Fay W P, Parker A C
Department of Internal Medicine (Cardiology), University of Michigan Medical School, and the Ann Arbor Veterans Affairs Hospital, USA.
Thromb Haemost. 1998 Aug;80(2):266-72.
Clinical trials suggest that the risk of thrombosis during coronary angioplasty is lower with ionic contrast agents than with nonionic contrast agents. However, the molecular mechanisms underlying this effect are unknown. This study examined the effects of contrast agents on thrombin formation and its interaction with substrates, inhibitors, and ligands to define potential mechanisms by which contrast agents affect thrombus formation. Two ionic agents, diatrizoate and ioxaglate, and one nonionic agent, ioversol, were studied. Ionic agents inhibited factor X activation by the tissue factor-factor VIIa complex more potently than ioversol (53 +/- 3.7, 43.0 +/- 1.9, and 26.5 +/- 2.4% inhibition by diatrizoate, ioxaglate, and ioversol, respectively, at concentrations of 5%). Ionic contrast agents were potent inhibitors of prothrombinase function, inhibiting thrombin formation by >75% at contrast concentrations of 0.6% (p <0.005). Ioversol inhibited prothrombinase to a significantly lesser extent than ionic agents. Clotting assays suggested that ioxaglate was the most potent inhibitor of thrombin generation in plasma despite having the least effect on fibrin polymerization. Contrast agents inhibited binding of thrombin to fibrin, with ionic agents producing a more potent effect than ioversol (p <0.02). However, contrast agents did not inhibit thrombin-mediated platelet activation, had only a minor effect on inhibition of thrombin by antithrombin III, and did not affect thrombin-hirudin interactions. In summary, these studies identify specific mechanisms by which radiographic contrast agents inhibit thrombin formation and function -- i.e. inhibition of tissue factor-dependent factor Xa generation, inhibition of the prothrombinase complex, and inhibition of thrombin binding to fibrin. These findings may help to explain the reduced risk of thrombosis during coronary angioplasty associated with ionic contrast agents.
临床试验表明，在冠状动脉血管成形术中，离子型造影剂导致血栓形成的风险低于非离子型造影剂。然而，这种效应背后的分子机制尚不清楚。本研究检测了造影剂对凝血酶形成及其与底物、抑制剂和配体相互作用的影响，以确定造影剂影响血栓形成的潜在机制。研究了两种离子型造影剂泛影葡胺和碘克沙醇，以及一种非离子型造影剂碘海醇。离子型造影剂比碘海醇更有效地抑制组织因子 - 因子VIIa复合物对因子X的激活（在5%浓度下，泛影葡胺、碘克沙醇和碘海醇的抑制率分别为53±3.7%、43.0±1.9%和26.5±2.4%）。离子型造影剂是凝血酶原酶功能的强效抑制剂，在造影剂浓度为0.6%时，抑制凝血酶形成>75%（p<0.005）。碘海醇对凝血酶原酶的抑制程度明显低于离子型造影剂。凝血试验表明，尽管碘克沙醇对纤维蛋白聚合的影响最小，但它是血浆中凝血酶生成的最有效抑制剂。造影剂抑制凝血酶与纤维蛋白的结合，离子型造影剂的作用比碘海醇更强（p<0.02）。然而，造影剂不抑制凝血酶介导的血小板激活，对抗凝血酶III抑制凝血酶的作用影响较小，且不影响凝血酶 - 水蛭素相互作用。总之，这些研究确定了放射造影剂抑制凝血酶形成和功能的具体机制，即抑制组织因子依赖性因子Xa的生成、抑制凝血酶原酶复合物以及抑制凝血酶与纤维蛋白的结合。这些发现可能有助于解释冠状动脉血管成形术中与离子型造影剂相关的血栓形成风险降低的原因。
