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Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology.

Vincent JL - Crit Care (2001)

Bottom Line: Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death.The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin.Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Intensive Care, Erasme University Hospital, Free University of Brussels, Belgium. jlvincen@ulb.ac.be

ABSTRACT
Severe sepsis, defined as sepsis associated with acute organ dysfunction, results from a generalized inflammatory and procoagulant host response to infection. Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death. The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin. In recent years, it has been recognized that chemicals produced by endothelial cells play a key role in the pathogenesis of sepsis. Thrombomodulin on endothelial cells coverts Protein C to Activated Protein C, which has important antithrombotic, profibrinolytic and anti-inflammatory properties. A number of studies have shown that Protein C levels are reduced in patients with severe infection, or even in inflammatory states without infection. Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.

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Related in: MedlinePlus

Procoagulant and anticoagulant substances that are expressed/released by endothelial cells. AT, antithrombin; NO, nitric oxide; PGI2, prostacyclin; TFPI, TF pathway inhibitor.
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Figure 3: Procoagulant and anticoagulant substances that are expressed/released by endothelial cells. AT, antithrombin; NO, nitric oxide; PGI2, prostacyclin; TFPI, TF pathway inhibitor.

Mentions: In recent years, it has been recognized that endothelial cells play a key role in the pathogenesis of sepsis, and that they produce important regulators of both coagulation and inflammation. They can express or release a number of substances, such as TF, endothelin-1 and PAI-1, which promote the coagulation process, as well as other substances, such as antithrombin, thrombomodulin, nitric oxide and prostacyclin, which inhibit it (Fig. 3). Thrombomodulin is to anticoagulation what TF is to coagulation. That is, the binding of thrombin to thrombomodulin on endothelial cells results in Protein C activation. Once activated, Protein C binds to its cofactor, Protein S (either freely circulating or bound to C4b-binding protein), and Activated Protein C inhibits the coagulation factors Va and VIIIa. Activated Protein C may also neutralize PAI-1, resulting in increased fibrinolysis, which represents an important difference between Activated Protein C and other anticoagulant substances, such as antithrombin. Activated Protein C also has important anti-inflammatory properties. It may inhibit E-selectin-mediated cell adhesion, or generation of interleukin-1 and TNF by monocytes, and may also uncouple the lipopolysaccharide (endotoxin) interaction with CD14 receptors.


Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology.

Vincent JL - Crit Care (2001)

Procoagulant and anticoagulant substances that are expressed/released by endothelial cells. AT, antithrombin; NO, nitric oxide; PGI2, prostacyclin; TFPI, TF pathway inhibitor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3300083&req=5

Figure 3: Procoagulant and anticoagulant substances that are expressed/released by endothelial cells. AT, antithrombin; NO, nitric oxide; PGI2, prostacyclin; TFPI, TF pathway inhibitor.
Mentions: In recent years, it has been recognized that endothelial cells play a key role in the pathogenesis of sepsis, and that they produce important regulators of both coagulation and inflammation. They can express or release a number of substances, such as TF, endothelin-1 and PAI-1, which promote the coagulation process, as well as other substances, such as antithrombin, thrombomodulin, nitric oxide and prostacyclin, which inhibit it (Fig. 3). Thrombomodulin is to anticoagulation what TF is to coagulation. That is, the binding of thrombin to thrombomodulin on endothelial cells results in Protein C activation. Once activated, Protein C binds to its cofactor, Protein S (either freely circulating or bound to C4b-binding protein), and Activated Protein C inhibits the coagulation factors Va and VIIIa. Activated Protein C may also neutralize PAI-1, resulting in increased fibrinolysis, which represents an important difference between Activated Protein C and other anticoagulant substances, such as antithrombin. Activated Protein C also has important anti-inflammatory properties. It may inhibit E-selectin-mediated cell adhesion, or generation of interleukin-1 and TNF by monocytes, and may also uncouple the lipopolysaccharide (endotoxin) interaction with CD14 receptors.

Bottom Line: Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death.The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin.Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Intensive Care, Erasme University Hospital, Free University of Brussels, Belgium. jlvincen@ulb.ac.be

ABSTRACT
Severe sepsis, defined as sepsis associated with acute organ dysfunction, results from a generalized inflammatory and procoagulant host response to infection. Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death. The molecule that is central to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction of prostacyclin. In recent years, it has been recognized that chemicals produced by endothelial cells play a key role in the pathogenesis of sepsis. Thrombomodulin on endothelial cells coverts Protein C to Activated Protein C, which has important antithrombotic, profibrinolytic and anti-inflammatory properties. A number of studies have shown that Protein C levels are reduced in patients with severe infection, or even in inflammatory states without infection. Because coagulopathy is associated with high mortality rates, and animal studies have indicated that therapeutic intervention may result in improved outcomes, it was rational to initiate clinical studies.

Show MeSH
Related in: MedlinePlus