The role of heparin and allied compounds in the treatment of sepsis

Cornet, Alexander D.; Smit, Ellen G. M.; Beishuizen, Albertus; Groeneveld, A. B. Johan

doi:10.1160/th07-01-0006

Cited by 71 publications

(69 citation statements)

References 124 publications

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“…However, the clinical trials performed discovered no evidence suggesting the effectiveness of recombinant APC for treating patients with severe sepsis or septic shock, and these trials have recently been discontinued (14). Comparatively, a number of in vitro and in vivo studies have suggested a potentially life-saving effect of heparin in the treatment of sepsis due to its beneficial anti-inflammatory actions (15)(16)(17)(18). Additionally, treatment with unfractionated heparin (UFH) can also attenuate coagulation in endotoxemic mice (19).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…The anticoagulant functions of heparin are diverse and include stimulation of the inhibition of various coagulation factors (thrombin, FIXa, FXa, FXIa, and FXIIa) by antithrombin as well as inhibition of platelet functions (14 -17). Apart from its anticoagulant functions, heparin also has anti-inflammatory properties as it modulates the production and release of proinflammatory factors (18).…”

mentioning

confidence: 99%

Identification of Surface Epitopes of Human Coagulation Factor Va That Are Important for Interaction with Activated Protein C and Heparin

Segers

Dahlbäck

Rosing

et al. 2008

Journal of Biological Chemistry

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Inactivation of factor Va (FVa) by activated protein C (APC) is a key reaction in the downThe protein C pathway provides a major anticoagulant mechanism for the regulation of hemostasis by nullification of the procoagulant activities of FVIIIa and FVa, the cofactors in the tenase and prothrombinase complexes, respectively. Protein C is a vitamin K-dependent protein composed of a heavy chain and a light chain that are connected through a single disulfide bridge (1). The light chain is composed of an N-terminal ␥-carboxyglutamic acid-rich domain and two epidermal growth factor-like domains. The heavy chain contains a short (12 amino acid) signal peptide and the serine protease (peptidase) domain.Previously, we and others have demonstrated that three surface loops (37, 70, and 148, chymotrypsin numbering) in the serine protease domain of APC 2 form an extended FVabinding site (2-4). Furthermore, a cluster of basic residues located on loops 37, 60, and 70 form a positively charged exosite on the surface of APC important for its interaction with thrombomodulin, protein C inhibitor, ␣1-antitrypsin, and heparin (2, 5-7).APC is able to cleave FVa, the nonenzymatic cofactor of FXa in the prothrombinase complex, at least at five peptide bonds, of which those at Arg 306 and Arg 506 are considered most important for the inactivation of FVa (8 -10). FVa is a multidomain protein that consists of a 71/74-kDa light chain (A3, C1, and C2 domains) and a 105-kDa heavy chain (A1 and A2 domains) that are noncovalently associated. All APC cleavage sites are located in the FVa heavy chain (8). In the presence of negatively charged phospholipids, the cleavages at Arg 506 and Arg 306 are primarily responsible for inactivation of FVa (11). Cleavage of Arg 506 is kinetically favored over the Arg 306 cleavage (up to 20-fold rate difference) and results in an FVa inactivation intermediate with partial cofactor activity, whereas cleavage at Arg 306 fully inactivates FVa (11,12). In the presence of its cofactor protein S, however, APC cleaves the Arg 306 peptide bond with a rate that is approximately similar to that of cleavage at Arg 506 (13). Heparin is a naturally occurring sulfated glycosaminoglycan that can be found in several organs and tissues of the human body, notably on the surface of endothelial cells that form the inner lining of our vasculature. Unfractionated heparin (UFH) and low molecular weight heparin are widely used as effective pharmacotherapeutics for the prevention and treatment of thrombosis. The anticoagulant functions of heparin are diverse and include stimulation of the inhibition of various coagulation factors (thrombin, FIXa, FXa, FXIa, and FXIIa) by antithrombin as well as inhibition of platelet functions (14 -17). Apart from its anticoagulant functions, heparin also has anti-inflammatory properties as it modulates the production and release of proinflammatory factors (18).* This work was supported by VIDI Grant 916-046-330 from the Dutch Organization for Scientific Research (to G. A. F. N.). The costs of publica...

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“…These agents include heparin and polyanethole sulfonate, which both neutralize these polymers' strong cationic properties, their toxicity to cells and also their ability to activate the complement cascade. However, heparin might also function mainly by abolishing the synergy between histone and additional pro-inflammatory agonists [32, 75,76]. A critical issue still to be clarified is how early after sepsis is suspected and diagnosed, should heparin be administered?…”

Section: "Miracle Histones": Is It a Breakthrough In Sepsis Research?mentioning

confidence: 99%

Synergistic Aspects to Explain the Pathophysiology of Sepsis and Septic Shock-An Opinion

Koren¹,

Ginsburg²

2015

J Infect Dis Ther

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The role of heparin and allied compounds in the treatment of sepsis

Cited by 71 publications

References 124 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

Identification of Surface Epitopes of Human Coagulation Factor Va That Are Important for Interaction with Activated Protein C and Heparin

Synergistic Aspects to Explain the Pathophysiology of Sepsis and Septic Shock-An Opinion

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