Thrombin-antithrombin system

Abstract

Antithrombin (AT) is the most abundant and most important physiological anticoagulant in the body [1]. AT deficiency in animal results in embryonic death, and mutations that reduce the AT levels result in severe thrombotic conditions. For example, AT-deficient fish exhibited consumptive coagulopathy or disseminated intravascular coagulation (DIC) following injury [2]. It is generally accepted that thrombin is produced as a result of activation of the innate immune system after injury, and natural anticoagulants play a role in preventing accidental clot formation. Since ancient times massive blood loss from trauma has been the most frequent life-threatening event encountered by humans. As a result, a heavy-duty coagulation system has evolved to promote hemostasis in the setting of injury. In the face of this natural thrombogenic tendency, impairment of anticoagulant mechanisms can easily induce problematic events in critical situations, including trauma [3]. As a result, the dysregulated over-activation in coagulation tends to occur under such circumstances. The disorder is represented by massive microvascular thrombi that contribute to decreased oxygen delivery and subsequent organ dysfunction. Accordingly, anticoagulant therapy is expected to play some role in alleviating this dangerous coagulation disorder [4]. Large-scale randomized controlled trials (RCTs) to examine the effects of anticoagulant therapies were conducted in the early 2000s, predominantly focused on sepsis [5-7], but none of the anticoagulant agents examined demonstrated a clear beneficial effect. As a result, no anticoagulant is currently approved for the clinical use in the treatment of coagulation disorder or DIC. However, some clinical trials have suggested that sepsis-associated DIC, but not sepsis itself, could benefit from anticoagulant therapies. Some subgroup analyses performed among the subjects with sepsis-associated DIC in the aforementioned clinical trials have revealed trends toward favorable effects of activated protein C and AT on the mortality [8, 9]. Recently, a small, but well-designed RCT succeeded in demonstrating the efficacy of a physiological dose of AT for obtaining DIC resolution in septic patients with DIC [10]. In addition, recombinant thrombomodulin has also shown a trend toward beneficial effects on the mortality in sepsis patients with coagulation disorder [11]. Analyses using a nationwide administrative database of patients with DIC in Japan revealed positive effects of AT supplementation on the mortality [12, 13]. However, there is still no concrete evidence of the efficacy of AT in patients with trauma-induced coagulopathy (TIC). In the following part of this chapter, the structure, unique characteristics of this naturally derived anticoagulant, and the theoretical background for the use of AT in systemic coagulation disorders are introduced.