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May 19, 2019

Recombinant Human Soluble Thrombomodulin in Patients With Sepsis-Associated Coagulopathy: Another Negative Sepsis Trial?

Author Affiliations
  • 1Center of Experimental and Molecular Medicine, Division of Infectious Diseases, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
JAMA. 2019;321(20):1978-1980. doi:10.1001/jama.2019.5792

Sepsis is a heterogeneous syndrome caused by an unbalanced host response to an infection resulting in organ dysfunction.1 Sepsis is associated with activation of the coagulation system, and 30% to 60% of patients have disseminated intravascular coagulation (DIC).2 Fulminant DIC is characterized by` activation of the coagulation system combined with an impaired function of endogenous anticoagulant mechanisms resulting in widespread microvascular thrombosis and concurrent hemorrhage secondary to consumption of clotting factors and platelets.3,4 Strong and bimodal interactions exist between coagulation and inflammation, wherein coagulation factors enhance inflammation and vice versa.4 Observational studies suggest a link between the severity of coagulopathy, organ dysfunction, and death in patients with sepsis. In addition, in several preclinical sepsis models, inhibition of coagulation reduces both systemic inflammation and mortality.3,4 These findings led to large randomized trials of several anticoagulant agents in patients with sepsis, most notably recombinant human activated protein C (APC), tissue factor pathway inhibitors, and antithrombin.5 None of these interventions improved survival, with the exception of APC in the PROWESS trial and those results were not upheld by subsequent trials.5

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