Folding to function Rising insights in nonsevere hemophilia A and DDAVP treatment

Hemophilia A (HA) is a bleeding disorder caused by a defect in the F8 gene, leading to decreased clotting factor VIII (FVIII) levels. Patients are classified based on residual FVIII concentration (FVIII:C) in the plasma. Severely affected patients have no detectable FVIII:C levels, whereas nonsevere patients have some activity.
The focus of this thesis is nonsevere HA. The mainstay of nonsevere HA treatment is the replacement of defective FVIII. Replacement therapy by using FVIII concentrates has three downsides. Unfortunately, there is a lifelong risk of the development of inhibiting antibodies against FVIII (inhibitors). When this occurs, the treatment of future bleeding episodes is jeopardized. Furthermore, the frequent intravenous administration of FVIII concentrate due to its short half-life is inconvenient for patients. Lastly, the costs of treatment are a major burden on national healthcare budgets. Resources are limited to treat patients in developing countries. For these reasons, the avoidance of FVIII concentrates by using safer, convenient and cheaper treatment options is preferable.
A safer and relatively cheaper treatment option is desmopressin (DDAVP). DDAVP is a synthetic hormone that increases endogenous FVIII in most, but not all nonsevere HA patients. Deciphering the biomolecular processes underlying the therapeutic effect of DDAVP may help to optimize treatment strategies. Despite rapid developments in the treatment or possible future cure of nonsevere HA, a permanent solution to restore hemostasis in these patients is not yet available. With this thesis I aimed to gain rising insights into nonsevere HA and DDAVP treatment.