Extravascular distribution of factor IX-review of experimental and clinical evidence, and relevance for hemophilia B replacement therapy.

Factor IX (FIX) is a relatively small molecule (55 kDa) that distributes physiologically beyond the plasma pool into the extravascular space. This contrasts with factor VIII, which is confined to the bloodstream as a consequence of its larger size (∼300 kDa) and binding to von Willebrand factor. The extravascular distribution of FIX may be significant in relation to factor replacement therapy in patients with hemophilia B. Given the increasing number of relevant publications over recent years, we critically reviewed and evaluated the experimental and clinical data relating to the extravascular distribution of FIX, considering both the native molecule and therapeutic products generated via biotechnological approaches. Endogenous FIX has an extensive distribution to tissues outside of plasma and is in dynamic equilibrium between plasma and the extravascular compartment. Approximately two-thirds of total FIX exists reversibly bound to type IV collagen in the vessel wall and extravascular space. This may produce an extravascular reservoir of FIX extending the plasma hemostatic role. Consequently, plasma FIX activity alone may not fully reflect the hemostatic potential of FIX prophylactic treatment. Extravascular FIX could be relevant for controlling and preventing both clinical and subclinical bleeds. When used as prophylactic treatment, extended half-life FIX products demonstrate similar annualized bleeding rates, but with a wide range of FIX trough levels and varying extents of extravascular distribution. Clinical implications of variation between FIX products remain to be fully understood; more knowledge is required. Further studies may help to address knowledge gaps, potentially informing treatment optimization.