Alteplase

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Alteplase
Clinical data
Trade names Activase, Actilyse, Cathflo Activase, others
Other namest-PA, rt-PA
AHFS/Drugs.com Monograph
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  • AU:B1
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administration 		Intravenous
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Chemical and physical data
Formula C2569H3928N746O781S40
Molar mass 59042.52 g·mol−1
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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 (a type of heart attack), pulmonary embolism associated with low blood pressure, and blocked central venous catheter. [5] Alteplase is given by injection into a vein or artery. [5] Alteplase is the same as the normal human plasminogen activator produced in vascular endothelial cells [6] and is synthesized via recombinant DNA technology in Chinese hamster ovary cells (CHO). Alteplase causes the breakdown of a clot by inducing fibrinolysis. [7]

Contents

It is on the World Health Organization's List of Essential Medicines. [8]

Blood flow obstructed by coagulated blood that could potentially be reversed with alteplase. "Localisation du thrombus et consequences 2" by Servier Medical Art is licensed under CC BY 2.0.jpg
Blood flow obstructed by coagulated blood that could potentially be reversed with alteplase.

Medical uses

Alteplase is indicated for the treatment of acute ischemic stroke, acute myocardial infarction, acute massive pulmonary embolism, and blocked catheters. [5] [2] [3] Similar to other thrombolytic drugs, alteplase is used to dissolve clots to restore tissue perfusion, but this can vary depending on the pathology. [9] [10] Generally, alteplase is delivered intravenously into the body. [7] To treat blocked catheters, alteplase is administered directly into the catheter. [7]

Ischemic stroke

In adults diagnosed with acute ischemic stroke, thrombolytic treatment with alteplase is the standard of care. [10] [11] Administration of alteplase is associated with improved functional outcomes and reduced incidence of disability. [12] Alteplase used in conjunction with mechanical thrombectomy is associated with better outcomes. [13] [14]

Pulmonary embolism

As of 2019, alteplase is the most commonly used medication to treat pulmonary embolism (PE). [15] Alteplase has a short infusion time of 2 hours and a half-life of 4–6 minutes. [15] Alteplase has been approved by the FDA, and treatment can be done via systemic thrombolysis or catheter-directed thrombolysis. [15] [16]

Systemic thrombolysis can quickly restore right ventricular function, heart rate, and blood pressure in patients with acute PE. [17] However, standard doses of alteplase used in systemic thrombolysis may lead to massive bleeding, such as intracranial hemorrhage, particularly in older patients. [15] A systematic review has shown that low-dose alteplase is safer than and as effective as the standard amount. [18]

Blocked catheters

Alteplase can be used in small doses to clear blood clots that obstruct a catheter, reopening the catheter so it can continue to be used. [3] [12] Catheter obstruction is commonly observed with a central venous catheter. [19] Currently, the standard treatment for catheter obstructions in the United States is alteplase administration. [6] Alteplase is effective and low risk for treating blocked catheters in adults and children. [6] [19] Overall, adverse effects of alteplase for clearing blood clots are rare. [20] Novel alternatives to treat catheter occlusion, such as tenecteplase, reteplase, and recombinant urokinase, offer the advantage of shorter dwell times than alteplase. [19]

Contraindications

A person should not receive alteplase treatment if testing shows they are not suffering from an acute ischemic stroke or if the risks of treatment outweigh the likely benefits. [10] Alteplase is contraindicated in those with bleeding disorders that increase a person's tendency to bleed and in those with an abnormally low platelet count. [14] Active internal bleeding and high blood pressure are additional contraindications for alteplase. [14] The safety of alteplase in the pediatric population has not been determined definitively. [14] Additional contraindications for alteplase when used specifically for acute ischemic stroke include current intracranial hemorrhage and subarachnoid hemorrhage. [21] Contraindications for use of alteplase in people with a STEMI are similar to those of acute ischemic stroke. [9] People with an acute ischemic stroke may also receive other therapies including mechanical thrombectomy. [10]

Adverse effects

Given that alteplase is a thrombolytic medication, a common adverse effect is bleeding, which can be life-threatening. [22] Adverse effects of alteplase include symptomatic intracranial hemorrhage and fatal intracranial hemorrhage. [22]

Angioedema is another adverse effect of alteplase, which can be life-threatening if the airway becomes obstructed. [2] Other side effects may rarely include allergic reactions. [5]

Mechanism of action

Depiction of the pathway that alteplase (t-PA) uses to promote the degradation of a blood clot (fibrin). Fibrinolysis.svg
Depiction of the pathway that alteplase (t-PA) uses to promote the degradation of a blood clot (fibrin).

Alteplase binds to fibrin in a blood clot and activates the clot-bound plasminogen. [7] Alteplase cleaves plasminogen at the site of its Arg561-Val562 peptide bond to form plasmin. [7] Plasmin is a fibrinolytic enzyme that cleaves the cross-links between polymerized fibrin molecules, causing the blood clot to break down and dissolve, a process called fibrinolysis. [7]

Regulation and inhibition

Plasminogen activator inhibitor 1 stops alteplase activity by binding to it and forming an inactive complex, which is removed from the bloodstream by the liver. [7] Fibrinolysis by plasmin is extremely short-lived due to plasmin inhibitors, which inactivate and regulate plasmin activity. [7]

History

In 1995, a study by the National Institute of Neurological Disorders and Stroke showed the effectiveness of administering intravenous alteplase to treat ischemic stroke. [23] This sparked a medical paradigm shift as it redesigned stroke treatment in the emergency department to allow for timely assessment and therapy for ischemic stroke patients. [23]

Society and culture

Alteplase was added to the World Health Organization's List of Essential Medicines in 2019, for use in ischemic stroke. [24] [25]

In May 1987, the United States FDA requested additional data for the drug rather than approve it outright, causing Genentech stock prices to fall by nearly one quarter. The decision was described as a surprise to the company as well as many cardiologists and regulators, [26] and it generated significant criticism of the FDA, including from The Wall Street Journal editorial board. [27] [28]

After results from two additional trials were obtained, [27] Alteplase was approved for medical use in the United States in November 1987 for the treatment of myocardial infarction. [5] [2] [29] [30] This was just seven years after the first efforts were made to produce recombinant t-PA, making it one of the fastest drug developments in history. [30]

Economics

The cost of alteplase in the United States increased by 111% between 2005 and 2014, despite there being no proportional increase in the costs of other prescription drugs. [31] However, alteplase continues to be cost-effective. [31]

Brand names

Alteplase is sold under brand names Actilyse, [32] Activase, [2] and Cathflo Activase. [3] [33]

Controversies

Alteplase is extremely underused in low- and middle-income countries. [34] This may be due to its high cost and the fact that it is often not covered by health insurance. [34]

There may be citation bias in the literature on alteplase in ischemic stroke, as studies reporting positive results for tissue plasminogen activator are more likely to be cited in following studies than those reporting negative or neutral results. [35]

There is a sex difference in the use of intravenous tissue plasminogen activator, as it is less likely to be used for women with acute ischemic stroke than men. [36] However, this difference has been improving since 2008. [36]

Related Research Articles

<span class="mw-page-title-main">Thrombosis</span> Formation of blood clots inside the blood vessels

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 a healthy blood vessel 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">Tissue-type plasminogen activator</span> Protein involved in the breakdown of blood clots

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 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.

<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">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.

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.

Embolectomy is the emergency interventional or surgical removal of emboli which are blocking blood circulation. It usually involves removal of thrombi, and is then referred to as thromboembolectomy or thrombectomy. Embolectomy is an emergency procedure often as the last resort because permanent occlusion of a significant blood flow to an organ leads to necrosis. Other involved therapeutic options are anticoagulation and thrombolysis.

<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.

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.

A cerebroprotectant is a drug that is intended to protect the brain after the onset of acute ischemic stroke. As stroke is the second largest cause of death worldwide and a leading cause of adult disability, over 150 drugs have been tested in clinical trials to provide cerebroprotection.

References

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