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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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Protein C levels (% of normal) in patients with meningococcaemia. Adapted from Powars et al [9].
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Figure 4: Protein C levels (% of normal) in patients with meningococcaemia. Adapted from Powars et al [9].

Mentions: A number of studies have now shown that Protein C levels are reduced in patients with severe infection. In the study by Powars et al [9], Protein C levels were reduced to approximately 50% of normal levels in patients with moderate meningococcaemia, and to approximately 30% of normal levels in critically ill patients (Fig. 4). Similarly, a study by Hemmer et al [10] in patients with malaria showed that those with complications had much higher levels of TNF and greatly reduced Protein C activity (Fig. 5). In patients who have undergone bone marrow transplantion, low antithrombin and Protein C levels are also the best predictors of multiple organ dysfunction [11]. In a subgroup of 70 patients with sepsis included in an ibuprofen trial [12], 90% were shown to have low Protein C levels and most also had other alterations in coagulation factors (elevated D-dimers, low fibrinogen level and low platelet count). In that study, there was a significant correlation between the increase in Protein C levels from 0 to 44 h, and 30-day mortality (P < 0.01). Furthermore, mortality was higher in patients with persistently low Protein C levels than in those whose Protein C levels recovered spontaneously without any treatment (45% versus 26%).


Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology.

Vincent JL - Crit Care (2001)

Protein C levels (% of normal) in patients with meningococcaemia. Adapted from Powars et al [9].
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Protein C levels (% of normal) in patients with meningococcaemia. Adapted from Powars et al [9].
Mentions: A number of studies have now shown that Protein C levels are reduced in patients with severe infection. In the study by Powars et al [9], Protein C levels were reduced to approximately 50% of normal levels in patients with moderate meningococcaemia, and to approximately 30% of normal levels in critically ill patients (Fig. 4). Similarly, a study by Hemmer et al [10] in patients with malaria showed that those with complications had much higher levels of TNF and greatly reduced Protein C activity (Fig. 5). In patients who have undergone bone marrow transplantion, low antithrombin and Protein C levels are also the best predictors of multiple organ dysfunction [11]. In a subgroup of 70 patients with sepsis included in an ibuprofen trial [12], 90% were shown to have low Protein C levels and most also had other alterations in coagulation factors (elevated D-dimers, low fibrinogen level and low platelet count). In that study, there was a significant correlation between the increase in Protein C levels from 0 to 44 h, and 30-day mortality (P < 0.01). Furthermore, mortality was higher in patients with persistently low Protein C levels than in those whose Protein C levels recovered spontaneously without any treatment (45% versus 26%).

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