Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden

Eitzman, Daniel T.; Westrick, Randal J.; Bi, Xiaoming; Manning, Sara L.; Wilkinson, John E.; Broze, George J.; Ginsburg, David

doi:10.1161/01.cir.0000017361.39256.82

Cited by 66 publications

(68 citation statements)

References 22 publications

(21 reference statements)

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“…162,163 Transgenic mice obtained by crossing mice with reduced levels of TFPI with mice homozygous for factor V LEIDEN resulted in mice with a lethal phenotype with fibrin deposition in multiple organs. 164 The observation of disseminated thrombosis in mice homozygous for the factor V LEIDEN mutation and low levels of TFPI is in keeping with the hypothesis suggested by in vitro data. 163 Thus, reduced TFPI levels may be a contributor to thrombosis in association with factor V LEIDEN .…”

Section: Potential Influence Of Combined Pathology Associated With Fasupporting

confidence: 83%

Factor V: a combination of Dr Jekyll and Mr Hyde

Mann

Kalafatis

2003

Blood

220

246

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Section: Potential Influence Of Combined Pathology Associated With Fasupporting

confidence: 83%

Factor V: a combination of Dr Jekyll and Mr Hyde

Mann

Kalafatis

2003

Blood

220

246

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“…Previous studies have demonstrated that Tfpi +/− contributes to a severe thrombosis in mice when in the presence of an underlying procoagulant state, such as the factor V Leiden mutation (26) or decreased thrombomodulin function (27). Conversely, studies performed here show that breeding of Tfpi +/− to F8 −/− mice does not alter the hemophilia bleeding phenotype, as assessed using whole-blood TEG and tail bleeding assays.…”

Section: Discussioncontrasting

confidence: 51%

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Maroney

Cooley

Ferrel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8 −/− ) did not rescue the embryonic death of TFPI null (Tfpi −/− ) mice. Tfpi +/− did not alter the bleeding phenotype of F8 −/− mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8 −/− mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi +/− ;F8 −/− mice with hematopoietic Tfpi −/− cells compared with Tfpi +/− ;F8 −/− mice with Tfpi +/+ hematopoietic cells. Additionally, following femoral vein injury, Tfpi +/− ;F8 −/− mice with Tfpi −/− hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi +/+ hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.hemostasis | Kunitz | coagulopathy

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“…44 TFPI from trophoblasts as well as from the maternal circulation in the TFPI Tie2 mice may be sufficient to maintain the TF-TFPI balance required for placental hemostasis and embryogenesis. When TFPI heterozygosity (TFPI ϩ/Ϫ ) is bred into mice with other prothrombotic genetic traits such as factor V Leiden 13 or thrombomodulin deficiency, 14 thrombotic disease occurs with multiple manifestations including intrauterine lethality, perinatal lethality, and hypercoagulability in surviving adult mice.…”

Section: Discussionmentioning

confidence: 99%

“…11 Heterozygotic deletion results in an increased response to acute and chronic vascular injury. [12][13][14] Conversely, vasculardirected overexpression of TFPI attenuates this response. 15 To better define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis, we generated mice with endothelial and monocytic-restricted deletion of exon 4, which encodes for the TFPI-K1 domain.…”

mentioning

confidence: 99%

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

White

Johnson

Zarzhevsky

et al. 2010

Blood

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The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI Flox ) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI Tie2 ) and myelomonocytic (TFPI LysM ) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI Tie2 (71% ؎ 0.9%, P < .001) and TFPI LysM (19% ؎ 0.6%, P < .001) compared with TFPI Flox littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI Tie2 mice but not TFPI LysM mice had increased ferric chlorideinduced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial-and myelomonocytic-derived TFPI. (Blood. 2010;116(10):1787-1794) IntroductionThe endothelium provides an antithrombotic interface with circulating blood which is generated in part by the coordinated expression of endothelial-derived anticoagulants. The regulated expression of these endothelial-derived proteins may account in part for differences in thrombotic phenotype among vessels. 1 Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor expressed in endothelial cells and regulates the initiation of coagulation by inhibiting tissue factor (TF)/factor VIIa activation of factor X.TFPI, originally known as lipoprotein associated coagulation inhibitor, was isolated from a hepatoma cell line. 2 TFPI circulates at low (nmol/L) levels in humans largely associated with lipoproteins. 3 Infusion of heparin increases circulating levels of TFPI in humans, and this increase has been attributed to displacement of TFPI from glycosoaminoglycans on the surface of endothelial cells. 4,5 As such, the endothelium has been thought to be the dominant source of circulating TFPI. However, TFPI is also expressed in platelets, vascular smooth muscle, cardiac myocytes, and monocyte/macrophages. 4,[6][7][8][9][10] The physiologic importance of TFPI is confirmed in that no known human deficiencies of TFPI have been reported. Homozygotic deletion of exon 4 in mice (which encodes the Kunitz 1 domain) resulted in embryonic lethality. 11 Heterozygotic deletion results in an increased response to acute and chronic vascular injury. [12][13][14] Conversely, vasculardirected overexpression of TFPI attenuates this response. 15 To better define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis, we generated mice with endothelial and monocytic-restricted deletion of exon 4, which encodes for the TFPI-K1 domain. We also used bone marrow transplantation as a means to generate ...

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Lethal Perinatal Thrombosis in Mice Resulting From the Interaction of Tissue Factor Pathway Inhibitor Deficiency and Factor V Leiden

Cited by 66 publications

References 22 publications

Factor V: a combination of Dr Jekyll and Mr Hyde

Factor V: a combination of Dr Jekyll and Mr Hyde

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis

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