Physiological Basis of Fibrinolysis
Thrombus formation in the body automatically triggers the fibrinolytic system. The central step in this process is the conversion of the inactive proenzyme plasminogen into the active enzyme plasmin (fibrinolysis). Under physiological conditions, this transition is initiated by tissue plasminogen activator (tPA), which is secreted by the vascular endothelium.
Plasmin performs the primary task: it hydrolyzes fibrin (the structural backbone of the thrombus) into soluble peptides. However, plasmin lacks absolute specificity. It can also degrade circulating fibrinogen and other clotting factors. To prevent total fibrinogen depletion (systemic fibrinogenolysis), natural inhibitors exist in the blood, primarily $\alpha_2$-antiplasmin, which rapidly inactivates free plasmin.
Mechanisms of Drug Action
All fibrinolytic agents aim to activate plasminogen, but they do so through three distinct pathways:
- Indirect activation (streptokinase). Streptokinase itself possesses no intrinsic proteolytic activity. It binds to the plasminogen molecule to form an equimolar complex. This complex acquires the ability to convert other plasminogen molecules into active plasmin.
- Direct activation (urokinase). These agents act as direct activators. They directly catalyze the conversion of plasminogen to plasmin, functioning similarly to the body's natural enzymes.
- Fibrin-specific activation (alteplase, alteplase, tenecteplase). These are recombinant analogues of endogenous tPA. Their key feature is high affinity for fibrin. They preferentially activate plasminogen that is already adsorbed onto fibrin strands within the clot. The presence of fibrin accelerates their activity by hundreds of times, ensuring localized action.
Profile of Major Agents
- Streptokinase. A highly purified protein derived from cultures of $\beta$-hemolytic streptococci. It acts systemically, activating plasminogen both within the thrombus and in circulating plasma. Due to its bacterial origin, it has pronounced antigenic properties and can cause allergic reactions up to anaphylactic shock (especially upon repeat administration). Circulating antibodies can also cause resistance to therapy.
- Alteplase and tenecteplase. Administered intravenously. Due to their fibrin specificity, their action is largely confined to the thrombus, while circulating molecules are bound by specific inhibitors in the general bloodstream. This minimizes their impact on circulating fibrinogen.
- Urokinase. An enzyme of human origin (normally produced by renal cells). The drug is harvested from human embryonic kidney cell cultures. It acts systemically, but unlike streptokinase, it possesses zero antigenic properties.
Indications and Adverse Effects
The primary goal of thrombolytic therapy is rapid clot dissolution in life-threatening conditions. These drugs are administered intravenously (dosed in international units [IU]).
Main Indications:
- Acute myocardial infarction (maximum efficacy is achieved within the first 3–6 hours for streptokinase and 6–12 hours for alteplase).
- Pulmonary embolism (PE).
- Deep vein thrombosis and acute peripheral arterial occlusion.
- Retinal artery occlusion (an additional indication for streptokinase).
The primary complication of any thrombolytic therapy is hemorrhage. Its pathogenesis relates to systemic activity: plasmin generated in the plasma degrades fibrinogen. This produces fibrinogen and fibrin degradation products (FDPs), which accumulate in the blood and impair platelet aggregation. In addition to bleeding, arterial hypotension and gastrointestinal disturbances (nausea, vomiting) may occur.