About Preprint OnlineArticles prepublished February 08, 2012
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Haemostatic safety of a unique recombinant plasmin molecule lacking kringles 2–5
V. J. Marder (1), S. Manyak (1), T. Gruber (1), A. Goyal (1), G. Moreno (1), J. Hunt (2), J. Bromirski (2), P. Scuderi (2), S. R. Petteway, Jr (2), V. Novokhatny (2)
(1) David Geffen School of Medicine at UCLA, Los Angeles, California, USA; (2) Talecris BioTherapeutics, Inc, Research Triangle Park, North Carolina, USA
Summary
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.
Keywords
Haemostasis, Plasmin, recombinant derivative
DOI
http://dx.doi.org/10.1160/TH09-10-0742You may also be interested in...
| 1. | ||
Marie-Christine Alessi, Irène Juhan-Vague Thrombosis and Haemostasis 2008 99 6: 995-1000 http://dx.doi.org/10.1160/TH07-11-0682 | ||
| 2. | ||
Frederick A. Ofosu1, John Freedman2, John W. Semple2 Thrombosis and Haemostasis 2008 99 5: 851-862 http://dx.doi.org/10.1160/TH07-10-0592 | ||
| 3. | ||
Christian Gachet Thrombosis and Haemostasis 2008 99 3: 466-472 http://dx.doi.org/10.1160/TH07-11-0673 | ||
Articles prepublished January 25, 2012
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Haemostatic safety of a unique recombinant plasmin molecule lacking kringles 2–5
V. J. Marder (1), S. Manyak (1), T. Gruber (1), A. Goyal (1), G. Moreno (1), J. Hunt (2), J. Bromirski (2), P. Scuderi (2), S. R. Petteway, Jr (2), V. Novokhatny (2)
(1) David Geffen School of Medicine at UCLA, Los Angeles, California, USA; (2) Talecris BioTherapeutics, Inc, Research Triangle Park, North Carolina, USA
Summary
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.
Keywords
Haemostasis, Plasmin, recombinant derivative
DOI
http://dx.doi.org/10.1160/TH09-10-0742You may also be interested in...
| 1. | ||
Marie-Christine Alessi, Irène Juhan-Vague Thrombosis and Haemostasis 2008 99 6: 995-1000 http://dx.doi.org/10.1160/TH07-11-0682 | ||
| 2. | ||
Frederick A. Ofosu1, John Freedman2, John W. Semple2 Thrombosis and Haemostasis 2008 99 5: 851-862 http://dx.doi.org/10.1160/TH07-10-0592 | ||
| 3. | ||
Christian Gachet Thrombosis and Haemostasis 2008 99 3: 466-472 http://dx.doi.org/10.1160/TH07-11-0673 | ||
Articles prepublished January 11, 2012
|
|
Haemostatic safety of a unique recombinant plasmin molecule lacking kringles 2–5
V. J. Marder (1), S. Manyak (1), T. Gruber (1), A. Goyal (1), G. Moreno (1), J. Hunt (2), J. Bromirski (2), P. Scuderi (2), S. R. Petteway, Jr (2), V. Novokhatny (2)
(1) David Geffen School of Medicine at UCLA, Los Angeles, California, USA; (2) Talecris BioTherapeutics, Inc, Research Triangle Park, North Carolina, USA
Summary
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.
Keywords
Haemostasis, Plasmin, recombinant derivative
DOI
http://dx.doi.org/10.1160/TH09-10-0742You may also be interested in...
| 1. | ||
Marie-Christine Alessi, Irène Juhan-Vague Thrombosis and Haemostasis 2008 99 6: 995-1000 http://dx.doi.org/10.1160/TH07-11-0682 | ||
| 2. | ||
Frederick A. Ofosu1, John Freedman2, John W. Semple2 Thrombosis and Haemostasis 2008 99 5: 851-862 http://dx.doi.org/10.1160/TH07-10-0592 | ||
| 3. | ||
Christian Gachet Thrombosis and Haemostasis 2008 99 3: 466-472 http://dx.doi.org/10.1160/TH07-11-0673 | ||
Articles prepublished December 21, 2011
|
|
Haemostatic safety of a unique recombinant plasmin molecule lacking kringles 2–5
V. J. Marder (1), S. Manyak (1), T. Gruber (1), A. Goyal (1), G. Moreno (1), J. Hunt (2), J. Bromirski (2), P. Scuderi (2), S. R. Petteway, Jr (2), V. Novokhatny (2)
(1) David Geffen School of Medicine at UCLA, Los Angeles, California, USA; (2) Talecris BioTherapeutics, Inc, Research Triangle Park, North Carolina, USA
Summary
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.
Keywords
Haemostasis, Plasmin, recombinant derivative
DOI
http://dx.doi.org/10.1160/TH09-10-0742You may also be interested in...
| 1. | ||
Marie-Christine Alessi, Irène Juhan-Vague Thrombosis and Haemostasis 2008 99 6: 995-1000 http://dx.doi.org/10.1160/TH07-11-0682 | ||
| 2. | ||
Frederick A. Ofosu1, John Freedman2, John W. Semple2 Thrombosis and Haemostasis 2008 99 5: 851-862 http://dx.doi.org/10.1160/TH07-10-0592 | ||
| 3. | ||
Christian Gachet Thrombosis and Haemostasis 2008 99 3: 466-472 http://dx.doi.org/10.1160/TH07-11-0673 | ||
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