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For: Huang Y, Kong C. Low-molecular-weight heparin alleviates sepsis-induced renal inflammatory response and improves kidney function. Minerva Med 2019;111:292-295. [PMID: 31282138 DOI: 10.23736/s0026-4806.19.06188-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]

For:	Huang Y, Kong C. Low-molecular-weight heparin alleviates sepsis-induced renal inflammatory response and improves kidney function. Minerva Med 2019;111:292-295. [PMID: 31282138 DOI: 10.23736/s0026-4806.19.06188-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]

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Cited by Other Article(s)

Fang S, Wang Y, Nan W, Feng Y, Su W, Wang Y, Jiang X. Unfractionated heparin may improve near-term survival in patients admitted to the ICU with sepsis attributed to pneumonia: an observational study using the MIMIC-IV database. Front Pharmacol 2025;16:1518716. [PMID: 40083381 PMCID: PMC11903409 DOI: 10.3389/fphar.2025.1518716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/11/2025] [Indexed: 03/16/2025] Open

Abstract

Introduction

Limited data are available on the use, duration, and dosage of anticoagulant therapy in patients with pneumonia-induced sepsis, and the survival benefits of heparin remain uncertain. This study aimed to assess whether heparin administration improves near-term survival in critically ill patients with pneumonia-induced sepsis and identify the optimal dosage and treatment duration.

Methods

This study utilized the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The variance inflation factor was employed to exclude highly collinear variables. Propensity score matching (PSM), the Cox proportional hazards model, and Cox regression subgroup analysis were used to evaluate the outcomes of subcutaneous heparin prophylactic anticoagulation after intensive care unit (ICU) admission. The primary outcomes were 30-, 45-, and 60-d mortality rates. Secondary outcomes included ICU length of stay (LOS_ICU), hospital length of stay (LOS_Hospital), in-hospital mortality, and the incidence of gastrointestinal bleeding.

Results

We enrolled 1,586 adult patients with pneumonia-induced sepsis. After PSM, 1,176 patients remained (588 in the heparin group and 588 in the non-heparin group). The 45-d survival rate was significantly higher in the heparin-treated group than that in the non-heparin group (84.4% vs. 79.4%; HR: 0.75; 95% CI: 0.572-0.83; adjusted HR: 0.73, 95% CI: 0.563-0.964; P < 0.05). LOS_ICU and LOS_Hospital were significantly shorter in the heparin group (P < 0.001), with no significant difference in gastrointestinal bleeding incidence between the two groups. Cox proportional hazards models demonstrated that heparin dose and duration were strongly associated with 45-d survival. Subgroup analysis indicated a significant survival advantage in patients aged 18-60 years, without diabetes, chronic obstructive pulmonary disease, or stage 1 acute kidney injury, who received a daily heparin dose of 3 mL for more than 7 d.

Conclusion

Our study found that early administration of heparin, particularly in sufficient doses (Heparin Sodium 5,000 units/mL, 1 mL per dose, three times daily (TID)) for more than 7 d, was associated with reduced near-term mortality in critically ill patients with pneumonia-induced sepsis. These findings underscore the potential benefits of anticoagulant therapy in this high-risk patient population.

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Chen TT, Lv JJ, Chen L, Li M, Liu LP. Heparanase inhibition leads to improvement in patients with acute gastrointestinal injuries induced by sepsis. World J Gastroenterol 2023;29:5154-5165. [PMID: 37744293 PMCID: PMC10514756 DOI: 10.3748/wjg.v29.i35.5154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/23/2023] [Accepted: 09/05/2023] [Indexed: 09/14/2023] Open

Abstract

BACKGROUND

Patients with sepsis are at high risk for acute gastrointestinal injury (AGI), but the diagnosis and treatment of AGI due to sepsis are unsatisfactory. Heparanase (HPA) plays an important role in septic AGI (S-AGI), but its specific mechanism is not completely understood, and few clinical reports are available.

AIM

To explore the effect and mechanism of HPA inhibition in S-AGI patients.

METHODS

In our prospective clinical trial, 48 patients with S-AGI were randomly assigned to a control group to receive conventional treatment, whereas 47 patients were randomly assigned to an intervention group to receive conventional treatment combined with low molecular weight heparin. AGI grade, sequential organ failure assessment score, acute physiology and chronic health evaluation II score, D-dimer, activated partial thromboplastin time (APTT), anti-Xa factor, interleukin-6, tumour necrosis factor-α, HPA, syndecan-1 (SDC-1), LC3B (autophagy marker), intestinal fatty acid binding protein, D-lactate, motilin, gastrin, CD4/CD8, length of intensive care unit (ICU) stay, length of hospital stay and 28-d survival on the 1st, 3rd and 7th d after treatment were compared. Correlations between HPA and AGI grading as well as LC3B were compared. Receiver operator characteristic (ROC) curves were generated to evaluate the diagnostic value of HPA, intestinal fatty acid binding protein and D-lactate in S-AGI.

RESULTS

Serum HPA and SCD-1 levels were significantly reduced in the intervention group compared with the control group (P < 0.05). In addition, intestinal fatty acid-binding protein, D-lactate, AGI grade, motilin, and gastrin levels and sequential organ failure assessment score were significantly decreased (P < 0.05) in the intervention group. However, LC3B, APTT, anti-Xa factor, and CD4/CD8 were significantly increased (P < 0.05) in the intervention group. No significant differences in interleukin-6, tumour necrosis factor-α, d-dimer, acute physiology and chronic health evaluation II score, length of ICU stay, length of hospital stay, or 28-d survival were noted between the two groups (P > 0.05). Correlation analysis revealed a significant negative correlation between HPA and LC3B and a significant positive correlation between HPA and AGI grade. ROC curve analysis showed that HPA had higher specificity and sensitivity in diagnosis of S-AGI.

CONCLUSION

HPA has great potential as a diagnostic marker for S-AGI. Inhibition of HPA activity reduces SDC-1 shedding and alleviates S-AGI symptoms. The inhibitory effect of HPA in gastrointestinal protection may be achieved by enhanced autophagy.

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Zou ZY, Huang JJ, Luan YY, Yang ZJ, Zhou ZP, Zhang JJ, Yao YM, Wu M. Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database. BURNS & TRAUMA 2022;10:tkac029. [PMID: 36168402 PMCID: PMC9501718 DOI: 10.1093/burnst/tkac029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/14/2022] [Indexed: 02/05/2023]

Abstract

Background

Minimal data exist on anticoagulation use and timing and the dose of heparin in patients with sepsis, and whether heparin use improves sepsis survival remains largely unclear. This study was performed to assess whether heparin administration would provide a survival advantage in critically ill patients with sepsis.

Methods

A retrospective cohort study of patients with sepsis in the Medical Information Mart for Intensive Care (MIMIC)-IV database was conducted. Cox proportional hazards model and propensity score matching (PSM) were used to evaluate the outcomes of prophylactic anticoagulation with heparin administered by subcutaneous injection within 48 h of intensive care unit (ICU) admission. The primary outcome was in-hospital mortality. Secondary outcomes included 60-day mortality, length of ICU stay, length of hospital stay and incidence of acute kidney injury (AKI) on day 7. E-Value analysis were used for unmeasured confounding.

Results

A total of 6646 adult septic patients were included and divided into an early prophylactic heparin group (n = 3211) and a nonheparin group (n = 3435). In-hospital mortality in the heparin therapy group was significantly lower than that in the nonheparin group (prematched 14.7 vs 20.0%, hazard ratio (HR) 0.77, 95% confidence interval (CI) [0.68-0.87], p < 0.001, and postmatched 14.9 vs 18.3%, HR 0.78, 95% CI [0.68-0.89], p < 0.001). Secondary endpoints, including 60-day mortality and length of ICU stay, differed between the heparin and nonheparin groups (p < 0.01). Early prophylactic heparin administration was associated with in-hospital mortality among septic patients in different adjusted covariates (HR 0.71-0.78, p < 0.001), and only administration of five doses of heparin was associated with decreased in-hospital mortality after PSM (HR 0.70, 95% CI 0.56-0.87, p < 0.001). Subgroup analysis showed that heparin use was significantly associated with reduced in-hospital mortality in patients with sepsis-induced coagulopathy, septic shock, sequential organ failure assessment score ≥ 10, AKI, mechanical ventilation, gram-positive bacterial infection and gram-negative bacterial infection, with HRs of 0.74, 0.70, 0.58, 0.74, 0.73, 0.64 and 0.72, respectively (p <0.001). E-Value analysis suggested robustness to unmeasured confounding.

Conclusions

This study found an association between early administration prophylactic heparin provided to patients with sepsis and reduced risk-adjusted mortality. A prospective randomized-controlled study should be designed to further assess the relevant findings.

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Affiliation(s)

Zhi-ye Zou Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
Jia-jia Huang Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China Postgraduate Education, Shantou University Medical College, Shantou 515041, China
Ying-yi Luan Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
Zhen-jia Yang Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China Postgraduate Education, Shantou University Medical College, Shantou 515041, China
Zhi-peng Zhou Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
Jing-jing Zhang Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China Postgraduate Education, Shantou University Medical College, Shantou 515041, China
Yong-ming Yao Trauma Research Center, Medical Innovation Research Department and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, China
Ming Wu Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China Postgraduate Education, Shantou University Medical College, Shantou 515041, China Guangxi University of Chinese Medicine, Nanning 530200, China

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Wang Z, Wang L, Cao C, Jin H, Zhang Y, Liu Y, Gao Y, Liang X, Li G, Shou S. Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury. Front Med (Lausanne) 2020;7:586652. [PMID: 33344474 PMCID: PMC7738632 DOI: 10.3389/fmed.2020.586652] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/07/2020] [Indexed: 12/11/2022] Open

Abstract

Histones are considered potential risk factors that contribute to the development of septic acute kidney injury (SAKI) by inducing apoptosis and inflammation. This study aimed to explore the protective effects of heparin on septic acute kidney injury through the neutralization of extracellular histones (EH) and to uncover the underlying mechanism. C57BL mice (16 each) were randomly divided into the sham group, the sepsis group (established by cecal ligation and puncture operation, CLP), and the heparin intervention group. Mice in the heparin intervention group received a subcutaneous injection of unfractionated heparin (0.03 IU/g) 4 h after CLP. At 6 h after the operation, nine mice from each group were sacrificed by the removal of the eyeballs to harvest blood samples; the upper half of the right kidney was used as the study sample. Mice renal tubular epithelial cells cultivated in six-well plates were equally divided into five groups. We cultured cells treated with either histone (40 U), histone (40 U) + heparin (25 IU/ml), histone(40U) + lipopolysaccharides (LPS; 10 μg/ml), or histone (40 U) + LPS (10 μg/ml) + heparin (25 IU/ml) for 6 h. For the histone + heparin group and the histone + LPS + heparin group, histone (and LPS) were treated with heparin simultaneously. Mice in the heparin intervention group showed decreased levels of EH4, neutrophil gelatinase-associated lipocalin (NAGL), kidney injury molecule-1 (KIM-1), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 in the blood serum, longer average 72-h survival rate, significantly decreased kidney tissue edema, and a clearer glomerular structure coupled with decreased protein and mRNA expression levels of kidney apoptosis-related proteins (cleaved Caspase-3/Caspase-3 and Bax/Bcl-2) compared with those in the sepsis group at 6 h after CLP (P < 0.05). Meanwhile, cells in the heparin intervention group exhibited lower expression levels of serum EH4 and inflammatory cytokines, a lower apoptosis rate, and decreased expression of apoptosis-related proteins, both at protein and mRNA levels, than those in the histone-stimulated group at 6 h after stimulation (P < 0.05). Heparin may alleviate apoptosis and inflammation through the neutralization of histones, thus playing a protective role against septic acute kidney injury.

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