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A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X
Author(s) -
TAI S. J.,
HERZOG R. W.,
MARGARITIS P.,
ARRUDA V. R.,
CHU K.,
GOLDEN J. A.,
LABOSKY P. A.,
HIGH K. A.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.02849.x
Subject(s) - factor (programming language) , transfer factor , factor x , biology , computer science , immunology , platelet , thrombin , programming language
Summary. Background: Activated factor X (FXa) is a vitamin K‐dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal. Objective: We sought to generate a viable mouse model of FX deficiency. Methods: We used a socket‐targeting construct to generate F10 ‐knockout mice by eliminating F10 exon 8 (knockout allele termed F10 tm1Ccmt , abbreviated as ‘−’; wild‐type ‘+’), and a plug‐targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4–9% normal in humans carrying the defect, Pro 343 →Ser, termed FX Friuli (mutant allele termed F10 tm2Ccmt , abbreviated as F)]. Results: F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [ F10 (F/F)] had FX activity levels of ∼5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age‐dependent iron deposition and cardiac fibrosis. Interestingly, F10 (−/F) mice with FX activity levels of 1–3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival. Conclusions: We demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1–3% is sufficient to rescue the lethal phenotype. This viable low‐FX mouse model will facilitate the development of FX‐directed therapies as well as investigation of the FX role in embryonic development.