Plasminogen thrombus

Summarizing the fibrinolytic therapy, it should be emphasized that efficient treatment needs urgent application of plasminogen activator (within a few hours) to prevent the formation of crosslinks in the fibrin structure (Fig. 2) and to find the localization of thrombus to emerge plasmin on the surface of fibrin to prevent rapid inactivation of the enzyme by the inhibitor system of fibrinolysis (Fig. 3). 

Alternatives to Plasminogen Activation Other Thrombolytics Thrombolytics currently in the market are plasminogen activators. Therefore, their activity is impacted by the amount of plasminogen in the thrombus. New drugs that do not depend on the availably of plasminogen are currently being evaluated for stroke therapy. 

Figure 22.5 (a) Injury to endothelial cells can lead to thrombosis. Healthy endothelial cells secrete two factors that inhibit thrombus formation (i) prostacyclins, which inhibit aggregation of platelets and (ii) a factor that facilitates conversion of plasminogen to plasmin. Injury to endothelial cells can facilitate thrombosis since (i) they do not secrete prostacyclins (ii) they do not secrete plasminogen activator and (iii) they secrete a factor that stimulates thrombosis. (b) Diagram of an atheroscle-rosed artery containing a thrombus. A thrombus is blocking the lumen of the artery that is not totally blocked by plaque. 

The fibrin thrombus resulting from blood clotting (see p. 290) is dissolved again by plasmin, a serine proteinase found in the blood plasma. For this purpose, the precursor plasminogen first has to be proteolyti-cally activated by enzymes from various tissues. This group includes the plasminogen activator from the kidney (urokinase) and tissue plasminogen activator (t-PA) from vascular endothelia. By contrast, the plasma protein a2-antiplasmin, which binds to active plasmin and thereby inactivates it, inhibits fibrinolysis. 

Aheplase Recombinant [tPA] (Activase) [Plasminogen ActlVator/ThrombolytlC Enzyme] Uses AMI, PE, acute ischemic stroke, CV cath occlusion Action Thrombolytic binds fibrin in thrombus, initiates fibrinolysis Dose AMI 15 mg IV over 1-2 min, then 0.75 mg kg (max 50 mg) over 30 min, then 0.5 mg/kg over next 60 min (max 35 mg) (ECC 2005) Stroke 0.09 mg/kg IV over 1 min, then 0.81 mg/kg max 90 mg) inf over 60 min... 

Plasminogen, an inactive precursor, is activated to plasmin which as a protease is able to break down fibrin clots. The thrombolytic agents in use promote the conversion of plasminogen to plasmin at the site of a thrombus. Indications include post-myocardial infarction treatment. The thrombolytic must be administered within 6 hours for an optimal effect. Other indications are treatment of acute pulmonary thromboembolism, deep-vein thrombosis, acute arterial thrombosis and thromboembolism, as well as in the clearance of arteriovenous catheters and can-nulae. Agents are streptokinase, anistreplase, urokinase, alteplase, reteplase and tenecteplase. 

Mechanism of Action A tissue plasminogen activator that acts as a CV-thrombolytic by binding to the fibrin in a thrombus and converting entrapped plasminogen to plas-min. This process initiates fibrinolysis. Therapeutic Effect Degrades fibrin clots, fibrinogen, and other plasma proteins. 

Mechanism of Action A tissue plasminogen activator that activates the fibrinolytic system by directly cleaving plasminogen to generate plasmin, an enzyme that degrades the fibrin ot the thrombus. Therapeutic Effect Exerts CV-thrombolytic action. Pharmacokinetics Rapidlycleared from plasma. Eliminated primarilyby the liverand kidney. Haif-Hfe 13-16 min. 

Mechanism of Action An enzyme that activates the fibrinolytic system by converting plasminogen to plasmin, an enzyme that degrades fibrin clots. Acts indirectlybyform ing a complex with plasminogen, which converts plasminogen to plasmin. Action oc-curs within the thrombus, on its surface, and in circulating blood. Therapeutic Effect Destroys thrombi. 

The antithrombotic effects of NO are also mediated by NO-dependent inhibition of platelet aggregation. Both endothelial cells and platelets contain eNOS, which acts to regulate thrombus formation. Thus, endothelial dysfunction and the associated decrease in NO generation may result in abnormal platelet function. As in vascular smooth muscle, cGMP mediates the effect of NO in platelets. NO may have an additional inhibitory effect on blood coagulation by enhancing fibrinolysis via an effect on plasminogen. 

Fibrinolysis refers to the process of fibrin digestion by the fibrin-specific protease, plasmin. The fibrinolytic system is similar to the coagulation system in that the precursor form of the serine protease plasmin circulates in an inactive form as plasminogen. In response to injury, endothelial cells synthesize and release tissue plasminogen activator (t-PA), which converts plasminogen to plasmin (Figure 34-3). Plasmin remodels the thrombus and limits its extension by proteolytic digestion of fibrin. 

Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci that combines with the proactivator plasminogen. This enzymatic complex catalyzes the conversion of inactive plasminogen to active plasmin. Urokinase is a human enzyme synthesized by the kidney that directly converts plasminogen to active plasmin. Plasmin itself cannot be used because naturally occurring inhibitors in plasma prevent its effects. However, the absence of inhibitors for urokinase and the streptokinase-proactivator complex permits their use clinically. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins, which allows it to lyse the thrombus from within. 

Plasminogen can also be activated endogenously by tissue plasminogen activators (t-PAs). These activators preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. Human t-PA is manufactured as alteplase by means of recombinant DNA technology. 

The central process of fibrinolysis is conversion of inactive plasminogen to the proteolytic enzyme plasmin. Injured cells release activators of plasminogen. Plasmin remodels the thrombus and limits the extension of thrombosis by proteolytic digestion of fibrin. 

Degradation of an unwanted thrombus and a beneficial hemostatic plug by plasminogen activators. 

Levi M, Biemond BJ, VanZonneveld AJ et al. (1992) Inhibition of plasminogen activator inhibitor-1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 85 305-312... 

Normal development, fertility, and survival serum is completely deficient in serum spreading factor and plasminogen activator inhibitor 1 binding activities delayed arterial and venous thrombus formation (Eitzman et al. 2000 Zheng et al. 1995). 

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