Personalizing Factor Replacement Therapy in Hemophilia

Hemophilia A is characterized by a (partial) deficiency of coagulation factor VIII (FVIII), caused by a mutation in the F8 gene. As FVIII is crucial to maintain adequate secondary hemostasis. A deficiency in FVIII leads to (spontaneous) bleeding in joints and muscles or (prolonged) bleeding after trauma and/or surgery. Mainstay of treatment in hemophilia, is the replacement of the deficient coagulation factor with intravenously administered factor concentrate, also called factor replacement therapy. However, dosing of FVIII concentrate is challenging. Standard practice is to dose based on bodyweight and crude estimations of in vivo recovery and FVIII clearance. Several studies have shown that large interindividual differences exist in FVIII concentrate pharmacokinetics (PK), resulting in underdosing with a higher risk of bleeding, or overdosing with concomitant unnecessary high costs. Dosing based on a patient’s individual PK takes interindividual differences of FVIII PK into account and therefore optimizes treatment. In this thesis, we focus on the conditions needed, strengths, limitations and potential applications of PK-guided dosing of FVIII concentrate in hemophilia A patients. In the first part, we focus on current practice with regard to diagnostics and treatment monitoring. In the second part, implementation of PK-guided dosing is addressed.

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