Thrombin monitoring direct inhibitors

Bivalirudin is a direct thrombin inhibitor that has found utility for reducing the rate of acute reocclusion in patients treated with PCI. It is preferential to heparin in PCI when HIT is present. This drug is a derivative of hirudin, which is a dedicated thrombin inhibitor with no other in vivo activities of significance. The molecule is semisynthetic the C-terminal of hirudin is linked by a polyglycine spacer to the tetrapeptide region of the N-terminal that reacts with the thrombin active site (22). It is monitored by the activated clotting time test. Its pharmacologic properties are shown in Table I. 

Nowak G. 2001. Clinical monitoring of hirudin and direct thrombin inhibitors. Semin. Thromb. Hemos-tas. 27 537-541. 

TABLE 1 9—23. Recommended Dose and Monitoring Parameters for Direct Thrombin Inhibitors to Treat Heparin-Induced Thrombocytopenia... 

Heparin has been fluorescently labeUed in a manner that does not alter the functional properties of the polysaccharide. The labelled polysaccharide has been used in conjunction with fluorescence polarization spectroscopy to monitor the binding of heparin to the L-serine proteases thrombin, factor XIa, factor Xa, and plasmin. The stoicheiometry and dissociation constants of the interactions have been measured. The kinetics of inactivation of the four proteases by anti-thrombin as a function of heparin concentration have also been measured. Evidence shows that the direct binding of heparin to anti-thrombin is probably responsible for the polysaccharide-dependent acceleration of hemostatic enzyme-inhibitor reactions. 

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