Hyperfibrinolysis
Encyclopedia
The fibrinolysis
system is responsible for removing blood clots. Hyperfibrinolysis describes a situation with markedly enhanced fibrinolytic activity, resulting in increased, sometimes catastrophic bleeding. Hyperfibrinolysis can be caused by acquired or congenital reasons. Among the congenital conditions for hyperfibrinolysis, deficiency of alpha-2-antiplasmin (alpha-2-plasmin inhibitor) or plasminogen activator inhibitor type 1 (PAI-1) are very rare. The affected individuals show a hemophilia-like bleeding phenotype. Acquired hyperfibrinolysis is found in liver disease
, in patients with severe trauma
, during major surgical procedures, and other conditions. A special situation with temporarily enhanced fibrinolysis is thrombolytic therapy with drugs which activate plasminogen, e.g. for use in acute ischemic events or in patients with stroke. In patients with severe trauma, hyperfibrinolysis is associated with poor outcome.
Bleeding is caused by the generation of fibrinogen
degradation products which interfere with regular fibrin
polymerization and inhibit platelet
aggregation. Moreover, plasmin which is formed in excess in hyperfibrinolysis can proteolytically activate or inactivate many plasmatic or cellular proteins involved in hemostasis. Especially the degradation of fibrinogen, an essential protein for platelet aggregation and clot stability, may be a major cause for clinical bleeding.
of these methods is limited because elevation of these biomarkers can also occur induced in other clinical
conditions. The classical coagulation
tests such as PT (prothrombin time
), aPTT (activated partial thromboplastin time) or thrombin time are not very sensitive for hyperfibrinolysis, and influenced by numerous other variables. The euglobulin lysis time
test is very time consuming and complex. Viscoelastic methods in whole blood, especially thromboelastometry
(TEM) when performed with special reagents detect hyperfibrinolysis very sensitively in a functional approach. The APTEM test, a tissue factor
activated, heparin
insensitive test performed in the presence of aprotinin
(fibrinolysis inhibitor, confirms hyperfibrinolysis by comparing the TEM result of this assay with the EXTEM test (same activator, but without aprotinin). A normalization or improvement of the TEMogram in APTEM versus EXTEM confirms hyperfibrinolysis. This in vitro approach can predict to a certain level if normal clot formation can be restored by use of an antifibrinolytic drug.
, epsilon-aminocaproic acid or other lysine
analogues. When used appropriately, antifibriolytic drugs may avoid unnecessary transfusions.
Fibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. This process has two types: primary fibrinolysis and secondary fibrinolysis...
system is responsible for removing blood clots. Hyperfibrinolysis describes a situation with markedly enhanced fibrinolytic activity, resulting in increased, sometimes catastrophic bleeding. Hyperfibrinolysis can be caused by acquired or congenital reasons. Among the congenital conditions for hyperfibrinolysis, deficiency of alpha-2-antiplasmin (alpha-2-plasmin inhibitor) or plasminogen activator inhibitor type 1 (PAI-1) are very rare. The affected individuals show a hemophilia-like bleeding phenotype. Acquired hyperfibrinolysis is found in liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
, in patients with severe trauma
Physical trauma
Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...
, during major surgical procedures, and other conditions. A special situation with temporarily enhanced fibrinolysis is thrombolytic therapy with drugs which activate plasminogen, e.g. for use in acute ischemic events or in patients with stroke. In patients with severe trauma, hyperfibrinolysis is associated with poor outcome.
Bleeding is caused by the generation of fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
degradation products which interfere with regular fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
polymerization and inhibit platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
aggregation. Moreover, plasmin which is formed in excess in hyperfibrinolysis can proteolytically activate or inactivate many plasmatic or cellular proteins involved in hemostasis. Especially the degradation of fibrinogen, an essential protein for platelet aggregation and clot stability, may be a major cause for clinical bleeding.
Diagnosis
The diagnosis of hyperfibrinolysis is made indirectly with immunochemical methods which detect the elevation of biomarkers such as D-Dimer (cross-linked fibrin degradation products), fibrinogen split products (FSP), complexes of plasmin and alpha-2-antiplasmin (PAP). However, the sensitivity and specificitySensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of these methods is limited because elevation of these biomarkers can also occur induced in other clinical
Illness
Illness is a state of poor health. Illness is sometimes considered another word for disease. Others maintain that fine distinctions exist...
conditions. The classical coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
tests such as PT (prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
), aPTT (activated partial thromboplastin time) or thrombin time are not very sensitive for hyperfibrinolysis, and influenced by numerous other variables. The euglobulin lysis time
Euglobulin lysis time
The euglobulin lysis time 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 a complex called the euglobulin fraction...
test is very time consuming and complex. Viscoelastic methods in whole blood, especially thromboelastometry
Thromboelastometry
Thromboelastometry is an established viscoelastic method for haemostatis testing in whole blood. TEM investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, blood cells, specifically platelets, during clotting and subsequent fibrinolysis...
(TEM) when performed with special reagents detect hyperfibrinolysis very sensitively in a functional approach. The APTEM test, a tissue factor
Tissue factor
Tissue factor, also called platelet tissue factor, factor III, thrombokinase, or CD142 is a protein present in subendothelial tissue, platelets, and leukocytes necessary for the initiation of thrombin formation from the zymogen prothrombin. An incorrect synonym is thromboplastin...
activated, heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
insensitive test performed in the presence of aprotinin
Aprotinin
The drug aprotinin , is the bovine version of the small protein basic pancreatic trypsin inhibitor, or BPTI, which inhibits trypsin and related proteolytic enzymes. Under the trade name Trasylol, aprotinin was used as a medication administered by injection to reduce bleeding during complex surgery,...
(fibrinolysis inhibitor, confirms hyperfibrinolysis by comparing the TEM result of this assay with the EXTEM test (same activator, but without aprotinin). A normalization or improvement of the TEMogram in APTEM versus EXTEM confirms hyperfibrinolysis. This in vitro approach can predict to a certain level if normal clot formation can be restored by use of an antifibrinolytic drug.
Treatment
Since the use of aprotinin has been abandoned due to major side effects, the treatment or prophylaxis of hyperfibrinolysis is made with synthetic drugs such as tranexamic acidTranexamic acid
Tranexamic acid is a drug used to treat or prevent excessive blood loss during surgery and in certain other conditions...
, epsilon-aminocaproic acid or other lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
analogues. When used appropriately, antifibriolytic drugs may avoid unnecessary transfusions.