The disease burden associated with non-severe haemophilia A is larger than expected, particularly within the inhibitor population, a Victorian study suggests.

Researchers from Monash University evaluated the mutations, inhibitor risk and health-care burden of the non-severe haemophilia A (HA) population, which was “under-scrutinised” despite making up most HA cases.

They conducted a single-centre observational study of 289 adult patients who were treated at the state-wide Alfred Health Haemophilia Treatment Centre and registered on the Australian Bleeding Disorders Registry as of July 2023.

Patients had minor and moderate HA with a baseline FVIII level of 1%–40%.

High rates of genotyping had been performed, covering 79% of the total cohort and 81% of the inhibitor analysis population. The latter consisted of 193 patients not on regular prophylaxis with at least one day of exposure to FVIII replacement.

Findings published in Haemophilia [link here] revealed a higher prevalence of inhibitors compared to previous reports, with inhibitors recorded in 6% of the total population and 7% of the inhibitor analysis population.

Within the inhibitor analysis population who were genotyped, 71% had a high-risk mutation, while 67% of the non-inhibitor population harboured a low-risk mutation.

The most frequently observed mutations were the p.Arg2169His, p.Arg612Cys, p.Ser2030Asn and p.Ser603Thr mutations and the highest inhibitor risk was in those harbouring the p.Arg2169 mutation, with a risk of 81% at 50 exposure days.

Of those with a high-risk mutation in the inhibitor analysis population, only 24% developed an inhibitor. In those with a low-risk mutation, 96% did not develop an inhibitor, excluding two patients who had a concomitant non-low-risk mutation.

Reassuring

The researchers, which included haematologists from the Australian Centre for Blood Diseases at Monash University, said this suggested that while harbouring a low-risk mutation was reassuring, high-risk mutations were not highly predictive.

Among other findings, the indication for the rFVIII product given just prior to the inhibitor was to treat bleeding in 43% of patients and surgery in 36% of patients.

The predominant FVIII product used prior to inhibitor development was a short-half-life (SHL) rFVIII product in 79% of inhibitor patients, with pdFVIII product used in the remaining group. Of those patients who developed an inhibitor on factor therapy, two were subsequently commenced on prophylactic emicizumab.

The cumulative incidence of inhibitor development at 75 exposure days was 31%.

“The burden of care imposed by the non-severe HA population is high. Large numbers of procedures and bleeding events occur in this population, with particularly high prevalence in those with an inhibitor,” the authors concluded.

“In addition, the per patient cost of bypassing agent (rFVIIa) use in the inhibitor population was calculated at a median of $57,087.50/year (AUD).

“This high cost, associated with the high numbers of bleeding and procedural events, confirms that the non-severe HA population with inhibitors places a significant burden on the healthcare system which may have been previously under-appreciated given the long-standing focus on severe HA.”

They said their findings warranted further investigation and consideration of measures to mitigate inhibitor development in a group that, compared to severe patients, was previously viewed as having a minor burden on healthcare resources.