Summary
Activation of humoral and cellular participants in inflammation enhances the risk
of postoperative bleeding and multiple organ damage in cardiopulmonary bypass (CPB).
We now compare the effects of heparin alone in combination with nafamostat mesilate
(NM), a protease inhibitor with specificity of trypsin-like enzymes, in an extracorporeal
circuit which simulates CPB. NM significantly inhibits the release of platelet (β-thromboglobulin
(βTG) at 60 and 120 min. Platelet counts do not differ. ADP-induced aggregation decreases
in circuits with NM, which is due to a direct effect of NM on platelet function. NM
prevents any significant release of neutrophil elastase; at 120 min, plasma elastase-α1antitrypsin complex is 0.16 μg/ml in the NM group and 1.24 μg/ml in the control group.
NM completely inhibits formation of complexes of C1 inhibitor with kallikrein and
FXIIa. NM does not alter markers of complement activation (C1-C1-inhibitor complex
and C5b-9), or indicators of thrombin formation (F1.2). However, at 120 min, thrombin
activity as measured by release of fibrinopeptide A is significantly decreased. The
data indicate that complement activation during CPB correlates poorly with neutrophil
activation and that either kallikrein or FXIIa or both may be more important agonists.
The ability of NM to inhibit two important contact system proteins and platelet and
neutrophil release raises the possibility of suppressing the inflammatory response
during clinical CPB.
