Haemostatic safety of a unique recombinant plasmin molecule lacking kringles 2-5.
We previously demonstrated a significant margin of haemostatic safety for full-length plasmin in comparison with tissue plasminogen activator (t-PA). We now report studies that compare haemostatic safety of full-length plasmin with a novel recombinant plasmin derivative, (Δ K2-5) plasmin, consisting of kringle 1 linked to the serine protease domain of plasmin. Agent was administered intravenously in a randomised, blinded manner in a rabbit model of fibrinolytic haemorrhage. A dose-related decrease in α2-antiplasmin, factor VIII, and fibrinogen followed administration of 1.8, 2.7, 3.7 and 4.6 mg/kg of (Δ K2-5) plasmin, with nadir fibrinogen concentrations of 65%, 40%, 30%, and 0% of initial levels, respectively. Mean primary bleeding time was undisturbed at 1.8 mg/kg (2.2 ± 0.7 minutes), minimally prolonged at 2.7 or 3.7 mg/kg (5 ± 2.9 and 4.4 ± 2.2 minutes), and prolonged at the purposefully toxic 4.6 mg/kg dose (12.8 ± 18.8 minutes). Equimolar amounts of (Δ K2-5) plasmin and full-length plasmin had equal in vitro clot lysis efficacy, but in the bleeding model, (Δ K2-5) plasmin showed better haemostatic competency than full-length plasmin. This safety advantage may be explained by higher residual amounts of plasma fibrinogen in animals given (Δ K2-5) plasmin rather than full-length plasmin. We demonstrate that a unique recombinant plasmin mutant, (Δ K2-5) plasmin, possesses an advantage in hemostatic safety over an equimolar amount of full-length plasmin.
Marder
Victor J
VJ
David Geffen School of Medicine at UCLA, Los Angeles, California 90095–1795, USA. vmarder@mednet.ucla.edu
Manyak
Steve
S
Gruber
Theresa
T
Goyal
Abha
A
Moreno
Guillermo
G
Hunt
Jennifer
J
Bromirski
John
J
Scuderi
Philip
P
Petteway
Stephen R
SR
Novokhatny
Valery
V
D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D018082:Kringles / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015912:Thrombolytic Therapy / Q000009:adverse effects; D013927:Thrombosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin