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Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia
Author(s) -
Leitner Judith M.,
Firbas Christa,
Mayr Florian B.,
Reiter Rosemarie A.,
Steinlechner Barbara,
Jilma Bernd
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.10.003
Subject(s) - antithrombin , placebo , recombinant dna , thrombin , anticoagulant , medicine , lipopolysaccharide , pharmacology , heparin , immunology , endocrinology , chemistry , platelet , biochemistry , pathology , alternative medicine , gene
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 μg/L [95% CI, 8–16 μg/L] in the 500% antithrombin group and 34 μg/L [95% CI, 20–48 μg/L] in the placebo group at 4 hours), and D‐dimer (0.2 μg/L [95% CI, 0.1–0.2 μg/L] in the 500% antithrombin group and 0.5 μg/L [95% CI, 0.4–0.7 μg/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. Clinical Pharmacology & Therapeutics (2006) 79 , 23–34; doi: 10.1016/j.clpt.2005.10.003