A new recombinant thrombolytic and antithrombotic agent with higher fibrin affinity - a staphylokinase variant. An in-vivo study.
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.
Szemraj
Janusz
J
Department of Medical Biochemistry, Medical University of Lódź, 92-215 Lódź Mazowiecka 6/8, Poland. jszemraj@csk.am.lodz.pl
Stankiewicz
Adrian
A
Rozmyslowicz-Szermińska
Wioletta
W
Mogielnicki
Andrzej
A
Gromotowicz
Anna
A
Buczko
Wlodzimierz
W
Oszajca
Katarzyna
K
Bartkowiak
Jacek
J
Chabielska
Ewa
E
D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005337:Fibrin / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced; D006629:Hirudins / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D008026:Ligation; D008297:Male; D008666:Metalloendopeptidases / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D013918:Thrombin Time; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014654:Vascular Patency / Q000187:drug effects*; D014684:Venae Cavae / Q000601:surgery; D020246:Venous Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism
D005343:Fibrinolytic Agents; D006629:Hirudins; D011993:Recombinant Fusion Proteins; C521927:SAK-RGD-K2-Hir; D005337:Fibrin; D010959:Tissue Plasminogen Activator; D008666:Metalloendopeptidases