Tissue plasminogen activator
Encyclopedia
Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein
involved in the breakdown of blood clots. It is a serine protease
found on endothelial cells, the cells that line the blood vessel
s. 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).
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.
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 RNA
s.
, 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. 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 stroke
s. 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. Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke.
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 amputation
s than those not treated with tPA.
In tPA overdose, aminocaproic acid
works as an antidote.
, and tenecteplase
(TNKase).
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.
with Fibrinogen alpha chain
, LRP1
and SERPINI1
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
involved in the breakdown of blood clots. It is a serine protease
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
found on endothelial cells, the cells that line the blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s. As an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, it catalyzes
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
the conversion of plasminogen to plasmin
Plasmin
Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...
, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine
Clinical Medicine
Clinical Medicine is a peer-reviewed medical journal published bimonthly by the Royal College of Physicians. It was established in 1966 as the Journal of the Royal College of Physicians of London. It was doubly named between 1998 and 2000, and since 2001 it has appeared as Clinical Medicine. Its...
to treat only embolic or thrombotic stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. Use is contraindicated in hemorrhagic stroke and head trauma.
tPA may be manufactured using recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
biotechnology techniques. tPA created this way may be referred to as recombinant tissue plasminogen activator (rtPA).
Function
Plasmin
Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...
. It does so by cleaving the single-chain plasminogen into two chains. These two chains are linked by a disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
and the resulting molecule is called plasmin.
Increased enzymatic activity causes hyperfibrinolysis
Hyperfibrinolysis
The fibrinolysis system is responsible for removing blood clots. Hyperfibrinolysis describes a situation with markedly enhanced fibrinolytic activity, resulting in increased, sometimes catastrophic bleeding. Hyperfibrinolysis can be caused by acquired or congenital reasons...
, which manifests as excessive bleeding. Decreased activity leads to hypofibrinolysis which can result in thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
or embolism
Embolism
In medicine, an embolism is the event of lodging of an embolus into a narrow capillary vessel of an arterial bed which causes a blockage in a distant part of the body.Embolization is...
.
Tissue plasminogen activator also plays a role in cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
and tissue remodeling.
Genetics
Tissue plasminogen activator is a proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by the PLAT gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, which is located on chromosome 8. The primary transcript
Primary transcript
A primary transcript is an RNA molecule that has not yet undergone any modification after its synthesis. For example, a precursor messenger RNA is a primary transcript that becomes a messenger RNA after processing, and a primary microRNA precursor becomes a microRNA after processing....
produced by this gene undergoes alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
, producing three distinct messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
s.
Clinical applications
tPA is used in diseases that feature blood clots, such as pulmonary embolismPulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
, myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, in a medical treatment called thrombolysis
Thrombolysis
Thrombolysis is the breakdown of blood clots by pharmacological means. It is colloquially referred to as clot busting for this reason...
. 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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, acute ischemic stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, and most cases of acute massive pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
, or administered through an arterial catheter directly to the site of occlusion in the case of peripheral arterial thrombi
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
and thrombi in the proximal deep veins of the leg. 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 stroke
Lacunar stroke
Lacunar stroke or lacunar infarct is a type of stroke that results from occlusion of one of the penetrating arteries that provides blood to the brain's deep structures...
s. 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. Nonagenarians may do as well as octogenarians following treatment with IV-tPA for acute ischemic stroke.
Streptokinase
Streptokinase
Streptokinase , a protein secreted by several species of streptococci can bind and activate human plasminogen. SK is used as an effective and inexpensive thrombolysis medication in some cases of myocardial infarction and pulmonary embolism...
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
Frostbite
Frostbite is the medical condition where localized damage is caused to skin and other tissues due to extreme cold. Frostbite is most likely to happen in body parts farthest from the heart and those with large exposed areas...
treated with tPA had fewer amputation
Amputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
s than those not treated with tPA.
In tPA overdose, aminocaproic acid
Aminocaproic acid
Aminocaproic acid is a derivative and analogue of the amino acid lysine, which makes it an effective inhibitor for enzymes that bind that particular residue. Such enzymes include proteolytic enzymes like plasmin, the enzyme responsible for fibrinolysis...
works as an antidote.
Recombinant tissue plasminogen activators
Recombinant tissue plasminogen activators (r-tPAs) include alteplase, reteplaseReteplase
Reteplase is a thrombolytic drug, used to treat heart attacks by breaking up the clots that cause them....
, and tenecteplase
Tenecteplase
Tenecteplase is an enzyme used as a thrombolytic drug.Tenecteplase is a tissue plasminogen activator produced by recombinant DNA technology using an established mammalian cell line...
(TNKase).
Alteplase is FDA-approved for treatment of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
with ST-elevation (STEMI), acute ischemic stroke (AIS), acute massive pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
, and central venous access devices (CVAD).
Reteplase
Reteplase
Reteplase is a thrombolytic drug, used to treat heart attacks by breaking up the clots that cause them....
is FDA-approved for acute myocardial infarction, where it has more convenient administration and faster thrombolysis than alteplase.
Tenecteplase
Tenecteplase
Tenecteplase is an enzyme used as a thrombolytic drug.Tenecteplase is a tissue plasminogen activator produced by recombinant DNA technology using an established mammalian cell line...
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
Desmoteplase
Desmoteplase is a novel, highly fibrin-specific thrombolytic agent in phase III of clinical development. In 2009, 2 large trials were started, and the results of these studies will determine whether desmoteplase will gain marketing authorization as a safe and effective treatment for patients with...
, are under clinical development.
Interactions
Tissue plasminogen activator has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Fibrinogen alpha chain
Fibrinogen alpha chain
Fibrinogen alpha chain is a protein that in humans is encoded by the FGA gene.-Interactions:Fibrinogen alpha chain has been shown to interact with Tissue plasminogen activator.-Further reading:...
, LRP1
LRP1
Low density lipoprotein receptor-related protein 1 , also known as alpha-2-macroglobulin receptor , apolipoprotein E receptor or cluster of differentiation 91 , is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis...
and SERPINI1
SERPINI1
Neuroserpin is a protein that in humans is encoded by the SERPINI1 gene.It is associated with Familial encephalopathy with neuroserpin inclusion bodies.-Interactions:SERPINI1 has been shown to interact with Tissue plasminogen activator....
.
Further reading
External links
- Tissue Plasminogen Activator from the American Heart AssociationAmerican Heart AssociationThe American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
- Widening the Window : Strategies to buy time in treating ischemic stroke - Scientific American Magazine (August 2005)
- Study expands window for effective stroke treatment - explained on YouTube