The kinetics and interplay of thrombin inhibition by 4 plasma proteinase inhibitors

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-07-05 DOI:10.1016/j.bvth.2025.100088

Allen Ma , Dougald M. Monroe , Maureane Hoffman

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Abstract

A novel therapeutic approach for restoring hemostasis in hemophilia is to reduce antithrombin (AT) to rebalance reduced thrombin generation. In plasma, multiple inhibitors including AT, heparin cofactor II (HCII), α₂-macroglobulin (A2M), and α₁-proteinase inhibitor (A1PI) play a role in thrombin inhibition. The goal was to study the kinetics of thrombin inhibition and the roles of various inhibitors across a broad range of AT levels. Thrombin inhibition was measured at varied concentrations of AT with and without A2M, HCII, and A1PI. Reducing AT to 0 from plasma levels in the presence HCII, A2M, and A1PI, results in slower thrombin inhibition with the time required to inhibit half the thrombin increasing approximately fourfold. Computational models of thrombin inhibition and thrombin generation in hemophilia were constructed and used to analyze thrombin inhibition and the relative contribution of each inhibitor. In a model of thrombin generation, decreased thrombin inhibition resulted in increased peak thrombin and increased area under the thrombin curve. Even at high concentrations of thrombin, all of the thrombin was inhibited with the relative contribution of other inhibitors increasing as AT was decreased. These studies show that in a system without heparin-like glycosaminoglycans, AT is the dominant inhibitor of thrombin, followed by A2M, HCII, and, finally, A1PI. As AT levels decrease, thrombin inhibition is slower, resulting in higher levels of thrombin in a computational model of thrombin generation. Ultimately, the other inhibitors compensate for AT to maintain a level of thrombin regulation.

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4种血浆蛋白酶抑制剂抑制凝血酶的动力学和相互作用

摘要血友病恢复止血的一种新的治疗方法是减少抗凝血酶（AT）以重新平衡减少的凝血酶生成。在血浆中，AT、肝素辅助因子II （HCII）、α2-巨球蛋白（A2M）、α1蛋白酶抑制剂（A1PI）等多种抑制剂发挥凝血酶抑制作用。目的是研究凝血酶抑制动力学和各种抑制剂在广泛AT水平范围内的作用。在不同浓度的at（含或不含A2M、HCII和A1PI）下测定凝血酶的抑制作用。在HCII、A2M和A1PI存在的情况下，将AT从血浆水平降至0，导致凝血酶抑制减慢，抑制一半凝血酶所需的时间增加约四倍。构建血友病中凝血酶抑制和凝血酶生成的计算模型，并用于分析凝血酶抑制和每种抑制剂的相对贡献。在凝血酶生成模型中，凝血酶抑制降低导致凝血酶峰值升高，凝血酶曲线下面积增大。即使在高浓度凝血酶下，所有凝血酶都被抑制，其他抑制剂的相对贡献随着at的减少而增加。这些研究表明，在没有肝素样糖胺聚糖的系统中，AT是凝血酶的主要抑制剂，其次是A2M、HCII，最后是A1PI。在凝血酶生成的计算模型中，随着AT水平的降低，凝血酶的抑制变慢，导致凝血酶水平升高。最终，其他抑制剂补偿AT以维持凝血酶调节水平。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Vessels, Thrombosis & Hemostasis

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