A new recombinant thrombolytic and antithrombotic agent with higher fibrin affinity - a staphylokinase variant. An in-vivo study.

Abstract

The recombinant protein SAK-RGD-K2-Hir is characterized by its fibrin-specific properties of plasminogen activation combined with antithrombin and antiplatelet activities. It was previously shown in our in-vitro studies to be a more potent and faster-acting thrombolytic agent compared with standard r-SAK. In order to document the effects of the thrombolytic potential of SAK-RGD-K2-Hir we examined this protein in an electrically induced carotid artery thrombosis model and stasis-induced venous model in rats. In the arterial thrombosis model, a bolus injection of SAK-RGD-K2-Hir was less effective than rt-PA and r-SAK. However, the most effective in the improvement and maintenance of carotid patency and in arterial thrombus mass reduction was SAK-RGD-K2. In contrast, all r-SAK derivatives reduced venous thrombus weight significantly in comparison to r-SAK and r-Hir. However, the most observable decrease in thrombus weight was obtained after application of recombinant proteins containing the r-Hir. The bleeding time was significantly prolonged in the animals treated with proteins containing r-Hir at a dose of 1.0 mg/kg. There were no observable changes in plasma fibrinogen concentration. In conclusion, our findings show thrombolytic activity in intravenous bolus injection of the novel thrombolytic agent SAK-RGD-K2-Hir in rats. Although this protein compares favourably with r-SAK in rat venous thrombolysis, we were unable to confirm the beneficial effects of SAK-RGD-K2-Hir over r-SAK and rt-PA in the carotid artery thrombolysis model. Furthermore, our results also suggest that SAK-RGD-K2-Hir bears a risk of bleeding, but this may be true for higher doses.

• Authors: Janusz Szemraj, Adrian Stankiewicz, Wioletta Rozmyslowicz-Szermińska, Andrzej Mogielnicki, Anna Gromotowicz, Wlodzimierz Buczko, Katarzyna Oszajca, Jacek Bartkowiak, Ewa Chabielska
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 97 Issue 6 Pg. 1037-45 (Jun 2007) ISSN: 0340-6245 [Print] Germany
• PMID: 17549308 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrinolytic Agents
• Hirudins
• Recombinant Fusion Proteins
• SAK-RGD-K2-Hir
• Fibrin
• Tissue Plasminogen Activator
• Metalloendopeptidases

Topics

• Animals
• Bleeding Time
• Blood Coagulation (drug effects)
• Carotid Artery Thrombosis (blood, drug therapy, metabolism, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Electric Stimulation
• Fibrin (metabolism)
• Fibrinolytic Agents (adverse effects, metabolism, pharmacology)
• Hemorrhage (chemically induced)
• Hirudins (adverse effects, metabolism, pharmacology)
• Ligation
• Male
• Metalloendopeptidases (adverse effects, metabolism, pharmacology)
• Partial Thromboplastin Time
• Rats
• Rats, Wistar
• Recombinant Fusion Proteins (adverse effects, metabolism, pharmacology)
• Thrombin Time
• Time Factors
• Tissue Plasminogen Activator (pharmacology)
• Vascular Patency (drug effects)
• Venae Cavae (surgery)
• Venous Thrombosis (blood, drug therapy, metabolism)