A Review on Recombinant Tissue Plasminogen Activator: In Vitro Synthesis and Its Use in Treatment of Acute Ischemic Stroke

DOI: 10.4236/oalib.1100603   PDF        1,530 Downloads   3,090 Views  


Tissue-type Plasminogen Activator (tPA) is a serine protease produced by endothelial cells. They target plasminogen, an inactive precursor of plasmin and convert the plasminogen into active plasmin, which degrades the fibrin component of thrombus to aid in dissolution of blood clots. Hence tPA is commonly used in treatment of acute Ischemic stroke in the form of recombinant tissue plasminogen activator (rtPA). rtPA is produced using recombinant technology from different types of vectors depending on the quantities required for the treatment of different diseases. Alteplase (intravenous rtPA) is the most common therapy drug used to treat ischemic strokes. This review gives an outline of the in vitro synthesis of rtPA and its usage in treatment of Acute Ischemic stroke.

Share and Cite:

Sukumaran, P. and Poulse, E. (2014) A Review on Recombinant Tissue Plasminogen Activator: In Vitro Synthesis and Its Use in Treatment of Acute Ischemic Stroke. Open Access Library Journal, 1, 1-6. doi: 10.4236/oalib.1100603.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Levin, E.G., Santell, L. and Osborn, K.G. (1997) The Expression of Endothelial Tissue Plasminogen Activator in Vivo: A Function Defined by Vessel Size and Anatomic Location. Journal of Cell Science, 110, 139-148.
[2] World Health Organisation (2005) Preventing Chronic Diseases: A Vital Investment. Geneva.
[3] Dalal, P., Bhattacharjee, M., Vairale, J. and Bhat, P. (2007) UN Millenium Development Goals: Can We Halt the Stroke Epidemic in India? Annals of Indian Academy of Neurology, 10, 130-136.
[4] Gupta, R., Joshi, P., Mohan, V., Reddy, S. and Yusuf, S. (2008) Epidemology and Causation of Coronary Heart Disease and Stroke in India. Heart, 94, 16-26.
[5] Feigin, V., Lawes, C., Bennet, D., Barker-Cello, S. and Parag, V. (2009) Worldwide Stroke Incidence and Early Case Fatality in 56 Population Based Studies: A Systemic Review. The Lancet Neurology, 8, 355-369.
[6] Shah, B. and Mathur, P. (2006) Workshop Report on Stroke Surveillance in India. Division of Noncommunicable Diseases, Indian Council of Medical Research, New Delhi.
[7] Taylor, F.C. (2012) Stroke in India, South Asia Network for Chronic Disease Fact Sheets
[8] Hoylaerts, M., Rijken, D.C., Lijnen, H.R. and Collen, D. (1982) Kinetics of the Activation of Plasminogen by Human Plasminogen Activator. Role of Fibrin. The Journal of Biological Chemistry, 257, 2912-2919.
[9] Ranby, M. (1982) Studies on Kinetics of Plasminogen Activation by Tissue Plasminogen Activator. Biochimica et Biophysica Acta (BBA), 704, 461-446.
[10] Kristensen, P., Larsson, L.-I., Nielsen, L.S., Grondahl-Hansen, J., Andreasen, P.A. and Dano, K. (1984) Human Endothelial Cells Contain One Type of Plasminogen Activator. FEBS Letters, 168, 33-37.
[11] Saksela, O., Moscatelli, D., Sommer, A. and Rifkin, D.B. (1988) Endothelial Cell-Derived Heparan Sulfate Binds Basic Fibroblast Growth Factor and Protects It from Proteolytic Degradation. The Journal of Cell Biology, 107, 743-751.
[12] Levin, E.G. and Loskutoff, D.K. (1982) Cultured Bovine Endothelial Cells Produce Both Urokinase and Tissue-Type Plasminogen Activators. The Journal of Cell Biology, 94, 631-636.
[13] Speiser, W., Anders, E., Preissner, K.T., Wagner, O. and Muller-Berghaus, G. (1987) Differences in Coagulant and Fibrinolytic Activities of Cultured Human Endothelial Cells Derived from Omental Tissue Microvessels and Umbilical Veins. Blood, 69, 964-967.
[14] Wojta, J., Jones, R.L., Binder, B.R. and Hoover, R.L. (1988) Reduction in P02 Decreases the Fibrinolytic Potential of Cultured Bovine Endothelial Cells Derived from Pulmonary Arteries and Lung Microvasculature. Blood, 71, 1703-1706.
[15] Van Zonneveld, A.J., Veerman, H. and Pannekoek, H. (1986) Autonomous Functions of Structural Domains on Human Tissue-Type Plasminogen Activator. Proceedings of the National Academy of Sciences of the United States of America, 83, 4670-4674.
[16] Van Zonneveld, A.J., Veerman, H. and Pannekoek, H. (1986) The Interaction of the Finger and the Kringle-2 Domain of Tissue-Type Plasminogen Activator with Fibrin: Inhibition of Kringle-2 Binding to Fibrin by Epsilon-Amino Caproic Acid. Journal of Biological Chemistry, 261, 14214-14218.
[17] Dudek, G.A., Kloczewiak, M., Budzyński, A.Z., Latallo, Z.S. and Kopec, M. (1970) Characterisation and Comparison of Macromolecular End Products of Fibrinogen and Fibrin Proteolysis by Plasmin. Biochimica et Biophysica Acta (BBA), Protein Structure, 214, 44-51.
[18] Corcoran, M.L., Hewitt, R.E., Kleiner Jr., D.E. and Stetler-Stevenson, W.G. (1996) MMP-2: Expression, Activation and Inhibition. Enzyme Protein, 49, 7-19.
[19] Keski-Oja, J., Lohi, J., Tuuttila, A., Tryggvason, K. and Vartio, T. (1992) Proteolytic Processing of the 72,000-Da Type IV Collagenase by Urokinase Plasminogen Activator. Experimental Cell Research, 202, 471-476.
[20] Ohira, T., Shahar, E., Chambless, L.E., Rosamond W.D., Mosley Jr., T.H. and Folsom, A.R. (2006) Risk Factors for Ischemic Stroke Subtypes: The Atherosclerosis Risk in Communities Study. Stroke, 37, 2493-2498.
[21] Arrastia, R.D. (2000) Homocysteine and Neurologic Disease. Archives of Neurology, 57, 1422-1426.
[22] Modi, M., Prabhakar, S., Majumdar, S., Khullar, M., Lal, V. and Das, C.P. (2005) Hyperhomocysteinemia as a Risk Factor for Ischemic Stroke: An Indian Scenario. Neurology India, 53, 297-301.
[23] (2005) Activase (Alteplase) Product Information. Genentech, South San Fransisco.
[24] Frendl, A. and Csiba, L. (2011) Pharmacological and Non-Pharmacological Recanalization Strategies in Acute Ischemic Stroke. Frontiers in Neurology, 2, 00032.
[25] Brown, D.L., Barsan, W.G., Lisabeth, L.D., Galler, M.E. and Morgenstern, L.B. (2005) Survey of Emergency Physicians about Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke. Annals of Emergency Medicine, 46, 56-60.
[26] The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue Plasminogen Activator for Acute Ischemic Stroke. The New England Journal of Medicine, 333, 1581-1587.
[27] Liang, B.A., Lew, R. and Zivin, J.A. (2008) Review of Tissue Plasminogen Activator, Ischemic Stroke, and Potential Legal Issues. Archives of Neurology, 65, 1429-1433.
[28] Griffiths, J.B. and Electricwala, A. (1987) Production of Tissue Plasminogen Activators from Animal Cells. Advances in Biochemical Engineering/Biotechnology, 34, 147-166.
[29] Sarmientos, P., Duchesne, M., Denèfle, P., Boiziau, J., Fromage, N., Delporte, N., Parker, F., Lelièvre, Y., Mayaux, J.F. and Cartwright, T. (1989) Synthesis and Purification of Active Human Tissue Plasminogen Activator from Escherichia coli. Nature Biotechnology, 7, 495-501.
[30] Qui, J., Swartz, J.R. and Georgiou, G. (1998) Expression of Active Human Tissue-Type Plasminogen Activator in Escherichia coli. Applied and Environmental Microbiology, 64, 4891-4896.
[31] Pennica, D., Holmes, W.E., Kohr, W.J., Harkins, R.N., Vehar, G.A., Ward, C.A., Bennett, W.F., Yelverton, E., Seeburg, P.H., Heyneker, H.L., Goeddel, D.V. and Collen, D. (1983) Cloning and Expression of Human Tissue-Type Plasminogen Activator cDNA in E. coli. Nature, 301, 214-221.
[32] de Vos, A.M., Ultsch, M.H., Kelley, R.F., Padmanabhan, K., Tulinsky, A., Westbrook, M.L. and Kossiakoff, A.A. (1992) Crystal Structure of the Kringle 2 Domain of Tissue Plasminogen Activator at 2.4-.ANG Resolution. Biochemistry, 31, 270-279.
[33] Furlong, A.M., Thomsen, D.R., Marotti, K.R., Post, L.E. and Sharma, S.K. (1988) Active Human Tissue Plasminogen Activator Secreted from Insect Cells Using a Baculovirus Vector. Biotechnology and Applied Biochemistry, 10, 454-464.
[34] Ogrydziak, D.M. (1993) Yeast Extracellular Proteases. Critical Reviews in Biotechnology, 13, 1-55.
[35] Lubiniecki, A., Arathoon, R., Polastri, G., Thomas, J., Wiebe, M., Garnick, R., Jones, A., van Reis, R. and Builder, S. (1990) Selected Strategies for Manufacture and Control of Recombinant Tissue Plasminogen Activator Prepared from Cell Culture. In: Spier, R.E., Griffiths, J.B., Stephenne, J. and Crooy, P.J., Eds., Advances in Animal Cell Biology and Technology for Bioprocesses, Butterworths, London, 442-451.
[36] Soleimani, M., Mahboudi, F., Davoudi, N., Amanzadeh, A., Azizi, M., Adeli, A., Rastegar, H., Barkhordari, F. and Mohajer-Maghari, B. (2007) Expression of Human Tissue Plasminogen Activator in the Trypanosomatid Protozoan Leishmania tarentolae. Biotechnology and Applied Biochemistry, 48, 55-61.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.