Anticoagulant and Anti-Inflammatory Effects of Recombinant Human Antithrombin in Man after LPS Challenge.

Background: Antithrombin (AT) had beneficial effects on mortality of septic patients in an a priori defined subpopulation of the Kypersept trial, which received no concomitant administration of heparin.

Objectives: We hypothesized that recombinant human (rh)AT (without concomitant heparin) has anticoagulant properties and may decrease cytokine production in a well standardized model of human endotoxemia.

Methods: This study was randomized, double-blind, placebo-controlled in parallel groups in 30 healthy male volunteers. The active treatment groups received bolus primed continuous infusion of rhAT (recombinant human Antithrombin) to increase AT-levels to 200% and 500% iv. before infusion of 2ng/kg endotoxin

Results: Infusion of rhAT rapidly decreased neutrophil (p<0.01) and monocyte counts (p<0.05) before LPS-challenge, demonstrating that rhAT directly interacts with these leukocyte subsets. rhAT exhibited intrinsic anticoagulant efficacy ex vivo as shown by thrombelastography ((p<0.01). More importantly, in vivo thrombin formation decreased in a dose dependent fashion as measured by prothrombin fragment (F1+2) and thrombin antithrombin complexes (TAT). rhAT significantly decreased interleukin-6 (IL-6) release by 40%.

Conclusion: rhAT exhibited intrinsic anticoagulant effects, which are stronger than the minor effects of drotrecogin alfa (rhAPC;