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 mopexin among Caucasians, and ALCAM, VCAM-1, TFPI and PF-4 among Asians.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

37 actor (TF), TF pathway inhibitor (TFPI), and TFPI-2 were low in the microcirculation of the liver, lu

38 ed lower levels of heparanase, TF, TFPI, and TFPI-2 in metastasis blood vessels compared to those in

39 with low levels of heparanase, TF, TFPI, and TFPI-2 in the microcirculation, which enables tumor cell

40 ecreased levels of heparanase, TF, TFPI, and TFPI-2, and the effect was reversed by a peptide-inhibit

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

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

43 susceptible to inactivation by both ZPI and TFPI.

44 a to inhibition by plasma inhibitors ZPI and TFPI.

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

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

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

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

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

50 the Kunitz 1 domain from membrane-associated TFPI.

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

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

53 Because TFPI is associated with lipoproteins and its carboxyl te

54 Because TFPI is sequestered within platelets and released follow

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

75 Decreased TFPI activity coincided with the release of tissue plasm

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

77 induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolase

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

79 for endothelial- and myelomonocytic-derived TFPI.

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

81 is required for TF inhibition, and disabling TFPI prevents aPL signaling, indicating a paradoxical pr

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

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

84 n might be aggravated by reduced endothelial TFPI.

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

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

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

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

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

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

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

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

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

94 fied mechanism of antibacterial activity for TFPI.

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

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

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

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

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

100 icating a paradoxical prothrombotic role for TFPI.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

142 Cell surface TF pathway inhibitor (TFPI) synthesized by monocytes is required for TF inhibi

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

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

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

146 e, tissue factor (TF), TF pathway inhibitor (TFPI), and TFPI-2 were low in the microcirculation of th

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

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

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

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

151 domain from tissue factor pathway inhibitor (TFPI).

152 function of tissue factor pathway inhibitor (TFPI).

153 activity of tissue factor pathway inhibitor (TFPI).

154 (EPCR), and tissue factor pathway inhibitor (TFPI).

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

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

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

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

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

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

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

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

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

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

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

166 Most TFPI in vivo associates with caveolae in endothelial cel

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

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

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

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

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

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

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

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

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

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

177 Blockage of TFPI inhibition may facilitate thrombin generation in a

178 for FXa to below the plasma concentration of TFPI.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

197 isms that regulate the natural expression of TFPI.

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

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

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

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

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

203 thrombin generation through inactivation of TFPI.

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

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

206 Inhibition of TFPI enhances coagulation in hemophilia models.

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

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

209 Messages for 2 isoforms of TFPI have been identified.

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

211 Knowledge of TFPI isoform expression and activity provides new insigh

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 Myeloid cell-specific TFPI inactivation has no effect on models of arterial or

257 ue functions for these alternatively spliced TFPI isoforms.

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

259 demonstrated lower levels of heparanase, TF, TFPI, and TFPI-2 in metastasis blood vessels compared to

260 to organs with low levels of heparanase, TF, TFPI, and TFPI-2 in the microcirculation, which enables

261 xpressed decreased levels of heparanase, TF, TFPI, and TFPI-2, and the effect was reversed by a pepti

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

263 They demonstrate that TFPI physiologically modulates thrombin-dependent platel

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

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

266 We hypothesize that TFPI has evolved sensitivity to proteolytic inactivation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

287 re aptamer binds tightly and specifically to TFPI.

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

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

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

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

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

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

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

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

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

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

298 0.4nM for TFPI(WT)) and not detectable with TFPI-(DeltaK3).

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

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

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

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

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