Anouk Donners

12 Chapter 1 Haemophilia A Haemophilia A is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor VIII (FVIII). The diagnosis is based on a person’s endogenous FVIII activity and is classified into severe (<1%), moderate (1 to 5%) or mild (>5 to 40%) haemophilia A [1]. Approximately eight out of 100,000 people have haemophilia A (PwHA) in the Netherlands [2]. These PwHA receive care at six dedicated Haemophilia Treatment Centers, of which Van Creveldkliniek, established in 1964, is the oldest. PwHA experience bleeding, predominantly into major joints, such as ankles, knees and elbows, leading to painful and disabling arthropathy. Intracranial bleeds and bleeding into internal organs may also occur among PwHA, which can be life-threatening. When left untreated, the bleeds occur spontaneously among those suffering from severe haemophilia. In contrast, persons with moderate and mild haemophilia present a milder phenotype in which trauma and surgical interventions can provoke uncontrolled bleeding. The life expectancy of PwHA has been extended from 10–15 years a century ago to a nearly normal life expectancy and quality of life today [3]. Pharmacotherapy for people with haemophilia A Haemophilia therapy has progressed remarkably throughout the twentieth century, progressing from no available therapy to complete blood and plasma infusions. The cornerstone of therapy for PwHA is the substitution of missing FVIII [4, 5]. In the 1960s, the discovery of cryoprecipitate, which involves concentrating FVIII in a pellet, led to the industrial manufacturing of plasma-derived FVIII (pdFVIII) in the 1970s [6]. This breakthrough provided the first efficacious treatment of bleeds and marked the beginning of home care and self-infusion. The success was overshadowed in the 1980s by the outbreak of serious and fatal blood-borne viral infections such as hepatitis and HIV/ AIDS in a large proportion of PwHA due to a lack of screening methods [7, 8]. Fortunately, safer products became available in the 1990s due to new DNA technology that provided recombinant FVIII (rFVIII) and manufacturing advancements in viral inactivation and virus removal, which provided safer pdFVIII [6, 9]. PwHA were burdened by frequent weekly intravenous injections due to the short half-lives (SHL) of rFVIII products. This drove the development of the extended half-life (EHL) rFVIII products in the 2010s, although maximum half-lives of only 20 hours were achieved [10, 11]. The improvements of EHL products included Fc-infusion, conjugation of polyethylene glycol or shortening of the protein sequence to increase stability [12]. Currently, 15 FVIII products are available on the Dutch market [13]. Substitution therapy with these FVIII products can be given prophylactically to prevent bleeds (especially for severe PwHA) or on-demand to treat bleeds. Prophylactic FVIII replacement therapy has effectively reduced the average treated bleeds from 20–30 to 1–4 per person per year [1, 14]. Moreover, prophylaxis can convert a severe phenotype into a moderate phenotype