Tissue-type plasminogen activator

Last updated
PLAT
Protein PLAT PDB 1a5h.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PLAT , T-PA, TPA, plasminogen activator, tissue type
External IDs OMIM: 173370 MGI: 97610 HomoloGene: 717 GeneCards: PLAT
Orthologs
SpeciesHumanMouse
Entrez

5327

18791

Ensembl

ENSG00000104368

ENSMUSG00000031538

UniProt

P00750

P11214

RefSeq (mRNA)

NM_033011
NM_000930
NM_000931
NM_001319189

NM_008872

RefSeq (protein)

NP_000921
NP_001306118
NP_127509

NP_032898

Location (UCSC) Chr 8: 42.17 – 42.21 Mb Chr 8: 23.25 – 23.27 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tissue-type plasminogen activator, short name tPA, is a protein that facilitates the breakdown of blood clots. It acts as an enzyme to convert plasminogen into its active form plasmin, the major enzyme responsible for clot breakdown. It is a serine protease (EC 3.4.21.68) found on endothelial cells lining the blood vessels. Human tPA is encoded by the PLAT gene, and has a molecular weight of ~70 kDa in the single-chain form. [5]

tPA can be manufactured using recombinant biotechnology 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, 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, 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. [6]

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. [9] Delayed presentation to the ED leads to decreased eligibility; as few as 3% of people qualify for this treatment. [10] 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. [11] 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. [12] [13]

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 ischemic stroke. 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). [19] 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. [19] 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." [19] Indeed, even the original publication of the IST-3 trial found that time-window effects were not significant predictors of outcome (p=0.61). [20] In the UK, concerns by stroke specialists have led to a review by the Medicines and Healthcare products Regulatory Agency. [21]

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]

Commercial r-tPA
Product NameNotes
Activase (Alteplase)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). [28]
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]
Tenecteplase Indicated in acute myocardial infarction, showing fewer bleeding complications but otherwise similar mortality rates after one year compared to Alteplase. [28]

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. Fibrinolysis.svg
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.

tPA cleaves the zymogen plasminogen at its Arg561 - Val562 peptide bond, into the serine protease plasmin. [34]

Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding and/or an increase of the vascular permeability. [35] Decreased activity leads to hypofibrinolysis, which can result in thrombosis or embolism.

In patients with ischemic strokes, decreased tPA activity was reported to be associated with an increase in plasma P-selectin concentration. [36]

Tissue plasminogen activator also plays a role in cell migration and tissue remodeling.[ citation needed ]

Physiology and regulation

In vivo mechanism of action of tPA within the fibrinolytic system. tPA can go one of three ways in the body; (1) uptaken by the liver and cleared through receptors therein, (2) inhibited by a plasminogen activator inhibitor (PAI) and subsequently cleared from the liver, or (3) through the activation of plasminogen to plasmin for degradation to result in fibrin degradation product. Tpa pathways .png
In vivo mechanism of action of tPA within the fibrinolytic system. tPA can go one of three ways in the body; (1) uptaken by the liver and cleared through receptors therein, (2) inhibited by a plasminogen activator inhibitor (PAI) and subsequently cleared from the liver, or (3) through the activation of plasminogen to plasmin for degradation to result in fibrin degradation product.

Once in the body, tPA has can cause the desired thrombolytic activity (see figure), or be inactivated and removed. In the bloodstream tPA has a half-life of 4 to 6 minutes. [39] 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). [38] 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 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. [37]

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. [40]

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. [41]

A theoretical full-length model of t-PA. The finger domain is in red, the EGF-like domain in green, the kringle 1 and 2 domains in blue and yellow respectively, and the serine protease domain in magenta. Tissue Plasminogen Activator 6.png
A theoretical full-length model of t-PA. The finger domain is in red, the EGF-like domain in green, the kringle 1 and 2 domains in blue and yellow respectively, and the serine protease domain in magenta.
A 360 view of t-PA showing its structure. Tissue Plasminogen Activator Spinning Animation.gif
A 360 view of t-PA showing its structure.

See also

Related Research Articles

<span class="mw-page-title-main">Thrombosis</span> Medical condition caused by blood clots

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 (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Thrombus</span> Blood clot

A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through healthy blood vessels in the circulatory system.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

<span class="mw-page-title-main">Ischemia</span> Restriction in blood supply to tissues

Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism. Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue i.e. hypoxia and microvascular dysfunction. It also implies local hypoxia in a part of a body resulting from constriction.

<span class="mw-page-title-main">Thrombolysis</span> Breakdown (lysis) of blood clots formed in blood vessels, using medication

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.

<span class="mw-page-title-main">Streptokinase</span> Pharmaceutical drug

Streptokinase is a thrombolytic medication activating plasminogen by nonenzymatic mechanism. As a medication it is used to break down clots in some cases of myocardial infarction, pulmonary embolism, and arterial thromboembolism. The type of heart attack it is used in is an ST elevation myocardial infarction (STEMI). It is given by injection into a vein.

<span class="mw-page-title-main">Urokinase</span> Human protein

Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947. Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.

<span class="mw-page-title-main">Alteplase</span> Thrombolytic medication

Alteplase, sold under the brand name Activase among others, is a biosynthetic form of human tissue-type plasminogen activator (t-PA). It is a thrombolytic medication used to treat acute ischemic stroke, acute ST-elevation myocardial infarction, pulmonary embolism associated with low blood pressure, and blocked central venous catheter. It is given by injection into a vein or artery. Alteplase is the same as the normal human plasminogen activator produced in vascular endothelial cells and is synthesized via recombinant DNA technology in Chinese hamster ovary cells (CHO). Alteplase causes the breakdown of a clot by inducing fibrinolysis.

<span class="mw-page-title-main">Plasminogen activator</span> Type of protein

Plasminogen activators are serine proteases that catalyze the activation of plasmin via proteolytic cleavage of its zymogen form plasminogen. Plasmin is an important factor in fibrinolysis, the breakdown of fibrin polymers formed during blood clotting. There are two main plasminogen activators: urokinase (uPA) and tissue plasminogen activator (tPA). Tissue plasminogen activators are used to treat medical conditions related to blood clotting including embolic or thrombotic stroke, myocardial infarction, and pulmonary embolism.

<span class="mw-page-title-main">Desmoteplase</span> Medication

Desmoteplase is a novel, highly fibrin-specific "clot-busting" (thrombolytic) drug in development that reached phase III clinical trials. The Danish pharmaceutical company, Lundbeck, owns the worldwide rights to Desmoteplase. In 2009, two large trials were started to test it as a safe and effective treatment for patients with acute ischaemic stroke. After disappointing results in DIAS-3, DIAS-4 was terminated, and in December 2014 Lundbeck announced that they would stop the development of desmoteplase.

<span class="mw-page-title-main">Cerebral infarction</span> Stroke resulting from lack of blood flow

Cerebral infarction, also known as an ischemic stroke, is the pathologic process that results in an area of necrotic tissue in the brain. In mid to high income countries, a stroke is the main reason for disability among people and the 2nd cause of death. It is caused by disrupted blood supply (ischemia) and restricted oxygen supply (hypoxia). This is most commonly due to a thrombotic occlusion, or an embolic occlusion of major vessels which leads to a cerebral infarct. In response to ischemia, the brain degenerates by the process of liquefactive necrosis.

Anistreplase is a thrombolytic drug. It is also known as anisoylated plasminogen streptokinase activator complex (APSAC). As a thrombolytic drug, it is used to treat blood clots in emergency situations.

Tenecteplase, sold under the trade names TNKase, Metalyse and Elaxim, is an enzyme used as a thrombolytic drug.

<span class="mw-page-title-main">Désiré Collen</span> Belgian chemist, physician

Désiré, Baron Collen is a Belgian physician, chemist, biotechnology entrepreneur and life science investor. He made several discoveries in thrombosis, haemostasis and vascular biology in many of which serendipity played a significant role. His main achievement has been his role in the development of tissue-type plasminogen activator (t-PA) from a laboratory concept to a life-saving drug for dissolving blood clots causing acute myocardial infarction or acute ischemic stroke. Recombinant t-PA was produced and marketed by Genentech Inc as Activase and by Boehringer Ingelheim GmbH as Actilyse, and is considered biotechnology's first life saving drug.

<span class="mw-page-title-main">Acute limb ischaemia</span> Occurs when there is a sudden lack of blood flow to a limb

Acute limb ischaemia (ALI) occurs when there is a sudden lack of blood flow to a limb, within 14 days of symptoms onset. It is different from another condition which is more chronic called critical limb ischemia (CLD). CLD is the end stage of peripheral vascular disease where there is still some collateral circulation (alternate circulation pathways} that bring some blood to the distal parts of the limbs. While limbs in both acute and chronic limb ischemia may be pulseless, a chronically ischemic limb is typically warm and pink due to a well-developed collateral artery network and does not need emergency intervention to avoid limb loss.

<span class="mw-page-title-main">Reperfusion therapy</span> Restoring blood flow post-heart attack

Reperfusion therapy is a medical treatment to restore blood flow, either through or around, blocked arteries, typically after a heart attack. Reperfusion therapy includes drugs and surgery. The drugs are thrombolytics and fibrinolytics used in a process called thrombolysis. Surgeries performed may be minimally-invasive endovascular procedures such as a percutaneous coronary intervention (PCI), which involves coronary angioplasty. The angioplasty uses the insertion of a balloon and/or stents to open up the artery. Other surgeries performed are the more invasive bypass surgeries that graft arteries around blockages.

This article describes disparities existing between men and women in accessing and receiving care for a stroke. This article also describes factors outside of the health care system which contribute to this disparity.

Thrombus perviousness is an imaging biomarker which is used to estimate clot permeability from CT imaging. It reflects the ability of artery-occluding thrombi to let fluid seep into and through them. The more pervious a thrombus, the more fluid it lets through. Thrombus perviousness can be measured using radiological imaging routinely performed in the clinical management of acute ischemic stroke: CT scans without intravenous contrast combined with CT scans after intravenously administered contrast fluid. Pervious thrombi may let more blood pass through to the ischemic brain tissue, and/or have a larger contact surface and histopathology more sensitive for thrombolytic medication. Thus, patients with pervious thrombi may have less brain tissue damage by stroke. The value of thrombus perviousness in acute ischemic stroke treatment is currently being researched.

A migrainous infarction is a rare type of ischaemic stroke which occurs in correspondence with migraine aura symptoms. Symptoms include headaches, visual disturbances, strange sensations and dysphasia, all of which gradually worsen causing neurological changes which ultimately increase the risk of an ischaemic stroke. Typically, women under the age of 45 who experience migraine with aura (MA) are at the greatest risk for developing migrainous infarction, especially when combined with smoking and use of oral contraceptives.

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  39. ↑ Khosravi, Arezoo; Baharifar, Hadi; Darvishi, Mohamad Hasan; Karimi Zarchi, Ali Akbar (December 2020). "Investigation of chitosan‐g‐PEG grafted nanoparticles as a half‐life enhancer carrier for tissue plasminogen activator delivery". IET Nanobiotechnology. 14 (9): 899–907. doi:10.1049/iet-nbt.2019.0304. ISSN   1751-8741. PMC   8676530 . PMID   33399124.
  40. ↑ Calabresi P, Napolitano M, Centonze D, Marfia GA, Gubellini P, Teule MA, Berretta N, Bernardi G, Frati L, Tolu M, Gulino A (March 2000). "Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory". The European Journal of Neuroscience. 12 (3): 1002–1012. doi:10.1046/j.1460-9568.2000.00991.x. PMID   10762331. S2CID   22764188.
  41. ↑ PLAT_ plasminogen activator, tissue type [ Homo sapiens (human) ], NCBI gene database Gene ID: 5327 https://www.ncbi.nlm.nih.gov/gene/5327
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