[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein

Nature Medicine volume 9, pages 458–462 (2003)Cite this article

Abstract

Tissue factor (TF) is an essential enzyme activator that forms a catalytic complex with FVIIa and initiates coagulation by activating FIX and FX, ultimately resulting in thrombin formation1. TF is found in adventitia of blood vessels2 and the lipid core of atherosclerotic plaques3. In unstable coronary syndromes, plaque rupture initiates coagulation by exposing TF to blood4,5. Biologically active TF has been detected in vessel walls and circulating blood6. Elevated intravascular TF has been reported in diverse pro-thrombotic syndromes such as myocardial infarction, sepsis, anti-phospholipid syndrome and sickle-cell disease7,8,9,10. It is unclear how TF circulates, although it may be present in pro-coagulant microparticles11,12. We now report identification of a form of human TF generated by alternative splicing. Our studies indicate that alternatively spliced human tissue factor (asHTF) contains most of the extracellular domain of TF but lacks a transmembrane domain and terminates with a unique peptide sequence. asHTF is soluble, circulates in blood, exhibits pro-coagulant activity when exposed to phospholipids, and is incorporated into thrombi. We propose that binding of asHTF to the edge of thrombi contributes to thrombus growth by creating a surface that both initiates and propagates coagulation.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification of asHTF.
Figure 2: Immunohistochemical analysis of spontaneous and ex vivo human thrombi.
Figure 3: Co-localization of asHTF and platelet aggregates.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Bach, R.R. Initiation of coagulation by tissue factor. CRC Crit. Rev. Biochem. 23, 339–368 (1988).

    Article  CAS  Google Scholar 

  2. Nemerson, Y. & Gentry, R. An ordered addition, essential activation model of the tissue factor pathway of coagulation: evidence for a conformational cage. Biochemistry 25, 4020–4033 (1986).

    Article  CAS  Google Scholar 

  3. Zaman, A.G., Helft, G., Worthley, S.G. & Badimon, J.J. The role of plaque rupture and thrombosis in coronary artery disease. Atherosclerosis 149, 251–266 (2000).

    Article  CAS  Google Scholar 

  4. Zeldis, S.M., Nemerson, Y., Pitlick, F.A. & Lentz, T.L. Tissue factor (thromboplastin): localization to plasma membranes by peroxidase-conjugated antibodies. Science 175, 766–768 (1972).

    Article  CAS  Google Scholar 

  5. Baumgartner, H.R., Turitto, V.T. & Weiss, H.J. Effects of shear rate on platelet interaction with subendothelium in citrated and native blood. II. Relationships among platelet adhesion, thrombus dimensions, and fibrin formation. J. Lab. Clin. Med. 95, 208–221 (1980).

    CAS  PubMed  Google Scholar 

  6. Giesen, P.L. et al. Blood-borne tissue factor: another view of thrombosis. Proc. Natl. Acad. Sci. USA 96, 2311–2315 (1999).

    Article  CAS  Google Scholar 

  7. Suefuji, H. et al. Increased plasma tissue factor levels in acute myocardial infarction. Am. Heart J. 134, 253–259 (1997).

    Article  CAS  Google Scholar 

  8. Gando, S., Nanzaki, S., Sasaki, S., Aoi, K. & Kemmotsu, O. Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. Crit. Care Med. 26, 2005–2009 (1998).

    Article  CAS  Google Scholar 

  9. Amengual, O., Atsumi, T., Khamashta, M.A. & Hughes, G.R. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb. Haemost. 79, 276–281 (1998).

    Article  CAS  Google Scholar 

  10. Key, N.S. et al. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 91, 4216–4223 (1998).

    CAS  PubMed  Google Scholar 

  11. Mallat, Z. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99, 348–353 (1999).

    Article  CAS  Google Scholar 

  12. Mallat, Z. et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 101, 841–843 (2000).

    Article  CAS  Google Scholar 

  13. Kelley, R.F., Costas, K.E., O'Connell, M.P. & Lazarus, R.A. Analysis of the factor VIIa binding site on human tissue factor: effects of tissue factor mutations on the kinetics and thermodynamics of binding. Biochemistry 34, 10383–10392 (1995).

    Article  CAS  Google Scholar 

  14. Rosseau, S. et al. Monocyte migration through the alveolar epithelial barrier: adhesion molecule mechanisms and impact of chemokines. J. Immunol. 164, 427–435 (2000).

    Article  CAS  Google Scholar 

  15. Carson, S. & Yoder, S. Monoclonal antibodies against the C-terminal peptide of human tissue factor for studies of the cytoplasmic domain. Blood Coagul. Fibrinolysis 3, 779–787 (1992).

    Article  CAS  Google Scholar 

  16. Badimon, L., Badimon, J.J., Galvez, A., Chesebro, J.H. & Fuster, V. Influence of arterial damage and wall shear rate on platelet deposition. Ex vivo study in a swine model. Arteriosclerosis 6, 312–320 (1986).

    Article  CAS  Google Scholar 

  17. Guo, W. et al. Effect of all-trans retinoic acid and arsenic trioxide on tissue factor expression in acute promyelocytic leukemia cells. Chin. Med. J. (Engl.) 114, 30–34 (2001).

    CAS  Google Scholar 

  18. Berckmans, R.J. et al. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb. Haemost. 85, 639–646 (2001).

    Article  CAS  Google Scholar 

  19. Parry, G.C., Erlich, J.H., Carmeliet, P., Luther, T. & Mackman, N. Low levels of tissue factor are compatible with development and hemostasis in mice. J. Clin. Invest. 101, 560–569 (1998).

    Article  CAS  Google Scholar 

  20. Pawlinski, R. et al. Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Proc. Natl. Acad. Sci. USA 99, 15333–15338 (2002).

    Article  CAS  Google Scholar 

  21. Berg, H.C. Diffusion to capture. In Random Walks in Biology Chap. 3, 37–47 (Princeton University Press, Princeton, New Jersey, 1993).

    Google Scholar 

  22. Ambrose, J.A., Almeida, O.D., Sharma, S.K., Dangas, G. & Ratner, D.E. Angiographic evolution of intracoronary thrombus and dissection following percutaneous transluminal coronary angioplasty (the Thrombolysis and Angioplasty in Unstable Angina [TAUSA] trial). Am. J. Cardiol. 79, 559–563 (1997).

    Article  CAS  Google Scholar 

  23. Turitto, V.T. & Hall, C.L. Mechanical factors affecting hemostasis and thrombosis. Thromb. Res. 92, S25–S31 (1998).

    Article  CAS  Google Scholar 

  24. Thiruvikraman, S.V. et al. In situ localization of tissue factor in human atherosclerotic plaques by binding of digoxigenin-labeled factors VIIa and X. Lab. Invest. 75, 451–461 (1996).

    CAS  PubMed  Google Scholar 

  25. Grabowski, E.F. Platelet aggregation in flowing blood at a site of injury to an endothelial cell monolayer: quantitation and real-time imaging with the TAB monoclonal antibody. Blood 75, 390–398 (1990).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M.B. Taubman, M.C. Moschella, and J.T. Fallon for discussions and advice, S. Carson for monoclonal antibody against membrane-bound TF, E. Grabowski for parallel-plate chamber, J.J. Badimon for specimens of ex vivo thrombi, and H. Vaananen for technical assistance. V.Y.B., V.B., J.H., O.V., M.L. and Y.N. are partially supported by the National Institutes of Health.

Author information

Author notes

  1. Vladimir Y. Bogdanov, Viji Balasubramanian and James Hathcock: V.Y.B., V.B. and J.H. contributed equally to this work.

Authors and Affiliations

  1. Division of Thrombosis Research, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

    Vladimir Y. Bogdanov, Viji Balasubramanian, James Hathcock, Oana Vele & Yale Nemerson

  2. The Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York, USA

    Mark Lieb

Authors
  1. Vladimir Y. Bogdanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viji Balasubramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James Hathcock
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oana Vele
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark Lieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yale Nemerson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yale Nemerson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bogdanov, V., Balasubramanian, V., Hathcock, J. et al. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 9, 458–462 (2003). https://doi.org/10.1038/nm841

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm841

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing