Introduction

Sepsis is a common and severe disease in the Intensive Care Unit (ICU), characterized by a dangerous condition and high mortality rate. Recent studies have found that the average 30-day mortality rate for septic shock is 34.7%, and the 90-day mortality rate is 38.5%. Furthermore, the average mortality rate increases by 1.8-3.3.3% for each additional point in the Sequential Organ Failure Assessment (SOFA) score1. The risk of death from sepsis increases with the severity of organ dysfunction, and its primary pathophysiological mechanism is the formation of microthrombi due to the interaction between dysregulated inflammatory responses and coagulation dysfunction, also known as sepsis-associated Disseminated Intravascular Coagulation (DIC)2. This type of DIC is less likely to result in hemorrhagic events3. Heparin, an anticoagulant that is readily available in clinical settings, is widely used for the treatment of DIC caused by various etiologies, thromboembolic diseases, and as an anticoagulant during certain invasive procedures. In vitro and animal studies have shown that heparin can reduce the cytotoxic effects of histones on cells, inhibit the binding of histones to platelets, thereby lessening the incidence of histone-induced thrombocytopenia, tissue damage, and multiple organ dysfunction, and consequently lower mortality rates4. The binding of heparin to the body’s cytokines or chemokines, acute-phase proteins, and complement may contribute to its anti-inflammatory effects. When heparin is used, levels of IL-6, IL-8, TNF-α, and C-reactive protein (CRP) decrease. Heparin can also inhibit the adhesion of leukocytes and neutrophils to the vascular endothelium by binding to P-selectin4,5. Theoretically, the use of heparin has positive implications for improving microcirculation in sepsis patients, maintaining organ function, and reducing mortality. Current studies suggest that the early intravenous administration of therapeutic doses of unfractionated heparin in patients diagnosed with septic shock may reduce mortality rates, especially in severe cases6,7. However, the results of these studies remain controversial. The 2021 Sepsis Treatment Guidelines (SSC) only recommend the use of low molecular weight heparin to prevent the formation of venous thrombosis8. In recent years, the early intravenous application of heparin in the treatment of septic patients has increasingly gained the attention of clinicians, but its effectiveness and safety are still debated. This study aims to determine the impact of continuous intravenous administration of unfractionated heparin on platelet count, DIC score, SOFA score, and mortality rate in septic patients through a randomized controlled trial, and to explore its clinical significance in improving the prognosis of septic patients. We hypothesize that continuous intravenous administration of heparin can significantly improve coagulation dysfunction and organ dysfunction in patients with sepsis/septic shock without increasing the risk of bleeding.

Materials and methods

Ethical statement

This study has been approved by the Institutional Review Board of the Affiliated Hospital of Hebei University, and informed consent to participate in this study has been obtained from the participants.The ethical approval number is HDFYLL-KY-2024-001.

Study subjects

Patients admitted to the Intensive Care Unit of the Affiliated Hospital of Hebei University with sepsis or septic shock between January 2017 and December 2023 were collected.

Inclusion criteria

1) Ages between 16 and 80 years old; 2) Suspected or confirmed microbial infection upon admission; 3) An acute increase of 2 or more points in the SOFA score due to infection.

Exclusion criteria

1) Patients with other types of shock (cardiogenic, hemorrhagic, obstructive); 2) Patients with acute coronary syndrome, myocardial infarction, deep vein thrombosis, or pulmonary embolism; 3) Patients who died or were discharged on their own within one week of enrollment; 4) Patients with acute fatal hemorrhage (cerebral hemorrhage, pulmonary hemorrhage, major gastrointestinal bleeding, and trauma-associated bleeding); 5) Patients who have had intracranial hemorrhage within the past 4 weeks; 6) Patients at risk of active bleeding in the gastrointestinal tract, thoracic cavity, abdominal cavity, and pelvic cavity, or within 24 hours of severe trauma; 7) Patients with a tendency to spontaneous bleeding due to primary coagulation dysfunction; 8) Patients allergic to heparin.

Groups

The selected patients were divided into the heparin treatment group and the control group based on whether they received continuous intravenous infusion of heparin.

Intervention measures

Both the control group and the heparin group received respiratory support, hemodynamic stabilization, anti-infective therapy, and symptomatic supportive treatment.

In addition to the above interventions, the control group was administered low-molecular-weight heparin sodium (5000 IU, once daily, subcutaneously). In contrast, the heparin group received unfractionated heparin via intravenous infusion instead of enoxaparin sodium, with an initial dosage of 5 U/kg/h.The heparin dosage was adjusted to maintain the activated partial thromboplastin time (APTT) at 1.0 to 1.5 times the normal value9,10. Treatment was discontinued after seven days.

Trial endpoint

The survival status of the patients on the 28th day after completing drug treatment and follow-up.

Observation indicators

Primary observation indicators: Platelet count, DIC score, and SOFA score on the 1 st, 2nd, 3rd, 4th, 5th, 6th, and 7th day of admission. 1.8.2 Secondary observation indicators: 28-day mortality rate and incidence of bleeding during the trial. 1.3.3 Bleeding risk assessment indicators: Symptoms of intracranial, respiratory system, gastrointestinal, skin, and mucosal bleeding in patients, or progressive decline in hemoglobin. 1.9.4 DIC Scoring: The standard for DIC scoring refers to the ISTH (International Society on Thrombosis and Haemostasis) criteria11.

Statistical methods

All data were analyzed using SPSS 26.0 statistical software. Measurement data are expressed as mean ± standard deviation. Continuous data were tested for normal distribution using the Shapiro-Wilk test. If the data were normally distributed, an independent sample t-test was used for comparison between groups; for non-normally distributed data, the median (Q1, Q3) was used, and the Mann-Whitney U test was applied for comparison between two groups. Count data were analyzed using the Chi-squared test. A P-value <0.05 was considered statistically significant.

Results

General patient data

A total of 98 patients with sepsis and septic shock were enrolled in the study, aged 16 to 80 years old. The control group consisted of 48 patients, while the heparin group included 50 patients. There were no statistical differences in gender, age, and BMI between the patients of the two groups (P>0.05) (Table 1).

Table 1 Comparison of general characteristics between the two groups of patients.
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Comparison of platelet count, DIC score, and SOFA score on the first day

On the first day of admission, there were no statistical differences in platelet count, DIC score, and SOFA score between the two groups (all P>0.05), indicating that the baseline data of the patients were comparable (Figure 1).

Fig. 1
figure 1

Comparison of platelet count, DIC score, and SOFA score between the two groups of patients on admission (Day 1).

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Platelet count in both groups

There was no statistical difference in platelet count between the two groups on the second day after enrollment. However, the platelet counts in the heparin group were significantly higher than those in the control group on the third, fourth, fifth, sixth, and seventh days after enrollment (p<0.05) (Table 2).

Table 2 Comparison of platelet count between the two groups of patients.
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DIC scores

There were no statistical differences in DIC scores between the two groups on the second and third days after enrollment. However, the DIC scores in the heparin group were significantly lower than those in the control group on the fourth, fifth, sixth, and seventh days of admission (p<0.05) (Table 3.).

Table 3 Comparison of DIC score between the two groups of patients.
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SOFA scores

There were no statistical differences in SOFA scores between the two groups on the second, third, and fourth days after enrollment. However, the SOFA scores in the heparin group were significantly lower than those in the control group on the fifth, sixth, and seventh days of admission (p<0.05) (Table 4.).

Table 4 Comparison of SOFA score between the two groups of patients.
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Mortality rate and bleeding risk

The 28-day mortality rate was 20% in the heparin group (10 out of 50 patients) compared to 35% in the control group (17 out of 48 patients), yielding an absolute difference of 15%. However, statistical analysis did not detect a significant difference (P = 0.088). No statistically significant difference in 28-day mortality risk was observed between the two groups (Table 5.).

Table 5 28-day mortality and 28-day bleeding risk in the two groups of patients.
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Discussion

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. During the pathophysiological process of sepsis, the interplay between the body’s immune response, coagulation system, tissue damage, inflammatory response, and anti-inflammatory response leads to the formation of microthrombi and multi-organ dysfunction12. In the process where hypercoagulability leads to microthrombi formation, a significant consumption of platelets occurs, clinically manifested as thrombocytopenia. The use of heparin to inhibit hypercoagulability may aid in the recovery of platelets. Our study found that after continuous intravenous infusion of heparin, the platelet count was significantly higher than that of the control group, which helps to improve the Disseminated Intravascular Coagulation (DIC) score and Sequential Organ Failure Assessment (SOFA) score of patients with sepsis without increasing the risk of bleeding. During sepsis, inflammatory responses and coagulation dysfunction promote each other, and most pro-inflammatory factors (such as tumor necrosis factor, interleukin-6, and interleukin-1) have been shown to activate the coagulation system, leading to DIC. Some procoagulant substances can not only promote coagulation but also induce the expression of inflammatory factors by binding to protease-activated receptors (PARs)13,14. Under physiological conditions, endothelial cells can maintain a relative homeostasis between endogenous coagulation and anticoagulation, while sepsis may reduce the production of physiological anticoagulants by endothelial cells (such as antithrombin III, activated protein C, protein S, thrombomodulin, and tissue factor pathway inhibitor), resulting in a hypercoagulable state15,16,17. This leads to the consumption of coagulation factors, which may indicate sepsis-associated DIC, and the severity of DIC is related to the severity of organ dysfunction18,19.

Heparin is a sulfated polysaccharide polymer (MW, 357 kDa) that occurs naturally in the human body and is produced by endothelial cells, basophils, and mast cells, with a potent anticoagulant effect and certain anti-inflammatory properties. Its anticoagulant mechanism mainly involves forming a heparin-antithrombin III complex, enhancing antithrombin’s inhibitory effect on coagulation factors (aIX, aX, XIa, XIIa) as well as thrombin. In addition to its role in coagulation, thrombin also mediates the production of inflammatory mediators20. Thus, heparin indirectly inhibits the generation of some inflammatory mediators by inhibiting thrombin. Moreover, heparin possesses anti-inflammatory effects independent of its anticoagulant properties, such as its binding to cytokines, chemokines, acute phase proteins, and complement components in the body, exerting a certain anti-inflammatory effect. Studies have shown that when heparin is used, levels of IL-6, IL-8, TNF-a, and CRP in the body decrease, and heparin can inhibit the adhesion of leukocytes and neutrophils to vascular endothelium by binding to P-selectin21,22. Some studies indicate that continuous intravenous administration of unfractionated heparin may improve tissue perfusion in patients with sepsis by reducing the activation of the coagulation system, thereby improving organ dysfunction and increasing survival rates7,23,24. The latest meta-analysis based on three randomized controlled trials found that these studies did not confirm that the use of heparin could improve the survival rate of patients with sepsis or sepsis-associated disseminated intravascular coagulation25.

Our study results show that, at the same time points, the platelet count in the heparin group was significantly higher than in the control group, and the DIC and SOFA scores were significantly lower. Intravenous administration of heparin helps improve organ dysfunction in patients with sepsis without increasing the risk of bleeding. The use of heparin can block the progression of sepsis-associated coagulation dysfunction and, to a certain extent, control the inflammatory response, which may be an active and effective treatment for improving organ function in patients with sepsis. Furthermore, heparin exhibits anti-inflammatory effects independent of its anticoagulant properties. However, concerns regarding bleeding risk limit its dosage, which may explain why heparin improved SOFA scores but failed to reduce mortality in both previous and current studies. Increasing the dosage of heparin—while avoiding bleeding complications or mitigating its potent anticoagulant effects—could potentially enhance its therapeutic efficacy in sepsis patients. Regarding mortality, the absolute reduction in the heparin group was 15% lower than that in the control group, though statistical significance was not reached, possibly due to the small sample size of this study. Nevertheless, the possibility of a clinically meaningful effect cannot be entirely ruled out. The condition of patients with sepsis is complex, the etiology is not singular, and the pathological process progresses rapidly. After a hypercoagulable state occurs, secondary hyperfibrinolysis sets in, entering a hypocoagulable phase, where the use of anticoagulant drugs may significantly increase the risk of bleeding in patients. There are no clear standards for the timing and dosage of heparin use. For patients with sepsis, how to standardize the use of heparin awaits further research. This study is a retrospective controlled study that selected sepsis patients from the same time period and the same ward based on Sepsis 3.0, divided into heparin and control groups. There were no significant statistical differences in the baseline levels of the observation indicators between the two groups, making them comparable, and the results are statistically significant, providing some reference for the clinical application of heparin in the treatment of sepsis. However, the study had a small sample size, and many non-research factors were uncontrollable. There may be differences in the underlying diseases and causes of infection between the two groups of patients, and the use of heparin could not be randomized. The indications for use and dosage also lacked clear standards, introducing certain biases. The therapeutic role of heparin in sepsis remains to be confirmed by more rigorous, larger-scale randomized controlled trials.

Conclusion

Continuous intravenous administration of heparin can significantly improve thrombocytopenia, DIC scores, and SOFA scores in patients with sepsis/septic shock. It plays a positive role in ameliorating coagulation dysfunction and organ dysfunction in these patients without increasing the risk of bleeding. However, the specific therapeutic effects of continuous intravenous heparin on patients with sepsis/toxic shock require further confirmation through larger sample sizes and more rigorous clinical studies.