title: Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation.
abstract: Thrombin substrate binding is mediated through fibrinogen recognition "exosite 1" in thrombin, resulting in fibrinopeptide cleavage to form fibrin. In addition, thrombin exhibits "non-substrate" binding to fibrin, an activity termed "Antithrombin I". Antithrombin I (AT-I) is characterized by two classes of thrombin binding sites, the first of "low affinity" in the fibrin E domain, and the other of high affinity, that is situated between C-terminal residues 414 and 427 of a variant gamma chain termed gamma'(1-427L), Plasma fibrinogen molecules containing gamma' chains ("fibrinogen 2") are virtually all heterodimers containing one gamma(A) chain (platelet-binding) and one gamma' chain. The remaining fibrinogen (approximately 85%) is homodimeric, lacks high affinity thrombin-binding potential, and is termed " fibrinogen 1" (gamma(A)/gamma(A)). Thrombin generation in recalcified fibrinogen-depleted or congenital afibrinogenemic plasma is increased. Repletion with fibrinogen 1 has a modest effect in normalizing thrombin generation, whereas repletion with fibrinogen 2 (gamma(A)/gamma') has a more marked effect. A post-translational gamma' chain derivative, gamma'(1-423P), accounts for 3%-34% of the gamma' chain population, lacks thrombin binding potential, and arises by proteolytic processing at the expense of gamma' (1-427L) chains. Little is known about its effect on plasma AT-I activity under normal or pathological circumstances. In summary, fibrin formation (Antithrombin I) inhibits thrombin generation in clotting blood by sequestering thrombin, and "high-affinity" thrombin-binding (i.e., via gamma' chains) plays a dominant role in this process. AT-1 should be considered when assessing the pathogenesis of thromboembolic disease.
authors.affiliation: The Blood Research Institute of the Blood Center of Southeastern Wisconsin, PO Box 2178, Milwaukee, WI 53201-2178, USA. mwmosesson@bcsew.edu
authors.forename: Michael W
authors.initials: MW
authors.lastname: Mosesson
mesh_terms: D001665:Binding Sites; D005337:Fibrin / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013927:Thrombosis / Q000209:etiology
chemical_list: D005337:Fibrin; D013917:Thrombin