The evolution of recombinant thrombolytics: Current status and future directions

Abstract

Cardiovascular disorders are on the rise worldwide due to alcohol abuse, obesity, hypertension, raised blood lipids, diabetes and age-related risks. The use of classical antiplatelet and anticoagulant therapies combined with surgical intervention helped to clear blood clots during the inceptive years. However, the discovery of streptokinase and urokinase ushered the way of using these enzymes as thrombolytic agents to degrade the fibrin network with an issue of systemic hemorrhage. The development of second generation plasminogen activators like anistreplase and tissue plasminogen activator partially controlled this problem. The third generation molecules, majorly t-PA variants, showed desirable properties of improved stability, safety and efficacy with enhanced fibrin specificity. Plasmin variants are produced as direct fibrinolytic agents as a futuristic approach with targeted delivery of these drugs using liposome technlogy. The novel molecules from microbial, plant and animal origin present the future of direct thrombolytics due to their safety and ease of administration.

Keywords: Plasminogen activators; streptokinase; thrombolytic enzymes; tissue plasminogen activator; urokinase.

Figure 1.

Overview of the coagulation (extrinsic and intrinsic) and thrombolytic cascades. In the extrinsic pathway (red arrow), membrane associated tissue factor (TF) binds to activated factor VII (VIIa) already present in circulation. This binary complex further activates factor X to factor Xa. Factor Xa then activates factor V to Va forming the prothrombinase complex that catalyzes activation of prothrombin to thrombin. Thrombin cleaves fibrinogen to fibrin that forms a mesh in which the RBCs, WBCs and platelets are entrapped to form the blood clot. In the intrinsic pathway (blue arrow), factor XII is activated via contact with negatively charged surfaces (collagen). Factor XIIa activates factor XI to XIa which catalyzes the activation of factor IX. Activated factor IXa forms a complex with factor VIIIa and mediates activation of factor X. The extrinsic and intrinsic pathways of blood coagulation merge at factor X activation (black arrow). The propagation of the fibrin clot is limited by the action of the serine protease, plasmin (green arrow). It is formed via the activation of plasminogen by plasminogen activators such as u-PA, t-PA, SK, APSAC etc. Plasmin cleaves fibrin into fibrin degradation products that are then removed by macrophages. A detailed mechanism has been described in the text.