After a few days, the fibrin clot is degraded by the fibrinolytic enzyme system. The central enzyme component in this system is the glycoprotein plasminogen present in plasma and most extravascular fluids. Plasminogen is a zymogen of a serine protease which, following partial cleavage by a plasminogen activator, is converted into its active form plasmin. Plasmin is involved in a variety of biological processes, including cell migration, growth, inflammation and tumour invasion, although its primary function is assumed to be lysis of fibrin in the vasculature.
Two plasminogen activators have been found in the human body, the tissue-type plasminogen activator t-PA and the urinary-type activator u-PA. Fibrinolysis is initiated and propagated mainly by the fibrin surface, which offers binding sites for an optimal contact between a number of the components of the fibrinolytic system, most notably plasminogen and t-PA.
This stimulatory effect ensures a high concentration of plasminogen and t-PA at the fibrin deposits and localizes the plasmin activity. Inhibitory regulation is provided by the plasminogen activator inhibitor-1 PAI-1 and the plasmin inhibitor. PAI-1 is the most efficient inhibitor of t-PA in plasma and the majority of circulating t-PA is bound to this inhibitor. Normally, there exists a carefully regulated balance between the formation of fibrin and its subsequent removal.
However, in certain pathological conditions and in hereditary deficiencies, this balance is disturbed.
Subjects with an inherited increase of fibrinolytic activity usually have severe bleedings. In contrast, a decreased fibrinolytic activity may be associated with thrombotic disease. The fibrinolytic system in vivo. Plasminogen is the proenzyme of plasmin, whose primary target is the degradation of fibrin in the vasculature.
The activation of plasminogen to plasmin in blood is catalyzed by t-PA secreted from endothelial cells. Fibrin provides binding sites for both plasminogen and t-PA, thereby optimizing contact between them. This mechanism ensures a high concentration of plasminogen and t-PA at the site of fibrin formation and localizes the action of plasmin.
Further regulation of the system is provided by PAI-1 and plasmin inhibitor. The molecule, is made up of five distinct domain structures with autonomous functions. The finger domain and the two kringle domains are involved in the binding of t-PA to fibrin, whereas the epidermal growth factor domain is implicated in the rapid hepatic clearance of the molecule.
The serine protease domain contains the active site region made up of serine, histidine and aspartic acid, which are situated relatively far apart from each other in the primary structure, but are in close proximity in the folded protein. This region cleaves the Arg -Val bond in plasminogen and thus activates it to plasmin. Domain structure of the human t-PA molecule. Abbreviations: F; finger domain K; kringle domains, EGF; epidermal growth factor domain, P; serine protease domain.
The catalytic triad made up of His , Asp and Ser , is illustrated by black dots. The cleavage site for converting the molecule into the two-chain form is shown by an arrow. Disulfide bridges are marked as thin lines. The latter situation occurs upon stimulation of certain endothelial cell receptors. Different regions of the vascular system secrete different amounts of t-PA. Upper extremities secrete about four times more t-PA than that of the lower extremities.
The single chain molecule is the native form of t-PA secreted from endothelial cells, whereas the two-chain form is the result of the proteolytic activity of plasmin. Both forms are catalytically active and have similar enzymatic properties in the presence of fibrin.
Although, t-PA has a high affinity for fibrin and binding increases its activating capacity up to 1,fold. This dramatic increase is attributed to specific binding sites on the fibrin surface that concentrate and correctly orientate t-PA with its substrate, as well as promoting efficient clot lysis.
This discrepancy between antigen and activity levels can be attributed to the fact that most of t-PA in plasma occurs in non-functional complexes, mainly with its principle inhibitor PAI An acute increase in t-PA levels is observed in response to stimuli, such as exercise, mental stress, venous occlusion and various drugs.
The normal half-life is about 4 minutes for free t-PA, although the half-life may decrease considerably if PAI-1 levels are elevated, as is the case in many subjects with a thrombotic tendency. It is a typical serine protease inhibitor serpin that acts as a pseudosubstrate for its target protease, with which it forms an equimolar and inactive complex i. PAI-1 is unique in the serpin family, in that the molecule exists in two forms. One form is active, but spontaneously loses its activity and has a halflife of 0,5 hour.
The second form is a non-active decay product of the active molecule. The reason why PAI-1 undergoes this change is unclear. PAI-1 is synthesized by several cell types including endothelial cells and hepatocytes and is present in platelets, placenta and serum.
Platelet PAI-1 is available for release when the platelets are activated, but is much less active than plasma PAI-1 in relation to the amount present. This large variability is partly due to the marked diurnal variation in PAI-1, with lower values in the afternoon than in the morning.
This latter correlation may seem confusing, since the increase in the total amount of t-PA results in a decrease of t-PA activity. Several studies have observed a fibrinolytic deficiency in subjects with idiopathic or recurrent deep venous thrombosis DVT. About one third of these subjects exhibited impaired fibrinolytic activity, either due to a poor release of t-PA after venous occlusion, or due to increased PAI-1 levels. In two prospective studies carried out on postoperative DVT in subjects subjected to hip replacement, preoperative values of increased PAI-1 appeared to be predictive of postoperative venous occlusion.
Studies regarding a reduced t-PA activity and elevated PAI-1 levels as a risk factor for thromboembolic disease remain to be further evaluated.
Elevations of t-PA antigen have been linked to persons at risk in several studies involving cardiovascular events in subjects with angina pectoris and coronary artery stenosis, myocardial infarction MI , and stroke. Furthermore, a strong support for the link between PAI-1 elevation and risk of having a MI was obtained from a study of men who had survived a first MI before the age of 45 years.
Reduced t-PA activity has been reported as predictive for MI, for MI in subjects with angina pectoris, and in ischaemic disease in younger men. The results from these studies put together suggest that a state of elevated t-PA and PAI-1 antigen and reduced activity is the condition associated with cardiovascular disease. The production of t-PA and u-PA by leukemic cells can be used to predict the prognosis and response to chemotherapy in subjects with acute myeloid leukemia. Subjects whose cells produce only t-PA have a lower chance of survival and fail to respond to chemotherapy.
In contrast, subjects with u-PA producing cancer cells have a higher chance of survival and a better response to chemotherapy. Cardiovascular diseases, such as acute myocardial infarction, stroke, and venous thromboembolism, are probably the major cause of death and disability in an adult population. The immediate underlying etiology in these conditions is often a thrombotic obstruction of critically situated blood vessels, causing a loss of blood flow to vital organs.
One approach to the treatment of thrombosis consists of the intravenous infusion of plasminogen activators as clot-dissolving drugs. The use of thrombolytic agents may occasionally require close monitoring of the components of the plasminogen activation system. Excessive thrombolytic activity is likely to cause bleeding, particulary cerebral hemorrhage, as a side-effect. An intriguing feature of the fibrinolytic system is the circadian variation in t-PA and PAI-1 that has been observed.
Free t-PA levels are lowest in the morning, increase during the day and reach their peak activity level in the late afternoon. It has been suggested that the high incidence of myocardial infarction and cerebral thrombosis in the morning hours, may be connected to the circadian rhythm of fibrinolytic activity. From mortality statistics in Greenland it is known that Eskimos have a low prevalence of myocardial infarction. This has been related to their diet, although it may also be due to the observation that Eskimos have a rapid increase in t-PA activity in the morning and a more rapid decrease in PAI-1 activity and antigen compared to Caucasians.
Because of the diurnal variation in fibrinolytic activity, sampling should always take place at the same time during the day usually between 8 a. Different stimuli, drugs, and environmental factors have been reported to modulate the fibrinolytic activity in the experimental animal as well as in humans. Examples of these are listed below in alphabetical order.
Most reports on alcohol and fibrinolysis show an increase in plasma PAI-1 levels following alcohol consumption that causes an acute decrease in t-PA activity. If you or a loved one has had a stroke or has received tPA for treatment of a stroke, expect a recovery that may take time.
Sign up for our Health Tip of the Day newsletter, and receive daily tips that will help you live your healthiest life. Patient education: Ischemic stroke treatment Beyond the Basics. Updated Apr 08, American Stroke Association. Why getting quick stroke treatment is important. Merck Manual Consumer Version.
Ischemic stroke. Updated February Multicenter study of adverse events after intravenous tissue-type plasminogen activator treatment of acute ischemic stroke. J Neurosci Nurs. Stroke symptoms. Preventing another stroke. Current and future perspectives on the treatment of cerebral ischemia. Expert Opin Pharmacother.
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