GENETICALLY-ENGINEERED SERINE-PROTEASE INHIBITOR FOR HEMOSTASIS AFTERCARDIAC OPERATIONS

Background. The serine protease inhibitor aprotinin has been widely re ported for its beneficial action in limiting blood loss after cardiopu lmonary bypass (CPB). A potent human serine protease inhibitor known a s protease nexin II or amyloid precursor protein has been recently iso lated. A recombinant protein known as recombinant Kunitz protease inhi bitor (rKPI; Scios Nova, Mountain View, CA) with sequence homology to the protease nexin II-amyloid precursor protein molecule has been manu factured. Methods. Recombinant Kunitz protease inhibitor was assessed in an ovine model of CPB as a hemostatic agent after CPB. Sheep (n = 2 2) underwent CPB for 90 minutes. Two thoracic drains were sited and dr ain losses collected for a period of 3 hours after CPB. Wounds were su bjectively assessed before closure for ''dryness'' using a visual anal ogue scale. Sheep were randomized to control (n = 8), aprotinin (n = 8 ), and rKPI (n = 6) groups. Results. Control animals had a drain loss of 409.4 +/- 39.4 mL/3 h, compared with 131.3 +/- 20.3 mL/3 h for the aprotinin group and 163.7 +/- 34.3 mL/3 h for the rKPI group (p = 0.16 ). Hemoglobin loss was 11.6 +/- 3.6, 6.02 +/- 2.1, and 4.6 +/- 1.2 g/3 h for the control, rKPI, and aprotinin groups respectively (p = 0.25) . The subjective analysis of the wounds at the end of CPB found aproti nin (1.25 +/- 0.16; p < 0.05) and rKPI (1.17 +/- 0.17; p < 0.05) anima ls to score significantly lower than control animals (2.63 +/- 0.42). Conclusions. On the basis of these in vivo findings, genetic modificat ion may yield a more efficacious serine protease inhibitor with the in herent advantages of using a human-based protein.