Dysfunctional endogenous FIX impairs prophylaxis in a mouse hemophilia B model

Brian Cooley, George J. Broze, David M. Mann, Feng Chang Lin, Lee G. Pedersen, Darrel W. Stafford

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1 Scopus citations

Abstract

Factor IX (FIX) binds to collagen IV (Col4) in the subendothelial basement membrane. In hemophilia B, this FIX-Col4 interaction reduces the plasma recovery of infused FIX and plays a role in hemostasis. Studies examining the recovery of infused BeneFix (FIXWT) in null (cross-reactive material negative, CRM2) hemophilia B mice suggest the concentration of Col4 readily available for binding FIX is ∼405 nM with a 95% confidence interval of 374 to 436 nM. Thus, the vascular cache of FIX bound to Col4 isseveral-fold the FIX level measured inplasma. In a mouse model of prophylactic therapy (testing hemostasis by saphenous vein bleeding 7 days after infusion of 150 IU/kg FIX), FIXWT and the increased half-life FIXs Alprolix (FIXFC) and Idelvion (FIXAlb) produce comparable hemostatic results in CRM2 mice. In bleeding CRM2hemophilia B mice, the times to first clot at a saphenous vein injury site after the infusions of the FIX agents are significantly different, at FIXWT < FIXFC < FIXAlb. Dysfunctional forms of FIX, however, circulate in the majority of patients with hemophilia B (CRM1). In the mouse prophylactic therapy model, none of the FIX products improves hemostasis in CRM1 mice expressing a dysfunctional FIX, FIXR333Q, that nevertheless competes with infused FIX for Col4 binding and potentially other processes involving FIX. The resultsinthis mouse model of CRM1hemophiliaB demonstrate that the endogenous expression of a dysfunctional FIX can deleteriously affect the hemostatic response to prophylactic therapy.

Original languageEnglish
Pages (from-to)2445-2451
Number of pages7
JournalBlood
Volume133
Issue number22
DOIs
StatePublished - May 30 2019

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    Cooley, B., Broze, G. J., Mann, D. M., Lin, F. C., Pedersen, L. G., & Stafford, D. W. (2019). Dysfunctional endogenous FIX impairs prophylaxis in a mouse hemophilia B model. Blood, 133(22), 2445-2451. https://doi.org/10.1182/blood.2018884015