Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis

Wang, Changsong; Chi, Chao; Guo, Lei; Wang, Xiaoyang; Guo, Liang; Sun, Jiaxiao; Sun, Bo; Liu, Shanshan; Chang, Xuenan; Li, Enyou

doi:10.1186/s13054-014-0563-4

Cited by 79 publications

(82 citation statements)

References 33 publications

(69 reference statements)

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“…The mechanisms of action of these protective effects may involve direct inhibition of sheddases and the maintenance of endothelial EPCR and TM expression. The preliminary clinical data suggest that heparin is associated with reduced mortality in patients with sepsis (37,38). The results of the present study support the potential therapeutic value of UFH as a treatment for sepsis; however, its efficacy and safety should be evaluated in future clinical trials.…”

Section: Discussionmentioning

confidence: 60%

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

et al. 2017

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Abstract. Activation of protein C is greatly enhanced by the presence of thrombomodulin (TM) and endothelial protein C receptor (EPCR) on the endothelial surface. Impairment of the anticoagulant protein C system occurs during endotoxemia and contributes to sepsis-associated hypercoagulability. Previous studies have demonstrated that unfractionated heparin (UFH) can attenuate coagulation in endotoxemic mice. However, whether UFH has an effect on the protein C system remains to be elucidated. The current study evaluated the therapeutic effect of UFH on the protein C system in a mouse model of lipopolysaccharide (LPS)-induced sepsis, and further investigated the effect of UFH on the expression of TM and EPCR in vitro using human umbilical vein endothelial cells (HUVECs). The in vivo data indicated that UFH preconditioning attenuated the decline in circulating activated protein C following LPS administration, and also reduced LPS-induced shedding of TM and EPCR. In HUVECs, LPS stimulation led to the downregulation of TM and EPCR expression, and UFH dose-dependently restored the mRNA and protein levels of TM and EPCR. In addition, UFH inhibited the LPS-induced activation of mitogen-activated protein kinase 14, proto-oncogene tyrosine-protein kinase Src and nuclear factor κB signaling in HUVECs. In summary, these results suggest that UFH has a protective effect on the protein C system during sepsis. Thus, UFH may be a candidate therapeutic agent for the treatment of patients with sepsis.

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Section: Discussionmentioning

confidence: 60%

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

et al. 2017

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“…Four systematic reviews and meta‐analyses have been published to date regarding the use of heparin as a potential treatment for septic patients (Liu et al , ; Wang et al , ; Zarychanski et al , ; Fan et al , ). A remarkable result in all these four systematic reviews was that treatment with low doses of heparin was associated with significantly reduced 28‐day mortality in sepsis.…”

Section: Clinical Trialsmentioning

confidence: 99%

“…A remarkable result in all these four systematic reviews was that treatment with low doses of heparin was associated with significantly reduced 28‐day mortality in sepsis. In the study by Wang et al (), 40% of the study group patients used UFH exclusively, the rest used either UFH or LMWH. Among the study group patients analysed by Zarychanski et al (), 151 of the 1325 patients used UFH exclusively (11%), the rest used LMWH, both UFH and LMWH or the combination of either UFH or LMWH with activated protein C (APC).…”

Section: Clinical Trialsmentioning

confidence: 99%

The role of heparin in sepsis: much more than just an anticoagulant

2017

Br J Haematol

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Despite progress in antibiotic treatment, mechanical ventilation, fluid resuscitation and blood glucose maintenance, sepsis remains a cause of high mortality in the intensive care unit to date, there are no proven treatment strategies for the routine management of septic patients. The extensive interaction between inflammation and coagulation contributes to the basic pathophysiology of sepsis. Thus, the agents that attenuate the activation of both inflammation and coagulation may improve the outcome in sepsis. Apart from the well-known anticoagulant effects of heparin, it also possesses various immunomodulatory properties and protects glycocalyx from shedding. Hence, heparin seems to be such an agent. Immunothrombosis plays an important role in early host defence against bacterial dissemination, thus the proper timing for anticoagulant therapy should be determined. We review the available experimental and clinical data supporting the use of heparin in sepsis. At this time the use of heparin in the treatment of sepsis is conflicting. Future trials of heparin therapy for sepsis should concentrate on the very severely ill patients, in whom benefit is most likely to be demonstrated.

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“…However, in a meta-analysis study, it was shown that heparin may reduce 28-day mortality in patients with severe sepsis, whereas there was no increase in the risk of bleeding in the heparin group. 81 …”

Section: Heparinmentioning

confidence: 97%

Coagulation abnormalities in sepsis

Tsao

2015

Acta Anaesthesiologica Taiwanica

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Although the pathophysiology of sepsis has been elucidated with the passage of time, sepsis may be regarded as an uncontrolled inflammatory and procoagulant response to infection. The hemostatic changes in sepsis range from subclinical activation of blood coagulation to acute disseminated intravascular coagulation (DIC). DIC is characterized by widespread microvascular thrombosis, which contributes to multiple organ dysfunction/failure, and subsequent consumption of platelets and coagulation factors, eventually causing bleeding manifestations. The diagnosis of DIC can be made using routinely available laboratory tests, scoring algorithms, and thromboelastography. In this cascade of events, the inhibition of coagulation activation and platelet function is conjectured as a useful tool for attenuating inflammatory response and improving outcomes in sepsis. A number of clinical trials of anticoagulants were performed, but none of them have been recognized as a standard therapy because recombinant activated protein C was withdrawn from the market owing to its insufficient efficacy in a randomized controlled trial. However, these subgroup analyses of activated protein C, antithrombin, and thrombomodulin trials show that overt coagulation activation is strongly associated with the best therapeutic effect of the inhibitor. In addition, antiplatelet drugs, including acetylsalicylic acid, P2Y12 inhibitors, and glycoprotein IIb/IIIa antagonists, may reduce organ failure and mortality in the experimental model of sepsis without a concomitant increased bleeding risk, which should be supported by solid clinical data. For a state-of-the-art treatment of sepsis, the efficacy of anticoagulant and antiplatelet agents needs to be proved in further large-scale prospective, interventional, randomized validation trials.

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Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis

Cited by 79 publications

References 33 publications

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

The role of heparin in sepsis: much more than just an anticoagulant

Coagulation abnormalities in sepsis

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