Fibrin Fibrinolysis

Under pathological conditions, e.g., (DIC), fibrinogen can be digested by the fibrinolytic enzyme plasmin. This leads to bleeding, even though clotting is also occurring. 

10 Vitamin K, Oral Anticoagulants, and Their Mechanisms of Action 

Vitamin K acts in the liver as an enzyme cofactor in the reactions that add an additional carboxyl group to particular Glu residues in the vitamin K-related coagulation 

Vitamin K action in protein Glu carboxylation. The formation of Gla from Glu requires abstraction of a H ion from the y position of Glu in the proteins that is followed by the addition of a carboxyl group from CO2. 

The proteins to be carboxylated are marked by a propeptide that serves as a signal for the vitamin K-dependent carboxylase. 

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Tranexamic acid competitively inhibits the binding of plasminogen and t-PA to fibrin and effectively blocks conversion of plasminogen to plasmin (which causes dissolution of fibrin) fibrinolysis is thus retarded. After an i.v. bolus injection it is excreted largely unchanged in the urine the t] is 1.5 h. It may also be administered orally or topically. 

The minor coagulation processes constantly taking place in the vascular system (whereby fibrin is deposited) are counteracted by simultaneous fibrinolysis. Coagulation and fibrinolysis are thus in continuous dynamic balance. Plasminogen is converted to plasmin by activators such as urokinase PA (isolated from urine) and tissue PA (isolated from tissue). The effect of tissue PA is strongly enhanced by the presence of fibrin. Fibrinolysis is stimulated by protein C, while plasmin activity is maintained in balance by inhibitors (e.g. a2-antiplasmin, a2-macroglo-bulin). (s.fig. 19.1)... 

There are several additional plasmin inhibitors in the blood, e.g., a2-macroglobulin, ai-proteinase inhibitor, antithrombin, but their role in the control of fibrinolysis is questionable, because their action on plasmin is eliminated by fibrin. 

Enzymology of proteases in a water-phase is well known, but its alteration in a compartment is poorly understood. There are dramatical changes in reaction rates, in enzyme contractions and in enzyme sensitivity to inhibitors, which are not exactly described. In addition, besides fibrin and platelets there are several cellular and molecular components present in a thrombus compartment, where their influence on the basic fibrinolytic reactions is not known. To study this aspect of fibrinolysis is a task of the near future [4]. 

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). 

Fibrinolysis A normal ongoing process that dissolves fibrin and results in the removal of small blood clots hydrolysis of fibrin. 

By far the most widely measured marker of hemostatic activation is D-dimer, which is a product formed by the action of plasmin on cross-linked fibrin (95). D-dimer levels in plasma are generally elevated in DIC. The consumption of platelets and coagulation proteins as a result of thrombin generation leads to the deposition of fibrin thrombi at multiple organ sites. This triggers fibrinolysis with an increase in the formation of fibrin degradation products, which can cause bleeding at multiple sites. Because DIC can have a variety of causes and may coexist with systemic fibrinolysis, such as in pulmonary embolism or deep vein thrombosis, the d-Dimer test is not specific for DIC (95). 

Von dem Borne P. A. K., Meijers J. C. M., Bouma B. N. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995 86, 3035 -42. 

The natural process of thrombosis functions to plug a damaged blood vessel, thus maintaining haemostasis until the damaged vessel can be repaired. Subsequent to this repair, the clot is removed via an enzymatic degradative process known as fibrinolysis. Fibrinolysis normally depends upon the serine protease plasmin, which is capable of degrading the fibrin strands present in the clot. 

Since apo(a) contains kringles that are almost identical to the kringles in plasminogen, with a moderate affinity to fibrin through their lysine-binding sites, the possible role of Lp(a) in fibrinolysis could be at that level (R17, R18). 

Another theory is that the inhibition of fibrinolysis is due to the interaction of Lp(a) with tPA bound to fibrin, and thereby influencing plasminogen activation (L10, R17, R18). Von Hodenberg (H32), however did not find a relationship between Lp(a) level and treatment success of thrombolysis in acute myocardial infarction with recombinant tPA. 

With alteplase, another endogenous plasminogen activator (tissue plasminogen activator, tPA) is available. With physiological concentrations this activator preferentially acts on plasminogen bound to fibrin. In concentrations needed for therapeutic fibrinolysis this preference is lost and the risk of bleeding does not differ with alteplase and streptokinase. Alteplase is rather short-Liillmann, Color Atlas of Pharmacology... 

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... 

Aminocaproic acid and tranexamic acid inhibit fibrinolysis by inhibiting plasminogen binding to fibrin or fibrinogen and the conversion of plasminogen to plasmin. 

Physiologically, the maintenance of blood circulating freely in the vascular system reflects a meticulous balance between coagulation and fibrinolysis. After microvascular injury subendothelial structures are exposed to which platelets adhere. This is followed by their aggregation and activation of the coagulation cascade with the ultimate conversion of fibrinogen to fibrin. 

Fibrinolysis. The hydrolysis of an elastic, filamentous protein (fibrin) derived from fibrinogen by the action of thrombin, which releases fibrinopeptides A and B (co-fibrins A and B) from fibrinogen in co-agulation of the blood. 

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. 

It is obtained from cultures of human renal cells in tissue culture and it is a proteolytic enzyme. It activates plasminogen directly. Plasmin acts on fibrin and fibrinolysis occurs. It is non antigenic. 

Anistreplase (streptokinase- plasminogen complex) streptococci protein streptococci plaminogen, which is then cleaved to form plasmin. Plasmin mediate fibrinolysis. Systemic lytic state and immunogenicity may limit its use. Because antistreplase is aheadly lined to plaminogen, the onset of fibrinolytic is faster. These enzymes are not fibrin-specific. 

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. 

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. 

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