Mechanisms of thrombosis and research progress on targeted antithrombotic drugs.

Currently-used thrombolytic agents are plasminogen activators (PA). While effective for treating thrombotic disease, PA use is associated with unavoidable hemorrhagic complications in susceptible individuals. Thus, there is an urgent need for new agents or approaches that provide greater hemostatic safety without sacrificing thrombolytic efficacy. Evidence now strongly indicates that 'direct-acting' thrombolytics, which do not require conversion of the precursor plasminogen to the active form plasmin, offer such a potential. The biochemical properties of plasmin provide a theoretical foundation for safe and effective therapy, based on thrombolytic efficacy upon local catheter delivery of agent and neutralization of circulating agent by its inhibitor (a-2 antiplasmin) to prevent bleeding complications. In vitro and animal studies support these predictions. In comparison with tissue-plasminogen activator (t-PA), plasmin shows a distinct benefit-to-risk advantage. First, plasmin is equally effective as t-PA in thrombolysis and may be superior for treating thrombi in totally-occluded vessels. Second, whereas t-PA causes bleeding from vascular trauma sites in animals when infused at dosages used for thrombolysis (0.5-1 mg/kg), plasmin exhibits safety at therapeutic dosages. In fact, plasmin can be used at several fold higher concentrations than is needed for thrombolysis, thereby providing a significant safety margin that is not attainable for t-PA or other PAs. Phase I trials with plasmin in hemodialysis graft occlusion and peripheral arterial occlusion have thus far confirmed the hemostatic safety of plasmin.

Pre-clinical studies of plasmin : Superior benefit-to-risk ratio of plasmin compared to tissue plasminogen activator

A marine fibrinolytic compound FGFC1 stimulating enzymatic kinetic parameters of a reciprocal activation system based on a single chain urokinase-type plasminogen activator and plasminogen

RGD and Scutellarin Conjugate (WK001) Targeting Platelet Glycoprotein IIb/IIIa Receptor Protects from Myocardial Ischemia/Reperfusion Injury: Synthesis, Characterization, and Bioactivity Evaluation.

Thrombosis, disease characterized to formation of blood clots, is a cause of death frequently
associated with myocardial infarction (IAM), stroke, deep-vein thrombosis, and pulmonary embolism.
Microplasmin is a low-molecular-weight protein termed with a molecular weight (Mr) of 28 KDa obtained
by Plasmin autolysis process in an alkaline solution. Microplasmin was prepared from pooled human
plasma by acetic acid precipitation (pH 6.1) in buffer sodium borate (pH 8.0). Microplasmin was purified
with affinity and anionic interchange chromatography. A protein peak with most of the fibrinolytic
activity of microplasmin adsorbed in the lysine-Sepharose column and eluted after washing the column
with 200 mM of Iµ-aminocaproic acid. The second peak eluted with 150 mM with fibrinolytic activity was
pooled to gel electrophoresis analysis. Protein named microplasmin with two chains was insolated of
human plasma showed fibrinolysis in vitro clot respect control.

Fibrinolysis with a new microplasmin purified of human plasma

Microplasminogen (μPlg), a truncated form of human plasminogen, has considerable potential as a direct-acting thrombolytic agent. To further develop μPlg into a thrombolytic agent with anti-thrombus properties, we constructed two μPlg variants containing tripeptide Arg-Gly-Asp (RGD) and tetrapeptide Gly-Pro-Arg-Pro (GPRP) by site-directed mutagenesis. The recombinant cDNAs were expressed in yeast (Pichia pastoris) and purified to high homogeneity by Ni–NTA affinity chromatography. The specific activities of RGD-μPlg and GPRP-μPlg were 7.7 and 13.3 U/mg, respectively, as determined using the fibrin-plate method. RGD-μPlg significantly inhibited ADP-induced platelet aggregation, which was 33.6- and 14.1-fold higher than the native μPlg and GPRP-μPlg, respectively. On the other hand, GPRP-μPlg prolonged thrombin-initialized fibrinogen polymerization in a concentration-dependent manner, which was 9.2- and 5.7-fold stronger than μPlg and RGD-μPlg, respectively. Under activation by urokinase, μPlg, RGD-μPlg, and GPRP-μPlg all showed over 80 % conversions to their active enzyme in 24 h. The structure models that docked RGD-μPlg and μPlg activation loops into the enzymatic active site of urokinase showed that Pro559 to Asp559 mutation of RGD-μPlg led to an alteration in the interaction, which possibly explains the slowed activation of RGD-μPlg by urokinase over an 80-min period. In conclusion, this study has presented two recombinant μPlg variants with anti-platelet aggregation and anti-fibrinogen clotting activity, thus suggesting the anti-thrombosis properties of these two μPlg derivatives.

In vitro fibrinolysis and antithrombosis characterizations of novel recombinant microplasminogen with RGD and GPRP peptides.

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In vitro fibrinolysis and antithrombosis characterizations of novel recombinant microplasminogen with RGD and GPRP peptides.