Study Examines Inhibitor Risk in Non-severe Hemophilia A

Intensive treatment with factor VIII, the clotting protein missing or defective in patients with hemophilia A, is associated with a greater risk of inhibitor development among patients with non-severe disease, a study has found.

The findings highlight the importance of closely monitoring these patients in order to prevent or delay the onset of inhibitor development.

Results were reported in the study “Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: a case-control study” published in the Journal of Thrombosis and Haemostasis.

Hemophilia A is caused by the lack of a blood-clotting protein, called  factor VIII (FVIII). Replacement therapy is one of the standard treatments for the disease, and involves administering FVIII to “replace” the missing or defective protein.

However, some patients will develop inhibitors, or neutralizing antibodies that bind to FVIII, preventing it from working effectively. The risk of inhibitors is higher among patients with severe disease (25–40%), but still present in 3–13% of those with non-severe disease.

Moreover, patients with non-severe disease have a lifelong risk of inhibitor development, the researchers said, with previous data suggesting that intensive administration of FVIII is a risk factor for inhibitor development.

Data from a previous case-control study in non-severe hemophilia A patients showed that surgery and a high dose of FVIII treatment were linked to an earlier risk for inhibitor development.

Now, a group of researchers in Europe and the U.K. assessed which risk factors are linked to inhibitor development in non-severe hemophilia A patients, and whether they remain a risk factor after more than 50 days of treatment.

In total, they analyzed data from 355 patients with non-severe hemophilia A, all of whom had received at least one FVIII treatment previously.

Out of the 355 patients, 63 developed inhibitors during the first 50 days of treatment (early inhibitor patients) and 26 patients after 50 days (late inhibitor patients). Each group was compared with age-matched patients who did not develop inhibitors and served as controls (195 controls for the early inhibitors group and 71 for the late inhibitors group).

Patients with early inhibitors developed them after a median of 18 days of exposure to FVIII, while those with late inhibitors developed the neutralizing antibodies after a median of 75 days of treatment exposure. The peak concentration of inhibitors was similar in both groups.

Patients in the late inhibitor group were generally older than their respective controls, with a median age difference of 18 years. As expected, more than 90% of patients who developed inhibitors — both early and late — were more prone to bleeding.

Compared with controls, both early and late inhibitor patients were treated more intensively. Also, these patients were more often submitted to surgeries in the last 10 days of FVIII exposure — 59% of early inhibitor patients vs. 44% controls, and 46% of late inhibitor patients vs. 25% controls.

Also, in the last 10 days of FVIII exposure, a higher percentage of patients with inhibitors were given peak treatment compared with controls — 37% of early inhibitor patients vs 24% controls, and 31% of late inhibitor patients vs .8% controls. Peak treatment increased the risk of inhibitors by nearly twofold in both patient groups.

Of note, peak treatment is an intensive treatment regimen in which patients are exposed to FVIII for a total of 10 days within less than 15 calendar days.

During this period, FVIII was administered at higher doses to patients with inhibitors compared with controls (44% of early inhibitor patients vs. 23% controls, and 27% of late inhibitor patients vs. 11% controls).

A higher mean dose of FVIII was linked to a 2.8-times higher risk of inhibitor development at early stages and a 4.5-times increased risk at later stages. After adjusting data to take into account peak treatment, investigators found that patients still had a 2.7-times higher risk of developing inhibitors early.

Overall, “our data suggest that intensive treatment with FVIII concentrates, increases the risk of inhibitor development in non-severe hemophilia A,” researchers wrote, adding that this was independent of the total number of FVIII exposure days.

“Therefore, persistent vigilance is required throughout the life-time treatment course of patients with non-severe hemophilia A, to prevent or early detect inhibitor development,” they concluded.