Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
June-2015 Volume 9 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
June-2015 Volume 9 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid

  • Authors:
    • Daniel Glenn Kindell
    • Rick Wayne Keck
    • Jerzy Jankun
  • View Affiliations / Copyright

    Affiliations: Urology Research Center, Department of Urology, University of Toledo, Health Science Campus, Toledo, OH 43614, USA
  • Pages: 2339-2343
    |
    Published online on: April 1, 2015
       https://doi.org/10.3892/etm.2015.2399
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Plasminogen activator inhibitor (PAI)-1 is a serpin glycoprotein that can stabilize blood clots by inhibiting fibrinolysis. However, wild‑type PAI‑1 has the disadvantage of a short half‑life of ~2 h. A very long half‑life (VLHL) PAI‑1 mutant was developed previously with an active‑form half‑life of >700 h, making it a possible candidate for use in hemorrhagic therapy. Current treatments for mitigating hemorrhage, other than inducers of blood clotting, are limited to lysine analog antifibrinolytics, including 6‑aminocaproic acid and tranexamic acid. VLHL PAI‑1 has been previously demonstrated to limit bleeding; however, the efficacy of this protein compared with lysine analog antifibrinolytics has not been investigated. The aim of the current study was to compare the clot stabilizing properties of the novel antifibrinolytic VLHL PAI‑1 with those of 6‑aminocaproic acid in reference plasma. Using thromboelastographic analysis, VLHL PAI‑1 exhibited an IC50 (half maximal inhibitory concentration) of 8.8x10‑8 mol/l, while 6‑aminocaproic acid showed an IC50 of 1.6x10‑4 mol/l. However, at doses of >9.0x10‑7 mol/l, VLHL PAI‑1 exhibited a delay in the onset of clot formation, which may be attributed to thrombin inhibition by excess PAI‑1. The inhibition of tissue plasminogen activator by VLHL PAI‑1 demonstrated improved efficacy over 6‑aminocaproic acid in mitigating hemorrhage. In addition, patients with a PAI‑1 deficiency, which causes blood clots to lyse rapidly resulting in profuse bleeding, may benefit from the application of VLHL PAI-1 as an antihemorrhagic therapy.
View Figures

Figure 1

Figure 2

View References

1 

Antun AG, Gleason S, Arellano M, et al: Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies. Cancer. 119:3784–3787. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Dhir A: Antifibrinolytics in cardiac surgery. Ann Card Anaesth. 16:117–125. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Jankun J and Skrzypczak-Jankun E: Plasminogen activator inhibitor with very long half-life (VLHL PAI-1) can reduce bleeding in PAI-1-deficient patients. Cardiovasc Hematol Disord Drug Targets. 13:144–150. 2013.PubMed/NCBI

4 

Mosesson MW: Fibrinogen and fibrin structure and functions. J Thromb Haemost. 3:1894–1904. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Rau JC, Beaulieu LM, Huntington JA and Church FC: Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost. 5:(Suppl 1). 102–115. 2007. View Article : Google Scholar : PubMed/NCBI

6 

Zorio E, Gilabert-Estellés J, España F, Ramón LA, Cosín R and Estellés A: Fibrinolysis: the key to new pathogenetic mechanisms. Curr Med Chem. 15:923–929. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Dellas C and Loskutoff DJ: Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost. 93:631–640. 2005.PubMed/NCBI

8 

Cesarman-Maus G and Hajjar KA: Molecular mechanisms of fibrinolysis. Br J Haematol. 129:307–321. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Egelund R, Schousboe SL, Sottrup-Jensen L, Rodenburg KW and Andreasen PA: Type-1 plasminogen-activator inhibitor - conformational differences between latent, active, reactive-centre-cleaved and plasminogen-activator-complexed forms, as probed by proteolytic susceptibility. Eur J Biochem. 248:775–785. 1997. View Article : Google Scholar : PubMed/NCBI

10 

Jankun J, Yang J, Zheng H, Han FQ, Al-Senaidy A and Skrzypczak-Jankun E: Remarkable extension of PAI-1 half-life surprisingly brings no changes to its structure. Int J Mol Med. 29:61–64. 2012.PubMed/NCBI

11 

Chorostowska-Wynimko J, Swiercz R, Skrzypczak-Jankun E, Wojtowicz A, Selman SH and Jankun J: A novel form of the plasminogen activator inhibitor created by cysteine mutations extends its half-life: relevance to cancer and angiogenesis. Mol Cancer Ther. 2:19–28. 2003. View Article : Google Scholar : PubMed/NCBI

12 

Jankun J, Aleem AM, Selman SH, et al: Highly stable plasminogen activator inhibitor type one (VLHL PAI-1) protects fibrin clots from tissue plasminogen activator-mediated fibrinolysis. Int J Mol Med. 20:683–687. 2007.PubMed/NCBI

13 

Jankun J, Keck R, Selman SH and Skrzypczak-Jankun E: Systemic or topical application of plasminogen activator inhibitor with extended half-life (VLHL PAI-1) reduces bleeding time and total blood loss. Int J Mol Med. 26:501–504. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Jankun J, Selman SH, Keck RW, Łysiak-Szydłowska W and Skrzypczak-Jankun E: Very long half-life plasminogen activator inhibitor type 1 reduces bleeding in a mouse model. BJU Int. 105:1469–1476. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Jankun J, Skotnicka M, Łysiak-Szydłowska W, Al-Senaidy A and Skrzypczak-Jankun E: Diverse inhibition of plasminogen activator inhibitor type 1 by theaflavins of black tea. Int J Mol Med. 27:525–529. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Jankun J and Skrzypczak-Jankun E: Yin and yang of the plasminogen activator inhibitor. Pol Arch Med Wewn. 119:410–417. 2009.PubMed/NCBI

17 

Jankun J, Aleem AM, Struniawski R, Lysiak-Szydłowska W, Selman SH and Skrzypczak-Jankun E: Accelerated thrombus lysis in the blood of plasminogen activator inhibitor deficient mice is inhibited by PAI-1 with a very long half-life. Pharmacol Rep. 61:673–680. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Morimoto Y, Yoshioka A, Imai Y, Takahashi Y, Minowa H and Kirita T: Haemostatic management of intraoral bleeding in patients with congenital deficiency of alpha2-plasmin inhibitor or plasminogen activator inhibitor-1. Haemophilia. 10:669–674. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Schulman S: Pharmacologic tools to reduce bleeding in surgery. Hematology Am Soc Hematol Educ Program. 2012:517–521. 2012.PubMed/NCBI

20 

Makhija N, Sarupria A, Kumar Choudhary S, Das S, Lakshmy R and Kiran U: Comparison of epsilon aminocaproic acid and tranexamic acid in thoracic aortic surgery: clinical efficacy and safety. J Cardiothorac Vasc Anesth. 27:1201–1207. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Harrop SJ, Jankova L, Coles M, et al: The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function. Structure. 7:43–54. 1999. View Article : Google Scholar : PubMed/NCBI

22 

Sharp AM, Stein PE, Pannu NS, et al: The active conformation of plasminogen activator inhibitor 1, a target for drugs to control fibrinolysis and cell adhesion. Structure. 7:111–118. 1999. View Article : Google Scholar : PubMed/NCBI

23 

Fergusson DA, Hébert PC, Mazer CD, et al: BART Investigators: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 358:2319–2331. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Howell N, Senanayake E, Freemantle N and Pagano D: Putting the record straight on aprotinin as safe and effective: results from a mixed treatment meta-analysis of trials of aprotinin. J Thorac Cardiovasc Surg. 145:234–240. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Iribarren JL, Jimenez JJ, Hernández D, et al: Postoperative bleeding in cardiac surgery: the role of tranexamic acid in patients homozygous for the 5G polymorphism of the plasminogen activator inhibitor-1 gene. Anesthesiology. 108:596–602. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Racanelli AL, Diemer MJ, Dobies AC, Dubin JR and Reilly TM: Comparison of recombinant plasminogen activator inhibitor-1 and epsilon amino caproic acid in a hemorrhagic rabbit model. Thromb Haemost. 67:692–696. 1992.PubMed/NCBI

27 

van Meijer M, Smilde A, Tans G, Nesheim ME, Pannekoek H and Horrevoets AJ: The suicide substrate reaction between plasminogen activator inhibitor 1 and thrombin is regulated by the cofactors vitronectin and heparin. Blood. 90:1874–1882. 1997.PubMed/NCBI

28 

Fay WP, Parker AC, Condrey LR and Shapiro AD: Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood. 90:204–208. 1997.PubMed/NCBI

29 

Jankun J and Skrzypczak-Jankun E: Bleeding diathesis is associated with an A15T heterozygous mutation in exon 2 of the plasminogen activator inhibitor type 1. Exp Ther Med. 1:575–577. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Mehta R and Shapiro AD: Plasminogen activator inhibitor type 1 deficiency. Haemophilia. 14:1255–1260. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Schleef RR, Higgins DL, Pillemer E and Levitt LJ: Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest. 83:1747–1752. 1989. View Article : Google Scholar : PubMed/NCBI

32 

Genét GF, Ostrowski SR, Sørensen AM and Johansson PI: Detection of tPA-induced hyperfibrinolysis in whole blood by RapidTEG, KaolinTEG, and functional fibrinogenTEG in healthy individuals. Clin Appl Thromb Hemost. 18:638–644. 2012. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Kindell DG, Keck RW and Jankun J: Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid. Exp Ther Med 9: 2339-2343, 2015.
APA
Kindell, D.G., Keck, R.W., & Jankun, J. (2015). Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid. Experimental and Therapeutic Medicine, 9, 2339-2343. https://doi.org/10.3892/etm.2015.2399
MLA
Kindell, D. G., Keck, R. W., Jankun, J."Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid". Experimental and Therapeutic Medicine 9.6 (2015): 2339-2343.
Chicago
Kindell, D. G., Keck, R. W., Jankun, J."Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid". Experimental and Therapeutic Medicine 9, no. 6 (2015): 2339-2343. https://doi.org/10.3892/etm.2015.2399
Copy and paste a formatted citation
x
Spandidos Publications style
Kindell DG, Keck RW and Jankun J: Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid. Exp Ther Med 9: 2339-2343, 2015.
APA
Kindell, D.G., Keck, R.W., & Jankun, J. (2015). Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid. Experimental and Therapeutic Medicine, 9, 2339-2343. https://doi.org/10.3892/etm.2015.2399
MLA
Kindell, D. G., Keck, R. W., Jankun, J."Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid". Experimental and Therapeutic Medicine 9.6 (2015): 2339-2343.
Chicago
Kindell, D. G., Keck, R. W., Jankun, J."Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid". Experimental and Therapeutic Medicine 9, no. 6 (2015): 2339-2343. https://doi.org/10.3892/etm.2015.2399
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team