[The reason I keep posting about these sepsis studies is that antithrombin treatment for sepsis has had mixed results, and it still isn’t clear whether AT therapy offers a bona fide treatment benefit for sepsis. GTCB evidently thinks that it does, however, because sepsis is on the company’s short list of possible acquired-deficiency indications for partner LEO to take into the clinic next year.]
>> Int J Infect Dis. 2005 Nov 10; [Epub ahead of print]
Decreased protein C, protein S, and antithrombin levels are predictive of poor outcome in Gram-negative sepsis caused by Burkholderia pseudomallei.
Larosa SP, Opal SM, Utterback B, Yan SC, Helterbrand J, Simpson AJ, Chaowagul W, White NJ, Fisher CJ Jr.
Division of Infectious Disease, Rhode Island Hospital, Gerry House 113, 593 Eddy Street, Providence, Rhode Island 02903, USA.
BACKGROUND: Acute septicemic melioidosis is associated with systemic release of endotoxin and the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin-1, and interleukin-6. Excessive release of these cytokines may lead to endothelial injury, depletion of naturally occurring endothelial modulators, microvascular thrombosis, organ failure, and death.
METHOD: Plasma samples drawn at baseline and after initial antimicrobial therapy in 30 patients with suspected acute severe melioidosis were assayed for D-dimer levels, protein C and protein S antigen levels, and antithrombin functional activities.
RESULTS: Both baseline and continued deficiencies of protein C, protein S, and antithrombin were statistically associated with a poor outcome by logistic regression. Baseline D-dimer levels were significantly higher in fatal cases than survivors and correlated inversely with protein C and antithrombin, suggesting both increased fibrin deposition and fibrinolysis.
CONCLUSION: The inflammatory response to systemic Burkholderia pseudomallei infection leads to depletion of the natural endothelial modulators protein C, protein S, and antithrombin. Both baseline and continued deficiency of these endothelial modulators is predictive of poor outcome in melioidosis. <<
Department of Clinical Pharmacology, Division of Immunohaematology, Medical University of Vienna, Austria; Department of Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Austria.
We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])-induced cytokine production. This was a randomized, double-blind, placebo-controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to 200% and 500% before infusion of 2 ng/kg endotoxin (LPS).
Infusion of antithrombin dose-dependently decreased coagulation (P < .01 by repeated-measures ANOVA): peak levels of prothrombin fragment (1.8 nmol/L [95% confidence interval (CI), 1.3-2.3 nmol/L] in the 500% antithrombin group and 4.4 nmol/L [95% CI, 2.7-6.2 nmol/L] in the placebo group at 4 hours), thrombin antithrombin complexes (12 mug/L [95% CI, 8-16 mug/L] in the 500% antithrombin group and 34 mug/L [95% CI, 20-48 mug/L] in the placebo group at 4 hours), and D-dimer (0.2 mug/L [95% CI, 0.1-0.2 mug/L] in the 500% antithrombin group and 0.5 mug/L [95% CI, 0.4-0.7 mug/L] in the placebo group). Recombinant human antithrombin decreased peak interleukin-6 levels by 40% (222 pg/mL [95% CI, 148-295 pg/mL] and 216 pg/mL [95% CI, 112-320 pg/mL] in the 500% and 200% antithrombin groups, respectively, versus 357 pg/mL [95% CI, 241-474 pg/mL] in the placebo group; P < .001 by ANOVA). Finally, infusion of recombinant human antithrombin rapidly and transiently decreased neutrophil counts (by 19% [95% CI, 8%-30%] in the 500% antithrombin group versus 6% [95% CI, 1%-10%] in the placebo group, P = .002 by Kruskal-Wallis ANOVA) and monocyte counts (by 30% [95% CI, 16%-44%] in the 500% antithrombin group and 18% [95% CI, 9%-28%] in the 200% antithrombin group versus 8% [95% CI, 5%-20%] in the placebo group, P = .04) before LPS challenge, indicating that recombinant human antithrombin directly interacts with these leukocyte subsets.
In summary, recombinant human antithrombin dose-dependently inhibited tissue factor-triggered coagulation. Effects on leukocytes and inhibition of interleukin-6 release seem to represent specific pharmacodynamic properties of recombinant human antithrombin. <<
News 
Market Data 
Discover 
AI
