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Tissue
Plasminogen
Activator

Plasminogen activator, tissue

PDB rendering based on 1a5h.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PLAT ; T-PA; TPA
External IDs OMIM173370 MGI97610 HomoloGene717 ChEMBL: 1873 GeneCards: PLAT Gene
EC number 3.4.21.68
RNA expression pattern
PBB GE PLAT 201860 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5327 18791
Ensembl ENSG00000104368 ENSMUSG00000031538
UniProt P00750 P11214
RefSeq (mRNA) NM_000930 NM_008872
RefSeq (protein) NP_000921 NP_032898
Location (UCSC) Chr 8:
42.03 – 42.07 Mb
Chr 8:
22.76 – 22.78 Mb
PubMed search [1] [2]

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 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).

Medical uses

tPA is used in some cases of diseases that feature blood clots, such as pulmonary embolism, myocardial infarction, and stroke, in a medical treatment called thrombolysis. The most common use is for ischemic stroke. It 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.

Ischemic stroke

There is significant debate regarding recombinant tPA's effectiveness in ischemic stroke. There have been twelve relevant, large scale, high-quality trials of rtPA in acute ischemic stroke. One common complaint about these studies is that they all have authors with significant conflicts of interest such as financial ties to Genentech, which manufactures tPA. A prominent 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, there was an excess of mortality in treated patients in the first week after the event, mostly from intracranial haemorrhage.

The NNT Group on evidence-based medicine concluded that it was inappropriate to combine these twelve trials into a single analysis, because of substantial clinical heterogeneity (i.e., variations in study design, setting, and population characteristics). Examining each study individually, the NNT group noted that two of these studies showed benefit to patients given tPA (and that, using analytical methods that they think flawed); four studies showed harm and had to be stopped before completion; and the remaining studies showed neither benefit nor harm. On the basis of this evidence, the NNT Group recommended against the use of tPA in acute ischaemic stroke.

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. Indeed, tPA has become widely considered standard of care in acute ischemic stroke, so long as the patient presents soon after the onset of stroke symptoms. 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. Because of this, only about 3% of people qualify for this treatment, since most patients do not seek medical assistance quickly enough.[citation needed] Similarly in the United States, the window of administration used to be 3 hours from onset of symptoms, but the newer guidelines also recommend use up to 4.5 hours after symptom onset. 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.

However, the NNT Group notes that the case for this time window arises largely from analysis of two trials: NINDS-2 and subgroup results from IST-3. "However, presuming that early (0-3h) administration is better than later administration (3-4.5h or 4.5-6h) the subgroup results of IST-3 suggest an implausible biological effect in which early administration is beneficial, 3-4.5h administration is harmful, and 4.5-6h administration is again beneficial." Indeed, even the original publication of the IST-3 trial found that time-window effects were not significant predictors of outcome (p=0.61).

Use of tPA in the United States in treatment of patients who are eligible for its use, no contra-indications 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.

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. Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke. In addition, people with frostbite treated with tPA had fewer amputations than those not treated with tPA.

Recombinant tissue plasminogen activators

Recombinant tissue plasminogen activators (r-tPAs) include alteplase, reteplase, and tenecteplase (TNKase).

Activase (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).

Reteplase is FDA-approved for acute myocardial infarction, where it has more convenient administration and faster thrombolysis than alteplase.

Tenecteplase is also indicated in acute myocardial infarction, showing fewer bleeding complications but otherwise similar mortality rates after one year compared to alteplase.

Additional r-tPAs, such as desmoteplase, are under clinical development.

Interactions

Tissue plasminogen activator has been shown to interact with:

Function

A simplified illustration demonstrates clot breakdown (fibrinolysis), with blue arrows denoting stimulation, and red arrows inhibition.

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.

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.

External links

 

 

Tissue Plasminogen Activator, T-PA
STROKE RECOVERY CARE, STROKE SURVIVOR CARE
, STROKE REHABILITATION CARE
Stroke Rehabilitation, Stroke Recovery, Respite Care, Hospice Care, In Home Care, Assisted Living, Respite, Stroke Recovery, Stroke Rehabilitation, Care Giver, Post-Stroke Rehabilitation, stroke rehabilitation, stroke, post stroke rehabilitation, stroke rehabilitation, rehabilitation, recovery from stroke, stroke therapy, stroke rehab, stroke recovery, information on stroke, stroke information, stroke rehabilitation information, stroke recovery technique, information about stroke rehabiliation, rehabilitation resources, NINDS, Orange County CA, Hoag Hospital Newport Beach, Saddleback Memorial Medical Center, Mission Viejo Hospital, Out Patient Services

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Tissue Plasminogen Activator, T-PA, Activase, alteplase, anti-thrombotics, antithrombotic agents, antithrombotics, brain attack, cerebral apoplexy, Cerebrovascular Accident, clot-busting drugs, CVA, drug treatment of disease, Ischemic stroke, medication treatment of disease, Stroke, Strokes, t-pa, thrombolytic agents, thrombolytic drugs, tissue plasminogen activator, tPA
Tissue Plasminogen Activator, T-PA