Alteplase (t-PA), a biosynthetic form of human tissue-type plasminogen activator (t-PA), is a

thrombolytic 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 (massive ...

, used to treat acute

ischemic stroke A stroke is a medical condition in which poor blood flow to 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 funct ...

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

pulmonary embolism Pulmonary embolism (PE) is a blockage of an 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 shortness of breath, chest pain particularly upon breathin ...

associated with

low blood pressure Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

, 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 ...

. It 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 nutrie ...

artery An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...

. 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 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 ...

Medical uses

Alteplase is mainly used to treat 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 or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...

, 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 nutrie ...

into the body. To treat blocked catheters, alteplase is administered directly into the catheter. Alteplase has also been used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...

for

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...

peripheral artery disease Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular dis ...

pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per k ...

in children, prosthetic valve thrombosis, frostbite, and peritonitis.

Ischemic stroke

In adults diagnosed with acute ischemic stroke, thrombolytic treatment with alteplase is the standard of care during early management (within 4.5 hours of symptom onset). When mechanical thrombectomy is not available, alteplase may be considered up to 9 hours after symptom onset. 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. Use is restricted, however, if there is a risk of major

bleeding 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, vag ...

or if there may be another cause of stroke symptoms. Alteplase is not recommended for those with non-disabling stroke. For patients with early recurrent ischemic stroke, repeated use of alteplase may be safe and efficacious. Alteplase is also commonly used in children, though guidelines are not yet standardized as they are for adults.

Myocardial infarction

Currently, the preferred treatment for ST-elevation myocardial infarction (

STEMI A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...

) is

percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a non-surgical procedure used to treat narrowing of the coronary arteries of the heart found in coronary artery disease. The process involves combining coronary angioplasty with stenting, which is the ...

(PCI). However, PCI is only available at 25% of hospitals in the United States; alteplase is recommended if the patient is at a non-PCI capable hospital and cannot be transferred to receive PCI in under 120 minutes. Alteplase can also be used before arriving at the hospital if transportation time is anticipated to be greater than 30 minutes. Alteplase may be used in conjunction with

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

and

heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treat ...

. An accelerated infusion of alteplase was found to significantly reduce mortality in comparison to a non-accelerated infusion, though it also slightly increases the risk of major bleeding. Alteplase should not be used in cases of

acute coronary syndrome Acute coronary syndrome (ACS) is a syndrome (a set of signs and symptoms) due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally l ...

other than STEMI.

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 (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

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 blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism (massive ...

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. Catheter-directed thrombolysis may be more efficient than systemic thrombolysis, as alteplase is locally administered to the occlusion site, and wash-away of the medication into other blood vessels is minimized. This procedure involves positioning a multi-sidehole catheter into the blood clot. Alteplase may be used to treat PE if patients have a high risk for complications, such as if: * they are

hypotensive Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...

with a

systolic blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

less than 90 mmHg * they are in

cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possi ...

presumed to be caused by a pulmonary embolism * their clinical exam shows signs of deterioration or worsening of symptoms

Blocked catheters

Alteplase can be used in small doses to clear

blood clots A thrombus (plural thrombi), 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 cr ...

that obstruct a

catheter In medicine, a catheter (/ˈkæθətər/) 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 surgi ...

, 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 include current

intracranial hemorrhage Intracranial hemorrhage (ICH), also known as intracranial bleed, is bleeding within the skull. Subtypes are intracerebral bleeds (intraventricular bleeds and intraparenchymal bleeds), subarachnoid bleeds, epidural bleeds, and subdural blee ...

and

subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain. Symptoms may include a severe headache of rapid onset, vomiting, decreased level of cons ...

. 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 interventional procedure of removing a blood clot (thrombus) from a blood vessel. It is commonly performed in the cerebral arteries (interventional neuroradiology). The effectiveness of throm ...

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, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

. Alteplase is a pregnancy category C drug.

Mechanism of action

Alteplase binds to

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

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 clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...

. 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 Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the ''SERPINE1'' gene. Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis ...

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.

Society and culture

Alteplase was added to 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 ...

in 2019, for use in ischemic stroke. As early use of alteplase is important for ischemic stroke, treatment delay is a serious concern. Many reasons for delay exist, including lack of access to healthcare, late presentation, late assessment, misdiagnosis, and management of

comorbidities In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

. Alteplase is extremely underused in

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

. 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 m ...

. 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 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.

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 marketed as Actilyse, Activase, and Cathflo or Cathflo Activase.

History

FDA approval and paradigm shift

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 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 vessels. As an enzyme, it catalyzes the conversion ...

, making it one of the fastest drug developments in 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.

Commercialization

Commercialization and large scale manufacture of human t-PA has been made possible through the generation of

Chinese hamster ovary cell Chinese hamster ovary (CHO) cells are an epithelial cell line derived from the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeutic proteins. They have found wide ...

s, which are capable of producing alteplase (recombinant human t-PA) with the use of recombinant DNA technology. Brands include Activase and Cathflo Activase, marketed by Genentech Inc. in the US, and Actilyse, marketed by

Boehringer Ingelheim C.H. Boehringer Sohn AG & Co. is the parent company of the Boehringer Ingelheim group, which was founded in 1885 by Albert Boehringer in Ingelheim am Rhein, Germany. As of 2018, Boehringer Ingelheim is one of the world's largest pharmaceutical ...

in Germany.

References

External links

* {{Portal bar, Medicine Antithrombotic enzymes Boehringer Ingelheim Genentech brands Hoffmann-La Roche brands World Health Organization essential medicines Wikipedia medicine articles ready to translate Ophthalmology drugs