Adverse effect of heparin in thrombin-antithrombin III interaction.

E Marciniak
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Abstract

Thrombin, while reacting in the presence of hepatin, impairs the inhibitory capacity of antithrombin III so that subsequent inhibition of thrombin or factor Xa is decreased or abolished. This adverse effect of hepatin has been observed directly with at least 1.5 Iowa units of thrombin per each unit of purified human antithrombin III participating in the reaction. The inhibitory capacity was then totally destroyed and some residual thrombin remained in the active form. With a lower enzyme/inhibitor ratio inactivation of thrombin in the presence of hepatin was fast and complete, however, a significant decrease of inhibitory capacity below that found in reaction without heparin, has been established by measuring the residual antithrombin III activity. In defibrinated human plasma at least 2 units of thrombin per each antithrombin III unit were required to demonstrate directly the adverse effect of heparin but a fast depletion of inhibitory capacity has been also observed after repeated additions of small thrombin portions into plasma heparinized in vitro or in vivo. Portions of enzyme initially added disappeared with great velocity; subsequent portions, however, accumulated building up a high thrombin level not seen in the absence of heparin. The accumulation of residual enzyme was more extensive in plasma containing about 1 heparin unit per ml than anticoagulant at lower concentrations and was particularly noticeable in antithrombin III deficient plasma. These results may have some bearings on the approach to heparin therapy in the event when thrombin continuously generates or when a marked deficiency of antithrombin III exists.

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肝素在凝血酶-抗凝血酶III相互作用中的不良反应。
凝血酶在肝素存在时发生反应,损害抗凝血酶III的抑制能力,使随后的凝血酶或Xa因子的抑制减弱或消除。肝素的这种不良作用已被直接观察到,每单位纯化的人抗凝血酶III参与反应至少有1.5爱荷华单位的凝血酶。抑制能力被完全破坏,残余凝血酶仍以活性形式存在。由于有肝素存在时凝血酶的酶抑制剂比较低,凝血酶的失活迅速而完全,然而,通过测量剩余的抗凝血酶III活性,可以确定其抑制能力明显低于无肝素时的反应。在去纤化的人血浆中,每个抗凝血酶III单位至少需要2个凝血酶单位来直接证明肝素的不良作用,但也观察到在体外或体内肝素化的血浆中反复添加少量凝血酶后,抑制能力会迅速耗尽。最初加入的部分酶以较快的速度消失;随后的部分,然而,积累建立一个高凝血酶水平没有见过在缺乏肝素。残留酶在含有1单位/毫升肝素的血浆中的积累比低浓度的抗凝血剂更广泛,在抗凝血酶III缺乏的血浆中尤其明显。这些结果可能对凝血酶持续产生或抗凝血酶III明显缺乏的情况下的肝素治疗方法有一定的影响。
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