Because extravascular FIX is physiologically important, its circulating levels do not independently predict hemostatic potential.
A saphenous vein hemophilia B mouse model shows that 7 days post infusion FIX-Fc and FIX provide equal hemostatic protection.
FIX binds tightly to collagen IV. Furthermore, a FIX mutant, FIXK5R, which binds better than wild-type FIX to collagen IV, provides better hemostasis than wild-type FIX, long after both are undetectable in the plasma. There is also credible evidence of extra-vascular FIX. Here, we use the saphenous vein bleeding model to compare the efficacy of recombinant FIXFc (Alprolix) and wild-type FIX (BeneFIX) in hemophilia B mice 7 days post-infusion. Although the terminal half-life of Alprolix is significantly longer than that of BeneFIX, at equal doses Alprolix is not better at controlling bleeding 7 days post-infusion, presumably because of the extravascular FIX. Both BeneFIX and Alprolix exhibit a linear response in clotting efficacy up to 150 IU/kg, where they appear to saturate an extravascular compartment, as there is no additional prophylactic benefit from higher doses. A robust pool of extravascular FIX is clearly observed surrounding blood vessels, localized to the same region as collagen IV, in two representative human tissues: liver and skeletal muscle. We see no increased risk for thrombosis at 250 IU/kg FIX at 6 hours post-infusion. In summary, 7 days post-infusion into hemophilia B mice, BeneFIX and Alprolix are hemostatically indistinguishable despite the latter's increased half-life. We predict that doses of FIX approximately 3 times higher than the currently recommended 40-50 IU/kg will, because of FIX's large extravascular compartment, efficiently prolong prophylactic hemostasis without thrombotic risk.
- Submitted January 28, 2016.
- Accepted April 20, 2016.
- Copyright © 2016 American Society of Hematology
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