Hyperfibrinolysis

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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 [1] (alpha-2-plasmin inhibitor) or plasminogen activator inhibitor type 1 (PAI-1) [2] are very rare. The affected individuals show a hemophilia-like bleeding phenotype. Acquired hyperfibrinolysis is found in liver disease, [3] in patients with severe trauma, [4] during major surgical procedures, [5] and other conditions. [6] 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. [7] Moreover, hyperfibrinolysis may be associated with blood brain barrier impairment, a plasmin-dependent effect due to an increased generation of bradykinin. [8]

Contents

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.

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 specificity 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. [9] 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 acid, epsilon-aminocaproic acid or other lysine analogues. When used appropriately, antifibriolytic drugs may avoid unnecessary transfusions. [10]

Related Research Articles

Thrombus Blood clot

A thrombus, 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 cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through healthy blood vessels in the circulatory system.

Coagulation Process by which blood changes from liquid into a gel, forming blood clots

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 of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

Disseminated intravascular coagulation Medical condition

Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.

Fibrinogen Soluble protein complex in blood plasma and involved in clot formation

Fibrinogen 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 clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.

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 cause.

Thrombolysis Breakdown (lysis) of blood clots formed in blood vessels, using 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.

Tissue plasminogen activator Protein involved in the breakdown of blood clots

Tissue plasminogen activator 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 of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Human tPA has a molecular weight of ~70 kDa in the single-chain form.

Plasmin Mammalian protein found in Homo sapiens

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 is encoded by the PLG gene.

D-dimer is a fibrin degradation product, 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-link, hence forming a protein dimer.

Factor XIII

Factor XIII or fibrin stabilizing factor is a zymogen found in blood of humans and some other animals. It is activated by thrombin to factor XIIIa. Factor XIIIa is an enzyme of the blood coagulation system that crosslinks fibrin. Deficiency of XIII worsens clot stability and increases bleeding tendency.

Alpha 2-antiplasmin Protein-coding gene in the species Homo sapiens

Alpha 2-antiplasmin is a serine protease inhibitor (serpin) responsible for inactivating plasmin. Plasmin is an important enzyme that participates in fibrinolysis and degradation of various other proteins. This protein is encoded by the SERPINF2 gene.

Plasminogen activator

Plasminogen activators are serine proteases that catalyze the activation of plasmin via proteolytic cleavage of its zymogen form plasminogen. Plasmin is an important factor in fibrinolysis, the breakdown of fibrin polymers formed during blood clotting. There are two main plasminogen activators: urokinase (uPA) and tissue plasminogen activator (tPA). Tissue plasminogen activators are used to treat medical conditions related to blood clotting including embolic or thrombotic stroke, myocardial infarction, and pulmonary embolism.

Aminocaproic acid

Aminocaproic 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 include proteolytic enzymes like plasmin, the enzyme responsible for fibrinolysis. For this reason it is effective in treatment of certain bleeding disorders, and it is sold under the brand name Amicar. Aminocaproic acid is also an intermediate in the polymerization of Nylon-6, where it is formed by ring-opening hydrolysis of caprolactam. The crystal structure determination showed that the 6-aminohexanoic acid is present as a salt, at least in the solid state.

Thromboelastography (TEG) is a method of testing the efficiency of blood coagulation. It is a test mainly used in surgery and anesthesiology, although increasingly used in resuscitations in Emergency Departments, intensive care units, and labor and delivery suites. More common tests of blood coagulation include prothrombin time (PT) and partial thromboplastin time (aPTT) which measure coagulation factor function, but TEG also can assess platelet function, clot strength, and fibrinolysis which these other tests cannot.

Aprotinin

The drug aprotinin, is a small protein bovine pancreatic trypsin inhibitor (BPTI), or basic trypsin inhibitor of bovine pancreas, which is an antifibrinolytic molecule that 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, such as heart and liver surgery. Its main effect is the slowing down of fibrinolysis, the process that leads to the breakdown of blood clots. The aim in its use was to decrease the need for blood transfusions during surgery, as well as end-organ damage due to hypotension as a result of marked blood loss. The drug was temporarily withdrawn worldwide in 2007 after studies suggested that its use increased the risk of complications or death; this was confirmed by follow-up studies. Trasylol sales were suspended in May 2008, except for very restricted research use. In February 2012 the European Medicines Agency (EMA) scientific committee reverted its previous standpoint regarding aprotinin, and has recommended that the suspension be lifted. Nordic became distributor of aprotinin in 2012.

Quebec platelet disorder Medical condition

Quebec platelet disorder (QPD) is a rare autosomal dominant bleeding disorder first described in a family from the province of Quebec in Canada. The disorder is characterized by large amounts of the fibrinolytic enzyme urokinase-type plasminogen activator (uPA) in platelets. This causes accelerated fibrinolysis which can result in bleeding.

Fibrin glue

Fibrin glue is a surgical formulation used to create a fibrin clot for hemostasis, cartilage repair surgeries or wound healing. It contains separately packaged human fibrinogen and human thrombin.

Thromboelastometry (TEM), previously named rotational thromboelastography (ROTEG) or rotational thromboelastometry (ROTEM), is an established viscoelastic method for hemostasis testing in whole blood. It is a modification of traditional thromboelastography (TEG). TEM investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, blood cells, specifically platelets, during clotting and subsequent fibrinolysis. The rheological conditions mimic the sluggish flow of blood in veins. While traditional thromboelastography is a global assay for blood clotting disorders and drug effects, TEM is primarily used in combination with appropriate differential assays. They allow testing in the presence of therapeutic heparin concentrations and provide differential diagnostic information to support decisions in therapy. In numerous publications the validity of the method is shown. Application of TEM at the point of care (POC) or in emergency laboratories is getting more and more popular. TEM detects both hypo- and hyperfunctional stages of the clotting process and is probably the only reliable rapid test for the diagnosis of hyperfibrinolysis. In contrast to standard clotting tests, the fibrin stabilizing effect of factor XIII contributes to the result. The rapid availability of results helps to discriminate surgical bleeding from a true haemostasis disorder and improves the therapy with blood products, factor concentrates, anticoagulants and protamine, hemostyptic and antifibrinolytic drugs. Several reports confirm that application of TEM is cost effective by reducing the consumption of blood products.

Factor I deficiency Medical condition

Factor I deficiency, also known as fibrinogen deficiency, is a rare inherited bleeding disorder related to fibrinogen function in the blood coagulation cascade. It is typically subclassified into four distinct fibrinogen disorders: afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.

Plasmin-α2-antiplasmin complex (PAP) is a 1:1 irreversibly formed inactive complex of the enzyme plasmin and its inhibitor α2-antiplasmin. It is a marker of the activity of the fibrinolytic system and a marker of net activation of fibrinolysis.

References

  1. ↑ Carpenter SL, Mathew P (2008). "Alpha-2-antiplasmin and its deficiency: fibrinolysis out of balance". Haemophilia. 14: 1250–4. doi: 10.1111/j.1365-2516.2008.01766.x . PMID   19141165.
  2. ↑ Takahashi Y, Tanaka T, Minowa H, Ookubo Y, Sugimoto M, Nakajima M, Miyauchi Y, Yoshioka A (July 1996). "Hereditary partial deficiency of plasminogen activator inhibitor-1 associated with a lifelong bleeding tendency". International Journal of Hematology. 64 (1): 61–8. PMID   8757969.
  3. ↑ Görlinger K (August 2006). "[Coagulation management during liver transplantation]". Hamostaseologie (in German). 26 (3 Suppl 1): S64–76. PMID   16953295.
  4. ↑ Levrat A, Gros A, Rugeri L, Inaba K, Floccard B, Negrier C, David JS (2008). "Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients". Br J Anaesth. 100: 792–7. doi: 10.1093/bja/aen083 .
  5. ↑ Vanek T, Jares M, Snircova J, Maly M (December 2007). "Fibrinolysis in coronary artery surgery: detection by thromboelastography". Interactive Cardiovascular and Thoracic Surgery. 6 (6): 700–4. doi: 10.1510/icvts.2007.161463 . PMID   17709365.
  6. ↑ Chapin JC, Hajjar KA (January 2015). "Fibrinolysis and the control of blood coagulation". Blood Reviews. 29 (1): 17–24. doi:10.1016/j.blre.2014.09.003. PMC   4314363 . PMID   25294122.
  7. ↑ Schöchl H (2008). "Hyperfibrinolysis:a prognostic marker of poor survival following major trauma?". Haemostaseologie. 28: A57.
  8. ↑ Marcos-Contreras, Oscar A.; Lizarrondo, Sara Martinez de; Bardou, Isabelle; Orset, Cyrille; Pruvost, Mathilde; Anfray, Antoine; Frigout, Yvann; Hommet, Yannick; Lebouvier, Laurent (2016-01-01). "Hyperfibrinolysis increases blood brain barrier permeability by a plasmin and bradykinin-dependent mechanism". Blood. 128: blood–2016-03-705384. doi: 10.1182/blood-2016-03-705384 . ISSN   0006-4971. PMID   27531677.
  9. ↑ Vorweg M, Hartmann B, Knüttgen D, Jahn MC, Doehn M (December 2001). "Management of fulminant fibrinolysis during abdominal aortic surgery". Journal of Cardiothoracic and Vascular Anesthesia. 15 (6): 764–7. doi:10.1053/jcan.2001.28337. PMID   11748531.
  10. ↑ Diprose P, Herbertson MJ, O'Shaughnessy D, Deakin CD, Gill RS (March 2005). "Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage". British Journal of Anaesthesia. 94 (3): 271–8. doi: 10.1093/bja/aei044 . PMID   15591329.
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