BACKGROUND: Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor (TFPI) has also been proposed as a risk factor for venous thrombosis and has been shown to enhance the prothrombotic effect of FVL in vitro. METHODS AND RESULTS: To examine the potential in vivo interaction between Tfpi and FvL, we analyzed crosses between mice carrying FvL and a deficiency of TFPI. The Fv(Q/Q),Tfpi(+/-) genotype was nearly completely fatal in the early perinatal period. Increased fibrin deposition was observed in multiple organs from the Fv(Q/Q),Tfpi(+/-) fetuses, suggesting disseminated thrombosis. CONCLUSIONS: These observations demonstrate the prothrombotic effect of modest variations in the level of TFPI expression and suggest that TFPI could be an important genetic modifier for the thrombosis associated with FVL in humans.
BACKGROUND:Factor V Leiden (FVL) is a common genetic risk factor for thrombosis in humans. The incomplete penetrance of FVL suggests important contributions from other genetic or environmental modifying factors. Variation in the expression of tissue factor pathway inhibitor (TFPI) has also been proposed as a risk factor for venous thrombosis and has been shown to enhance the prothrombotic effect of FVL in vitro. METHODS AND RESULTS: To examine the potential in vivo interaction between Tfpi and FvL, we analyzed crosses between mice carrying FvL and a deficiency of TFPI. The Fv(Q/Q),Tfpi(+/-) genotype was nearly completely fatal in the early perinatal period. Increased fibrin deposition was observed in multiple organs from the Fv(Q/Q),Tfpi(+/-) fetuses, suggesting disseminated thrombosis. CONCLUSIONS: These observations demonstrate the prothrombotic effect of modest variations in the level of TFPI expression and suggest that TFPI could be an important genetic modifier for the thrombosis associated with FVL in humans.
Authors: Randal J Westrick; Kärt Tomberg; Amy E Siebert; Guojing Zhu; Mary E Winn; Sarah L Dobies; Sara L Manning; Marisa A Brake; Audrey C Cleuren; Linzi M Hobbs; Lena M Mishack; Alexander J Johnston; Emilee Kotnik; David R Siemieniak; Jishu Xu; Jun Z Li; Thomas L Saunders; David Ginsburg Journal: Proc Natl Acad Sci U S A Date: 2017-08-21 Impact factor: 11.205
Authors: Xunzhen Zheng; Weihong Li; Jian-Ming Gu; Dongfeng Qu; Gary L Ferrell; Naomi L Esmon; Charles T Esmon Journal: Blood Date: 2006-10-05 Impact factor: 22.113
Authors: Susan A Maroney; Brian C Cooley; Josephine P Ferrel; Catherine E Bonesho; Lone V Nielsen; Peter B Johansen; Mette B Hermit; Lars C Petersen; Alan E Mast Journal: Proc Natl Acad Sci U S A Date: 2012-02-21 Impact factor: 11.205