Lindhout T, Blezer R, Hemker H C
Department of Biochemistry, University of Limburg, Maastricht, The Netherlands.
Thromb Haemost. 1990 Nov 30;64(3):464-8.
We studied the inhibitory action of recombinant desulphatohirudin (CGP 39393) on thrombin generation in whole plasma. Human plasma was activated either with thromboplastin or factor IXa. Hirudin delayed thrombin generation, but it was unable to prevent the explosive appearance of thrombin. The dose-dependent prolongation of the lag phase of the intrinsic and extrinsic thrombin generation curve was not the result of titration of thrombin activity by hirudin but the result of a delayed formation of the prothrombin converting complex (prothrombinase). In case of extrinsic activation, hirudin did not affect factor Xa generation, but prolonged the lag phase of the factor Va generation curve, causing its appearance when factor Xa generation was already in the decay phase. Because of its inhibitory action on the thrombin-mediated activation of factor VIII, hirudin prolonged the lag phase of the factor X converting complex that consists of factor IXa and factor VIIIa. Our observations with hirudin are in keeping with the notion that inhibition of the thrombin-mediated amplification reactions in blood coagulation is a very efficient way to delay or inhibit completely thrombin generation. However, although hirudin neutralizes stoichiometric amounts of thrombin, the interaction between in situ generated thrombin and hirudin appears not to be fast enough to prevent trace amounts of thrombin to activate factors VIII and V. Consequently, an explosive thrombin generation is observed even when free hirudin is present.
我们研究了重组去硫酸水蛭素（CGP 39393）对全血中凝血酶生成的抑制作用。用人凝血活酶或因子IXa激活人血浆。水蛭素延迟了凝血酶的生成，但无法阻止凝血酶的爆发性出现。内源性和外源性凝血酶生成曲线滞后相的剂量依赖性延长并非水蛭素滴定凝血酶活性的结果，而是凝血酶原转化复合物（凝血酶原酶）形成延迟的结果。在外源性激活的情况下，水蛭素不影响因子Xa的生成，但延长了因子Va生成曲线的滞后相，导致其在因子Xa生成已进入衰减期时出现。由于其对凝血酶介导的因子VIII激活的抑制作用，水蛭素延长了由因子IXa和因子VIIIa组成的因子X转化复合物的滞后相。我们对水蛭素的观察结果与以下观点一致，即抑制血液凝固中凝血酶介导的放大反应是延迟或完全抑制凝血酶生成的非常有效的方法。然而，尽管水蛭素能按化学计量中和凝血酶，但原位生成的凝血酶与水蛭素之间的相互作用似乎不够快，无法阻止痕量凝血酶激活因子VIII和V。因此，即使存在游离水蛭素，也会观察到爆发性的凝血酶生成。
