EFFECTS OF RADIOGRAPHIC CONTRAST AGENTS ON THROMBIN FORMATION AND ACTIVITY

Clinical trials suggest that the risk of thrombosis during coronary an gioplasty is lower with ionic contrast agents than with nonionic contr ast agents. However: the molecular mechanisms underlying this effect a re unknown. This study examined the effects of contrast agents on thro mbin formation and its interaction with substrates, inhibitors, and li gands to define potential mechanisms by which contrast agents affect t hrombus formation. Two ionic agents, diatrizoate and ioxaglate, and on e nonionic agent, ioversol, were studied. Ionic agents inhibited facto r 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 concentratio ns of 5%). Ionic contrast agents were potent inhibitors of prothrombin ase function, inhibiting thrombin formation by >75% at contrast concen trations of 0.6% (p <0.005), Ioversol inhibited prothrombinase to a si gnificantly lesser extent than ionic agents. Clotting assays suggested that ioxaglate was the most potent inhibitor of thrombin generation i n plasma despite having the least effect on fibrin polymerization. Con trast agents inhibited binding of thrombin to fibrin, with ionic agent s producing a more potent effect than ioversol (p <0.02). However, con trast agents did not inhibit thrombin-mediated platelet activation, ha d only a minor effect on inhibition of thrombin by antithrombin III, a nd did not affect thrombin-hirudin interactions. In summary, these stu dies identify specific mechanisms by which radiographic contrast agent s inhibit thrombin formation and function - i.e, inhibition of tissue factor-dependent factor Xa generation, inhibition of the prothrombinas e complex, and inhibition of thrombin binding to fibrin. These finding s may help to explain the reduced risk of thrombosis during coronary a ngioplasty associated with ionic contrast agents.