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INTRODUCTION

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Obstruction of arterial or venous blood flow to vital vessels can have a dramatic impact on mortality and morbidity. Prior to thrombolytic agents, open surgical procedures were preformed to restore vessel patency and preserve vital organs. Antithrombotic agents are currently the mainstay therapy for achieving fibrinolysis during an acute ischemic event. Indications include acute myocardial infarction, ischemic stroke, deep venous thrombosis, pulmonary embolism, limb ischemia, and central line occlusion. Therefore, antithrombotic agents are used to target these blood clots directly using a catheter-directed thrombolysis or a systemic approach to dissolve the existing obstruction.

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The ideal thrombolytic agent would include a high fibrin specificity while still remaining affordable. It should allow easy administration and rapid lysis response time with a limited side effect profile. It should be able to monitor drug level and its fibrinolysis effectiveness to predict potential hemorrhagic complications. Plasminogen activators were initially discovered from biological sources (streptokinase and urokinase). Later, genetically produced recombinant forms were developed (alteplase, reteplase, tenecteplase). The direct-acting thrombolytic drugs (alfimeprase, human plasmin) are a growing area of recent research. A new wave of novel plasminogen activators (staphylokinase, desmoteplase) are not yet commercially available.

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MECHANISM OF ACTION

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Plasminogen is the inactive precursor form of the enzyme plasmin, which is the primary catalyst for fibrinolysis. Plasminogen activators such as tissue plasminogen activators (t-PA) or urokinase plasminogen activators (u-PA) activate the initial stage for fibrin degradation. Likewise, it is highly regulated at two different levels. These include plasminogen activator inhibitors (PAI-1), which prevent excessive activation of plasminogen. Second, when plasmin is generated, it is further regulated by a competitive inhibitor, alpha-2 antiplasmin, to prevent the breakdown of fibrin. To override this system, large amount of plasmin conversion can outcompete alpha-2 plasmin for fibrinolysis. This endogenous balance ensures a counterbalance between excessive fibrin crosslinking and fibrin degradation.

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The inactive protein, plasminogen, exists in the bloodstream as a circulating plasminogen and fibrin-bound plasminogen. Activation of the circulating plasminogen results in unopposed plasmin to degrade fibrinogen and clotting factors. This will trigger a “systemic lysis state,” reducing the hemostatic potential of blood but increasing the risk of bleeding. These are considered nonspecific activators, which include streptokinase, urokinase, and anistreplase. Activation of fibrin-bound plasminogen begins the specific phase of fibrinolysis commonly seen with alteplase. A tertiary complex is assembled when plasminogen and t-PA specifically bind to fibrin. This complex generates large amount of bound plasmin, which is relatively shielded away from the inactivation of alpha-2 antiplasmin. This sequence promotes efficient plasminogen activation and propagation. The fibrin degradation exposes itself to more binding sites for additional plasminogen and t-PA, which amplifies the fibrinolytic process.

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The fibrin specificity of plasminogen activators reflects their capacity to distinguish between fibrin-bound and circulating plasminogens, which depends on their affinity for fibrin. Plasminogen activators with high affinity for fibrin preferentially activate fibrin-bound plasminogen. This results in the generation of plasmin on the fibrin ...

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