Fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes rescue thrombocytopenic rabbits from non-compressible liver hemorrhage.
BACKGROUND
We developed a fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV [H12])-coated, ADP-encapsulated liposome (H12-[ADP]-liposome) that accumulates at bleeding sites via interaction with activated platelets via glycoprotein IIb-IIIa and augments platelet aggregation by releasing ADP.


OBJECTIVE
To evaluate the efficacy of H12-(ADP)-liposomes for treating liver hemorrhage in rabbits with acute thrombocytopenia.


METHODS
Thrombocytopenia (platelets < 50 000 μL(-1)) was induced in rabbits by repeated blood withdrawal (100 mL kg(-1) in total) and isovolemic transfusion of autologous washed red blood cells. H12-(ADP)-liposomes with platelet-poor plasma (PPP), platelet-rich plasma (PRP), PPP, ADP liposomes with PPP or H12-(PBS)-liposomes/PPP, were administered to the thrombocytopenic rabbits, and liver hemorrhage was induced by penetrating liver injury.


RESULTS
Administration of H12-(ADP)-liposomes and of PRP rescued all thrombocytopenic rabbits from liver hemorrhage as a result of potent hemostasis at the liver bleeding site, although rabbits receiving PPP or ADP liposomes showed 20% survival in the first 24 h. Administration of H12-(ADP)-liposomes and of PRP suppressed both bleeding volume and time from the site of liver injury. H12-(phosphate-buffered saline)-liposomes lacking ADP also improved rabbit survival after liver hemorrhage, although their hemostatic effect was weaker. In rabbits with severe thrombocytopenia (25 000 platelets μL(-1)), the hemostatic effects of H12-(ADP)-liposomes tended to be attenuated as compared with those of PRP treatment. Histologic examination revealed that H12-(ADP)-liposomes accumulated at the bleeding site in the liver. Notably, neither macrothombi nor microthrombi were detected in the lung, kidney or liver in rabbits treated with H12-(ADP)-liposomes.


CONCLUSIONS
H12-(ADP)-liposomes appear to be a safe and effective therapeutic tool for acute thrombocytopenic trauma patients with massive bleeding.
Departments of Traumatology and Critical Care Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
K
K
Nishikawa
K
K
Hagisawa
M
M
Kinoshita
S
S
Shono
S
S
Katsuno
M
M
Doi
R
R
Yanagawa
H
H
Suzuki
K
K
Iwaya
D
D
Saitoh
T
T
Sakamoto
S
S
Seki
S
S
Takeoka
M
M
Handa
D000208:Acute Disease; D000244:Adenosine Diphosphate / Q000008:administration & dosage*; D000818:Animals; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005340:Fibrinogen / Q000008:administration & dosage*; D006470:Hemorrhage / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006487:Hemostasis / Q000187:drug effects; D006490:Hemostatics / Q000008:administration & dosage*; D008081:Liposomes; D008107:Liver Diseases / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D016253:Microscopy, Immunoelectron; D009842:Oligopeptides / Q000008:administration & dosage*; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D011817:Rabbits; D013921:Thrombocytopenia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D014950:Wounds, Penetrating / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D006490:Hemostatics; D008081:Liposomes; D009842:Oligopeptides; C027539:fibrinopeptides gamma; D000244:Adenosine Diphosphate; D005340:Fibrinogen