Tissue-type plasminogen activator
PLAT | |||
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Sources:Amigo / QuickGO |
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Location (UCSC) | Chr 8: 42.17 – 42.21 Mb | Chr 8: 23.25 – 23.27 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Tissue-type plasminogen activator, short name tPA, is a
tPA can be manufactured using
Medical uses
tPA is used in some cases of diseases that feature
Ischemic stroke
Statistics
There have been 12 large scale, high-quality trials of rtPA in acute ischemic stroke. A meta-analysis of these trials concluded that rtPA given within 6 hours of a stroke significantly increased the odds of being alive and independent at final follow-up, particularly in patients treated within 3 hours. However a significant mortality rate was noted, mostly from intracranial haemorrhage at 7 days, but later mortality was not significant amongst treated and non-treated patients.[7]
It has been suggested that if tPA is effective in ischemic stroke, it must be administered as early as possible after the onset of stroke symptoms, given that patients present to an ED in a timely manner.[7][8] Many national guidelines including the AHA have interpreted this cohort of studies as suggesting that there are specific subgroups who may benefit from tPA and thus recommend its use within a limited time window after the event. Protocol guidelines require its use intravenously within the first three hours of the event, after which its detriments may outweigh its benefits.
For example, the Canadian Stroke Network guideline states "All patients with disabling acute ischemic stroke who can be treated within 4.5 hours of symptom onset should be evaluated without delay to determine their eligibility for treatment" with tPA.
Administration criteria
Use of tPA in the United States in treatment of patients who are eligible for its use, have no contraindications, and arrival at the treating facility less than 3 hours after onset of symptoms, is reported to have doubled from 2003 to 2011. Use on patients with mild deficits, of nonwhite race/ethnicity, and oldest old age increased. However, many patients who were eligible for treatment were not treated.[14][15]
tPA has also been given to patients with acute ischemic stroke above age 90 years old. Although a small fraction of patients 90 years and above treated with tPA for acute ischemic stroke recover, most patients have a poor 30-day functional outcome or die.[16] Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke.[17] In addition, people with frostbite treated with tPA had fewer amputations than those not treated with tPA.[18]
General consensus on use
There is consensus amongst stroke specialists that tPA is the standard of care for eligible stroke patients, and benefits outweigh the risks. There is significant debate mainly in the emergency medicine community regarding recombinant tPA's effectiveness in
Pulmonary embolism
Pulmonary embolism (blood clots that have moved to the lung arteries) is usually treated with heparin generally followed by warfarin. If pulmonary embolism causes severe instability due to high pressure on the heart ("massive PE") and leads to low blood pressure, recombinant tPA is recommended.[22][23][24]
Recombinant tissue plasminogen activators (r-tPA)
tPA was first produced by recombinant DNA techniques at Genentech in 1982.[25]
Tissue-type plasminogen activators were initially identified and isolated from mammalian tissues after which a cDNA library was established with the use of reverse transcriptase and mRNA from human melanoma cells. The aforementioned mRNA was isolated using antibody based immunoprecipitation. The resulting cDNA library was subsequently screened via sequence analysis and compared to a whole genome library for confirmation of specific protein isolation and accuracy. cDNA was cloned into a synthetic plasmid and initially expressed in E. coli cells, followed by yeast cells with successful results confirmed via sequencing before attempting in mammalian cells. The transformants were selected with the use of Methotrexate. Methotrexate strengthens selection by inhibiting DHFR activity which then compels the cells to express more DHFR (exogenous) and consequently more recombinant protein to survive. The highly active transformants were subsequently placed in an industrial fermenter. The tPA which was then secreted into the culture medium was isolated and collected for therapeutic use. For pharmaceutical purposes, tPA was the first pharmaceutical drug produced synthetically with the use of mammalian cells, specifically Chinese hamster ovarian cells (CHO). Recombinant tPA is commonly referred to as r-tPA and sold under multiple brand names.[26][27]
Product Name | Notes |
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Activase (Alteplase) | FDA-approved for treatment of central venous access devices (CVAD).[28]
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Reteplase | FDA-approved for acute myocardial infarction, where it has more convenient administration and faster thrombolysis than alteplase. This is because it is a second generation engineered TPA, hence its half life is up to 20 minutes which allows it to be administered as a bolus injection rather than an infusion like Alteplase.[28]
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Tenecteplase | Indicated in acute myocardial infarction, showing fewer bleeding complications but otherwise similar mortality rates after one year compared to Alteplase.[28]
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Interactions
Tissue plasminogen activator has been shown to
Function
tPA and plasmin are the key enzymes of the fibrinolytic pathway in which tPA-mediated plasmin generation occurs.
To be specific, tPA cleaves the zymogen plasminogen at its Arg561 - Val562 peptide bond, into the serine protease plasmin.[citation needed]
Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding and/or an increase of the vascular permeability.[34] Decreased activity leads to hypofibrinolysis, which can result in thrombosis or embolism.
In ischemic stroke patients, decreased tPA activity was reported to be associated with an increase in plasma P-selectin concentration.[35]
Tissue plasminogen activator also plays a role in cell migration and tissue remodeling.[citation needed]
Physiology and regulation
Once in the body, tPA has three main routes it can take, with one resulting in desired thrombolytic activity (see figure). For starters, following administration and release, tPA can be absorbed by the liver and cleared from the body through receptors present therein. One of the specific receptors responsible for this processes is a scavenger protein, specifically the LDL Receptor-Related Protein (LRP1).[37] tPA additionally can be bound by a plasminogen activator inhibitor (PAI), resulting in inactivation of its activity, and following clearing from the body by the liver. Lastly, tPA can bind plasminogen, cleaving off the bound plasmin from it. Plasmin, another type of protease, can either be bound by a plasmin inhibitor, or work to degrade fibrin clots, which is the highest utilized and desired pathway.[36]
Synaptic plasticity
tPA is known to participate in some forms of synaptic plasticity, in particular long-term depression and consequently mediate some aspects of memory.[38]
Genetics
Tissue plasminogen activator is a protein encoded by the PLAT gene, which is located on chromosome 8. The primary transcript produced by this gene undergoes alternative splicing, producing three distinct messenger RNAs.[39]
Gallery
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000104368 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031538 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Tissue plasminogen activator human". Sigma-Aldrich. 9 July 2017. Retrieved 11 May 2018.
- ^ Rivera-Bou WL, Cabanas JG, Villanueva SE (2008-11-20). "Thrombolytic Therapy". Medscape.
- ^ PMID 22632907.
- PMID 22818644.
- ^ Lindsay, Gubitz G, Bayley M, Hill MD, Davies-Schinkel C, Singh S, Phillips S (8 December 2010). "Hyperacute stroke management". Canadian best practice recommendations for stroke care. Ottawa, ON: Canadian Stroke Network. pp. 55–84. Archived from the original on 3 December 2013. Retrieved 30 November 2013.
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ignored (help) - PMID 18353121.
- PMID 19407232.
- S2CID 226218304.
- PMID 28830843.
- ^ Bankhead C, Agus ZS (2013-08-23). "Clot-Busting Drugs Used More Often in Stroke". Medpage Today.
- PMID 24046398.
The frequency of IV tPA use among all AIS patients, regardless of contraindications, nearly doubled from 2003 to 2011. Treatment with tPA has expanded to include more patients with mild deficits, nonwhite race/ethnicity, and oldest old age
- PMID 19339651.
- PMID 20576948.
- PMID 17576891.
- ^ a b c Newman, David (March 25, 2013). "Thrombolytics for Acute Ischemic Stroke: No benefit found". NNT Group. Retrieved 30 November 2013.
- PMID 22632908.
- ^ Brimelow, Adam (2014-08-22). "Safety review into stroke clot-buster drug alteplase". BBC News. British Broadcasting Corporation. Retrieved 29 June 2015.
- PMID 25173341.
- National Institute for Health and Clinical Excellence. Clinical guideline 144: Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. London, 2012.
- PMID 18574259.
- ^ "(TPA) Produced By Recombinant DNA Techniques". Biology Discussion. 1982-07-23. Archived from the original on 2018-09-13. Retrieved 2019-01-05.
- ^ "Pharmaceutical Products of Recombinant DNA Technology". Biology Discussion. 2015-09-21. Retrieved 2017-12-10.
- S2CID 39846803.
- ^ a b c Wanda L Rivera-Bou; José G Cabañas; Salvador E Villanueva (2017-05-02). "Thrombolytic Therapy: Background, Thrombolytic Agents, Thrombolytic Therapy for Acute Myocardial Infarction". Medscape.
- PMID 11170397.
- PMID 3088041.
- PMID 10632583.
- PMID 1502153.
- PMID 12354288.
- PMID 27531677.
- S2CID 22979258.
- ^ a b "Tissue Plasminogen Activator (tPA)". diapharma.com. Retrieved 2017-12-10.
- ^ PMID 18208365.
- S2CID 22764188.
- ^ PLAT_ plasminogen activator, tissue type [ Homo sapiens (human) ], NCBI gene database Gene ID: 5327 https://www.ncbi.nlm.nih.gov/gene/5327
External links
- History of Discovery: The Tissue-Type Plasminogen Activator Story, Collen, D., Lijnen, H.R.
- Genentech Press Release 1982 Archived 2018-09-13 at the Wayback Machine
- Tissue Plasminogen Activator from the American Heart Association
- Widening the Window : Strategies to buy time in treating ischemic stroke - Scientific American (August 2005)
- Study expands window for effective stroke treatment - explained on YouTube