Background
Plasma-derived bovine thrombin is used as a topical agent to improve surgical hemostasis, but development of antibodies to bovine hemostatic proteins has been associated with increased bleeding and thrombotic complications. Recombinant human thrombin could reduce the risk of these complications.
Study Design
The objective of this randomized, double-blind, comparative trial was to compare the efficacy, safety, and antigenicity of recombinant human thrombin (rhThrombin) and bovine thrombin as adjuncts to hemostasis in liver resection, spine, peripheral arterial bypass, and dialysis access surgery. Blinded study drug was applied topically to bleeding sites with an absorbable gelatin sponge. The primary efficacy end point was time to hemostasis, summarized as the incidence of hemostasis within 10 minutes. Safety analyses were conducted for 1 month after operation, and the development of antibodies to rhThrombin or to the bovine product was evaluated.
Results
Four hundred one patients completed this trial. Hemostasis was achieved at the time-to-hemostasis evaluation site within 10 minutes in 95% of patients in each treatment group. Overall complications, including operative mortality, adverse events, and laboratory abnormalities, were similar between groups. Forty-three (21.5%) patients receiving bovine thrombin developed antibodies to the product; three patients (1.5%; p < 0.0001) in the rhThrombin group developed antibodies to rhThrombin. None of the three patients who developed antirhThrombin antibodies had abnormal coagulation laboratory results or bleeding, thromboembolic, or hypersensitivity events.
Conclusions
Results of this trial suggest that rhThrombin has comparable efficacy, a similar safety profile, and is considerably less immunogenic than bovine thrombin when used for surgical hemostasis.
Friday
FDA Approves Human Thrombin for Topical Use in Surgery
The U.S. Food and Drug Administration approved Evithrom (Human Thrombin), a blood-clotting protein used to help control bleeding during surgery.
Evithrom is the first human thrombin approved since 1954 and is the only product currently licensed. It is derived from human plasma obtained from carefully screened and tested U.S. donors and has undergone steps to further reduce the risk for transfusion-transmitted diseases.
Evithrom is indicated as an aid to stop oozing and minor bleeding from capillaries and small veins and when control of bleeding by standard surgical techniques is ineffective or impractical. The product is applied to the surface of bleeding tissue and may be used in conjunction with an absorbable gelatin sponge. Evithrom must not be injected into blood vessels, which would result in serious clinical complications and may even be fatal.
"The approval of Evithrom offers an important additional option for surgeons and their patients to help control surgical bleeding," said Jesse L. Goodman, M.D., M.P.H., director of FDA's Center for Biologics Evaluation and Research. "Surgeons will now be able to choose between human thrombin and thrombin derived from cattle plasma."
In a clinical trial involving several hundred subjects, Evithrom was found comparable to cattle-derived thrombin in both safety and effectiveness.
Evithrom is manufactured by Omrix Biopharmaceuticals, Ltd., Ramat Gan, Israel, and will be distributed by Johnson & Johnson Wound Management, a division of Ethicon, Inc., Somerville, N.J.
Evithrom is the first human thrombin approved since 1954 and is the only product currently licensed. It is derived from human plasma obtained from carefully screened and tested U.S. donors and has undergone steps to further reduce the risk for transfusion-transmitted diseases.
Evithrom is indicated as an aid to stop oozing and minor bleeding from capillaries and small veins and when control of bleeding by standard surgical techniques is ineffective or impractical. The product is applied to the surface of bleeding tissue and may be used in conjunction with an absorbable gelatin sponge. Evithrom must not be injected into blood vessels, which would result in serious clinical complications and may even be fatal.
"The approval of Evithrom offers an important additional option for surgeons and their patients to help control surgical bleeding," said Jesse L. Goodman, M.D., M.P.H., director of FDA's Center for Biologics Evaluation and Research. "Surgeons will now be able to choose between human thrombin and thrombin derived from cattle plasma."
In a clinical trial involving several hundred subjects, Evithrom was found comparable to cattle-derived thrombin in both safety and effectiveness.
Evithrom is manufactured by Omrix Biopharmaceuticals, Ltd., Ramat Gan, Israel, and will be distributed by Johnson & Johnson Wound Management, a division of Ethicon, Inc., Somerville, N.J.
Monday
Role of the Endothelium in the Vascular Effects of the Thrombin Receptor (Protease-Activated Receptor Type 1) in Humans
Objectives
The purpose of this study was to determine the role of the endothelium in the vascular actions of protease-activated receptor type 1(PAR-1) activation in vivo in man.
Background
Thrombin is central to the pathophysiology of atherothrombosis. Its cellular actions are mediated via PAR-1. Protease-activated receptor type 1 activation causes arterial vasodilation, venoconstriction, platelet activation, and tissue-type plasminogen activator release in man.
Methods
Dorsal hand vein diameter was measured in 6 healthy volunteers before and after endothelial denudation. Forearm arterial blood flow, plasma fibrinolytic factors, and platelet activation were measured in 24 healthy volunteers during venous occlusion plethysmography. The effects of inhibition of prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor on PAR-1 responses were assessed during coadministration of aspirin, the “NO clamp” (L-NG-monomethyl arginine and sodium nitroprusside), and tetraethylammonium ion, respectively.
Results
Endothelial denudation did not affect PAR-1–evoked venoconstriction (SFLLRN; 0.05 to 15 nmol/min). Although aspirin had no effect, SFLLRN-induced vasodilation (5 to 50 nmol/min) was attenuated by the NO clamp (p < 0.0001) and tetraethylammonium ion (p < 0.05) and abolished by their combination (p < 0.01). The NO clamp augmented SFLLRN-induced tissue-type plasminogen activator and plasminogen activator inhibitor type 1 antigen (p < 0.0001) release, but tetraethylammonium ion and aspirin had no effect. SFLLRN-induced platelet activation was unaffected by NO or prostacyclin inhibition.
Conclusions
Acting via PAR-1, thrombin causes contrasting effects in the human vasculature and has a major interaction with the endothelium. This highlights the critical importance of endothelial function during acute arterial injury and intravascular thrombosis, as occurs in cardiovascular events including myocardial infarction and stroke.
Role of the Endothelium in the Vascular Effects of the Thrombin Receptor (Protease-Activated Receptor Type 1) in Humans
Thrombin is central to the pathophysiology of atherothrombosis and exerts its vascular effects via protease activated receptor type 1 (PAR-1). We report the contrasting role of the endothelium in PAR-1 activation in vivo in man, where it mediates arterial PAR-1–induced vasodilation and tissue plasminogen activator release but does not provide a major contribution to venous tone or plasminogen activator inhibitor type 1 release. Our findings provide evidence of a major interaction between the endothelium and thrombin in vivo. This highlights the critical importance of endothelial function during acute arterial injury and thrombosis, as occurs in acute coronary syndromes.
Ingibjörg J. Gu mundsdóttir, Ninian N. Lang, Nicholas A. Boon, Christopher A. Ludlam, David J. Webb, Keith A. Fox, David E. Newby
The purpose of this study was to determine the role of the endothelium in the vascular actions of protease-activated receptor type 1(PAR-1) activation in vivo in man.
Background
Thrombin is central to the pathophysiology of atherothrombosis. Its cellular actions are mediated via PAR-1. Protease-activated receptor type 1 activation causes arterial vasodilation, venoconstriction, platelet activation, and tissue-type plasminogen activator release in man.
Methods
Dorsal hand vein diameter was measured in 6 healthy volunteers before and after endothelial denudation. Forearm arterial blood flow, plasma fibrinolytic factors, and platelet activation were measured in 24 healthy volunteers during venous occlusion plethysmography. The effects of inhibition of prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor on PAR-1 responses were assessed during coadministration of aspirin, the “NO clamp” (L-NG-monomethyl arginine and sodium nitroprusside), and tetraethylammonium ion, respectively.
Results
Endothelial denudation did not affect PAR-1–evoked venoconstriction (SFLLRN; 0.05 to 15 nmol/min). Although aspirin had no effect, SFLLRN-induced vasodilation (5 to 50 nmol/min) was attenuated by the NO clamp (p < 0.0001) and tetraethylammonium ion (p < 0.05) and abolished by their combination (p < 0.01). The NO clamp augmented SFLLRN-induced tissue-type plasminogen activator and plasminogen activator inhibitor type 1 antigen (p < 0.0001) release, but tetraethylammonium ion and aspirin had no effect. SFLLRN-induced platelet activation was unaffected by NO or prostacyclin inhibition.
Conclusions
Acting via PAR-1, thrombin causes contrasting effects in the human vasculature and has a major interaction with the endothelium. This highlights the critical importance of endothelial function during acute arterial injury and intravascular thrombosis, as occurs in cardiovascular events including myocardial infarction and stroke.
Role of the Endothelium in the Vascular Effects of the Thrombin Receptor (Protease-Activated Receptor Type 1) in Humans
Thrombin is central to the pathophysiology of atherothrombosis and exerts its vascular effects via protease activated receptor type 1 (PAR-1). We report the contrasting role of the endothelium in PAR-1 activation in vivo in man, where it mediates arterial PAR-1–induced vasodilation and tissue plasminogen activator release but does not provide a major contribution to venous tone or plasminogen activator inhibitor type 1 release. Our findings provide evidence of a major interaction between the endothelium and thrombin in vivo. This highlights the critical importance of endothelial function during acute arterial injury and thrombosis, as occurs in acute coronary syndromes.
Ingibjörg J. Gu mundsdóttir, Ninian N. Lang, Nicholas A. Boon, Christopher A. Ludlam, David J. Webb, Keith A. Fox, David E. Newby
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