Fibrinolysis is a
process
A process is a series or set of activities that interact to produce a result; it may occur once-only or be recurrent or periodic.
Things called a process include:
Business and management
*Business process, activities that produce a specific se ...
that prevents
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 ...
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.
[Dugdale, David et al.]
Primary or secondary fibrinolysis
, Medline Plus. Retrieved 7 August 2011.
In fibrinolysis, a
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 platele ...
clot, the product of
coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...
, is broken down.
Its main
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
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 encoded ...
cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s or by the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
and
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
.
Physiology
Plasmin is produced in an inactive form,
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 encode ...
, in the liver. Although plasminogen cannot cleave fibrin, it still has an affinity for it, and is incorporated into the clot when it is formed.
Tissue plasminogen activator
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 ...
(t-PA)
and
urokinase
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 i ...
are the agents that convert plasminogen to the active plasmin, thus allowing fibrinolysis to occur. t-PA is released into the blood slowly by the damaged
endothelium
The endothelium 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 rest of the vessel ...
of the blood vessels, such that, after several days (when the bleeding has stopped), the clot is broken down. This occurs because plasminogen became entrapped within the clot when it formed; as it is slowly activated, it breaks down the fibrin mesh. t-PA and urokinase are themselves inhibited by
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
P ...
and
plasminogen activator inhibitor-2
Plasminogen activator inhibitor-2 (placental PAI, SerpinB2, PAI-2), a serine protease inhibitor of the serpin superfamily, is a coagulation factor that inactivates tissue plasminogen activator and urokinase. It is present in most cells, especially ...
(PAI-1 and PAI-2). In contrast, plasminogen further stimulates plasmin generation by producing more active forms of both
tissue plasminogen activator
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 ...
(tPA) and urokinase.
α2-Antiplasmin and
α2-macroglobulin inactivate plasmin. Plasmin activity is also reduced by
thrombin-activatable fibrinolysis inhibitor (TAFI), which modifies fibrin to make it more resistant to the tPA-mediated plasminogen.
Measurement
Plasmin breaks down fibrin into soluble parts called
fibrin degradation product
Fibrin degradation products (FDPs), also known as fibrin split products, are components of the blood produced by clot degeneration.
Clotting, also called coagulation, at the wound site produces a mass of fibrin threads called a net that remains in ...
s (FDPs). FDPs compete with thrombin, and thus slow down clot formation by preventing the conversion of fibrinogen to fibrin. This effect can be seen in the thrombin clotting time (TCT) test, which is prolonged in a person that has active fibrinolysis.
FDPs, and a specific FDP, the
D-dimer
D-dimer (or D dimer) is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein joined by a cross ...
, can be measured using antibody-antigen technology. This is more specific than the TCT, and confirms that fibrinolysis has occurred. It is therefore used to indicate
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 ...
,
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 p ...
,
DIC and efficacy of treatment in acute
myocardial infarction
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 ...
. Alternatively, a more rapid detection of fibrinolytic activity, especially hyperfibrinolysis, is possible with
thromboelastometry
Thromboelastometry (TEM), previously named rotational thromboelastography (ROTEG) or rotational thromboelastometry (ROTEM), is an established viscoelasticity, viscoelastic method for hemostasis testing in whole blood. It is a modification of trad ...
(TEM) in whole blood, even in patients on
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 treatm ...
. In this assay, increased fibrinolysis is assessed by comparing the TEM profile in the absence or presence of the fibrinolysis inhibitor
aprotinin
The drug aprotinin (Trasylol, previously Bayer and now Nordic Group pharmaceuticals), is a small protein bovine pancreatic trypsin inhibitor (BPTI), or basic trypsin inhibitor of bovine pancreas, which is an antifibrinolytic molecule that inhibits ...
. Clinically, the TEM is useful for near real-time measurement of activated fibrinolysis for at-risk patients, such as those experiencing significant blood loss during surgery.
Testing of overall fibrinolysis can be measured by a
euglobulin lysis time
The euglobulin lysis time (ELT) is a test that measures overall fibrinolysis. The test is performed by mixing citrated platelet-poor plasma with acid in a glass test tube. This acidification causes the precipitation of certain clotting factors in ...
(ELT) assay. The ELT measures fibrinolysis by clotting the euglobulin fraction (primarily the fibrinolytic factors
fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clo ...
,
PAI-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
P ...
,
tPA,
α2-antiplasmin, and
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 encode ...
) from plasma and then observing the time required for clot dissolution. A shortened lysis time indicates a hyperfibrinolytic state and bleeding risk. Such results can be seen in peoples with liver disease,
PAI-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
P ...
deficiency or
α2-antiplasmin deficiency. Similar results are also seen after administration of
DDAVP
Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, nocturnal enuresis, bedwetting, hemophilia A, von Willebrand disease, and uremia, high blood urea levels. In hemophilia A and von Willeb ...
or after severe stress.
Role in disease
Few
congenital
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
disorders of the fibrinolytic system have been documented. Nevertheless, excess levels of PAI and α
2-antiplasmin have been implicated in
metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndrome ...
and various other disease states.
However, acquired disturbance of fibrinolysis (hyperfibrinolysis), is not uncommon. Many trauma patients have an overwhelming activation of tissue factor and thus massive hyperfibrinolysis.
[Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: Its pathophysiology and treatment in the injured patient. World J Surg 2007;31:1055-64] Hyperfibrinolysis may occur in other disease states. It could lead to massive bleeding if not diagnosed and treated early enough.
The fibrinolytic system is closely linked to control of
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
, and plays a role in disease states associated with inflammation. Plasmin, in addition to lysing fibrin clots, also cleaves the
complement system
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
component C3, and fibrin degradation products have some vascular permeability inducing effects.
Pharmacology
In a process called
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 p ...
(the breakdown of a thrombus), fibrinolytic drugs are used. They are given following a
heart attack
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 ...
to dissolve the thrombus blocking the
coronary artery
The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ of ...
; experimentally after a
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 functionin ...
to allow blood flow back to the affected part of the brain; and in the event of
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 p ...
.
Thrombolysis refers to the dissolution of the thrombus due to various agents while fibrinolysis refers specifically to the agents causing fibrin breakdown in the clot.
Antifibrinolytic Antifibrinolytics are a class of medication that are inhibitors of fibrinolysis. Examples include aminocaproic acid (ε-aminocaproic acid) and tranexamic acid
Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss fr ...
s, such as
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 incl ...
(ε-aminocaproic acid) and
tranexamic acid
Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken eith ...
are used as inhibitors of fibrinolysis. Their application may be beneficial in patients with hyperfibrinolysis because they arrest bleeding rapidly if the other components of the haemostatic system are not severely affected. This may help to avoid the use of blood products such as fresh frozen plasma with its associated risks of infections or anaphylactic reactions.
Fibrinolytic enzymes
*
Anistreplase
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.
Uses
Anistreplase is used to treat blood ...
*
Desmoteplase
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 ...
*
Streptokinase
Streptokinase (SK) 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 (heart attack), pulmonary embolism, and arterial thromboemboli ...
*
Nattokinase
Nattokinase (pronounced ) is an enzyme extracted and purified from a Japanese food called nattō. Nattō is produced by fermentation by adding the bacterium '' Bacillus natto'', which also produces the enzyme, to boiled soybeans. While other soy ...
*
Lumbrokinase Lumbrokinase is a fibrinolytic enzyme present in the earthworm '' Lumbricus bimastus''. It is a clinically approved and proven antithrombotic
An antithrombotic agent is a drug that reduces the formation of blood clots (thrombi).http://cancerweb.ncl ...
*
Serrapeptase
Serratiopeptidase (Serratia E-15 protease, also known as serralysin, serrapeptase, serratiapeptase, serratia peptidase, serratio peptidase, or serrapeptidase) is a proteolytic enzyme (protease) produced by enterobacterium ''Serratia'' sp. E-1 ...
*
Papain
Papain, also known as papaya proteinase I, is a cysteine protease () enzyme present in papaya (''Carica papaya'') and mountain papaya (''Vasconcellea cundinamarcensis''). It is the namesake member of the papain-like protease family.
It has wide ...
*
DNase Deoxyribonuclease (DNase, for short) refers to a group of glycoprotein endonucleases which are enzymes that catalyze the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA. The role of the DNase enzyme in cells ...
*
Bromelain
Bromelain is an enzyme extract derived from the stems of pineapples, although it exists in all parts of the fresh pineapple. The extract has a history of folk medicine use. As an ingredient, it is used in cosmetics, as a topical medication, and as ...
*
Honokiol
Honokiol is a lignan isolated from the bark, seed cones, and leaves of trees belonging to the genus ''Magnolia''. It has been identified as one of the chemical compounds in some traditional eastern herbal medicines along with magnolol, 4-O-methyl ...
References
External links
Graphical representationof the fibrinolytic pathway (site not available)
{{Coagulation physiology
Fibrinolytic system