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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.

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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.

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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.

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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

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  1. Vladimir Y. Bogdanov
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  6. Yale Nemerson
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Correspondence to Yale Nemerson.

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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

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