Review Series INHERITED BLEEDING DISORDERS Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens

The key to a successful long-term outcome in patients with hemophilia is an efficient prophylaxis that prevents bleeding in joints for children and adults with hemophilia. Efficient prophylaxis requires taking into account the available resources (clotting factor concentrate, trough levels), the bleeding trigger (activity levels, chronic synovitis, already existing arthropathy), and most importantly the number of acceptable bleeds, especially joint bleeds (Figure 1). Depending on the available resources, the treatment objectives can vary between countries and treatment centers. In an almost ideal setting, the number of spontaneous bleeds should be minimized in order to prevent the manifestation of joint arthropathy. The severity of joint arthropathy mirrors as a kind of cumulative memory the number of experienced joint bleeds and, thus, reflects the overall quality of the prophylactic treatment regimen. Once joint damage has occurred, it will progress over the patient’s lifetime even if no further bleeds occur in the affected joints. As a consequence, primary prophylaxis should aim to prevent any joint damage. Early diagnosis of joint damage currently represents a challenge with routine imaging and clinical diagnosis tools. Moreover, joint arthropathy in a patient on primary prophylaxis develops very slowly, over a decade or even longer time periods. Both the subtle development of joint arthropathy and the limitations of its early detection hamper timely diagnosis and adequate action on treatment regimen. Depending on the patient’s age and underlying conditions, prophylaxis and its subsequent prevention of bleeds have different objectives, which are reflected by the International Society on Thrombosis and Haemostasis (ISTH)definitions.According to thesedefinitions,primary prophylaxis begins in early childhood in the absence of documented joint disease and before the second clinically evident joint bleed and before the age of 3 years. Patients treated in this way have the potential of a life without joint arthropathy. Secondary prophylaxis commences after 2 or more joint bleeds, but before the onset of joint disease as documented by physical examination and/or imaging studies. These patients may already have a significant risk of developing joint arthropathy. Tertiary prophylaxis is defined as treatment initiation after the onset of joint disease at anyageof thepatient.Objectives in thosepatients include slowing down progression of joint disease, reducing pain and inflammation, and maintaining mobility, especially in adult hemophiliacs with already advanced joint disease. Although primary, and to a lesser extent secondary, prophylaxis represents the established gold standard for children in most developed countries, tertiary prophylaxis in adults is just recently becoming increasingly considered. Current approaches improving prophylaxis outcome include best use of availablility of factor concentrate and individualization of treatment regimens with respect to dose, intervals, and type of concentrate, considering trough levels andbleeding triggers in the respective patients.