Fibrinolytic system

In Fibrinolytic system the clots are broken down regularly to maintain the blood flow. I case of certain disease this system is altered and produce coagulation abnormalities and diseases like MI , stroke etc.

1. FIBRINOLYTIC SYSTEM DR. JITENDRA KUMAR JAIN IInd YEAR RESIDENT JMC ,JHALAWAR

2. Fibrinolysis   Is a process that prevents blood clots from growing and becoming problematic.  the dissolution of intravascular thrombi and  extravascular  deposits of fibrin by the enzyme  fibrinolysin .  Fibrinolysis  is important for  keeping the blood liquid and the blood vessels and glandular ducts patent.  This process has two types: primary fibrinolysis and secondary fibrinolysis . The primary type is a normal body process, whereas secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause. In fibrinolysis , a fibrin clot, the product of coagulation, is broken down. It’s main enzyme  plasmin  cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other proteases or by the kidney and liver.

3. History of Fibrinolysis The term was proposed by the French physiologist A. Dastre  in 1893. Uncoagulated  blood was first discovered in the blood vessels of persons who died suddenly by the Italian physician G.  Morgagni  (1769) and the Scotch anatomist J. Hunter (1794).  In 1906 the German researcher P.  Morawitz  showed that  such blood lacks fibrinogen and fibrin. He attributed the  absence of these proteins in plasma to the action of a  specific enzyme.  The enzymatic nature of  fibrinolysis  was  demonstrated by the Soviet scientist V. S.  Il’in  between 1948 and 1955.

4. The  fibrinolysis  system consists of four components:  profibrinolysin  (or  plasminogen ),   fibrinolysin  (or  plasmin ),   profibrinolysin  activators   fibrinolysin  inhibitors.  Profibrinolysin  is converted in the body by the action of enzymatic activators (plasma and tissue  activators and  urokinase ) to  fibrinolysin , which under normal physiological conditions is bound by inhibitors— antiplasmins . In certain pathological conditions—thromboses caused by the breakdown of the clotting mechanism, the bond with the  antiplasmins  is broken,  and  fibrinolysin  hydrolyzes the fibrin of thrombi.  

5. Normally, the activity of the  fibrinolysis  enzymatic system in the  body is low. In the presence of stress, during physical exertion, or  after the injection of adrenaline, it may increase sharply. The formation of excessive  fibrinolysin  by the release of large  quantities of tissue activator, resulting  from changes in the  permeability of blood vessels or injury to them, produces extreme  activation of  fibrinolysis , which causes bleeding, for example, during obstetrical complications, in cirrhosis of the liver, and during  transfusions of incompatible blood.  Bleeding is arrested by injection of artificial  fibrinolysin  inhibitors. A decrease in activity  ofthe   fibrinolysis  system is associated with the  development of atherosclerosis and  thromboembolic complications. In such conditions,  fibrinolysis  is used for  thrombolytic therapy.

6. Plasmin Plasmin is 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)and  urokinase are the agents that convert plasminogen to the active plasmin , thus allowing fibrinolysis to occur. t-PA is released into the blood very slowly by the damaged endothelium 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.

7. t-PA and urokinase are themselves inhibited by  plasminogen activator inhibitor-1 and  plasminogen activator inhibitor-2 (PAI-1 and PAI-2). In contrast, plasminogen further stimulates plasmin generation by producing more active forms of both tissue plasminogen activator ( tPA ) and urokinase . Alpha 2-antiplasmin and alpha 2-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 .

8. Plasmin breakdown When plasmin breaks down fibrin, a number of soluble parts are produced. These are called fibrin 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, the D- 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 indicate deep-vein thrombosis, pulmonary embolism, DIC and efficacy of treatment in acute myocardial infarction.

9. Alternatively, a more rapid detection of fibrinolytic activity, especially hyperfibrinolysis , is possible with  thromboelastometry  (TEM) in whole blood, even in patients on heparin. In this assay, increased fibrinolysis is assessed by comparing the TEM profile in the absence or presence of the fibrinolysis inhibitor  aprotinin . 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

10. Testing of overall fibrinolysis can be measured by a  euglobulin lysis time (ELT) assay. The ELT measures fibrinolysis by clotting the euglobulin fraction (primarily the important fibrinolytic factors fibrinogen, PAI-1,  tPA , alpha 2-antiplasmin, and  plasminogen ) 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 deficiency or alpha 2-antiplasmin deficiency. Similar results are also seen after administration of DDAVP or after severe stress.

11. Role in disease Few congenital disorders of the fibrinolytic system have been documented. Nevertheless, excess levels of PAI and alpha 2-antiplasmin have been implicated in the metabolic syndrome and various other disease states. However, acquired disturbance of fibrinolysis ( Hyperfibrinolysis ), is not uncommon. Many trauma patients suffer from an overwhelming activation of tissue factor and thus massive hyperfibrinolysis . Also in other disease states hyperfibrinolysis may occur. It could lead to massive bleeding if not diagnosed and treated early enough. The fibrinolytic system is closely linked to control of inflammation, and plays a role in disease states associated with inflammation.  Plasmin , in addition to lysing fibrin clots, also cleaves the complement system component C3, and fibrin degradation products have some vascular permeability inducing effects.

12. Pharmacology In a process called  thrombolysis  (the breakdown of a thrombus), fibrinolytic drugs are used. They are given following a heart attack to dissolve the thrombus blocking the coronary artery; experimentally after a stroke to allow blood flow back to the affected part of the brain; and in the event of a massive pulmonary 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 as  aminocaproic acid (ε- aminocaproic acid) and  tranexamic acid 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. The antifibrinolytic drug aprotinin was abandoned after identification of major side effects, especially on kidney.

13. Fibrinolytic enzymes Anistreplase Desmoteplase Streptokinase Nattokinase Lumbrokinase Papain DNase Bromelain

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