Hemostatic effects of phospholipid vesicles carrying fibrinogen gamma chain dodecapeptide in vitro and in vivo.
We studied prototypes of platelet substitutes that bear on their surface a dodecapeptide, HHLGGAKQAGDV (H12). The peptide is a fibrinogen gamma chain carboxy-terminal sequence (gamma400-411) and recognizes specifically the active form of glycoprotein (GP) IIb/IIIa on the surface of activated platelets. We conjugated H12 to the end of poly(ethylene glycol) chains on the surface of a phospholipid vesicle with an average diameter of 220 nm to prepare H12-PEG-vesicles. The half-life of the H12-PEG-vesicles was significantly prolonged by PEG modification, and the ability of H12 on the surface of the vesicle to recognize GPIIb/IIIa was maintained even though the surface was modified with PEG chains. The H12-PEG-veiscles enhanced the in vitro thrombus formation of platelets that were adhering to a collagen-immobilized plate, when thrombocytopenia-imitation blood was passed over the plate. Based on the flow cytometric analyses of PAC-1 binding and P-selectin expression, the H12-PEG-vesicles were shown not to cause platelet activation. Furthermore, the H12-PEG-vesicles dose-dependently shortened the tail bleeding time of thrombocytopenic rats. It was confirmed that the H12-PEG-vesicles had a hemostatic effect and may be a suitable candidate for an alternative to human platelet concentrates transfused into thrombocytopenic patients.
Okamura
Yosuke
Y
Graduate School of Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.
Maekawa
Ippei
I
Teramura
Yuji
Y
Maruyama
Hitomi
H
Handa
Makoto
M
Ikeda
Yasuo
Y
Takeoka
Shinji
S
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D016503:Drug Delivery Systems; D005340:Fibrinogen / Q000737:chemistry; D006207:Half-Life; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010743:Phospholipids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D013921:Thrombocytopenia / Q000188:drug therapy; D013927:Thrombosis / Q000139:chemically induced
D006490:Hemostatics; D010446:Peptide Fragments; D010743:Phospholipids; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011092:Polyethylene Glycols; D005340:Fibrinogen