ライフサイエンスコーパス: TFPI

1 TFPI can also inhibit prothrombinase assembly by directl

2 TFPI co-localized with TF and FVII on endothelium and le

3 TFPI did not affect CD26 activity, migration, or homing

4 TFPI inactivation is mediated by proteolysis since Weste

5 TFPI is an essential reversible inhibitor of activated f

6 TFPI is expressed on the platelet surface following dual

7 TFPI is produced by megakaryocytes but is not expressed

8 TFPI is the TF pathway inhibitor that is involved in coa

9 TFPI Kunitz domain 3 is required for this enhancement to

10 TFPI Kunitz domain 3 residue Glu226 is essential for enh

11 TFPI levels were elevated for the duration of the study

12 TFPI-2 (~7 nM) in plasma of women at the onset of labor

13 TFPI-2 expression was diminished or absent in 16 of 32 c

14 TFPI-2 has recently been recognized as a tumor suppresso

15 TFPI-2 promoter methylation was observed in one of five

16 ) gene or tissue factor pathway inhibitor 1 (TFPI) gene results in embryonic lethality, indicating th

17 ified was tissue factor pathway inhibitor 2 (TFPI-2), which encodes for a broad-spectrum serine prote

18 Tissue factor pathway inhibitor-2 (TFPI-2) inhibits factor XIa, plasma kallikrein, and fact

19 Tissue factor pathway inhibitor-2 (TFPI-2) is a homologue of TFPI-1 and contains three Kuni

20 Human tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type proteinase inhibitor that regul

21 ession of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signa

22 egy and generated mice with a floxed exon 4 (TFPI(Flox)) which encodes for the TFPI-K1 domain.

23 A TFPI Lys86Ala mutation between the Kunitz 1 and 2 domain

24 Protein S is a TFPI cofactor, enhancing the efficiency of FXa inhibitio

25 patients (p = 0.0002), and no patient with a TFPI/TF MP ratio >0.7 had a history of clinical thrombos

26 ffinity (K(D) = 25pM) mAb, mAb 2021, against TFPI was investigated.

27 Blocking antibodies against TFPI increased fibrin deposition in septic baboon lungs,

28 a) by tissue factor pathway inhibitor-alpha (TFPI-alpha) in the presence of Ca(2+) and phospholipids.

29 Wild-type TFPI-alpha (TFPI(WT)), TFPI-alpha lacking the K3 domain (TFPI-(Delta

30 the TFPI(Tie2) (71% +/- 0.9%, P < .001) and TFPI(LysM) (19% +/- 0.6%, P < .001) compared with TFPI(F

31 lasmon resonance data reveal that TFPI-2 and TFPI-1 bind FV-1033 with K(d) ~36-48 nM and bind FVa wit

32 When both AT and TFPI were present, active IXabeta formation significantl

33 lacking the K3 domain (TFPI-(DeltaK3)), and TFPI-alpha containing a single amino acid change at the

34 alpha involves an interaction between PS and TFPI-alpha, which requires the K3 domain of TFPI-alpha.

35 ntigen and mRNA decreased during sepsis, and TFPI activity diminished abruptly at 2 hours.

36 mbryonic fibroblasts (MEFs), we found TF and TFPI are differentially expressed in the PAK1-KO MEFs in

37 udy the transcriptional regulation of TF and TFPI by PAK1, a serine/threonine kinase.

38 an imbalance between microparticulate TF and TFPI may predispose to thrombosis.

39 t implications for the regulation of TF- and TFPI-dependent biologic responses and for fine tuning of

40 Warfarin treatment and TFPI overexpression both had a protective effect on fibr

41 nts demonstrated that FXa bound TFPI(WT) and TFPI-(DeltaK3) but not the isolated K3 domain, whereas P

42 a to inhibition by plasma inhibitors ZPI and TFPI.

43 susceptible to inactivation by both ZPI and TFPI.

44 intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding.

45 Caveolae-associated TFPI supports the co-localization of the quaternary comp

46 ar disease correlates with low EC-associated TFPI, we sought to identify mechanisms that regulate the

47 inhibitor-1 led to decreased lung-associated TFPI and unforeseen massive fibrin deposition.

48 Lung-associated TFPI antigen and mRNA decreased during sepsis, and TFPI

49 the Kunitz 1 domain from membrane-associated TFPI.

50 d with silencing and repressive chromatin at TFPI-2.

51 We have modelled antisense RNA expression at TFPI-2 in transgenic mouse embryonic stem (ES) cells and

52 Because TFPI is associated with lipoproteins and its carboxyl te

53 Because TFPI is sequestered within platelets and released follow

54 oarrays revealed strong coexpression between TFPI and the uncharacterized protein encoded by C6ORF105

55 nd subsequently optimized peptides that bind TFPI and block its anticoagulant activity.

56 ARC19499 blocks TFPI inhibition of both factor Xa and the TF/factor VIIa

57 veolae regulate the inhibition by cell-bound TFPI of the active protease production by the extrinsic

58 ance experiments demonstrated that FXa bound TFPI(WT) and TFPI-(DeltaK3) but not the isolated K3 doma

59 PS bound TFPI efficiently, independently of Zn(2+) content (K(d)(

60 not the isolated K3 domain, whereas PS bound TFPI(WT) and the K3 domain but not TFPI-(DeltaK3).

61 ition of TF-FVIIa-catalyzed FX activation by TFPI (EC50 = 2 nM).

62 in VAP and may not be adequately balanced by TFPI.

63 iven coagulation not adequately countered by TFPI may underlie the widespread thrombotic complication

64 system, compound 3 blocked FXa inhibition by TFPI (EC50 = 11 nM) and inhibition of TF-FVIIa-catalyzed

65 expression, and increases FXa inhibition by TFPI in an ADTRP- and caveolin-1-dependent manner.

66 PS-mediated enhancement of FXa inhibition by TFPI-alpha involves an interaction between PS and TFPI-a

67 ation and the anticoagulant role of caveolar TFPI are not yet known.

68 d in F8(-/-) mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation.

69 Murine models of combined TFPI and factor VIII deficiency were used to examine the

70 In conclusion, TFPI-2 in platelets from normal or pregnant subjects and

71 Imaging and Triton X-114-extraction confirm TFPI and ADTRP association with lipid rafts/caveolae.

72 ells, and bone marrow megakaryocytes contain TFPI-2.

73 o of TFPI positive to TF positive MP counts (TFPI/TF) was significantly lower in Th+ versus Th- BS pa

74 Decreased TFPI activity coincided with the release of tissue plasm

75 d into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI(Tie2)) and myelomonocytic (

76 ured ECs, and we named it androgen-dependent TFPI-regulating protein (ADTRP).

77 for endothelial- and myelomonocytic-derived TFPI.

78 lized both endothelium- and platelet-derived TFPI by cleaving the protein between the Kunitz (K) 1 an

79 TFPI(WT)), TFPI-alpha lacking the K3 domain (TFPI-(DeltaK3)), and TFPI-alpha containing a single amin

80 PI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid me

81 n might be aggravated by reduced endothelial TFPI.

82 -Cre lines to delete TFPI-K1 in endothelial (TFPI(Tie2)) and myelomonocytic (TFPI(LysM)) cells result

83 ecombinant B-domain-deleted FV could enhance TFPI-mediated inhibition of FXa in the presence of prote

84 th arrest-specific 6, were unable to enhance TFPI.

85 d/activated by thrombin or FXa also enhanced TFPI-mediated inhibition of FXa approximately 12-fold in

86 ulates both the native and androgen-enhanced TFPI expression and activity in cultured ECs, and we nam

87 mediated FXa inhibition, it further enhanced TFPI in the presence of protein S, resulting in an appro

88 FV(DeltaIIa) (but not activated FV) enhanced TFPI function in the presence of protein S.

89 es, while over-expression of ADTRP enhances, TFPI mRNA and activity and the colocalization of TF-FVII

90 (EC(50) 61.8 +/- 13.4nM vs 8.0 +/- 0.4nM for TFPI(WT)) and not detectable with TFPI-(DeltaK3).

91 fied mechanism of antibacterial activity for TFPI.

92 I-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation

93 induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state.

94 itz domain 3 residue Glu226 is essential for TFPI enhancement by protein S.

95 Hence, we present a novel role for TFPI and GPC3 in regulating HSC homing as well as retent

96 mbryonic development and identify a role for TFPI in dampening intravascular procoagulant stimuli tha

97 Recent studies have found TFPI inhibits prothrombinase activity during the initiat

98 Further, TFPI-1 (but not TFPI-1161) competes with TFPI-2 in bindi

99 IX through the formation of the TF-FVIIa-FXa-TFPI complex.

100 ivity and the colocalization of TF-FVIIa-FXa-TFPI with caveolin-1.

101 ut did not affect formation of the loose FXa-TFPI complex.

102 (TF-FVIIa) via formation of a quaternary FXa-TFPI-TF-FVIIa complex.

103 d transition from the loose to the tight FXa-TFPI complex, but did not affect formation of the loose

104 the transition of the loose to the tight FXa-TFPI complex.

105 antisense to the metastasis-suppressor gene TFPI-2.

106 stantially greater than that of TFPI(K3P1) > TFPI-(DeltaK3) in normal plasma and PS-deficient plasma

107 However, TFPI(Tie2) mice but not TFPI(LysM) mice had increased fe

108 ation during thrombus formation, implicating TFPI in modulating platelet procoagulant activity.

109 Importantly, TFPI-2 in platelets and in plasma of pregnant women inhi

110 Thrombin-generation assays in TFPI-depleted plasma identified a novel variant, TFPI E2

111 r IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the

112 een a shorter form of factor V and increased TFPI levels, resulting in severely reduced thrombin gene

113 DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 e

114 Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression i

115 lasma, we hypothesized that FV may influence TFPI inhibitory function.

116 und that although FV alone did not influence TFPI-mediated FXa inhibition, it further enhanced TFPI i

117 F expression and its physiological inhibitor TFPI would allow us to understand the critical step that

118 sing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p < 0.0001).

119 It inhibits tissue factor pathway inhibitor (TFPI) activity and accelerates clotting of human hemophi

120 identified tissue-factor pathway inhibitor (TFPI) as a biological inhibitor of CD26 in murine and hu

121 Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood

122 Tissue factor pathway inhibitor (TFPI) blocks tissue factor-factor VIIa (TF-FVIIa) activa

123 Tissue factor pathway inhibitor (TFPI) down-regulates the initiation of coagulation by in

124 ith reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inh

125 Tissue factor pathway inhibitor (TFPI) is a critical anticoagulant protein present in end

126 Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits

127 Tissue factor pathway inhibitor (TFPI) is a major regulator of blood clotting.

128 Tissue factor (TF) pathway inhibitor (TFPI) is a well-characterized activated factor X (FXa)-d

129 ticoagulant tissue factor pathway inhibitor (TFPI) is also highly sensitive to proteolysis by Pla and

130 Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits tissue f

131 Tissue Factor Pathway Inhibitor (TFPI) is the major inhibitor of tissue factor-factor VII

132 Tissue factor pathway inhibitor (TFPI) is the major physiologic inhibitor of the extrinsi

133 Tissue factor pathway inhibitor (TFPI) is the primary physiologic inhibitor of tissue fac

134 of the tissue factor (TF) pathway inhibitor (TFPI) isoforms, TFPIalpha and TFPIbeta, have provided ne

135 Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulate

136 Tissue factor pathway inhibitor (TFPI) plays an important role in regulating TF-initiated

137 Tissue factor pathway inhibitor (TFPI) produces factor Xa-dependent feedback inhibition o

138 endent tissue factor (TF) pathway inhibitor (TFPI) regulating protein] gene increases the risk of cor

139 ofactor for tissue factor pathway inhibitor (TFPI) that critically reduces the inhibition constant fo

140 d levels of tissue factor pathway inhibitor (TFPI) were strongly increased.

141 ofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X

142 r (ZPI) and tissue factor pathway inhibitor (TFPI), effectively inhibit the activity of activated fac

143 s were stained for TF, TF-pathway inhibitor (TFPI), factor VII (FVII), and markers for endothelial ce

144 Tissue factor pathway inhibitor (TFPI), the main inhibitor of initiation of coagulation,

145 egulated by tissue factor pathway inhibitor (TFPI), which inhibits both factor VIIa and its product,

146 domain from tissue factor pathway inhibitor (TFPI).

147 function of tissue factor pathway inhibitor (TFPI).

148 activity of tissue factor pathway inhibitor (TFPI).

149 ARC19499 is an aptamer that inhibits TFPI, thereby enabling clot initiation and propagation v

150 However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated t

151 ion of caveolin-1 (Cav-1) in 293 cells keeps TFPI exposed on the plasmalemma surface, decreases the m

152 are the first adult mice described that lack TFPI with unaltered TF.

153 Mice lacking TFPI (Tfpi(-/-)) die in utero from disseminated intravas

154 Because full-length TFPI associates with FV in plasma, we hypothesized that

155 Full-length TFPI-2 or its isolated first Kunitz domain (KD1) also in

156 We observed low-level TFPI expression in endothelial cells in the bone marrow

157 In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin.

158 in cell lines that harbored fully methylated TFPI-2.

159 es with unmethylated or partially methylated TFPI-2, but failed to induce the expression in cell line

160 Most TFPI in vivo associates with caveolae in endothelial cel

161 endothelial (TFPI(Tie2)) and myelomonocytic (TFPI(LysM)) cells resulted in viable and fertile offspri

162 However, TFPI(Tie2) mice but not TFPI(LysM) mice had increased ferric chloride-induced ar

163 PS bound TFPI(WT) and the K3 domain but not TFPI-(DeltaK3).

164 Further, TFPI-1 (but not TFPI-1161) competes with TFPI-2 in binding to FV.

165 e Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extens

166 to plasma was able to reverse the ability of TFPI to prolong TF-initiated clotting times in FXI- or F

167 DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells.

168 e the in vitro antiproliferative activity of TFPI is mediated through interaction with the VLDL recep

169 Addition of TFPI(WT), TFPI(K3P1), or TFPI-(DeltaK3) produced compara

170 hat platelets contain significant amounts of TFPI-2 derived from megakaryocytes.

171 We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to i

172 Blockage of TFPI inhibition may facilitate thrombin generation in a

173 for FXa to below the plasma concentration of TFPI.

174 (-/-)) did not rescue the embryonic death of TFPI null (Tfpi(-/-)) mice.

175 topoietic stem cells, and for development of TFPI-blocking pharmaceuticals to treat hemophilia.

176 high affinity to the Kunitz-1 (K1) domain of TFPI (Kd approximately 1 nM).

177 The K1 domain of TFPI binds and inhibits FVIIa and the K2 domain similarl

178 deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice.

179 The N-terminal domain of TFPI-2 is the only inhibitory domain, and it inhibits pl

180 The role of the Kunitz-3 domain of TFPI-alpha, however, has remained an enigma.

181 TFPI-alpha, which requires the K3 domain of TFPI-alpha.

182 ient plasma, but the anticoagulant effect of TFPI(WT) was substantially greater than that of TFPI(K3P

183 sidue Glu226 is essential for enhancement of TFPI by protein S.

184 assays in which no protein S enhancement of TFPI E226Q was detected.

185 olecular mechanism underlying enhancement of TFPI function, in the present study, we produced a panel

186 pe 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using su

187 nts, we show further that the enhancement of TFPI-mediated FXa inhibition by protein S and FV depends

188 rotein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free prote

189 PAK1 negatively regulates the expression of TFPI and additionally contributes to increased TF activi

190 Expression of TFPI on the platelet surface may be the optimal location

191 s not cause release or surface expression of TFPI, demonstrating that TFPI is not stored within plate

192 showed that, with either over-expression of TFPI-2 or after treatment with exogenous rTFPI-2, breast

193 isms that regulate the natural expression of TFPI.

194 Our studies show that the form of TFPI released by PIPLC treatment of cultured endothelial

195 have suggested that the predominant form of TFPI released from cells by phosphatidylinositol-specifi

196 udy, we identify a 23-amino acid fragment of TFPI (TFPIc23) localized to the C-terminus, which mediat

197 thway inhibitor-2 (TFPI-2) is a homologue of TFPI-1 and contains three Kunitz-type domains and a basi

198 eficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia.

199 e demonstrate that bacterial inactivation of TFPI requires omptin expression.

200 thrombin generation through inactivation of TFPI.

201 Induction of TFPI-2 by distinct, yet cooperative mechanisms involving

202 Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment res

203 Inhibition of TFPI enhances coagulation in hemophilia models.

204 ults demonstrate that ARC19499 inhibition of TFPI may be an effective alternative to current treatmen

205 In the nucleus, interaction of TFPI-2 with Ap-2alpha attenuated the binding of AP-2alph

206 Messages for 2 isoforms of TFPI have been identified.

207 re of this peptide in complex with the K1 of TFPI at 2.55-A resolution.

208 Knowledge of TFPI isoform expression and activity provides new insigh

209 et function would compensate for the lack of TFPI and rescue TFPI-null embryonic lethality, Tfpi(+/-)

210 PI mice have increased circulating levels of TFPI antigen, we examined whether TFPIct may act to alte

211 Nuclear localization of TFPI-2 contributed to inhibition of MMP-2 mRNA expressio

212 Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines.

213 Loss of TFPI-2 expression was associated with aberrant hypermeth

214 , we investigated the potential mechanism of TFPI-2 in the suppression of breast cancer growth and in

215 , decreases the membrane lateral mobility of TFPI, and increases the TFPI-dependent inhibition of TF-

216 This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option

217 These studies suggest that overexpression of TFPI lowers plasma cholesterol through the interaction o

218 ing that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding.

219 y revealed that the inhibitory properties of TFPI were diminished in EC lacking Cav-1, apparently thr

220 However, the anticoagulant properties of TFPI-2 or KD1 would diminish its antifibrinolytic functi

221 the Th- group, but had a lower proportion of TFPI positive MPs (p < 0.05).

222 Rates of TFPI inactivation were much higher than rates of plasmin

223 Consequently, the ratio of TFPI positive to TF positive MP counts (TFPI/TF) was sig

224 st, the Xa-dependent inhibitory reactions of TFPI play a primary role in limiting zymogen consumption

225 indicate that the C-terminal basic region of TFPI-2 is similar to that of TFPI-1 and plays a role in

226 de that the ADTRP-dependent up-regulation of TFPI expression and activity by androgen represents a no

227 Here we define the cellular sources of TFPI and their role in development, hemostasis, and thro

228 I(WT) was substantially greater than that of TFPI(K3P1) > TFPI-(DeltaK3) in normal plasma and PS-defi

229 basic region of TFPI-2 is similar to that of TFPI-1 and plays a role in binding to the FV B-domain ac

230 duced a panel of Kunitz domain 3 variants of TFPI encompassing all 12 surface-exposed charged residue

231 Addition of TFPI(WT), TFPI(K3P1), or TFPI-(DeltaK3) produced comparable prolongation of FXa-i

232 cipal physiologic inhibitors of this pathway TFPI and antithrombin III (AT).

233 Plasma TFPI activity was reduced in the TFPI(Tie2) (71% +/- 0.9

234 However, plasma TFPI-2 levels are negligible (</=20 pM) in the context o

235 reater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool o

236 These findings implicate platelet TFPI as a primary physiological regulator of bleeding in

237 g their activation, the function of platelet TFPI was examined in F8(-/-) mice lacking hematopoietic

238 xpression on the surface of coated platelets TFPI is also released in microvesicles or as a soluble p

239 on-related molecules (SERPINB2, PLAU, PLAUR, TFPI, THBD).

240 nge at the putative P1 residue of K3 (R199L, TFPI(K3P1)) produced equivalent FXa inhibition in the ab

241 Receipt of recombinant TFPI (rTFPI) protected animals from death in Escherichia

242 rapeutic implications for use of recombinant TFPI to treat severe sepsis in community-acquired pneumo

243 Altered forms of recombinant TFPI-alpha were used to determine the structures within

244 56% of colorectal tumours exhibiting reduced TFPI-2 expression.

245 Dihydrotestosterone up-regulates TFPI and ADTRP expression, and increases FXa inhibition

246 d compensate for the lack of TFPI and rescue TFPI-null embryonic lethality, Tfpi(+/-) mice lacking th

247 otein S and FV depends on a direct protein S/TFPI interaction and that the TFPI C-terminal tail is no

248 nstrated that in addition to being secreted, TFPI-2 was also distributed throughout the cytoplasm and

249 -fat diet, smooth muscle 22alpha (SM22alpha)-TFPI/apoE(-/-) mice were shown to have less aortic plaqu

250 Because SM22alpha-TFPI mice have increased circulating levels of TFPI anti

251 se aortic smooth muscle cells from SM22alpha-TFPI and wild-type mice.

252 se aortic smooth muscle cells from SM22alpha-TFPI mice demonstrated higher VLDL binding and internali

253 Furthermore, SM22alpha-TFPI mice fed a high-fat diet had lower cholesterol leve

254 g tissue factor pathway inhibitor (SM22alpha-TFPI) were subjected to pIVCL or sham.

255 Unexpectedly, SM22alpha-TFPI/apoE(-/-) had lower plasma cholesterol levels compa

256 ue functions for these alternatively spliced TFPI isoforms.

257 Fragmented rTFPI and C-terminal TFPI peptide activities against pathogenic E. coli strai

258 Samples were assayed for PC, TF, TFPI, and thrombin-antithrombin complex (TATc).

259 They demonstrate that TFPI physiologically modulates thrombin-dependent platel

260 rface expression of TFPI, demonstrating that TFPI is not stored within platelet alpha granules.

261 e factor (TF) deficiency, demonstrating that TFPI modulates TF function in vivo.

262 We hypothesize that TFPI has evolved sensitivity to proteolytic inactivation

263 rotein (VLDL) receptor, we hypothesized that TFPI overexpression may regulate lipoprotein distributio

264 s of plasminogen activation, indicating that TFPI is a better substrate for omptins.

265 f surface plasmon resonance data reveal that TFPI-2 and TFPI-1 bind FV-1033 with K(d) ~36-48 nM and b

266 ELISA data reveal that TFPI-2 binds factor V (FV) and partially B-domain-delete

267 -down assays and Western blots, we show that TFPI-2 is associated with platelet FV/FVa.

268 ysis since Western blot analysis showed that TFPI cleavage correlated with loss of anticoagulant func

269 We have previously shown that TFPI is also a potent inhibitor of endothelial prolifera

270 peak of plasmin generation, suggesting that TFPI could undergo proteolytic inactivation by plasmin.

271 the TFPI-2 promoter activity, augmented the TFPI-2 expression in cell lines with unmethylated or par

272 ed exon 4 (TFPI(Flox)) which encodes for the TFPI-K1 domain.

273 Plasma TFPI activity was reduced in the TFPI(Tie2) (71% +/- 0.9%, P < .001) and TFPI(LysM) (19%

274 lateral mobility of TFPI, and increases the TFPI-dependent inhibition of TF-FVIIa.

275 s secrete TFPIalpha, greater than 95% of the TFPI released by PIPLC treatment from the surface of end

276 phorbol ester (PMA), known to stimulate the TFPI-2 promoter activity, augmented the TFPI-2 expressio

277 rect protein S/TFPI interaction and that the TFPI C-terminal tail is not essential for this enhanceme

278 lets and endothelial cells, suggest that the TFPI isoforms may act through distinct mechanisms to inh

279 We conclude that the TFPI Kunitz domain 3 residue Glu226 is essential for TFP

280 nning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay

281 Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa an

282 to wild-type TFPI, but almost no binding to TFPI E226Q.

283 Factor V Amsterdam binds to TFPI, prolonging its half-life and concentration.

284 re aptamer binds tightly and specifically to TFPI.

285 -dependent binding of protein S to wild-type TFPI, but almost no binding to TFPI E226Q.

286 Wild-type TFPI-alpha (TFPI(WT)), TFPI-alpha lacking the K3 domain

287 Using TFPI and protein S variants, we show further that the en

288 evelopment, hemostasis, and thrombosis using TFPI conditional knockout mice.

289 -depleted plasma identified a novel variant, TFPI E226Q, which exhibited minimal enhancement by prote

290 suggest that one of the mechanisms by which TFPI-2 inhibits breast cancer cell invasion could be via

291 irm ADTRP expression and colocalization with TFPI and caveolin-1 in ECs.

292 imately 8-fold reduction in Ki compared with TFPI alone.

293 LysM) (19% +/- 0.6%, P < .001) compared with TFPI(Flox) littermate controls.

294 er, TFPI-1 (but not TFPI-1161) competes with TFPI-2 in binding to FV.

295 0.4nM for TFPI(WT)) and not detectable with TFPI-(DeltaK3).

296 Treatment of HSPCs with TFPI in vitro led to enhanced HSPC migration toward CXCL

297 a inhibition produced by PS was reduced with TFPI(K3P1) (EC(50) 61.8 +/- 13.4nM vs 8.0 +/- 0.4nM for

298 were used to determine the structures within TFPI-alpha that may be involved in this PS-dependent eff

299 Wild-type TFPI-alpha (TFPI(WT)), TFPI-alpha lacking the K3 domain (TFPI-(DeltaK3)), and T

300 Addition of TFPI(WT), TFPI(K3P1), or TFPI-(DeltaK3) produced comparable prolon