collision are linked with a greater risk of bleeding in people with moderately severe hemophilia A, a six-month U.S. study reports.

This risk was higher for people using on-demand versus preventive replacement factor VIII (FVIII) therapies, the researchers found, and they suggested that further studies into treatment timing prior to an activity are needed to lower bleeding risk in active patients.

The study “A Prospective Observational Study of Antihemophilic Factor (Recombinant) Prophylaxis Related to Physical Activity Levels in Patients with Hemophilia A in the United States (SPACE)” was published in the Journal of Blood Medicine.

Intense physical activity can increase the risk of bleeding in people with hemophilia A, and their participation is usually discouraged. But tailoring replacement FVIII therapies to a patient’s physical activity may lower the risk of bleeds.

“Individualized prophylactic regimens that aim to tailor FVIII levels to lifestyle and physical activity requirements are likely to offer further beneficial effects in minimizing bleeding risk while facilitating the physical and psychosocial benefits of exercise,” the researchers wrote.

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However, “limited data exist on the relationship between FVIII levels and bleeding risk in [hemophilia A patients] and physically active lifestyles,” they added.

To investigate further, the six-month observational SPACE trial (Study of Prophylaxis, ACtivity and Effectiveness, NCT02190149) enrolled patients with severe or moderately severe hemophilia A treated with Takeda’s Advate, a man-made (recombinant) form of FVIII, the clotting protein missing or defective in people with hemophilia A.

The study’s main goal was to assess the link between physical activity levels, FVIII infusion, and occurrence of bleeding episodes.

Its 54 patients (mean age of 23.7; range 11–58 years) were physically active and had Advate infusion data available.

These patients had a mean of five bleeding episodes in the six months before joining the trial, and preventive treatment (prophylaxis) was their most frequent choice (47 patients) compared with on-demand treatment (seven patients).

Enrolled hemophilia A patients kept with their treatment and were given a customized eDiary smartphone application and a wearable activity tracker. These devices were used to record their levels of physical activity, intervals between infusions and physical activity, and bleedings during these study’s six months.

In total, 42 patients completed the study, with physical activity intensity data recorded via the eDiary available for 34 patients at its end.

A total of 4,980 intervals were recorded between FVIII infusion and a next physical activity (morning, noon or night). Most infusions were administered 24 hours or more before starting a physical activity (64.7%). Rarely did patients administer an infusion five or more days in advance (9.6%) of an activity.

Overall, 27.8% of patients took FVIII within one to two days before starting an activity, and this was maintained regardless of activity level. Of note, physical activity risks were ranked according to National Hemophilia Foundation criteria, where risk 1 covers activities not expected to have a significant risk of collisions (like golf), risk 2 for those with a possibility of significant collisions (like bowling or touch football), and risk 3 for activities in which significant collisions are inevitable (like boxing or tackle football).

Most of the 4,980 total intervals assessed were considered low-risk activities (75.5%), with 3.9% considered of high risk.

Regarding the occurrence of bleeding episodes, 17 of the 54 patients (31.5%) reported no bleeding episodes, and the remaining 37 had 185 bleeding events.

Among those on preventive treatment (31 patients), a mean of 3.02 bleeds were registered per patient, of which 1.26 were reported as activity-related. In the six patients using on-demand treatment 6.14 bleeds were reported per person, of which 2.29 were considered activity-related.

At the study’s end, the mean annualized bleeding rate for all bleeds was 8.14. This value was higher among patients receiving on-demand therapy versus those on preventive treatment — 19.14 vs. 6.92.

Joint bleedings showed the same trend, 15.59 in the on-demand therapy group versus 2.81 among those on preventive treatment.

Overall, the risk of bleeding due to physical activity “tended to increase commensurately with physical activities classified as higher risk,” the researchers wrote. For those on preventive treatment, the risk of a level 3 activity-related bleed was five times that of patients not engaging in physical activity.

No significant relationship was seen between bleeds recorded in the eDiary as activity-related and timing of the last FVIII infusion prior to the start of physical activity. However, a longer time between a last FVIII infusion and an activity’s start — 24 hours or less, or more than 24 hours — significantly associated with a higher risk of spontaneous bleeds.

“The risk of bleeding reported by patients as spontaneous increased with prolonging time … from last infusion to physical activity start” the researchers wrote.

Factor “infusion was timed more closely to physical activity and occurred more frequently among patients engaging in higher-risk activities, although 60% of infusion intervals for level 2.5–3 activities exceeded 24 hours,” they added. “Together, these findings suggest that less than half of patients adjusted [their factor] infusion timing for higher-risk physical activities.”

The study was not powered to assess whether patients with more joint disease at its start were at higher risk of injury-related bleeds and reported spontaneous bleeding.

Overall, the findings suggest that “activities with a high risk of collision lead to an increased risk of bleeding,” the researchers concluded.

“Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding,” they wrote.