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Dysfunctional endogenous FIX impairs prophylaxis in a mouse hemophilia B model.
- Source :
-
Blood [Blood] 2019 May 30; Vol. 133 (22), pp. 2445-2451. Date of Electronic Publication: 2019 Apr 16. - Publication Year :
- 2019
-
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 (FIX <subscript>WT</subscript> ) in null (cross-reactive material negative, CRM <superscript>-</superscript> ) 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 is several-fold the FIX level measured in plasma. In a mouse model of prophylactic therapy (testing hemostasis by saphenous vein bleeding 7 days after infusion of 150 IU/kg FIX), FIX <subscript>WT</subscript> and the increased half-life FIXs Alprolix (FIX <subscript>FC</subscript> ) and Idelvion (FIX <subscript>Alb</subscript> ) produce comparable hemostatic results in CRM <superscript>-</superscript> mice. In bleeding CRM <superscript>-</superscript> hemophilia B mice, the times to first clot at a saphenous vein injury site after the infusions of the FIX agents are significantly different, at FIX <subscript>WT</subscript> < FIX <subscript>FC</subscript> < FIX <subscript>Alb</subscript> Dysfunctional forms of FIX, however, circulate in the majority of patients with hemophilia B (CRM <superscript>+</superscript> ). In the mouse prophylactic therapy model, none of the FIX products improves hemostasis in CRM <superscript>+</superscript> mice expressing a dysfunctional FIX, FIX <subscript>R333Q</subscript> , that nevertheless competes with infused FIX for Col4 binding and potentially other processes involving FIX. The results in this mouse model of CRM <superscript>+</superscript> hemophilia B demonstrate that the endogenous expression of a dysfunctional FIX can deleteriously affect the hemostatic response to prophylactic therapy.<br /> (© 2019 by The American Society of Hematology.)
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 133
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 30992271
- Full Text :
- https://doi.org/10.1182/blood.2018884015