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.

<p>Microbial Modulation of Coagulation Disorders in Venous Thromboembolism</p>

“…Plasminogen activation to plasmin may also occur with the participation of bacterial plasminogen activators such as streptokinase (SK). 40,41 The bacterial infection leads to large changes in the balance between coagulation and fibrinolysis. 42 Some bacteria use the host's hemostatic system to bypass the immune defense.…”

“…Plasminogen activation to plasmin may also occur with the participation of bacterial plasminogen activators such as streptokinase (SK). 40 , 41 …”

Purification and characterization of recombinant Streptokinase expressed in E.coli from Streptococcus equisimilis with N-terminal methionine

“…The compositions of proteins and peptides were determined on a Beckman model 119Cl analyzer equipped for single column methodology. The samples were lyophilized (1 to 5 nmol) in hydrolysis ampoules and vacuum hydrolyzed for 24 h at 1l0'C in 1 Intens.…”

“…24 To Solution 1 2000 μL of 1 mg/mL human plasminogen (Human plasminogen, Hyphen Biomed, France) was added and to Solution 2, 500 μL of thrombin (10 NIH unit/vial, from human plasma, Sigma-Aldrich, USA) was added. By mixing solutions (1) and (2) in a Petri dish, clot formation was initiated for 30 min and maintained at 4ºC. Dilutions were prepared in the range of 100-1000 IU/mL, with Milli-Q water from the international standard and loaded, as duplicate, onto fibrin plate and incubated for eighth.…”

“…The Major cause of cardiovascular complications are alcohol abuse, obesity, physical inactivity, unhealthy diet, lifestyle, tobacco use, hypertension, raised blood lipids, diabetes, air pollution, high salt intake combined with age-related risks. 1 Streptococcus equisimilis GCS strain H46A (ATCC 12449) was the first streptococci to be introduced as a high-yield SK secreting bacteria for production purpose by Christensen et al in 1945. Further, another Streptococcus.…”