Alteplase, sold under the brand name Activase among others, is a biosynthetic form of human

tissue-type plasminogen activator 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 ser ...

(t-PA). It is a thrombolytic medication used to treat acute

ischemic stroke Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop ...

, acute ST-elevation myocardial infarction (a type of heart attack),

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 ...

associated with

low blood pressure Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

, and blocked

central venous catheter A central venous catheter (CVC), also known as a central line (c-line), central venous line, or central venous access catheter, is a catheter placed into a large vein. It is a form of venous access. Placement of larger catheters in more centr ...

. Alteplase is given by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

artery An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

. Alteplase is the same as the normal human plasminogen activator produced in

vascular endothelial cells 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 the res ...

and is synthesized via recombinant DNA technology in

Chinese hamster ovary cell Chinese hamster ovary (CHO) cells are a family of immortalized cell lines derived from epithelial cells of the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therap ...

s (CHO). Alteplase causes the breakdown of a clot by inducing

fibrinolysis 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 c ...

. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

Medical uses

Alteplase is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of acute ischemic stroke, acute myocardial infarction, acute massive pulmonary embolism, and blocked catheters. Similar to other thrombolytic drugs, alteplase is used to dissolve clots to restore tissue

perfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ (anatomy), organ or a tissue (biology), tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion may also refer t ...

, but this can vary depending on the pathology. Generally, alteplase is delivered

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

into the body. To treat blocked catheters, alteplase is administered directly into the catheter.

Ischemic stroke

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

Pulmonary embolism

As of 2019, alteplase is the most commonly used medication to treat pulmonary embolism (PE). Alteplase has a short infusion time of 2 hours and 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 4–6 minutes. Alteplase has been approved by the FDA, and treatment can be done via systemic

thrombolysis Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of thrombus, blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism ( ...

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

Blocked catheters

Alteplase can be used in small doses to clear

blood clots A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulati ...

that obstruct a

catheter In medicine, a catheter ( ) is a thin tubing (material), tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. ...

, reopening the catheter so it can continue to be used. Catheter obstruction is commonly observed with a

. Currently, the standard treatment for catheter obstructions in the United States is alteplase administration. Alteplase is effective and low risk for treating blocked catheters in adults and children. Overall, adverse effects of alteplase for clearing blood clots are rare. Novel alternatives to treat catheter occlusion, such as tenecteplase, reteplase, and recombinant urokinase, offer the advantage of shorter dwell times than alteplase.

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. 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. Active internal bleeding and high blood pressure are additional contraindications for alteplase. The safety of alteplase in the pediatric population has not been determined definitively. Additional contraindications for alteplase when used specifically for

acute ischemic stroke Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop ...

include current

intracranial hemorrhage Intracranial hemorrhage (ICH) refers to any form of Hemorrhage, bleeding Internal bleeding, within the Human skull, skull. It can result from trauma, vascular abnormalities, hypertension, or other medical conditions. ICH is broadly categorized ...

and

subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid (brain), arachnoid membrane and the pia mater surrounding the human brain, brain. Symptoms may include a thunderclap headache, severe heada ...

. Contraindications for use of alteplase in people with a STEMI are similar to those of acute ischemic stroke. People with an acute ischemic stroke may also receive other therapies including mechanical

thrombectomy Mechanical thrombectomy, or simply thrombectomy, is the removal of a blood clot (thrombus) from a blood vessel, often and especially endovascularly as an interventional radiology procedure called endovascular thrombectomy (EVT). It thus contr ...

Adverse effects

Given that alteplase is a thrombolytic medication, a common adverse effect is bleeding, which can be life-threatening. Adverse effects of alteplase include symptomatic

and fatal intracranial hemorrhage.

Angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

is another adverse effect of alteplase, which can be life-threatening if the airway becomes obstructed. Other side effects may rarely include

allergic reactions Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

Mechanism of action

Alteplase binds to

fibrin Fibrin (also called Factor Ia) is a fibrous protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...

in a blood clot and activates the clot-bound

plasminogen Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is enco ...

. Alteplase cleaves plasminogen at the site of its Arg561-Val562 peptide bond to 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 ...

. Plasmin is a fibrinolytic enzyme that cleaves the

cross-link In chemistry and biology, a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...

s between polymerized fibrin molecules, causing the blood clot to break down and dissolve, a process called

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. Fibrinolysis by plasmin is extremely short-lived due to plasmin inhibitors, which inactivate and regulate plasmin activity.

History

In 1995, a study by the

National Institute of Neurological Disorders and Stroke The National Institute of Neurological Disorders and Stroke (NINDS) is a part of the U.S. National Institutes of Health (NIH). It conducts and funds research on brain and nervous system disorders and has a budget of just over US$2.03 billion. The ...

showed the effectiveness of administering intravenous alteplase to treat ischemic stroke. 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.

Society and culture

Alteplase was added to the

in 2019, for use in ischemic stroke.

Legal status

In May 1987, the United States FDA requested additional data for the drug rather than approve it outright, causing

Genentech Genentech, Inc. is an American biotechnology corporation headquartered in South San Francisco, California. It operates as an independent subsidiary of holding company Roche. Genentech Research and Early Development operates as an independent cent ...

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, and it generated significant criticism of the FDA, including from ''The Wall Street Journal'' editorial board. After results from two additional trials were obtained, Alteplase was approved for medical use in the United States in November 1987 for the treatment of myocardial infarction. 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.

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. However, alteplase continues to be cost-effective.

Brand names

Alteplase is sold under brand names Actilyse, Activase, and Cathflo Activase.

Controversies

Alteplase is extremely underused in

low- and middle-income countries A developing country is a sovereign state with a less-developed industrial base and a lower Human Development Index (HDI) relative to developed countries. However, this definition is not universally agreed upon. There is also no clear agreemen ...

. This may be due to its high cost and the fact that it is often not covered by

health insurance Health insurance or medical insurance (also known as medical aid in South Africa) is a type of insurance that covers the whole or a part of the risk of a person incurring medical expenses. As with other types of insurance, risk is shared among ma ...

. 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. There is a

sex difference Sexual dimorphism is the condition where sexes of the same species exhibit different morphological characteristics, including characteristics not directly involved in reproduction. The condition occurs in most dioecious species, which consis ...

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

References

{{Authority control Antithrombotic enzymes Drugs developed by Boehringer Ingelheim Drugs developed by Genentech Drugs developed by Hoffmann-La Roche World Health Organization essential medicines Wikipedia medicine articles ready to translate Ophthalmology drugs Fibrinolytic enzymes