Tuesday, April 8, 2014

Assignment #3:
Tissue plasminogen activator (tPA) is a protein that will change your life. This protein is a natural enzyme in your body, but has now been made as a drug to breakdown blood clots featured in some particular diseases. tPA is used to treat myocardial infarction, pulmonary embolism, stroke, and even frostbite at times.
"Tissue plasminogen activator improved tissue perfusion and reduced amputations when administered within 24 hours of injury... this modality represents the first clinically significant advancement in the treatment of frostbite in more than 25 years." (Barclay)Tissue plasminogen activator is a fibrin specific activator for the conversion of plasminogen to plasmin, causing thrombolysis and restoring blood flow. tPA works as a serine protease, increasing the plasmin to cause hyperfibrinolysis. The enzyme cleaves the zymogen plasminogen at Arg561 to Val 562 peptide bond into the serine protease plasmin, which lyses clots. Plasmin is an important enzyme in blood that breaks down blood plasma proteins and fibrin clots (fibrinolysis). File:Fibrinolysis.png
tPA also acts as a cytokine to activate receptor-mediated signaling events and has been shown to modulate inflammatory responses in tissue injury. This means that tPA could also be used to target autoimmune and inflammatory diseases. How it works in this situation,  "A: tPA binds to LRP-1 and induces activation of NF-κB. B: tPA promotes the aggregation of annexin A2 and integrin CD11b, leading to activation of ILK, phosphorylation and degradation of IκB, and eventually activation of NF-κB. C: tPA forms complex with LRP-1, PAI-1, and Mac-1, which results in the increased macrophage migration." An external file that holds a picture, illustration, etc.
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For stroke where it is most often used, it can dissolve the blood clots in the brain and decrease the chances of death or disability if used within 4.5 hours after the onset of stroke symptoms. They are now working on a version that will only work at the site of the clot so as not to allow hemorrhaging elsewhere for the patient so it is safer to use.The cost of rt-PA was estimated to be $2,750 and more expensive than standard care for ischemic stroke in the short term, owing to the cost of the drug and the need for additional resources. However, the drug and treatment is associated with lower costs in the long term, since it reduces the risk of subsequent disability. So although tPA might be an expensive drug, it is cost effective and worthwhile generally, especially when treating cases such as acute Ischemic stroke (AIS) as it is one of the only FDA approved medications for AIS. tPA use can help lower the estimated direct medical costs of stroke in the United States as in 2007 the costs were $25 billion, as tPA would help decrease health care costs long term.

The amino acid sequence of the first domain of tPA has eight residues that are highly conserved in the type 1 finger domains of human fibronectin. The overall fold of the t-PA finger domain similarity to that of the seventh type 1 repeat of human fibronectin with the side-chains of conserved residues lying in similar conformations is rather striking. One significant difference between the two molecules is that hydrophobic residues cover the exposed surface of the principal beta-sheet region in the t-PA finger domain. One idea is that one face of this region may interact with parts of the complete t-PA protein.
tPA also plays a role in tissue remodeling and cell migration.

The tPA gallery:


References:Barclay, Laurie. "Thrombolytic Therapy May Reduce Amputation in Frostbite Injury."Medscape. 19 June 2007. 08 Apr. 2014 <http://www.medscape.com/viewarticle/558507>.Collen, D., and H. R. Lijnen. "The Tissue-Type Plasminogen Activator Story." The Tissue-Type Plasminogen Activator Story. 2009. American Heart Association. 08 Apr. 2014 <http://atvb.ahajournals.org/content/29/8/1151.full>.Lin, Ling, and Kebin Hu. "Abstract." National Center for Biotechnology Information. 27 Feb. 2014. U.S. National Library of Medicine. 08 Apr. 2014 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960759/>."Tissue plasminogen activator." Wikipedia. 04 May 2014. Wikimedia Foundation. 08 Apr. 2014 <http://en.wikipedia.org/wiki/Tissue_plasminogen_activator>.
tPA proteint: Tissue Plasminogen Activator: 10.2210/pdb1tpm/pdb
Wechsler, Lawrence R. Intravenous Thrombolytic Therapy for Acute Ischemic Stroke. New England Journal of Medicine 364:2138-2146, 2011.

4 comments:

  1. I am interested on how tPA may be applied to autoimmune disorders, but I found the diagram and very technical language in that paragraph somewhat confusing/distracting. Any information on the success rate of tPA on stroke treatment, considering it is the only FDA approved treatment for some types of stroke? I liked the information about how much the drug costs and how it is cost-effective in the long run, and also how you connected breakdown of blood clotting to many different applications. How does it play a role in tissue migration and cell remodeling? It might be helpful if you put the structure information at the beginning of the post.

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  2. I would also recommend playing with the font size and inserting hyperlinks to the original sources for figures that you didn't create. But overall you did a good job.

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  3. Great protein! I understand that tPA can dissolve blood clots. However, I would like to know the mechanisms underlying the reaction. What are the components of blood clots? How is tPA acting on the blood clots to dissolve them? If tPA is natural in our body, why our body doesn't secret more in the conditions of heart diseases? Thanks!

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  4. The font size is small, but it looks like you changed that in the later one, so that's awesome! I like the first diagram, I found that very helpful. tPA seems like a cool protein!

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