Thrombin inhibition by the serpins

Abstract

To cite this article: Huntington JA. Thrombin inhibition by the serpins. J Thromb Haemost 2013; 11 (Suppl. 1): 254-64.Summary. Thrombin is the central protease in the blood coagulation network. It has multiple substrates and cofactors, and it appears that four serpins are responsible for inhibiting the thrombin produced in haemostasis and thrombosis. Structural studies conducted over the last 10 years have resolved how thrombin recognises these serpins with the aid of cofactors. Although antithrombin (AT), protein C inhibitor (PCI), heparin cofactor II (HCII) and protease nexin-1 (PN1) all share a common fold and mechanism of protease inhibition, they have evolved radically different mechanisms for cofactorassisted thrombin recognition. This is likely to be due to the varied environments in which thrombin is found. In this review, I discuss the unusual structural features of thrombin that are involved in substrate and cofactor recognition, the serpin mechanism of protease inhibition and the fate of thrombin in the complex, and how the four thrombin-specific serpins exploit the special features of thrombin to accelerate complex formation.

Pharmacology of Heparin and Related Drugs

“…Heparin cofactor II (HCII), another serpin that is potentiated by heparin, is a coagulation inhibitor that inhibits only thrombin; HCII is reported to also inhibit Pharmacology of Heparin and Related Drugs chymotrypsin and neutrophil cathepsin G (Huntington, 2013). HCII is present in plasma at similar levels to AT (Tollefsen, 1997), but HCII cannot substitute for AT in AT deficiency.…”

“…The combination of GAGinitiated reactive center loop expulsion with exposure of a protease-binding exosite is controlled by AT and HCII in contrasting ways, as shown in Fig. 5B (Huntington, 2013(Huntington, , 2014.…”

Procoagulant and fibrinolytic activity after polytrauma in rat

“…Thrombin and plasmin are serine proteases that are converted from their inactive zymogen forms (prothrombin and plasminogen) by the prothrombinase complex, and by tissue plasminogen activator (tPA), respectively (17,30,37). Suppression of thrombin and plasmin is accomplished by inhibiting the generation of the active enzymes, and/or by removing the active enzymes, from the circulation.…”

COMP: an endogenous thrombin inhibitor

“…3 A number of inhibitors of thrombin have been identified that limit the vascular consequences of inadvertent or pathophysiological thrombin generation, including antithrombin III, heparin cofactor II, protein C inhibitor, and nexin I, all of which belong to the serpin family of protease inhibitors. 4 In contrast, COMP is a member of the thrombospondin (TSP) protein family. COMP, also known as TSP5, is an abundant extracellular matrix protein expressed in tissues of the musculoskeletal system including cartilage and tendon.…”