Tissue-type plasminogen activator, short name tPA, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that facilitates the
breakdown of blood clots. It acts as an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
to convert
plasminogen into its active form
plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin thrombus, clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) i ...
, the major enzyme responsible for clot breakdown. It is a
serine protease () found on
endothelial cell
The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and th ...
s lining the
blood vessel
Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
s. Human tPA is encoded by the ''PLAT'' gene, and has a molecular weight of ~70 kDa in the single-chain form.
tPA can be manufactured using
recombinant biotechnology
Biotechnology is a multidisciplinary field that involves the integration of natural sciences and Engineering Science, engineering sciences in order to achieve the application of organisms and parts thereof for products and services. Specialists ...
techniques, producing types of recombinant tissue plasminogen activator (rtPA) such as
alteplase,
reteplase, and
tenecteplase. These drugs are used in
clinical medicine to treat
embolic or
thrombotic stroke
Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
, but they are contraindicated and dangerous in cases of
hemorrhagic stroke and head trauma. The antidote for tPA in case of toxicity is
aminocaproic acid.
Medical uses
tPA is used in some cases of diseases that feature
blood clots, such as
pulmonary embolism
Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...
,
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
, and
stroke
Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
, 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
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
,
acute ischemic stroke, and most cases of acute massive
pulmonary embolism
Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...
, 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
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.
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.
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.
Delayed presentation to the ED leads to decreased eligibility; as few as 3% of people qualify for this treatment. 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, depending on the patient's presentation, past medical history, current
comorbidities and medication usage.
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
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...
with its use.
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.
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
amputation
Amputation is the removal of a Limb (anatomy), limb or other body part by Physical trauma, trauma, medical illness, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as cancer, malign ...
s than those not treated with tPA.
[; and repeated by ]
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
ischemic stroke. The NNT Group on
evidence-based medicine
Evidence-based medicine (EBM) is "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. It means integrating individual clinical expertise with the best available exte ...
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.
The NNT Group notes that the case for the 3-hour 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).
In the UK, concerns by stroke specialists have led to a review by the
Medicines and Healthcare products Regulatory Agency.
Pulmonary embolism
Pulmonary embolism (blood clots that have moved to the lung arteries) is usually treated with
heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...
generally followed by
warfarin
Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...
. 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.
Recombinant tissue plasminogen activators (r-tPA)
tPA was first produced by recombinant DNA techniques at Genentech in 1982.
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
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
from human melanoma cells. The aforementioned
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
was isolated using antibody based
immunoprecipitation. The resulting cDNA library was subsequently screened via
sequence analysis
In bioinformatics, sequence analysis is the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. It can be performed on the entire genome ...
and compared to a whole
genome library for confirmation of specific protein isolation and accuracy. cDNA was cloned into a synthetic
plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria and ...
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.
Interactions
Tissue plasminogen activator has been shown to
interact with:
*
Fibrinogen alpha chain
*
LRP1
*
SERPINI1
Function

tPA and plasmin are the key enzymes of the fibrinolytic pathway in which tPA-mediated plasmin generation occurs.
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 and/or an increase of the vascular permeability.
Decreased activity leads to
hypofibrinolysis, which can result in
thrombosis
Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...
or
embolism.
In patients with ischemic strokes, decreased tPA activity was reported to be associated with an increase in plasma P-selectin concentration.
Tissue plasminogen activator also plays a role in
cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryogenesis, embryonic development, wound healing and immune system, immune responses all require the orchestrated movemen ...
and
tissue remodeling.
Physiology and regulation

Once in the body, tPA has can cause the desired
thrombolytic
Thrombolysis, also called fibrinolytic therapy, is the breakdown ( lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism (massiv ...
activity (see figure), or be inactivated and removed. In the bloodstream tPA has a
half-life Half-life is a mathematical and scientific description of exponential or gradual decay.
Half-life, half life or halflife may also refer to:
Film
* Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang
* ''Half Life: ...
of 4 to 6 minutes. tPA can be bound by a plasminogen activator inhibitor, resulting in inactivation of its activity. The protein is then removed from the bloodstream by the liver. One of the specific receptors responsible for this processes is a protein known as the
LDL Receptor-Related Protein (LRP1), which clears tPA which is bound to the
Plasminogen Activator Inhibitor 1 (PAI-1).
However, when present in a high enough concentration to counteract the effects of plasminogen activator inhibitor, tPA can bind plasminogen, cleaving off the bound
plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin thrombus, clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) i ...
from it. Plasmin, another type of
protease, can either be bound by a plasmin inhibitor, or work to degrade
fibrin clots, which is the main therapeutic pathway.
Synaptic plasticity
tPA is known to participate in some forms of
synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...
, in particular
long-term depression and consequently mediate some aspects of
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...
.
Genetics
Tissue plasminogen activator is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
encoded by the ''PLAT''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
, which is located on
chromosome 8. The
primary transcript produced by this gene undergoes
alternative splicing
Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...
, producing three distinct
messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
s.
[PLAT_ plasminogen activator, tissue type Homo sapiens (human) NCBI gene database Gene ID: 5327 https://www.ncbi.nlm.nih.gov/gene/5327]
Gallery
See also
*
Streptokinase
*
Ultrasound-enhanced systemic thrombolysis
References
External links
History of Discovery: The Tissue-Type Plasminogen Activator Story Collen, D., Lijnen, H.R.
Genentech Press Release 1982
Tissue Plasminogen Activatorfrom the
American Heart Association
The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate Heart, cardiac care in an effort to reduce disability ...
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
{{DEFAULTSORT:Tissue Plasminogen Activator
Antithrombotic enzymes
EC 3.4.21