Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy

Abstract

Background and aim: Sepsis is a syndromic response to infection and is associated with high mortality, thus imposing a significant global burden of disease. Although low-molecular-weight heparin (LMWH) has been recommended to prevent venous thromboembolism, its anticoagulant and anti-inflammatory effects in sepsis remain controversial. Owing to the modification of the Sepsis-3 definition and diagnostic criteria, further evaluation of the efficacy and benefit population of LMWH is required.

Methods: We performed a retrospective cohort study to assess whether LMWH improved the inflammation, coagulopathy, and clinical outcomes against Sepsis-3 and to identify the target patients. All patients diagnosed with sepsis at the First Affiliated Hospital of Xi'an Jiaotong University (the largest general hospital in northwest China) from January 2016 to December 2020 were recruited and re-evaluated using Sepsis-3 criteria.

Results: After 1:1 propensity score matching, 88 pairs of patients were categorized into the treatment and control groups based on subcutaneous LMWH administration. Compared with the control group, a significantly lower 28-day mortality was observed in the LMWH group (26.1 vs. 42.0%, p = 0.026) with a comparable incidence of major bleeding events (6.8 vs. 8.0%, p = 0.773). Cox regression analysis showed that LMWH administration was the independent protective factor for septic patients (aHR, 0.48; 95% CI, 0.29-0.81; p = 0.006). Correspondingly, the LMWH treatment group showed a significant improvement in inflammation and coagulopathy. Further subgroup analysis showed that LMWH therapy was associated with favorable outcomes in patients younger than 60 years and diagnosed with sepsis-induced coagulopathy (SIC), ISTH overt DIC, non-septic shock, or non-diabetics and in patients included in the moderate-risk group (APACHE II score 20-35 or SOFA score 8-12).

Conclusion: Our study results showed that LMWH improves 28-day mortality by improving inflammatory response and coagulopathy in patients meeting Sepsis-3 criteria. The SIC and ISTH overt DIC scoring systems can better identify septic patients who are likely to benefit more from LMWH administration.

Keywords: disseminated intravascular coagulation; low-molecular-weight heparin; mortality; propensity score; sepsis.

Figure 1

Flow diagram of the population included in the study.

Figure 2

Kaplan–Meier estimates of 28-day cumulative survival probabilities of septic patients in the treatment group and the control group. Treatment with LMWH was associated with a significantly higher rate of survival (Log-rank p = 0.0046 by Cox regression analysis).

Figure 3

Dynamic changes in inflammation and coagulation indicators including CRP (A), PLT (B), NLR (C), PDW (D), SII (E), and INR (F) in the treatment group and the control group in patients with sepsis. The p-values were calculated by comparing the changes from days 0 to 14 between the two groups. CRP, C-reactive protein; PLT, platelet; NLR, neutrophil-to-lymphocyte ratio; PDW, red blood cell distribution width; SII, systemic immune-inflammation index; INR, international normalized ratio.

Figure 4

The association between LMWH administration and 28-day mortality in the overall population and subgroups.