Direct fibrinolytics

Direct Fibrinolytics Alfimeprase is a recombinant tmncated form of fibrolase, a fibrinolytic zinc metalloproteinase isolated from the venom of the Southern copperhead snake. It degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This may result in faster recanalization and a decreased risk of hemorrhagic conversion. The initial data on the safety and efficacy of alfimeprase in peripheral arterial occlusion disease appeared very promising, but recent communication from the sponsor revealed that the phase III trials of the drug in peripheral arterial disease and catheter obstruction (NAPA-2 and SONOMA-2) failed to meet their primary and key secondary endpoints of revascularization. A trial for I AT in acute stroke (CARNEROS-1) is planned to begin soon. 

Plasminogen activators, direct fibrinolytics, fibrinog-enolytic agents... 

Local intra-arterial thrombolysis (lAT) has several theoretical advantages over IV thrombolysis. For instance, by using coaxial microcatheter techniques, the occluded intracranial vessel is directly accessible and the fibrinolytic agent can be infused directly into the thrombus. This permits a smaller dose of fibrinolytic agent to reach a higher local concentration than that reached by systemic infusion, and ideally it allows for more complete recanalization with lower total doses of thrombolytic. With the smaller dose, complications from systemic fibrinolytic effects, including ICH, can theoretically be reduced. 

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. 

Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction results from the GUSTO-lib Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-lib) Investigators. J Am Coll Cardiol, 1998.31(7) 1493-8. 

Antifibrinolytic compounds can block the conversion of plasminogen to plasmin, or directly bind to the active site of plasmin to inhibit fibrinolysis. The plasma protein, a 2-macroglobulin, is a primary physiological inhibitor of plasmin. Plasmin released from fibrin is also very rapidly inactivated by a2-antiplasmin, which plays a role in the regulation of the fibrinolytic process (Aoki and Harpel, 1984). 2-anti plasmin inactivates plasmin in a very rapid reaction, interferes with plasminogen binding to fibrin, and is ligated to fibrin by Factor Xllla (Sakata and Aoki, 1980). After a2-antiplasmin is covalendy linked to fibrin s G-terminal a chain, it retains it ability to inhibit plasmin, a function that helps to prevent premature clot lysis. 

Drugs that decrease the coagulability of blood, such as coumarins and heparin (A) are employed for the prophylaxis of thromboses. In addition, attempts are directed, by means of acetylsalicylic acid, at inhibiting the aggregation of blood platelets, which are prominently involved in intra-arterial thrombogenesis (p.152). For the therapy of thrombosis, drugs are used that dissolve the fibrin meshwork-fibrinolytics (P-150). 

The inflammatory process in sepsis is also directly linked to the coagulation system. Proinflammatory mechanisms that promote sepsis are also procoagulant and antiflbrinolytic, whereas fibrinolytic mechanisms may be anti-inflammatory. A key endogenous substance involved in the inflammation of sepsis is activated protein C, which enhances fibrinolysis and inhibits inflammation. Levels of protein C are reduced in patients with sepsis. ... 

The close relationship of the chief proteolytic enzyme system of plasma, the plasminogen system, to coagulation changes has led to many studies on the relationship of heparin to fibrinolysin. Heparin does not inhibit plasmin, or the fibrinolytic activity of Aspergillus proteus, but inhibits various fibrinolytic activators directly . For antifibrinolytic activity, heparin requires a co-factor found only in plasma, and this may be the heparin cofactor itself. Heparin therefore may lack antifibrinolytic activity on a purified system due to the lack of this factor . Buluk and Januszko report that fibrinolysis of... 

From the standpoint of blood clotting on the surfaces of artificial organs, the activity and structural changes of proteins bound on surfaces have been studied (36-41). The enzyme used in our studies were thrombin, plasmin, trypsin, phosphatase and peroxidase. Thrombin and plasmin are, respectively, key components of the coagulation and fibrinolytic systems. Kinetic parameters were obtained by direct measurement of the activities of enzymes bound on porous glass by mixing the porous glass with solutions of the substrate. 

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