Benzoyl-thrombin

Rgure 7 Course of fibrinogen clotting (measured Unhid i metrically) an addition of 5 NIH-U tfirombin (T) and benzoyl-thrombin [Pg.62]

To demonstrate the effect of the active-site acylated enzyme, we prepared the benzoyl derivatives of bovine thrombin [22,23]. If benzoyl-thrombin is added to blood plasma, the clotting process is retarded in accordance with the deacylation rate (Fig. 7). 

Of special interest would be the cellular reaction of acyl-thrombin. By incubation of platelet suspension with benzoyl thrombin, the platelet reactivity was diminished. The same phenomenon could be observed in platelet suspensions where small amounts of thrombin were added slowly [25]. Further studies on nonhemostatic reactions of acyl-thrombin have not yet been carried out. 

In vivo, the infusion of small amounts of thrombin (<200 NIH-U/kg/h) causes defibrinogenation. Because of the slow transformation of fibrinogen, the fibrin monomers formed are eliminated via reactive fibrinolysis and RES without precipitation of fibrin. Upon infusion of higher amounts of thrombin, these clearance mechanisms fail to offset the thrombin action, which then leads to the formation of microthrombi in the peripheral circulation. Correspondingly, the bolus injection of 1500 NIH-U thrombin/kg caused death of the experimental animals. However, a bolus injection of benzoyl-thrombin at a dose corresponding to the amount of 1500 NIH-U/kg caused defibrinogenation only. Therefore, bolus application of acyl-thrombin may initiate an infusion regimen [26]. 

Other molecules have been suggested as being useful lung-specific bioadhesive agents [137,138], for example, insulin, transferrin, prostaglandins, hirudin-inhibited thrombin (which binds thrombomodulin), anionic polysaccharides, oligosaccharides (such as dextran sulfate, dermatan sulfate, chondroitin sulfate, hyaluronic acid), peptides (such as benzoyl-phe-ala-pro [BPAPI] that... 

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