Clinical practice of prophylaxis in severe haemophilia: navigating between the burden of treatment and risk of arthropathy

Haemophilia is a rare hereditary disorder that impairs blood coagulation due to lack of functional clotting factor. Patients with haemophilia suffer from spontaneous as well as trauma related bleeding. Bleeds are most common in ankles, knees, elbows and muscles and should be treated as quickly as possible by intravenous administration of clotting factor. Delayed treatment and/or repeated joint bleeding can lead to irreversible joint damage, known as haemophilic arthropathy. Clotting factor replacement therapy for patients with severe haemophilia has moved from on-demand treatment (at the time of clinically evident bleeding) to prophylaxis (regular infusions to prevent bleeding) in countries with the necessary resources. Keeping up this regular treatment is very costly and poses a heavy burden on some patients. Treatment decisions are driven by navigating between the burden of treatment and risk of arthropathy, both for haemophilia health care providers as well as patients. This thesis focusses on two critical points in prophylactic treatment: starting prophylaxis in early childhood and stopping prophylaxis in adulthood. Early initiation of prophylaxis is critical for prevention of arthropathy, yet venous access in young children is challenging. Since 1990 European haemophilia treatment centres started prophylaxis earlier and after fewer bleeds, using less frequent infusions and central venous access devices (CVADs). Different regimens to start prophylaxis were identified. Compared with starting with an infusion regimen of 3x/week, using lower frequency regimens resulted in a strong reduction of CVAD use, number of infusions and clotting factor consumption, but also in two additional joint bleeds by the age of four years. It is unclear whether these differences result in differences on long-term joint health, as multi-centre comparison of prophylactic regimens on routine physical examination of joint health was obscured by inter-observer differences. Regarding the start of prophylaxis, we demonstrated that joint bleeding before prophylaxis had a stronger association with long-term joint health, than age at starting prophylaxis. Starting before the second joint bleed resulted in better long-term outcome compared with starting later, but we could not differentiate between starting before or after the first joint bleed. Even though prophylaxis is the recommended treatment for children with severe haemophilia A, whether prophylaxis should be continued in adulthood is still under debate. Our assessment of long-term consequences of discontinuing prophylaxis showed favourable patient-reported outcome (annual joint bleeding and limitations in activities). However, objective assessment of joint health (on physical examination and X-rays) showed increased arthropathy after 10 years of on-demand treatment. These results support continuation of long-term prophylaxis in adults and demonstrate the need for objective tools in monitoring joint status. Routine outcome assessment should balance comprehensiveness and burden. To support choosing the best set of tools, correlations between currently used tools in haemophilia were calculated. We demonstrated that outcome assessment should not depend on self-reported bleeding only, but should include objective outcome assessment as well as self-reported limitations in activities and quality of life.