M. LAFFAN E-mail: [email protected] Extending the half-life of infused coagulation factors offers the possibility to improve treatment for patients either by reducing the frequency of injections, Epigenetics Compound Library price by increasing the sustained level of protection from bleeds or by some combination of both. Unfortunately, in the case of FVIII the natural physiology of the molecule

is a significant barrier to extensive prolongation. Nonetheless, some progress has been made with FVIII molecules modified by the addition of other molecules such as polyethylene glycol (PEG) and the Fc portion of immunoglobulin. So far, these molecules appear to have a favourable safety profile and low immunogenicity. However, complications arising from their behaviour in in vitro assays have AZD1208 chemical structure yet to be fully explored. Extending the half-life of FVIII has been the aim of research in haemophilia for some time. The anticipated benefits include reducing the frequency of injections, achieving higher trough levels of FVIII and using fewer units of FVIII overall, possibly resulting in reduced cost of treatment. With very large increases in the half-life all three may be achieved, but with more modest increases there will have to be some compromise between these three objectives. This will require a decision as to which is the most important, both for health services and

for the patient. When considering the ways in which FVIII half-life could be increased it is very important to consider

first the normal physiology of FVIII, as this will have a major impact on progress. FVIII is normally synthesized in many tissues but most notably in hepatocytes and endothelial cells, including those of the hepatic sinusoids. Within endothelial cells, von Willebrand factor (VWF) is transported to the Weibel–Palade bodies where it is co-stored with FVIII. In plasma, FVIII binds rapidly to VWF with a very high affinity and a Kd of <1 nmol [101]. As a result of this, approximately 95% of plasma FVIII is bound to VWF multimers. The importance of this selleck chemicals llc relationship is immediately apparent from the situation in type 3 von Willebrand disease where a complete absence of VWF is associated with very low levels of FVIII. This is because free FVIII in plasma has a half-life of approximately 2 h, which in normal circumstances is greatly extended to approximately 12 h by binding to VWF [102]. In this sense the vast majority of FVIII already exists in plasma as an extended half-life preparation. That is to say we have a small molecule with a very short half-life attached to a much larger molecule with a longer half-life which then dictates the half-life of the small molecule. It therefore seems unlikely that we will be able to prolong the half-life of the FVIII–VWF complex by modifying the FVIII molecule. Thus, we are limited to modifying the survival of the free 5% of FVIII that is not bound to VWF and which has a short half-life.