Leitner Judith M, Firbas Christa, Mayr Florian B, Reiter Rosemarie A, Steinlechner Barbara, Jilma Bernd
Department of Clinical Pharmacology, Division of Immunohaematology, Medical University of Vienna, Austria.
Clin Pharmacol Ther. 2006 Jan;79(1):23-34. doi: 10.1016/j.clpt.2005.10.003.
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 microg/L [95% CI, 8-16 microg/L] in the 500% antithrombin group and 34 microg/L [95% CI, 20-48 microg/L] in the placebo group at 4 hours), and D-dimer (0.2 microg/L [95% CI, 0.1-0.2 microg/L] in the 500% antithrombin group and 0.5 microg/L [95% CI, 0.4-0.7 microg/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.
我们推测，输注重组人抗凝血酶而不同时使用肝素会具有剂量依赖性抗凝特性，并有可能减少内毒素（脂多糖[LPS]）诱导的细胞因子产生。这是一项随机、双盲、安慰剂对照的平行组研究，纳入了30名健康男性志愿者。活性治疗组在输注2 ng/kg内毒素（LPS）前接受重组人抗凝血酶输注，以使抗凝血酶水平分别提高至200%和500%。抗凝血酶的输注呈剂量依赖性地降低凝血功能（重复测量方差分析，P <.01）：凝血酶原片段的峰值水平（500%抗凝血酶组在4小时时为1.8 nmol/L[95%置信区间（CI），1.3 - 2.3 nmol/L]，安慰剂组为4.4 nmol/L[95% CI，2.7 - 6.2 nmol/L]）、凝血酶抗凝血酶复合物（500%抗凝血酶组在4小时时为12 μg/L[95% CI，8 - 16 μg/L]，安慰剂组为34 μg/L[95% CI，20 - 48 μg/L]）以及D - 二聚体（500%抗凝血酶组为0.2 μg/L[95% CI，0.1 - 0.2 μg/L]，安慰剂组为0.5 μg/L[95% CI，0.4 - 0.7 μg/L]）。重组人抗凝血酶使白细胞介素 - 6的峰值水平降低了40%（500%和200%抗凝血酶组分别为222 pg/mL[95% CI，148 - 295 pg/mL]和216 pg/mL[95% CI，112 - 320 pg/mL]，而安慰剂组为357 pg/mL[95% CI，241 - 474 pg/mL]；方差分析，P <.001）。最后，在LPS激发前，重组人抗凝血酶的输注迅速且短暂地降低了中性粒细胞计数（500%抗凝血酶组降低了19%[95% CI，8% - 30%]，安慰剂组降低了6%[95% CI，1% - 10%]，Kruskal - Wallis方差分析，P =.002）和单核细胞计数（500%抗凝血酶组降低了30%[95% CI，16% - 44%]，200%抗凝血酶组降低了18%[95% CI，9% - 28%]，安慰剂组降低了8%[95% CI，5% - 20%]，P =.04），表明重组人抗凝血酶与这些白细胞亚群直接相互作用。总之，重组人抗凝血酶呈剂量依赖性地抑制组织因子触发的凝血。对白细胞的影响以及对白细胞介素 - 6释放的抑制似乎代表了重组人抗凝血酶的特定药效学特性。
