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Continuous Antithrombin III Infusion in a Clinically Relevant Sepsis Model.

Naoki Hayase1, Rohit R Chari, Alef A C Dos Santos

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Shock (Augusta, Ga.)
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Summary
This summary is machine-generated.

Continuous antithrombin-III (AT) infusion after sepsis onset improved survival in mice. This delayed, continuous AT delivery outperformed bolus injections, suggesting a new therapeutic approach for sepsis.

Keywords:
Cecal ligation and puncturebacterial loadextravasationliver injury

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Area of Science:

  • Sepsis research
  • Pharmacological interventions
  • Animal models of disease

Background:

  • Antithrombin-III (AT) showed promise in preclinical sepsis models but failed in clinical trials.
  • Discrepancies in insult types and drug administration schedules may explain trial failures.
  • This study re-evaluated AT using a clinically relevant polymicrobial sepsis model (cecal ligation and puncture, CLP).

Purpose of the Study:

  • To investigate the efficacy of delayed, continuous antithrombin-III (AT) infusion in a clinically relevant polymicrobial sepsis model.
  • To compare continuous AT infusion with conventional bolus AT administration.
  • To explore the impact of AT on survival, organ injury, and inflammatory markers in sepsis.

Main Methods:

  • Mice underwent cecal ligation and puncture (CLP) surgery to induce polymicrobial sepsis.
  • Osmotic minipumps delivered either AT or saline continuously, starting approximately 6 hours after sepsis induction.
  • Survival rates and organ injury (liver, kidney, lung) were assessed at 7 days and 48 hours, respectively.

Main Results:

  • Delayed, continuous AT infusion significantly improved 7-day survival compared to saline (65% vs. 29%) and bolus AT (65% vs. 19%).
  • Continuous AT attenuated liver injury, vascular leakage, and inflammatory cytokines, correlating with high bacterial and thrombin accumulation in the liver.
  • Kidney and lung injury were not significantly affected by AT treatment.

Conclusions:

  • Delayed, continuous AT infusion enhances survival in a CLP sepsis model, outperforming bolus administration.
  • The liver appears critical in abdominal sepsis due to bacterial load and thrombin generation, where AT demonstrates protective effects.
  • AT's benefits may stem from mitigating thrombin-induced vascular leakage and inflammation in the liver; combination therapies may be needed for broader organ protection.