PLATSAK, a potent antithrombotic and fibrinolytic protein, inhibits arterial and venous thrombosis in a baboon model.
Antiplatelet-antithrombin-staphylokinase (PLATSAK) is a chimeric protein that was recombinantly produced in Escherichia coli cells. The protein was designed to target haemostasis at three different levels. It consists of staphylokinase for activation of fibrinolyis, the Arg-Gly-Asp sequence for the prevention of platelet aggregation, and an antithrombotic peptide for the inhibition of thrombin. The in vivo activity of PLATSAK was evaluated by assessing its effect on platelet deposition in a baboon model of arterial and venous thrombosis. Dacron vascular graft segments and expansion chambers, inserted as extensions into permanent femoral arteriovenous shunts, were used to simulate arterial and venous thrombosis, respectively. PLATSAK (3.68 mg/kg) was administered as a bolus 10 minutes before placement of the thrombogenic devices. Platelet deposition onto the graft surface and in the expansion chamber was imaged in real time with a scintillation camera as the deposition of 111In-labeled platelets. After 2 hours, platelet deposition in the graft segments and expansion chambers was inhibited by 50% and 85%, respectively, when compared to control studies. The activated partial thromboplastin time was lengthened to greater than 120 seconds. Interestingly, the level of fibrinogen degradation products in plasma did not increase after administration of PLATSAK. These results demonstrate that PLATSAK effectively inhibited platelet deposition in both arterial- and venous-type thrombosis in an animal model.
van Zyl
W B
WB
Department of Haematology and Cell Biology, University of the Orange Free State, Bloemfontein, South Africa.
Pretorius
G H
GH
Lamprecht
S
S
Roodt
J P
JP
Kotzé
H F
HF
D000818:Animals; D000990:Antithrombin III / Q000187:drug effects / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology; D001807:Blood Vessel Prosthesis; D003952:Diagnostic Imaging; D004195:Disease Models, Animal; D005069:Evaluation Studies as Topic; D005338:Fibrin Fibrinogen Degradation Products / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D015902:Gamma Cameras; D007205:Indium Radioisotopes; D008297:Male; D010215:Papio; D010314:Partial Thromboplastin Time; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control*; D013997:Time Factors
D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D007205:Indium Radioisotopes; C112515:PLATSAK protein, recombinant; D011993:Recombinant Fusion Proteins; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases