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Michael W. Mosesson
Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation
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 chain termed 1-427L, Plasma fibrinogen molecules containing chains (fibrinogen 2) are virtually all heterodimers containing one A chain (platelet-binding) and one chain. The remaining fibrinogen ( 85%) is homodimeric, lacks high affinity thrombin-binding potential, and is termed fibrinogen 1 (A/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 (A/) has a more marked effect. A post-translational chain derivative, 1-423P, accounts for 3%34% of the chain population, lacks thrombin binding potential, and arises by proteolytic processing at the expense of 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 chains) plays a dominant role in this process. AT-1 should be considered when assessing the pathogenesis of thromboembolic disease.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 89, 01/2003
Pages: 9 - 12