Tissue plasminogen activator
Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein involved in the breakdown of blood clots. It is a serine protease (EC 3.4.21.68) found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat only embolic or thrombotic stroke. Use is contraindicated in hemorrhagic stroke and head trauma.
tPA may be manufactured using recombinant biotechnology techniques. tPA created this way may be referred to as recombinant tissue plasminogen activator (rtPA).
Function
The classic role of tPA is in the clotting system. To be specific, tPA catalyzes the conversion of plasminogen into plasmin. It does so by cleaving the single-chain plasminogen into two chains. These two chains are linked by a disulfide bond and the resulting molecule is called plasmin.
Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding. Decreased activity leads to hypofibrinolysis which can result in thrombosis or embolism.
Tissue plasminogen activator also plays a role in cell migration and tissue remodeling.
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.
Clinical applications
tPA is used in diseases that feature blood clots, such as pulmonary embolism, myocardial infarction, and stroke, in a medical treatment called thrombolysis. To be most effective in ischemic stroke, tPA must be administered as early as possible after the onset of symptoms. Protocol guidelines require its use intravenously within the first three hours of the event, after which its detriments may outweigh its benefits. They can either be administered systemically, in the case of acute myocardial infarction, acute ischemic stroke, and most cases of acute massive pulmonary embolism, or administered through an arterial catheter directly to the site of occlusion in the case of peripheral arterial thrombi and thrombi in the proximal deep veins of the leg.[1] The guideline in Ontario, Canada hospitals for ischemic strokes is that tPA must be given within 4.5 hours of the onset of symptoms. Because of this, only about 3% of patients qualify for this treatment, since most patients do not seek medical assistance quickly enough. In the United States, the window of administration is 3 hours from onset of symptoms. tPA appears to show benefit not only for large artery occlusions but also for lacunar strokes. Since tPA dissolves blood clots, there is risk of hemorrhage with its use.
tPA has also been given to patients with acute ischemic stroke above age 90 years old. Although a 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. [2] Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke. [3]
Streptokinase is a cheaper alternative that can be used as a thrombolytic in acute treatment.
Recently, tPA has been used to dissolve thrombi associated with ischemic strokes and brain injury.
In addition, people with frostbite treated with tPA had fewer amputations than those not treated with tPA.[4]
In tPA overdose, aminocaproic acid works as an antidote.[5]
Recombinant tissue plasminogen activators
Recombinant tissue plasminogen activators (r-tPAs) include alteplase, reteplase, and tenecteplase (TNKase).[1]
Alteplase is FDA-approved for treatment of myocardial infarction with ST-elevation (STEMI), acute ischemic stroke (AIS), acute massive pulmonary embolism, and central venous access devices (CVAD).[1]
Reteplase is FDA-approved for acute myocardial infarction, where it has more convenient administration and faster thrombolysis than alteplase.[1]
Tenecteplase is also indicated in acute myocardial infarction, showing fewer bleeding complications but otherwise similar mortality rates after one year compared to alteplase.[1]
Additional r-tPAs, such as desmoteplase, are under clinical development.
Interactions
Tissue plasminogen activator has been shown to interact with Fibrinogen alpha chain,[6][7] LRP1[8][9] and SERPINI1.[10]
See also
References
- ^ a b c d e eMedicine Specialties > Thrombolytic Therapy Author: Wanda L Rivera-Bou; Coauthors: Jose G Cabanas and Salvador E Villanueva. Updated: Nov 20, 2008
- ^ Mateen FJ, Nasser M et al. (2009). "Outcomes of intravenous tissue plasminogen activator for acute ischemic stroke in patients aged 90 years or older". Mayo Clin Proceedings. 84 (4): 384–8. http://www.ncbi.nlm.nih.gov/pubmed/19339651.
- ^ Mateen FJ, Buchan AM, Hill MD, for the CASES investigators (2010). "Outcomes of thrombolysis for acute ischemic stroke in octogenarians versus nonagenarians". Stroke. 41 (8): 1833–5. doi:10.1161/STROKEAHA.110.586438. PMID 20576948. http://www.ncbi.nlm.nih.gov/pubmed/20576948.
- ^ Bruen KJ, Ballard JR, Morris SE, Cochran A, Edelman LS, Saffle JR (June 2007). "Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy". Arch Surg 142 (6): 546–51; discussion 551–3. doi:10.1001/archsurg.142.6.546. PMID 17576891.
- ^ Quizlet > Toxins and Antidotes
- ^ Tsurupa, G; Medved L (Jan. 2001). "Identification and characterization of novel tPA- and plasminogen-binding sites within fibrin(ogen) alpha C-domains". Biochemistry (United States) 40 (3): 801–8. doi:10.1021/bi001789t. ISSN 0006-2960. PMID 11170397.
- ^ Ichinose, A; Takio K, Fujikawa K (Jul. 1986). "Localization of the binding site of tissue-type plasminogen activator to fibrin". J. Clin. Invest. (UNITED STATES) 78 (1): 163–9. doi:10.1172/JCI112546. ISSN 0021-9738. PMC 329545. PMID 3088041. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=329545.
- ^ Zhuo, M; Holtzman D M, Li Y, Osaka H, DeMaro J, Jacquin M, Bu G (Jan. 2000). "Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation". J. Neurosci. (UNITED STATES) 20 (2): 542–9. PMID 10632583.
- ^ Orth, K; Madison E L, Gething M J, Sambrook J F, Herz J (Aug. 1992). "Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 89 (16): 7422–6. doi:10.1073/pnas.89.16.7422. ISSN 0027-8424. PMC 49722. PMID 1502153. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=49722.
- ^ Parmar, Parmjeet K; Coates Leigh C, Pearson John F, Hill Rena M, Birch Nigel P (Sep. 2002). "Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells". J. Neurochem. (England) 82 (6): 1406–15. doi:10.1046/j.1471-4159.2002.01100.x. ISSN 0022-3042. PMID 12354288.
Further reading
- Rijken DC (1988). "Relationships between structure and function of tissue-type plasminogen activator". Klin. Wochenschr. 66 Suppl 12: 33–9. PMID 3126346.
- Bode W, Renatus M (1998). "Tissue-type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function". Curr. Opin. Struct. Biol. 7 (6): 865–72. doi:10.1016/S0959-440X(97)80159-5. PMID 9434908.
- Collen D, Billiau A, Edy J, De Somer P., Identification of the human plasma protein which inhibits fibrinolysis associated with malignant cells, Biochim Biophys Acta. 1977 Sep 29;499(2):194-201
- Anglés-Cano E, Rojas G (2003). "Apolipoprotein(a): structure-function relationship at the lysine-binding site and plasminogen activator cleavage site". Biol. Chem. 383 (1): 93–9. doi:10.1515/BC.2002.009. PMID 11928826.
- Ny T, Wahlberg P, Brändström IJ (2003). "Matrix remodeling in the ovary: regulation and functional role of the plasminogen activator and matrix metalloproteinase systems". Mol. Cell. Endocrinol. 187 (1–2): 29–38. doi:10.1016/S0303-7207(01)00711-0. PMID 11988309.
- Teesalu T, Kulla A, Asser T et al. (2002). "Tissue plasminogen activator as a key effector in neurobiology and neuropathology". Biochem. Soc. Trans. 30 (2): 183–9. doi:10.1042/BST0300183. PMID 12023848.
- Pang PT, Lu B (2005). "Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF". Ageing Res. Rev. 3 (4): 407–30. doi:10.1016/j.arr.2004.07.002. PMID 15541709.
- Sheehan JJ, Tsirka SE (2005). "Fibrin-modifying serine proteases thrombin, tPA, and plasmin in ischemic stroke: a review". Glia 50 (4): 340–50. doi:10.1002/glia.20150. PMID 15846799.
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PDB gallery
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1a5h: CATALYTIC DOMAIN OF HUMAN TWO-CHAIN TISSUE PLASMINOGEN ACTIVATOR COMPLEX OF A BIS-BENZAMIDINE
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1bda: CATALYTIC DOMAIN OF HUMAN SINGLE CHAIN TISSUE PLASMINOGEN ACTIVATOR IN COMPLEX WITH DANSYL-EGR-CMK (DANSYL-GLU-GLY-ARG CHLOROMETHYL KETONE)
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1pk2: SOLUTION STRUCTURE OF THE TISSUE-TYPE PLASMINOGEN ACTIVATOR KRINGLE 2 DOMAIN COMPLEXED TO 6-AMINOHEXANOIC ACID AN ANTIFIBRINOLYTIC DRUG
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1pml: KRINGLE-KRINGLE INTERACTIONS IN MULTIMER KRINGLE STRUCTURES
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1rtf: COMPLEX OF BENZAMIDINE WITH THE CATALYTIC DOMAIN OF HUMAN TWO CHAIN TISSUE PLASMINOGEN ACTIVATOR [(TC)-T-PA]
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1tpg: F1-G MODULE PAIR RESIDUES 1-91 (C83S) OF TISSUE-TYPE PLASMINOGEN ACTIVATOR (T-PA) (NMR, 298K, PH2.95, REPRESENTATIVE STRUCTURE)
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1tpk: CRYSTAL STRUCTURE OF THE KRINGLE-2 DOMAIN OF TISSUE PLASMINOGEN ACTIVATOR AT 2.4-ANGSTROMS RESOLUTION
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1tpm: SOLUTION STRUCTURE OF THE FIBRIN BINDING FINGER DOMAIN OF TISSUE-TYPE PLASMINOGEN ACTIVATOR DETERMINED BY 1H NUCLEAR MAGNETIC RESONANCE
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1tpn: SOLUTION STRUCTURE OF THE FIBRIN BINDING FINGER DOMAIN OF TISSUE-TYPE PLASMINOGEN ACTIVATOR DETERMINED BY 1H NUCLEAR MAGNETIC RESONANCE
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