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Semin Thromb Hemost 2014; 40(08): 881-886
DOI: 10.1055/s-0034-1395153
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Tissue Factor Pathway Inhibitor: Then and Now[*]

Paul E. R. Ellery
1   Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin
,
Murray J. Adams
2   School of Health Sciences, University of Tasmania, Launceston, Tasmania, Australia
› Author Affiliations
Further Information

Publication History

Publication Date:
06 November 2014 (online)

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Abstract

Tissue factor pathway inhibitor (TFPI) is the major physiological regulator of tissue factor (TF)-induced blood coagulation. TFPI inhibits the TF-activated factor VII (FVIIa) complex in an activated factor X (FXa)-dependent manner, helping to control thrombin generation and ultimately fibrin formation. The importance of TFPI is demonstrated in models of hemophilia where lower levels of FVIII or FIX are insufficient to overcome its inhibitory effect, resulting in a bleeding phenotype. There are two major isoforms in vivo; TFPIα contains three Kunitz-type inhibitory domains (designated K1, K2, and K3), is secreted by endothelial cells and requires protein S to enhance its anticoagulant activity. In contrast, TFPIβ contains only the K1 and K2 domains, but it is attached to the endothelial surface via a glycosylphosphatidylinositol anchor. This review will initially provide a brief history of the major discoveries related to TFPI, and then discuss new insights into the physiology of TFPI, including updates on its association with protein S and FV, as well as the current understanding of its association with disease.

Keywords

tissue factor - thrombosis - protein S - hemophilia - factor V

* This article is dedicated to Robert (Bob) Oostryck. In 1992, while a Senior Lecturer in Hematology at Curtin University at Curtin University of Technology, Bob asked M.J.A., who was then an undergraduate student interested in research, “Why do hemophiliacs bleed?” The explanation of a lack of factor VIII or factor IX was not only superficially correct, but it also did not take into account the important physiological effects of tissue factor pathway inhibitor (TFPI). Bob was our first mentor, a great teacher, and now friend, who ignited a passion for research and an interest in TFPI that we both still share. Although now retired, Bob retains a keen interest in all things related to coagulation, TFPI, and hemostasis.


 

  • References

  • 1 Wood JP, Ellery PE, Maroney SA, Mast AE. Biology of tissue factor pathway inhibitor. Blood 2014; 123 (19) 2934-2943
    CrossrefPubMedGoogle Scholar
  • 2 Loeb L, Fleisher MS, Tuttle L. The interaction between blood serum and tissue extract in the coagulation of blood: II. A comparison between the effects of the stroma of erythrocytes and of tissue extracts, unheated and heated, on the coagulation of the blood, and on the mechanism of the interaction of these substances with blood serum. J Biol Chem 1922; 51: 485-506
    PubMedGoogle Scholar
  • 3 Loeb L, Fleisher MS, Tuttle L. The interaction between blood serum and tissue extract in the coagulation of blood: I. The combined action of serum and tissue extract on fluoride, hirudin, and peptone plasma; the effect of heating on serum. J Biol Chem 1922; 51: 461-483
    PubMedGoogle Scholar
  • 4 Schneider CL. The active principle of placental toxin; thromboplastin; its inactivator in blood; antithromboplastin. Am J Physiol 1947; 149 (1) 123-129
    PubMedGoogle Scholar
  • 5 Thomas L. Studies on the intravascular thromboplastic effect of tissue suspensions in mice: a factor in normal rabbit serum which inhibits the thromboplastic effect of the sedimentable tissue component. Bull Johns Hopkins Hosp 1947; 81 (1) 26-42
    PubMedGoogle Scholar
  • 6 Hjort PF. Intermediate reactions in the coagulation of blood with tissue thromboplastin; convertin, accelerin, prothrombinase. Scand J Clin Lab Invest 1957; 9 (Suppl. 27) 1-183
    CrossrefPubMedGoogle Scholar
  • 7 Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science 1964; 145 (3638) 1310-1312
    CrossrefPubMedGoogle Scholar
  • 8 MacFarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 1964; 202: 498-499
    CrossrefPubMedGoogle Scholar
  • 9 Biggs R, MacFarlane RG. The reaction of haemophilic plasma to thromboplastin. J Clin Pathol 1951; 4 (4) 445-459
    CrossrefPubMedGoogle Scholar
  • 10 Biggs R, Nossel HL. Tissue extract and contact reaction in blood coagulation. Thromb Diath Haemorrh 1961; 6: 1-14
    PubMedGoogle Scholar
  • 11 Marciniak E, Tsukamura S. Two progressive inhibitors of factor Xa in human blood. Br J Haematol 1972; 22 (3) 341-351
    CrossrefPubMedGoogle Scholar
  • 12 Barrowcliffe TW, Eggleton CA, Stocks J. Studies of anti-Xa activity in human plasma. II: The role of lipoproteins. Thromb Res 1982; 27 (2) 185-195
    CrossrefPubMedGoogle Scholar
  • 13 Carson SD. Plasma high density lipoproteins inhibit the activation of coagulation factor X by factor VIIa and tissue factor. FEBS Lett 1981; 132 (1) 37-40
    CrossrefPubMedGoogle Scholar
  • 14 Marlar RA, Kleiss AJ, Griffin JH. An alternative extrinsic pathway of human blood coagulation. Blood 1982; 60 (6) 1353-1358
    PubMedGoogle Scholar
  • 15 Morrison SA, Jesty J. Tissue factor-dependent activation of tritium-labeled factor IX and factor X in human plasma. Blood 1984; 63 (6) 1338-1347
    PubMedGoogle Scholar
  • 16 Sanders NL, Bajaj SP, Zivelin A, Rapaport SI. Inhibition of tissue factor/factor VIIa activity in plasma requires factor X and an additional plasma component. Blood 1985; 66 (1) 204-212
    PubMedGoogle Scholar
  • 17 Hubbard AR, Jennings CA. Inhibition of tissue thromboplastin-mediated blood coagulation. Thromb Res 1986; 42 (4) 489-498
    CrossrefPubMedGoogle Scholar
  • 18 Broze Jr GJ, Miletich JP. Isolation of the tissue factor inhibitor produced by HepG2 hepatoma cells. Proc Natl Acad Sci U S A 1987; 84 (7) 1886-1890
    CrossrefPubMedGoogle Scholar
  • 19 Rao LV, Rapaport SI. Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation. Blood 1987; 69 (2) 645-651
    PubMedGoogle Scholar
  • 20 Broze Jr GJ, Warren LA, Girard JJ, Miletich JP. Isolation of the lipoprotein associated coagulation inhibitor produced by HepG2 (human hepatoma) cells using bovine factor Xa affinity chromatography. Thromb Res 1987; 48 (2) 253-259
    CrossrefPubMedGoogle Scholar
  • 21 Broze Jr GJ, Miletich JP. Characterization of the inhibition of tissue factor in serum. Blood 1987; 69 (1) 150-155
    PubMedGoogle Scholar
  • 22 Girard T, Tissue factor pathway inhibitor. In: Sasahara AA, Loscalzo J. , eds. New Therapeutic Agents in Thrombosis and Thrombolysis. New York, NY: M. Dekker; 1997: 225-260
    Google Scholar
  • 23 Wun TC, Kretzmer KK, Girard TJ, Miletich JP, Broze Jr GJ. Cloning and characterization of a cDNA coding for the lipoprotein-associated coagulation inhibitor shows that it consists of three tandem Kunitz-type inhibitory domains. J Biol Chem 1988; 263 (13) 6001-6004
    Google Scholar
  • 24 Wun TC, Huang MD, Kretzmer KK , et al. Immunoaffinity purification and characterization of lipoprotein-associated coagulation inhibitors from Hep G2 hepatoma, Chang liver, and SK hepatoma cells. A comparative study. J Biol Chem 1990; 265 (27) 16096-16101
    PubMedGoogle Scholar
  • 25 Novotny WF, Palmier M, Wun TC, Broze Jr GJ, Miletich JP. Purification and properties of heparin-releasable lipoprotein-associated coagulation inhibitor. Blood 1991; 78 (2) 394-400
    PubMedGoogle Scholar
  • 26 Piro O, Broze Jr GJ. Comparison of cell-surface TFPIalpha and beta. J Thromb Haemost 2005; 3 (12) 2677-2683
    CrossrefPubMedGoogle Scholar
  • 27 Chang JY, Monroe DM, Oliver JA, Roberts HR. TFPIbeta, a second product from the mouse tissue factor pathway inhibitor (TFPI) gene. Thromb Haemost 1999; 81 (1) 45-49
    Google Scholar
  • 28 Zhang J, Piro O, Lu L, Broze Jr GJ. Glycosyl phosphatidylinositol anchorage of tissue factor pathway inhibitor. Circulation 2003; 108 (5) 623-627
    Google Scholar
  • 29 Girard TJ, Warren LA, Novotny WF, Bejcek BE, Miletich JP, Broze Jr GJ. Identification of the 1.4 kb and 4.0 kb messages for the lipoprotein associated coagulation inhibitor and expression of the encoded protein. Thromb Res 1989; 55 (1) 37-50
    CrossrefPubMedGoogle Scholar
  • 30 Ellery PE, Maroney SA, Martinez ND, Wickens MP, Mast AE. Translation of human tissue factor pathway inhibitor-β mRNA is controlled by alternative splicing within the 5′ untranslated region. Arterioscler Thromb Vasc Biol 2014; 34 (1) 187-195
    CrossrefPubMedGoogle Scholar
  • 31 Bajaj MS, Kuppuswamy MN, Saito H, Spitzer SG, Bajaj SP. Cultured normal human hepatocytes do not synthesize lipoprotein-associated coagulation inhibitor: evidence that endothelium is the principal site of its synthesis. Proc Natl Acad Sci U S A 1990; 87 (22) 8869-8873
    CrossrefPubMedGoogle Scholar
  • 32 Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SM. Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 1993; 69 (4) 366-369
    Google Scholar
  • 33 Maroney SA, Cunningham AC, Ferrel J , et al. A GPI-anchored co-receptor for tissue factor pathway inhibitor controls its intracellular trafficking and cell surface expression. J Thromb Haemost 2006; 4 (5) 1114-1124
    CrossrefPubMedGoogle Scholar
  • 34 Crawley J, Lupu F, Westmuckett AD, Severs NJ, Kakkar VV, Lupu C. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol 2000; 20 (5) 1362-1373
    CrossrefPubMedGoogle Scholar
  • 35 Lupu C, Hu X, Lupu F. Caveolin-1 enhances tissue factor pathway inhibitor exposure and function on the cell surface. J Biol Chem 2005; 280 (23) 22308-22317
    CrossrefPubMedGoogle Scholar
  • 36 Lupu C, Goodwin CA, Westmuckett AD , et al. 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 1997; 17 (11) 2964-2974
    CrossrefPubMedGoogle Scholar
  • 37 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 2002; 22 (12) 2099-2104
    CrossrefPubMedGoogle Scholar
  • 38 Ellery PE, Hardy K, Oostryck R, Adams MJ. Further insight into the heparin-releasable and glycosylphosphatidylinositol-lipid—anchored forms of tissue factor pathway inhibitor. Clin Appl Thromb Hemost 2008; 14 (3) 267-278
    CrossrefPubMedGoogle Scholar
  • 39 Girard TJ, Tuley E, Broze Jr GJ. TFPI β is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes. Blood 2012; 119 (5) 1256-1262
    CrossrefPubMedGoogle Scholar
  • 40 Piro O, Broze Jr GJ. Role for the Kunitz-3 domain of tissue factor pathway inhibitor-alpha in cell surface binding. Circulation 2004; 110 (23) 3567-3572
    Google Scholar
  • 41 Iversen N, Sandset PM, Abildgaard U, Torjesen PA. Binding of tissue factor pathway inhibitor to cultured endothelial cells-influence of glycosaminoglycans. Thromb Res 1996; 84 (4) 267-278
    CrossrefPubMedGoogle Scholar
  • 42 Lupu C, Poulsen E, Roquefeuil S, Westmuckett AD, Kakkar VV, Lupu F. Cellular effects of heparin on the production and release of tissue factor pathway inhibitor in human endothelial cells in culture. Arterioscler Thromb Vasc Biol 1999; 19 (9) 2251-2262
    Google Scholar
  • 43 Tiemann C, Brinkmann T, Kleesiek K. Detection of the three Kunitz-type single domains of membrane-bound tissue factor pathway inhibitor (TFPI) by flow cytometry. Eur J Clin Chem Clin Biochem 1997; 35 (11) 855-860
    PubMedGoogle Scholar
  • 44 Sandset PM. Tissue factor pathway inhibitor (TFPI)—an update. Haemostasis 1996; 26 (Suppl. 04) 154-165
    PubMedGoogle Scholar
  • 45 Novotny WF, Girard TJ, Miletich JP, Broze Jr GJ. Purification and characterization of the lipoprotein-associated coagulation inhibitor from human plasma. J Biol Chem 1989; 264 (31) 18832-18837
    Google Scholar
  • 46 Broze Jr GJ, Lange GW, Duffin KL, MacPhail L. Heterogeneity of plasma tissue factor pathway inhibitor. Blood Coagul Fibrinolysis 1994; 5 (4) 551-559
    PubMedGoogle Scholar
  • 47 Novotny WF, Brown SG, Miletich JP, Rader DJ, Broze Jr GJ. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood 1991; 78 (2) 387-393
    PubMedGoogle Scholar
  • 48 Hansen JB, Huseby KR, Huseby NE, Sandset PM, Hanssen TA, Nordøy A. Effect of cholesterol lowering on intravascular pools of TFPI and its anticoagulant potential in type II hyperlipoproteinemia. Arterioscler Thromb Vasc Biol 1995; 15 (7) 879-885
    CrossrefPubMedGoogle Scholar
  • 49 Augustsson C, Hilden I, Petersen LC. Inhibitory effects of LDL-associated tissue factor pathway inhibitor. Thromb Res 2014; 134 (1) 132-137
    CrossrefPubMedGoogle Scholar
  • 50 Novotny WF, Girard TJ, Miletich JP, Broze Jr GJ. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood 1988; 72 (6) 2020-2025
    Google Scholar
  • 51 Maroney SA, Haberichter SL, Friese P , et al. Active tissue factor pathway inhibitor is expressed on the surface of coated platelets. Blood 2007; 109 (5) 1931-1937
    CrossrefPubMedGoogle Scholar
  • 52 Jayachandran M, Sanzo A, Owen WG, Miller VM. Estrogenic regulation of tissue factor and tissue factor pathway inhibitor in platelets. Am J Physiol Heart Circ Physiol 2005; 289 (5) H1908-H1916
    CrossrefPubMedGoogle Scholar
  • 53 Novotny W, Day K, Wun T-C, Nieces G. Platelet LACI is present in novel granules. Blood 1990; 76 (Suppl. 01) 469
    PubMedGoogle Scholar
  • 54 Maroney SA, Cooley BC, Ferrel JP, Bonesho CE, Mast AE. Murine hematopoietic cell tissue factor pathway inhibitor limits thrombus growth. Arterioscler Thromb Vasc Biol 2011; 31 (4) 821-826
    CrossrefPubMedGoogle Scholar
  • 55 Winckers K, ten Cate H, Hackeng TM. The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Rev 2013; 27 (3) 119-132
    CrossrefPubMedGoogle Scholar
  • 56 Adams M. Tissue factor pathway inhibitor: new insights into an old inhibitor. Semin Thromb Hemost 2012; 38 (2) 129-134
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Adams MJ, Oostryck R. A comparative study of functional assays for tissue factor pathway inhibitor using normal plasma and clinical samples. Blood Coagul Fibrinolysis 2000; 11 (4) 327-333
    CrossrefPubMedGoogle Scholar
  • 58 Knappe S, Gorczyca ME, Jilma B , et al. Plasmatic tissue factor pathway inhibitor is a major determinant of clotting in factor VIII inhibited plasma or blood. Thromb Haemost 2013; 109 (3) 450-457
    Article in Thieme ConnectPubMedGoogle Scholar
  • 59 Maroney SA, Cooley BC, Ferrel JP , et al. Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia. Proc Natl Acad Sci U S A 2012; 109 (10) 3927-3931
    CrossrefPubMedGoogle Scholar
  • 60 Tardy-Poncet B, Piot M, Chapelle C, Berger C, Tardy B. Difference in TFPI levels between haemophilia A and B patients. Haemophilia 2011; 17 (2) 312-313
    CrossrefPubMedGoogle Scholar
  • 61 Erhardtsen E, Ezban M, Madsen MT , et al. Blocking of tissue factor pathway inhibitor (TFPI) shortens the bleeding time in rabbits with antibody induced haemophilia A. Blood Coagul Fibrinolysis 1995; 6 (5) 388-394
    CrossrefPubMedGoogle Scholar
  • 62 Hilden I, Lauritzen B, Sørensen BB , et al. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood 2012; 119 (24) 5871-5878
    CrossrefPubMedGoogle Scholar
  • 63 Prasad S, Lillicrap D, Labelle A , et al. Efficacy and safety of a new-class hemostatic drug candidate, AV513, in dogs with hemophilia A. Blood 2008; 111 (2) 672-679
    CrossrefPubMedGoogle Scholar
  • 64 Dockal M, Hartmann R, Fries M , et al. Small peptides blocking inhibition of factor Xa and tissue factor-factor VIIa by tissue factor pathway inhibitor (TFPI). J Biol Chem 2014; 289 (3) 1732-1741
    CrossrefPubMedGoogle Scholar
  • 65 Waters EK, Genga RM, Schwartz MC , et al. Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor. Blood 2011; 117 (20) 5514-5522
    CrossrefPubMedGoogle Scholar
  • 66 Dockal M, Hartmann R, Knappe S , et al. Effect of increased tissue factor pathway inhibitor (TFPI) levels on factor Xa inhibition and global hemostasis in the presence of TFPI-antagonistic aptamer BAX 499. Blood 2012; 120 ; 2207
    PubMedGoogle Scholar
  • 67 Dockal M, Pachlinger R, Hartmann R , et al. Biological explanation of clinically observed elevation of TFPI plasma levels after treatment with TFPI-antagonistic aptamer BAX 499 [Abstract]. Blood 2012; 120: 1104
    PubMedGoogle Scholar
  • 68 Hackeng TM, Seré KM, Tans G, Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci U S A 2006; 103 (9) 3106-3111
    CrossrefPubMedGoogle Scholar
  • 69 Peraramelli S, Suylen DP, Rosing J, Hackeng TM. The Kunitz 1 and Kunitz 3 domains of tissue factor pathway inhibitor are required for efficient inhibition of factor Xa. Thromb Haemost 2012; 108 (2) 266-276
    Article in Thieme ConnectPubMedGoogle Scholar
  • 70 Peraramelli S, Thomassen S, Heinzmann A , et al. Direct inhibition of factor VIIa by TFPI and TFPI constructs. J Thromb Haemost 2013; 11 (4) 704-714
    CrossrefPubMedGoogle Scholar
  • 71 Ndonwi M, Tuley EA, Broze Jr GJ. The Kunitz-3 domain of TFPI-alpha is required for protein S-dependent enhancement of factor Xa inhibition. Blood 2010; 116 (8) 1344-1351
    CrossrefPubMedGoogle Scholar
  • 72 Ahnström J, Andersson HM, Hockey V , et al. Identification of functionally important residues in TFPI Kunitz domain 3 required for the enhancement of its activity by protein S. Blood 2012; 120 (25) 5059-5062
    CrossrefPubMedGoogle Scholar
  • 73 Wood JP, Ellery PE, Maroney SA, Mast AE. Protein S is a cofactor for platelet and endothelial tissue factor pathway inhibitor-α but not for cell surface-associated tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol 2014; 34 (1) 169-176
    CrossrefPubMedGoogle Scholar
  • 74 Reglińska-Matveyev N, Andersson HM, Rezende SM , et al. TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain. Blood 2014; 123 (25) 3979-3987
    CrossrefPubMedGoogle Scholar
  • 75 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 2010; 8 (2) 294-300
    CrossrefPubMedGoogle Scholar
  • 76 Dahm AE, Sandset PM, Rosendaal FR. The association between protein S levels and anticoagulant activity of tissue factor pathway inhibitor type 1. J Thromb Haemost 2008; 6 (2) 393-395
    CrossrefPubMedGoogle Scholar
  • 77 Bos MH, Camire RM. A bipartite autoinhibitory region within the B-domain suppresses function in factor V. J Biol Chem 2012; 287 (31) 26342-26351
    CrossrefPubMedGoogle Scholar
  • 78 Kane WH, Davie EW. Cloning of a cDNA coding for human factor V, a blood coagulation factor homologous to factor VIII and ceruloplasmin. Proc Natl Acad Sci U S A 1986; 83 (18) 6800-6804
    CrossrefPubMedGoogle Scholar
  • 79 Kane WH, Ichinose A, Hagen FS, Davie EW. Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats. Biochemistry 1987; 26 (20) 6508-6514
    CrossrefPubMedGoogle Scholar
  • 80 Jenny RJ, Pittman DD, Toole JJ , et al. Complete cDNA and derived amino acid sequence of human factor V. Proc Natl Acad Sci U S A 1987; 84 (14) 4846-4850
    CrossrefPubMedGoogle Scholar
  • 81 Smith CM, Hanahan DJ. The activation of factor V by factor Xa or alpha-chymotrypsin and comparison with thrombin and RVV-V action. An improved factor V isolation procedure. Biochemistry 1976; 15 (9) 1830-1838
    CrossrefPubMedGoogle Scholar
  • 82 Foster WB, Nesheim ME, Mann KG. The factor Xa-catalyzed activation of factor V. J Biol Chem 1983; 258 (22) 13970-13977
    PubMedGoogle Scholar
  • 83 Odegaard B, Mann K. Proteolysis of factor Va by factor Xa and activated protein C. J Biol Chem 1987; 262 (23) 11233-11238
    PubMedGoogle Scholar
  • 84 Viskup RW, Tracy PB, Mann KG. The isolation of human platelet factor V. Blood 1987; 69 (4) 1188-1195
    PubMedGoogle Scholar
  • 85 Monković DD, Tracy PB. Functional characterization of human platelet-released factor V and its activation by factor Xa and thrombin. J Biol Chem 1990; 265 (28) 17132-17140
    PubMedGoogle Scholar
  • 86 Wood JP, Bunce MW, Maroney SA, Tracy PB, Camire RM, Mast AE. Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation. Proc Natl Acad Sci U S A 2013; 110 (44) 17838-17843
    CrossrefPubMedGoogle Scholar
  • 87 Ndonwi M, Girard TJ, Broze Jr GJ. The C-terminus of tissue factor pathway inhibitor α is required for its interaction with factors V and Va. J Thromb Haemost 2012; 10 (9) 1944-1946
    CrossrefPubMedGoogle Scholar
  • 88 Duckers C, Simioni P, Spiezia L , et al. Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency. Blood 2008; 112 (9) 3615-3623
    CrossrefPubMedGoogle Scholar
  • 89 Vincent LM, Tran S, Livaja R, Bensend TA, Milewicz DM, Dahlbäck B. Coagulation factor V(A2440G) causes east Texas bleeding disorder via TFPIα. J Clin Invest 2013; 123 (9) 3777-3787
    CrossrefPubMedGoogle Scholar
  • 90 Mast AE, Broze Jr GJ. Physiological concentrations of tissue factor pathway inhibitor do not inhibit prothrombinase. Blood 1996; 87 (5) 1845-1850
    PubMedGoogle Scholar
  • 91 Schuijt TJ, Bakhtiari K, Daffre S , et al. Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: lessons from a tick salivary protein. Circulation 2013; 128 (3) 254-266
    CrossrefPubMedGoogle Scholar