Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection

Summary

Sepsis is the leading cause of death in intensive care units and a major public health concern in the world. Heparin, a widely used anticoagulant medicine to prevent or treat thrombotic disorders, has been demonstrated to prevent organ damage and lethality in experimental sepsis models. However, the efficacy of heparin in the treatment of clinical sepsis is not consistent. Caspase-11, a cytosolic receptor of LPS, triggers lethal immune responses in sepsis. Recently, we have revealed that heparin prevents cytosolic delivery of LPS and caspase-11 activation in sepsis through inhibiting the heparanase-mediated glycocalyx degradation and the HMGB1- LPS interaction, which is independent of its anticoagulant properties. In our study, it is found that heparin treatment could prevent lethal responses in endotoxemia or Gram-negative sepsis, while caspase-11 deficiency or heparin treatment failed to confer protection against sepsis caused by Staphylococcus aureus, a type of Gram-positive bacterium. It is probably that other pathogens such as Gram-positive bacteria might cause death through mechanisms distinct from that of Gram-negative bacteria. Peptidoglycan, a cell-wall component of Gram-positive bacteria, can cause DIC and impair survival in primates by activating both extrinsic and intrinsic coagulation pathways, which might not be targeted by heparin. We speculate that the discrepancy between the previous clinical trials of heparin might be due to the difference in infected pathogens. Thus, stratification of patients based on the type of invading pathogens might improve the therapeutic efficiency of heparin in sepsis, and this merits future investigations.

Conditions

• Sepsis
• Gram-Negative Bacterial Infections
• Heparin

Interventions

DRUG

Unfractionated Heparin

10 unit/kgBW/hour continuous infusion for 5 days

Sponsors & Collaborators

• Xiangya Hospital of Central South University

  collaborator OTHER

• Central South University

  collaborator OTHER

• The Second Hospital University of South China

  collaborator OTHER

• Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

  collaborator OTHER

• The Affiliated Yantai Yuhuangding Hospital of Qingdao University

  collaborator UNKNOWN

• The Third Xiangya Hospital of Central South University

  lead OTHER

Principal Investigators

• Hong Yuan, MD · The third Xiangya Hospital, Central South University

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-05-11

Primary Completion

2023-12-30

Completion

2024-07-30

Countries

• China

Study Locations