Local administration of recombinant human antithrombin in a mouse model of peritoneal sepsis

Sepsis is a clinical syndrome characterized by a harmful host response to infection mostly caused by toxin-producing bacteria, and is associated with a disruption in homeostasis through uncontrolled coagulation, inflammation and fibrinolysis [1,2]. Sepsis ultimately leads to global tissue hypoxia and multiorgan failure aggravated by disseminated intravascular coagulation (DIC), which is a determinant of a poor clinical outcome [3]. The pathogenesis of DIC in a patient with sepsis is characterized by immune triggered activation of coagulation pathways and down regulation of natural anticoagulant and fibrinolytic mechanisms, due to the generation of pro-inflammatory cytokines, including tumor necrosis factor a, interleukin (IL)-1b, Il-6 and Il-8 [4–6]. These inflammatory mediators induce tissue factor (TF) on circulating blood cells as well as in critical organs including the kidney, which facilitates enhanced thrombin generation. The coagulation proteases generated may further engage inflammatory pathways through TF and protease-activated receptors (PARs) such that a vicious circle of inflammation–coagulation interactions ensues [6,7]. With the accumulating evidence of extensive interactions between immune and blood coagulation systems, experimental and subsequent clinical studies have addressed the potential utility of anticoagulant agents to counteract multiorgan failure in sepsis. These studies were encouraged by a series of experiments in baboons subjected to lethal E. coli sepsis, showing that administration of protein C [8], antithrombin (AT) [9] and subsequently tissue factor pathway inhibitor (TFPI) [10] all effectively reduced mortality. It was also noted, however, that not all anticoagulants were effective in reducing organ damage due to sepsis because, in the same baboon model, active site blocked factor Xa, which blunted coagulation activity in blood, did not reduce mortality [11]. More than 10 years later, recombinant human activated protein C (APC) was the first anticoagulant that was shown to reduce mortality in the randomized, placebo-controlled PROWESS trial (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) in patients with severe sepsis, although its efficacy and indication have been debated since and treatment was associated with an increased risk of bleeding [12]. In the anticoagulant arena and in spite of promising experimental studies in baboons [10], administration of TFPI had no effect on mortality in patients with sepsis and was associated with an increased risk of bleeding [13]. AT has also been tested as a therapeutic agent in sepsis models, based on the notion that an acquired deficiency of this important inhibitor frequently occurs in sepsis and DIC [3].