Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation

Summary

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 throm-bin 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 γ chain termed γ’ ^1-427L. Plasma fibrinogen molecules containing γ ’ chains (“fibrino-gen 2”) are virtually all heterodimers containing one γ_A chain (platelet-binding) and one γ’ chain. The remaining fibrinogen (~ 85%) is homodimeric, lacks high affinity thrombin-binding potential, and is termed “fibrinogen 1” (γ_A/γ_A). Thrombin generation in recalcified fibrinogen-depleted or congenital afibrinogenemic plasma is increased. Repletion with fibrino-gen 1 has a modest effect in normalizing thrombin generation, whereas repletion with fibrinogen 2 (γ_A/γ’) has a more marked effect. A post-translational γ’ chain derivative, γ’ ^1-423P, accounts for 3%-34% of the γ’ chain population, lacks thrombin binding potential, and arises by proteolytic processing at the expense of γ’ ^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 throm-bin generation in clotting blood by sequestering thrombin, and “high-affinity” thrombin-binding (i.e., via γ’ chains) plays a dominant role in this process. AT-1 should be considered when assessing the pathogenesis of thromboembolic disease.

Keywords

Fibrin - thrombin - antithrombin - thrombin inhibition

• References

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