Fibrinolytic Therapy A

Fibrin is formed from fibrinogen through thrombin (factor IIa)-catalyzed proteolytic removal of two oligopeptide fragments. Individual fibrin molecules polymerize into a fibrin mesh that can be split into fragments and dissolved by plasmin. Plasmin derives by proteolysis from an inactive precursor, plasmino-gen. Plasminogen activators can be infused for the purpose of dissolving clots (e.g., in myocardial infarction). Thrombolysis is not likely to be successful unless the activators can be given very soon after thrombus formation. Urokinase is an endogenous plasminogen activator obtained from cultured human kidney cells. Urokinase is better tolerated than is streptokinase. By itself, the latter is enzymatically inactive; only after binding to a plasminogen molecule does the complex become effective in converting plasminogen to plasmin. Strep-tokinase is produced by streptococcal bacteria, which probably accounts for the frequent adverse reactions. Strepto-kinase antibodies may be present as a result of prior streptococcal infections. Binding to such antibodies would neutralize streptokinase molecules.

With alteplase, another endogenous plasminogen activator (tissue plasminogen activator, tPA) is available. With physiological concentrations this activator preferentially acts on plasmin-ogen 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 lived (inactivation by complexing with plasminogen activator inhibitor, PAI) and has to be applied by infusion. Rete-plase, however, containing only the proteolytic active part of the alteplase molecule, allows more stabile plasma levels and can be applied in form of two injections at an interval of 30 min.

Inactivation of the fibrinolytic system can be achieved by "plasmin inhibitors," such as e-aminocaproic acid, p-aminomethylbenzoic acid (PAMBA), tranexamic acid, and aprotinin, which also inhibits other proteases.

Lowering of blood fibrinogen concentration. Ancrod is a constituent of the venom from a Malaysian pit viper. It enzymatically cleaves a fragment from fibrinogen, resulting in the formation of a degradation product that cannot undergo polymerization. Reduction in blood fibrinogen level decreases the coagulability of the blood. Since fibrinogen (MW -340 000) contributes to the viscosity of blood, an improved "fluidity" of the blood would be expected. Both effects are felt to be of benefit in the treatment of certain disorders of blood flow.

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