Abstract
Deregulated interplay between inflammation and coagulation plays a pivotal role in the pathogenesis of sepsis. Therapeutic approaches that simultaneously target both inflammation and coagulation hold great promise for the treatment of sepsis. Thrombomodulin is an endogenous anticoagulant protein that, in cooperation with protein C and thrombin-activatable fibrinolysis inhibitor, serves to maintain the endothelial microenvironment in an anti-inflammatory and anticoagulant state. A recombinant soluble form of thrombomodulin has been approved to treat patients suffering from disseminated intravascular coagulation (DIC) and has thus far shown greater therapeutic potential than heparin. A phase II clinical trial is currently underway in the USA to study the efficacy of thrombomodulin for the treatment of sepsis with DIC complications. This paper focuses on the critical roles that thrombomodulin plays at the intersection of inflammation and coagulation and proposes the possible existence of interactions with integrins via protein C. Finally, we provide a rationale for the clinical application of thrombomodulin for alleviating sepsis.
Highlights
Septic shock is a leading cause of death in intensive care units and represents a substantial financial burden on the healthcare system in Japan, in the United States, and in many other developed nations [1, 2]
Inflammation deregulates coagulation cascades, thereby inducing intravascular blood coagulation at inflamed endothelial cells, which reflects the tendency of septic shock to manifest various coagulopathies that lead to disseminated intravascular coagulation (DIC) [5]
A recombinant form of activated protein C (APC) (Drotrecogin alfa-activated (DrotAA)) has been used in the treatment of severe septic shock [6]. We focus on another important endogenous anticoagulant protein, thrombomodulin (TM)
Summary
Septic shock is a leading cause of death in intensive care units and represents a substantial financial burden on the healthcare system in Japan, in the United States, and in many other developed nations [1, 2]. Uncontrolled and systemically spreading inflammatory responses that are initiated by infection play critical roles in the pathogenesis of septic shock. Inflammation deregulates coagulation cascades, thereby inducing intravascular blood coagulation at inflamed endothelial cells, which reflects the tendency of septic shock to manifest various coagulopathies that lead to disseminated intravascular coagulation (DIC) [5]. Current consensus on septic shock pathogenesis holds that dysregulation occurs simultaneously in both the inflammation and coagulation systems, thereby complicating pathogenesis in patients and reducing the therapeutic. Critical Care Research and Practice effectiveness of targeting either inflammation or coagulation. A better understanding of the crosstalk that occurs between inflammation and coagulation is critical to developing novel, effective treatments for sepsis. A recombinant form of APC (Drotrecogin alfa-activated (DrotAA)) has been used in the treatment of severe septic shock [6]. We examine the basic biology of TM with a particular emphasis on its role at the intersection of inflammation and coagulation and discuss its potential application for septic shock
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