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1 2014; 25 1 : Novel findings and clinical application of tissue factor pathway inhibitor (TFPI) Kenichi OGIWARA, Keiji NOGAMI TFPI tissue factor pathway inhibitor TFPIα TFPIβ TFPIα C 2 V FV S PS FV FXa PS TFPI cofactor TFPI TFPI TFPI Key words: tissue factor pathway inhibitor (TFPI), factor V, protein S, hemophilia A 1 2 TFPI TFPI tissue factor pathway inhibitor C PC S PS AT TFPI TFPI TFPI 1 10 TFPI 10 roc-noga@naramed-u.ac.jp TFPI TFPI TFPI N 3 Kunitz-type K1 K2 K3 C 5 K1 FVIIa K2 FXa 2 TFPI-FXa TF/FVIIa 3 K3 C TFPI 5 TFPIα K3 C TFPIβ TFPIδ 4 TFPIβ K2 C GPI glycosylphosphatidyl inositol GPI 5 TFPIδ 4 TFPIα TFPIβ
2 12 1 TFPIαTFPIβ TFPIα N 3 Kunitz K1 K2 K3 C C TFPIβ N K1 K2 3 C GPI C GPI TFPI TFPIα TFPI GPI phosphatidylinositol-specific phospholipase C PIPLC TFPI 10 6 PIPLC TFPI C TFPIα GPI TFPIα coreceptor PIPLC TFPI K3 TFPI TFPIβ 7 / TFPI TFPI TFPIα α 8 TFPIα TFPI 20 C TFPIα TFPI 10 4 TFPI 80 K3 C LDL TFPI TFPIα TFPIβ TFPIδ 4 TFPI Broze 4 Girard 7 1 TFPI TFPIα C K1 K2 K3 C TFPIα TFPIα 3 TFPIα K2 FXa K1 FVIIa/TF 1 TFPI TFPI TFPI TFPIα N +K1+K2 N +K1+K2+K3 N +K1+K2+K3+C TFPIα 10 TFPIα 80 PIPLC > # TFPIβ 10 TFPIα 10 TFPIα TFPIα 10 TFPIα 10 TFPIα >300 ## TFPIα total TFPI 100Broze 4 TFPI total TFPI # 5 4 TFPIα TFPIβ 7 Broze ## TFPIα 30
3 13 FXa FVIIa/TF TFPIα TFPIβ 2 TFPIα FXa TFPIβ 20 9 K3 C K3 TFPIα PS 10 C 11 FV 12 TFPIα 13 TFPIα K3 C FV 2008 Duckers FV 10 FV FV TFPI 14 TFPI FV FV 15 FV TFPIα i Bos FV-B basic region: BR acidic region: AR FV FXa 2 3A 16 ii 12 FV A2440G 17 Vincent FV FV FV short 18 FV short B FV 2 TFPIα gainof-function TFPIα iii Wood TFPIα-C LIKTKRKRK FV-B BR LIKTRKKKK FV short BR AR α FV FVa AR FV short BR 2 2 FV FV short B FV B FXa FXa R 709 R 1018 AR FV FVa AR FIIa R 1545 FV FVa FXa FV short B AR TFPIα FV TFPIα C BR FV-BR FVa AR FXa FXa-FVa TFPIα 3A 19 K1 K2 K2 C TFPIα polyphosphate TFPIα PS TFPIα cofactor 3B 2006 PS APC cofactor FVa FVIIIa TFPIα FXa TFPI cofactor 20 TFPIα FXa PS 10 K i ; 4.5 nm 0.5 nm nm TFPIα FXa
4 14 A TFPIα FV FV AR 2A α TFPIα C FV AR B AR B TFPIα PS FXa FVIIa/TF TF FVIIa FXa FXa TFPIα K2 PS TFPIα K3 FXa FXa/TFPIα K1 FVIIa/TF TFPIα TF C TFPIβ FVIIa/TF TFPIβ PS FV GPI TF TF 3 TFPIα TFPIβ
5 15 K3 PS 10 PS PC TFPI TFPI polyphosphate polyp G TFPIα neutrophil extracellular traps NETsNETs TFPIα 22 polyp β TFPIα FVa 23 polyp TFPIα C BR 19 TFPIα TFPI TFPIα TFPIα 1 TFPIα B Maroney TFPI TFPI 24 TFPI 25 TFPI TFPI TFPIα TFPIα 25 4 TFPIβ TFPIβ TFPI 7 TFPIβ TF 3C TFPI K1 K2 FVIIa/TF Xa TFPIβ TFPIα TFPIβ K3 C GPI 5 Maroney CHO TFPIβ TFPIα TF/FVIIa FXa 26 TFPIβ GPI caveolae 27 TF/FVIIa 28 caveolae TFPI TFPI ADTRP: androgen-dependent TFPI-regulating protein 29 TFPIα TFPIβ TF TF TF FVIIa PAR-1 protease activated receptor-1 PAR-2 FVIIa/TF 30, 31 PAR TF TF 32, 33 TFPIβ PAR CHO TFPIβ TF TFPIα TFPI 3 26 TF SCID TFPIβ 26 TFPIβ TF 25 1
6 16 2 TFPI TFPIα/ Caputure Detect ng/ml TFPI # TFPI Imubind total TFPI TFPI K1 57.3±17.7 American Diagnostica Porta ±14.3 Mitchell 38 Asserachrom Total TFPI K2 K1K2 85.3±11.9 Diagnostica Stago Golino Dahm 40 TFPI K1 K2 63±21 Furumoto ±19.1 Kawaguchi 42 TFPIα TFPI Asserachrom Free TFPI K2 K3 11.3±2.1 13% Diagnostica Stago Golino % Dahm 40 K3 K1 K2 19±16 30% Furumoto ±6.3 21% Kawaguchi 42 C K2 ng/ml Hackeng, Maastricht Uni. Maurissen 35 C Broze, Washington Uni. Mast 6 Human TFPI Quantikine K3 TFPI R&D system Girard 7 # TFPI 5 TFPIα TFPI TFPIα TFPI TFPI 5 TFPI TFPI TFPI TFPI TFPI TFPI TFPIα global assay FV PS TFPI TFPI 2 6, 7, 35, TFPI K1 K2 K1 K2 TFPI ng/ml nm TFPI TFPI C PIPLC TFPI TFPIα 6 K3 K3 TFPIβ 7 K3 TFPI K1-K2-C 34 TFPIβ C C TFPI TFPIα K3
7 17 TFPI TFPIα 35 TFPI TFPIα FV PS TFPIα FV FVIII PS TFPIα TFPI TFPIα ng/ml nm TFPIα TFPI TFPI TFPIα TFPIβ TFPI FVIIa/TF FXa PT TFPI FVIIa/TF Actichrome TFPI activity assay 43 TF FVIIa FX FVIIa/TF FXa TFPI TFPIα TFPI TFPI 44 TFPI FXa TFPIα TF/FVIIa PS FXa 45 PT dpt PT TFPI PT 46 TFPI 47 global assay in vivo 48 Hemcker Calibrated Automated Thrombogram CAT TFPI PS PC FV AT 14, 20, 49, 50 CAT 5 20 dpt μl 50 μl CAT μl 80 μl 51 CAT TFPI TF <10 pm TFPI TFPIα FVIII A 52 TFPI CAT TFPI 4 Maurissen CAT TFPI PS TFPI- PS 35 CAT TFPIα 15 TFPIβ 6 TFPI TFPI rtfpi rtfpi 2000 II III III rtfpi rtfpi TFPIα TFPIβ 25 1
8 18 4 TFPI 2 A FVIII: C<1 TF 1 pm a b TFPIα TFPI TFPI b a b TFPIα 56 TF TFPI TFPI TFPI Winckers 57 TFPI 83 TFPI TFPI 59 TFPI 40 TFPI DIC TFPI TFPI rtfpi TFPI PS TFPI 61 TF i TF/FVIIa PAR2 ii iii 32 TF TF ALT-836 ClinicalTrials.gov ID NCT TFPI TF 26 TFPI TFPI 62, 63 TFPI
9 19 FVIII QOL 2 3 FVIII FIX 64 TFPI TFPI 56 3 a TFPI BAX499 ARC BAX499 TFPIα TFPI FXa TF/ FVIIa 67 TFPIα K1 K3 C 3 TFPIβ 68 A 67 ex vivo A 69 I/II ClinicalTrials.gov ID NCT b Non-Anticoagulant Sulfated Polysaccharide NASP - TFPI inhibitor: BAX513 AV513 NSAP NSAP TFPI 70 Liu Thromb Haemost 2006 BAX513 A 71 BAX513 TFPI C 72 TFPIα I ID NCT c TFPI NN7415 mab 2012 K2 K d 25 pmtfpi FXa TF/FVIIa in vivo 7 73 I ID NCT I A ID NCT TFPIα TFPI TFPI PS TFPI TFPIα FVa FV TFPI TFPIβ COI 1TFPI 14: , Girard TJ, Warren LA, Novotny WF, Likert KM, Brown SG, Miletich JP, Broze GJ: Functional significance of the Kunitztype inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 338: , Crawley JT, Lane DA: The haemostatic role of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 28: , Broze GJ, Girard TJ: Tissue factor pathway inhibitor: structure-function. Front Biosci (Landmark Ed) 17: , Zhang J, Piro O, Lu L, Broze GJ: Glycosyl phosphatidylinositol anchorage of tissue factor pathway inhibitor. Circulation 108: , Mast AE, Acharya N, Malecha MJ, Hall CL, Dietzen DJ: Characterization of the association of tissue factor pathway inhibitor with human placenta. Arterioscler Thromb Vasc Biol 22: , Girard TJ, Tuley E, Broze GJ: TFPIβ is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes. Blood 119: , Maroney SA, Haberichter SL, Friese P, Collins ML, Ferrel JP, 25 1
10 20 Dale GL, Mast AE: Active tissue factor pathway inhibitor is expressed on the surface of coated platelets. Blood 109: , Wesselschmidt R, Likert K, Girard T, Wun TC, Broze GJ: Tissue factor pathway inhibitor: the carboxy-terminus is required for optimal inhibition of factor Xa. Blood 79: , Ndonwi M, Tuley EA, Broze GJ: The Kunitz-3 domain of TFPI-alpha is required for protein S-dependent enhancement of factor Xa inhibition. Blood 116: , Hamik A, Setiadi H, Bu G, McEver RP, Morrissey JH: Downregulation of monocyte tissue factor mediated by tissue factor pathway inhibitor and the low density lipoprotein receptor-related protein. J Biol Chem 274: , Ndonwi M, Girard TJ, Broze GJ Jr: The C-terminus of tissue factor pathway inhibitor α is required for its interaction with factors V and Va. J Thromb Haemost 10: , Wesselschmidt R, Likert K, Huang Z, MacPhail L, Broze GJ: Structural requirements for tissue factor pathway inhibitor interactions with factor Xa and heparin. Blood Coagul Fibrinolysis 4: , Duckers C, Simioni P, Spiezia L, Radu C, Gavasso S, Rosing J, Castoldi E: Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency. Blood 112: , Duckers C, Simioni P, Spiezia L, Radu C, Dabrilli P, Gavasso S, Rosing J, Castoldi E: Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms. Blood 115: , Bos MH, Camire RM: A bipartite autoinhibitory region within the B-domain suppresses function in factor V. J Biol Chem 287: , Kuang SQ, Hasham S, Phillips MD, Wolf D, Wan Y, Thiagarajan P, Milewicz DM: Characterization of a novel autosomal dominant bleeding disorder in a large kindred from east Texas. Blood 97: , Vincent LM, Tran S, Livaja R, Bensend TA, Milewicz DM, Dahlbäck B: Coagulation factor V (A2440G) causes east Texas bleeding disorder via TFPIα. 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Blood 119: , Maroney SA, Cooley BC, Ferrel JP, Bonesho CE, Mast AE: Murine hematopoietic cell tissue factor pathway inhibitor limits thrombus growth. Arterioscler Thromb Vasc Biol 31: , Maroney SA, Cooley BC, Ferrel JP, Bonesho CE, Nielsen LV, Johansen PB, Hermit MB, Petersen LC, Mast AE: Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia. Proc Natl Acad Sci USA 109: , Maroney SA, Ellery PE, Wood JP, Ferrel JP, Martinez ND, Mast AE: Comparison of the inhibitory activities of human tissue factor pathway inhibitor (TFPI) α and TFPIβ. J Thromb Haemost 11: , Lupu C, Goodwin CA, Westmuckett AD, Emeis JJ, Scully MF, Kakkar VV, Lupu F: Tissue factor pathway inhibitor in endothelial cells colocalizes with glycolipid microdomains/ caveolae. Regulatory mechanism(s) of the anticoagulant properties of the endothelium. Arterioscler Thromb Vasc Biol 17: , Maroney SA, Ellery PE, Wood JP, Ferrel JP, Bonesho CE, Mast AE: Caveolae optimize tissue factor-factor VIIa inhibitory activity of cell-surface-associated tissue factor pathway inhibitor. Biochem J 443: , Lupu C, Zhu H, Popescu NI, Wren JD, Lupu F: Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen. Blood 118: , Bromberg ME, Bailly MA, Konigsberg WH: Role of protease-activated receptor 1 in tumor metastasis promoted by tissue factor. Thromb Haemost 86: , Hjortoe GM, Petersen LC, Albrektsen T, Sorensen BB, Norby PL, Mandal SK, Pendurthi UR, Rao LV: Tissue factor-factor VIIa-specific up-regulation of IL-8 expression in MDA- MB-231 cells is mediated by PAR-2 and results in increased cell migration. Blood 103: , Ruf W: Tissue factor and cancer. Thromb Res 130 (Suppl 1): S84 87, Ma L, Dorling A: The roles of thrombin and protease-activated receptors in inflammation. Semin Immunopathol 34: 63 72, Mast AE, Stadanlick JE, Lockett JM, Dietzen DJ, Hasty KA, Hall CL: Tissue factor pathway inhibitor binds to platelet thrombospondin-1. J Biol Chem 275: , Maurissen LF, Castoldi E, Simioni P, Rosing J, Hackeng TM: Thrombin generation-based assays to measure the activity of the TFPI-protein S pathway in plasma from normal and protein S-deficient individuals. J Thromb Haemost 8: , Castoldi E, Simioni P, Tormene D, Rosing J, Hackeng TM: Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma. J Thromb Haemost 8: , 2010.
11 21 37 Porta B, Baldassarre D, Camera M, Amato M, Arquati M, Brusoni B, Fiorentini C, Montorsi P, Romano S, Tremoli E, Cortellaro M; MIAMI Study Group: E-selectin and TFPI are associated with carotid intima-media thickness in stable IHD patients: the baseline findings of the MIAMI study. Nutr Metab Cardiovasc Dis 18: , Mitchell CT, Kamineni A, Palmas W, Cushman M: Tissue factor pathway inhibitor, vascular risk factors and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 207: , Golino P, Ravera A, Ragni M, Cirillo P, Piro O, Chiariello M: Involvement of tissue factor pathway inhibitor in the coronary circulation of patients with acute coronary syndromes. Circulation 108: , Dahm A, Van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM: Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 101: , Furumoto T, Fujii S, Saito N, Mikami T, Kitabatake A: Relationships between brachial artery flow mediated dilation and carotid artery intima-media thickness in patients with suspected coronary artery disease. Jpn Heart J 43: , Kawaguchi A, Miyao Y, Noguchi T, Nonogi H, Yamagishi M, Miyatake K, Kamikubo Y, Kumeda K, Tsushima M, Yamamoto A, Kato H: Intravascular free tissue factor pathway inhibitor is inversely correlated with HDL cholesterol and postheparin lipoprotein lipase but proportional to apolipoprotein A-II. Arterioscler Thromb Vasc Biol 20: , Bognacki J, Hammelburger J: Functional and immunologic methods for the measurement of human tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 6 (Suppl 1): S65 72, Dahm AE, Andersen TO, Rosendaal F, Sandset PM: A novel anticoagulant activity assay of tissue factor pathway inhibitor I (TFPI). J Thromb Haemost 3: , Thomassen S, Heinzmann A, Herfs L, Rosing J, Hackeng TM, Hartmann R, Scheiflinger F, Dockal M: TFPI expresses anticoagulant activity independent of TF-FVIIa. ASH abstract # 3563, Nordfang O, Kristensen HI, Valentin S, Ostergaard P, Wadt J: The significance of TFPI in clotting assays--comparison and combination with other anticoagulants. Thromb Haemost 70: , Hansen JB, Huseby KR, Huseby NE, Ezban M, Nordøy A: Tissue factor pathway inhibitor in complex with low density lipoprotein isolated from human plasma does not possess anticoagulant function in tissue factor-induced coagulation in vitro. Thromb Res 85: , Shima M, Matsumoto T, Ogiwara K: New assays for monitoring haemophilia treatment. Haemophilia 14 (Suppl 3): 83 92, Castoldi E, Brugge JM, Nicolaes GA, Girelli D, Tans G, Rosing J: Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. 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12 22 180, Raps M, Helmerhorst FM, Fleischer K, Dahm AE, Rosendaal FR, Rosing J, Reitsma P, Sandset PM, van Vliet HA: The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI. Thromb Haemost 109: , Amirkhosravi A, Meyer T, Chang JY, Amaya M, Siddiqui F, Desai H, Francis JL: Tissue factor pathway inhibitor reduces experimental lung metastasis of B16 melanoma. Thromb Haemost 87: , Stavik B, Tinholt M, Sletten M, Skretting G, Sandset PM, Iversen N: TFPIα and TFPIβ are expressed at the surface of breast cancer cells and inhibit TF-FVIIa activity. J Hematol Oncol 6: 5, : , Nordfang O, Valentin S, Beck TC, Hedner U: Inhibition of extrinsic pathway inhibitor shortens the coagulation time of normal plasma and of hemophilia plasma. Thromb Haemost 66: , Bouchard PR, Hutabarat RM, Thompson KM: Discovery and development of therapeutic aptamers. Annu Rev Pharmacol Toxicol 50: , Waters EK, Genga RM, Schwartz MC, Nelson JA, Schaub RG, Olson KA, Kurz JC, McGinness KE: Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor. Blood 117: , Waters EK, Genga RM, Thomson HA, Kurz JC, Schaub RG, Scheiflinger F, McGinness KE: Aptamer BAX 499 mediates inhibition of tissue factor pathway inhibitor via interaction with multiple domains of the protein. J Thromb Haemost 11: , Gorczyca ME, Nair SC, Jilma B, Priya S, Male C, Reitter S, Knoebl P, Gilbert JC, Schaub RG, Dockal M, McGinness KE, Pabinger I, Srivastava A: Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma. J Thromb Haemost 10: , Liu T, Scallan CD, Broze GJ, Patarroyo-White S, Pierce GF, Johnson KW: Improved coagulation in bleeding disorders by Non-Anticoagulant Sulfated Polysaccharides (NASP). Thromb Haemost 95: 68 76, Prasad S, Lillicrap D, Labelle A, Knappe S, Keller T, Burnett E, Powell S, Johnson KW: Efficacy and safety of a new-class hemostatic drug candidate, AV513, in dogs with hemophilia A. Blood 111: , Palige M, Redl C, Knappe S, Ehrlich HJ, Dockal M, Scheiflinger F: Procoagulant activity of Laminaria japonica derived fucoidan (BAX513) depends on the interaction with the C-terminus of tissue factor pathway inhibitor. ASH abstract# 4417, Hilden I, Lauritzen B, Sørensen BB, Clausen JT, Jespersgaard C, Krogh BO, Bowler AN, Breinholt J, Gruhler A, Svensson LA, Petersen HH, Petersen LC, Balling KW, Hansen L, Hermit MB, Egebjerg T, Friederichsen B, Ezban M, Bjørn SE: Hemostatic effect of a monoclonal antibody mab 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood 119: , 2012.
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診断 治療 技術講座 2018; 29 4 : 413-420 APTT 波形解析 APTT waveform Hideo WADA Key words: APTT, waveform, hemophilia, anticoagulant therapy 1978 1982 1982 1983 1985 NIH 1985 2000 / 2008 1 activated partial thromboplastin
Figure 1 Mechanisms of blood coagulation and its regulation pathways. AT, antithrombin; HCII, heparin cofactor II; TFPI, tissue factor pathway inhibit
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日本血栓止血学会サイトお役立ちリンク集 日本血栓止血学会サイトに掲載しているおすすめコンテンツのリンクをご紹介します 診療ガイドライン 研修医のお役立ち論文コンテンツ 用語集 本編は次ページより掲載しております
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