Unfractionated Heparin Improves the Clinical Efficacy in Adult Sepsis Patients

A Systematic Review and Meta-analysis

Sifeng Fu; Sihan Yu; Liang Wang; Xiaochun Ma; Xu Li


BMC Anesthesiol. 2022;22(28) 

In This Article


Sepsis is defined as life-threatening organ dysfunction by a dysregulated host response to infection.[1] The pathophysiology of sepsis is complicated, involving both pro-inflammatory and anti-inflammatory pathways, as well as a whole array of immunological and non-immunological mechanisms,[2] such as the coagulation system and the neuroendocrine system.[3]

Many research studies focused on the possibility that anticoagulant therapy could improve the mortality of sepsis patients. However, there is a considerable controversy regarding the treatment of coagulopathy in sepsis. There is positive results in Yamakawa et al's group which meant anticoagulant therapy was associated with better outcome according to the deterioration of both DIC and disease severity for septic patients.[4] Whereas, there were negative results in Walkey et al's team that among patients with Atrial Fibrillation during sepsis, parenteral anticoagulation was not associated with reduced risk of ischemic stroke and was associated with higher bleeding rates.[5] There is no anticoagulant therapy has been proven effective, which is probably due to the importance of coagulation activation in host defense mechanisms during sepsis.[6] Thus, it's difficulty to choose the appropriate target, the right timing, and the adequate dose.

Heparin is a widely used anticoagulant which can prevent venous thromboembolism (VTE). In 2016, Surviving Sepsis Campaign (SSC) guideline first evaluated the use of heparin for the treatment of sepsis and septic shock.[7] The Japanese guideline for management of sepsis was against the use of heparin or heparin analogs as a standard treatment in sepsis-associated DIC.[8] The World Health Organization (WHO) recommended heparin use in critically ill patients with COVID-19 to prevent thromboembolism in 2020.[9] All of these indicated that anticoagulant therapy has attracted worldwide attention and is still controversial. The role of heparin in sepsis still needs to be verified by randomized controlled trials (RCTs).

Heparin contains UFH and low molecular weight heparin (LMWH). The mechanisms of action for UFH and LMWH are different in sepsis, so their effects are various. UFH mainly inhibits the activity of thrombin and factor (F) Xa by binding to antithrombin (AT). The inhibition of thrombin requires a heparin chain comprising of at least 18 saccharide units. Therefore, LMWH can only exert anticoagulant effect by inhibiting the action of FXa. Furthermore, recent research studies proved that UFH possesses various biological properties, such as anti-inflammatory and immunomodulatory effects.[10]

UFH seems to be more promising in the treatment of sepsis because of its multiple biological activities. Our previous studies have shown that UFH could protect endothelial cells, improve endothelial barrier dysfunction, and inhibit inflammatory response to preserve organ function and improve the prognosis of septic patients.[11,12] Therefore, RCTs were included in our study that researched the function of UFH in sepsis.. Although three meta-analysis have discussed the effect of heparin in sepsis, none of them highlighted the UFH application in clinical practice.[13–15] Therefore, this article aimed to assess the clinical efficacy of UFH in adult patients with sepsis, septic shock, or DIC.