Fibrinolysis

Fibrinolysisis aprocessthat preventsblood clotsfrom growing and becoming problematic.Primary fibrinolysis is a normal body process, while secondary fibrinolysis is thebreakdown of clotsdue to a medicine, a medical disorder, or some other cause.

In fibrinolysis, afibrinclot, the product ofcoagulation,is broken down.Its mainenzymeplasmincuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by otherproteasesor by thekidneyandliver.

Physiology

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

Plasminis produced in an inactive form,plasminogen,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(t-PA)andurokinaseare the agents that convert plasminogen to the active plasmin, thus allowing fibrinolysis to occur. t-PA is released into the blood slowly by the damagedendotheliumof 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 byplasminogen activator inhibitor-1andplasminogen activator inhibitor-2(PAI-1 and PAI-2). In contrast, plasminogen further stimulates plasmin generation by producing more active forms of bothtissue plasminogen activator(tPA) and urokinase.

α₂-Antiplasminandα₂-macroglobulininactivate plasmin. Plasmin activity is also reduced bythrombin-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 calledfibrin degradation products(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, theD-dimer,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 indicatedeep-vein thrombosis,pulmonary embolism,DICand efficacy of treatment in acutemyocardial infarction.Alternatively, a more rapid detection of fibrinolytic activity, especially hyperfibrinolysis, is possible withthromboelastometry(TEM) in whole blood, even in patients onheparin.In this assay, increased fibrinolysis is assessed by comparing the TEM profile in the absence or presence of the fibrinolysis inhibitoraprotinin.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 aeuglobulin lysis time(ELT) assay. The ELT measures fibrinolysis by clotting the euglobulin fraction (primarily the fibrinolytic factorsfibrinogen,PAI-1,tPA,α₂-antiplasmin,andplasminogen) 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-1deficiency orα₂-antiplasmindeficiency. Similar results are also seen after administration ofDDAVPor after severe stress.

Role in disease

Fewcongenitaldisorders of the fibrinolytic system have been documented. Nevertheless, excess levels of PAI and α₂-antiplasmin have been implicated inmetabolic syndromeand 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.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 ofinflammation,and plays a role in disease states associated with inflammation. Plasmin, in addition to lysing fibrin clots, also cleaves thecomplement systemcomponent C3, and fibrin degradation products have some vascular permeability inducing effects.

Pharmacology

In a process calledthrombolysis(the breakdown of a thrombus), fibrinolytic drugs are used. They are given following aheart attackto dissolve the thrombus blocking thecoronary artery;experimentally after astroketo allow blood flow back to the affected part of the brain; and in the event ofpulmonary embolism.

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.

Antifibrinolytics,such asaminocaproic acid(ε-aminocaproic acid) andtranexamic acidare 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
• Desmoteplase
• Streptokinase
• Nattokinase
• Lumbrokinase
• Serrapeptase
• Papain
• DNase
• Bromelain
• Honokiol

External links

• Graphical representationof the fibrinolytic pathway (site not available)