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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 A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
(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 ...
, and
arterial thromboembolism Arterial embolism is a sudden interruption of blood flow to an organ or body part due to an embolus adhering to the wall of an artery blocking the flow of blood, the major type of embolus being a blood clot ( thromboembolism). Sometimes, pulmo ...
. The type of heart attack it is used in is an
ST elevation myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom is retr ...
(STEMI). 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 nutr ...
. Side effects include nausea, bleeding,
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
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 ...
. A second use in a person's lifetime is not recommended. While no harm has been found with use in
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
, it has not been well studied in this group. Streptokinase is in the
antithrombotic An antithrombotic agent is a drug that reduces the formation of blood clots ( thrombi).http://cancerweb.ncl.ac.uk/cgi-bin/omd?antithrombotic Antithrombotics can be used therapeutically for prevention ( primary prevention, secondary prevention) or ...
family of medications and works by turning on the
fibrinolytic 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 c ...
. Streptokinase was discovered in 1933 from beta-hemolytic streptococci. 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 ...
. It is no longer commercially available in the United States.


Medical uses

If
percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a minimally invasive non-surgical procedure used to treat stenosis, narrowing of the coronary artery, coronary arteries of the heart found in coronary artery disease. The procedure is used to place and ...
(PCI) is not available within 90–120 minutes of first contact, streptokinase is recommended
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 ...
as soon as possible after the onset of a
ST elevation myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom is retr ...
(STEMI). As streptokinase is a
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
l product, the body has the ability to build up an immunity to it. Therefore, it is recommended that this medication should not be used again after four days from the first administration, as it may not be as effective and can also cause an
allergic reaction 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 Allergic rhinitis, hay fever, Food allergy, food al ...
. For this reason, it is usually given only for a person's first heart attack. Further thrombotic events could be treated with tissue plasminogen activator (tPA). Overdose of streptokinase or tPA can be treated with
aminocaproic acid Aminocaproic acid (also known as ε-aminocaproic acid, ε-Ahx, or 6-aminohexanoic 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 inc ...
.


Contraindications


Absolute

* Any prior
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 ...
* Known structural cerebral vascular lesion (e.g.,
arteriovenous malformation An arteriovenous malformation (AVM) is an abnormal connection between arteries and veins, bypassing the capillary system. Usually congenital, this vascular anomaly is widely known because of its occurrence in the central nervous system (usually ...
) * Known
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
inside the skull (primary or metastatic) * Ischemic
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
more than 4.5 hours and less than 3 months ago * Suspected
aortic dissection Aortic dissection (AD) occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart. In most cases, this is associated with a sudden onset of agonizing ches ...
* Active bleeding or bleeding problem other than
menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...
* Significant closed-head or facial trauma within 3 months * Intracranial or intraspinal surgery within 2 months * Severe uncontrolled
high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...
(unresponsive to emergency therapy) * For streptokinase, prior treatment within the previous 6 months


Relative

* History of chronic, severe, poorly controlled hypertension * Significant hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg) * History of prior ischemic stroke more than 3 month ago *
Dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
* Known intracranial pathology not covered in absolute contraindications * Traumatic or prolonged (>10 min) CPR * Major surgery less than three weeks ago * Recent (within 2 to 4 wk) internal bleeding * Noncompressible vascular punctures * Active peptic ulcer * Oral anticoagulant therapy


Mechanism of action

Streptokinase belongs to a group of medications known as fibrinolytics, and complexes of streptokinase with human plasminogen can hydrolytically activate other unbound plasminogen by activating through
bond cleavage In chemistry, bond cleavage, or bond fission, is the splitting of chemical bonds. This can be generally referred to as dissociation when a molecule is cleaved into two or more fragments. In general, there are two classifications for bond cleava ...
to produce
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 ...
. There are three domains to streptokinase, denoted α (residues 1–150), β (residues 151–287), and γ (residues 288–414). Each domain binds plasminogen, although none can activate plasminogen independently. Plasmin is produced in the
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...
to break down
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. ...
, the major constituent of blood
thrombi 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 coagulatio ...
, thereby dissolving clots once they have fulfilled their purpose of stopping bleeding. Extra production of plasmin caused by streptokinase breaks down unwanted blood clots, for example, in the
lungs The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...
(pulmonary embolism). The usual activation of plasminogen is by
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...
of the Arg561—Val562 bond. The amino group of Val562 then forms a salt-bridge with Asp740, which triggers a conformational change producing the active protease plasmin. When streptokinase is present, it binds to plasminogen to form a complex (streptokinase·plasminogen) that converts substrate plasminogen to plasmin. Residues 1–59 of streptokinase regulate its capacity to induce an active site in bound plasminogen by a nonproteolytic mechanism and to activate
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...
plasminogen in a fibrin-independent manner. This complex subsequently rearranges to an active complex although the Arg561–Val562 bond remains intact. Therefore, another residue must substitute for the free amino group of Val562 and provide a counterion for Asp740 in this active complex. Two candidates for this counterion have been suggested: Ile1 of streptokinase and Lys698 of plasminogen. Deletion of Ile1 of streptokinase markedly inhibits its capacity to induce an active site in plasminogen, which supports the hypothesis that establishment of a salt bridge between Ile1 of streptokinase and Asp740 of plasminogen is necessary for streptokinase to induce an active site in plasminogen by a nonproteolytic mechanism. In contrast with the Ile1 substitutions, the Lys698 mutations also decreased the dissociation constant of the streptokinase complex by 15 to 50 fold. These observations suggest that Lys698 is involved in formation of the initial streptokinase·plasminogen complex.


Biology

Streptokinase is naturally produced by ''Streptococci'' spp. bacteria, which use this enzyme to break up blood clots so that they can spread from the initial site of infection. It can also activate
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. ...
. It is similar, both in function and in structure, to
staphylokinase Staphylokinase (SAK; also known as staphylococcal fibrinolysin or Müller's factor) is a protein produced by ''Staphylococcus aureus''. It contains 136 amino acid residues and has a molecular mass of 15kDa. Synthesis of staphylokinase occurs in la ...
(Sak) found in ''Staphylococcus aureus''. Staphylokinase is considered a virulence factor, although its presence after the establishment of infection actually decreases disease severity. Both enzymes are carried by phages.


History

After many years of work along with his student Sol Sherry, William S. Tillett discovered streptokinase in 1933. Initially used in treatment of fibrinous pleural exudates, hemothorax and tuberculous meningitis, its role in acute myocardial infarction was serendipitous.


Research

Streptokinase may find a use in helping to prevent postoperative adhesions, a common complication of surgery, especially abdominal surgery (
appendectomy An appendectomy (American English) or appendicectomy (British English) is a Surgery, surgical operation in which the vermiform appendix (a portion of the intestine) is removed. Appendectomy is normally performed as an urgent or emergency procedur ...
,
gall stones A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of mi ...
,
hysterectomy Hysterectomy is the surgical removal of the uterus and cervix. Supracervical hysterectomy refers to removal of the uterus while the cervix is spared. These procedures may also involve removal of the ovaries (oophorectomy), fallopian tubes ( salpi ...
, etc.) One study using animal models (rats) found that when used with a PHBV membrane drug-delivery system, it was 90 percent effective in preventing adhesions. However, it has not been shown to be effective in humans in a clinical trial.


Marketing

It is marketed in Chile as Streptase by Alpes Selection, under license of
CSL Behring CSL Behring is a biopharmaceutical company, manufacturing plasma-derived and recombinant therapeutic products. The company is a combination of Behringwerke, founded in 1904 in Marburg, Germany by Emil von Behring, and the Commonwealth Serum La ...
Germany. Available in Vietnam under the name Mutose. Available in Cuba, Venezuela, Ecuador and other Latin American countries under the trademark Heberkinasa, commercialized by Heber Biotech,
Havana Havana (; ) is the capital and largest city of Cuba. The heart of La Habana Province, Havana is the country's main port and commercial center.Cuba Cuba, officially the Republic of Cuba, is an island country, comprising the island of Cuba (largest island), Isla de la Juventud, and List of islands of Cuba, 4,195 islands, islets and cays surrounding the main island. It is located where the ...
. Available in India under the name STPase by Cadila Pharmaceuticals, and Myokinase by Biocon Limited.


References


External links

* {{Portal bar, Medicine Antithrombotic enzymes Virulence factors Streptococcal proteins World Health Organization essential medicines Wikipedia medicine articles ready to translate Withdrawn drugs Fibrinolytic enzymes