A genetically engineered human Kunitz protease inhibitor with increased kallikrein inhibition in an ovine model of cardiopulmonary bypass.

A recombinant human serine protease inhibitor known as Kunitz protease inhibitor (KPI) wild type has functional similarities to the bovine Kunitz inhibitor, aprotinin, and had shown a potential to reduce bleeding in an ovine model of cardiopulmonary bypass (CPB). The aim of this study was to assess KPI-185, a modification of KPI-wild type that differs from KPI-wild type in two amino acid residues and which enhances anti-kallikrein activity in a further double-blind, randomized study in an ovine model of CPB, and to compare with our previous study of KPI-wild type and aprotinin in the same ovine model. Post-operative drain losses and subjective assessment of wound 'dryness' showed no significant differences between KPI-185 and KPI-wild type, despite the significant enhancement of kallikrein inhibition using KPI-185 seen in serial kallikrein inhibition assays. These preliminary findings support the hypothesis that kallikrein inhibition is not the major mechanism by which Kunitz inhibitors such as aprotinin reduce perioperative bleeding.

Autotransfusion decreases blood usage following cardiac surgery -- a prospective randomized trial.

INTRODUCTION: 10% of blood issued by the National Blood Service (220,000) is utilised in cardiac procedures. Transfusion reactions, infection risk and cost should stimulate us to decrease this transfusion rate. We tested the efficacy of autotransfusion of washed postoperative mediastinal fluid in a prospective randomized trial. PATIENTS AND METHODS: 166 patients undergoing coronary artery bypass grafting (CABG), valve or CABG + valve procedures were randomized into three groups. The indication for transfusion was a postoperative haemoglobin (Hb) < 10 g/l or a packed cell volume (PCV) < 30. When applicable, group A patients received washed post-operative drainage fluid. Group B all received blood processed from the cardiopulmonary bypass (CPB) circuit following separation from CPB and if appropriate washed post-operative drainage fluid. Group C were controls. Groups were compared using analysis of variance. RESULTS: There was no significant difference in age, sex, type of operation, CPB time and preoperative Hb and PCV between the groups. Blood requirements were as shown. [table - see text] Twelve patients in group A and 10 in group B did not require a homologous transfusion following processing of the mediastinal drainage fluid. CONCLUSION: Autotransfusion of washed postoperative mediastinal fluid can decrease the amount of homologous blood transfused following cardiac surgery. There was no demonstrable benefit in processing blood from the CPB circuit as well as mediastinal drainage fluid.

Autotransfusion of washed shed mediastinal fluid decreases the requirement for autologous blood transfusion following cardiac surgery: a prospective randomized trial.

OBJECTIVES: The National Blood Service issues 2.2 million units of blood per year, 10% of these (220000) are utilized in cardiac procedures. Transfusion reactions, infection risk and cost should stimulate us to decrease this transfusion rate. We test the efficacy of autotransfusion following surgery in a prospective randomized trial. METHODS: One hundred and twelve patients undergoing CABG, valve or CABG + valve procedures were randomized into two groups. Group A received washed postoperative drainage fluid and group C were controls. The indication for transfusion was a postoperative haemoglobin (Hb) < 10 g/l or a PCV < 30. There was no significant difference in preoperative and operative variables between the groups. RESULTS: Twenty-eight patients in group A and 46 in group C required homologous transfusion (P = 0.0008). Group A patients required 298+/-49 ml of banked blood per patient, group C 508+/-49 ml (P = 0.003). There was no difference in total blood required (volume autotransfused + volume banked blood transfused) between the groups (group A 404+/-50 ml, group C 508+/-50 ml) or in mean total mediastinal fluid drainage (group A 652+/-51 ml, group C 686+/-50ml). The mean Hb concentration was significantly higher in group A on day 1 (11.2 g/dl+/-51 vs. 10.6 g/dl+/-13 (P = 0.002)). No morbidity was associated with autotransfusion. CONCLUSION: Autotransfusion can decrease the amount of homologous blood transfused following cardiac surgery. This represents a benefit to the patient and a decrease in cost to the health service.

Genetically engineered serine protease inhibitor for hemostasis after cardiac operations.

BACKGROUND: The serine protease inhibitor aprotinin has been widely reported for its beneficial action in limiting blood loss after cardiopulmonary bypass (CPB). A potent human serine protease inhibitor known as protease nexin II or amyloid precursor protein has been recently isolated. A recombinant protein known as recombinant Kunitz protease inhibitor (rKPI; Scios Nova, Mountain View, CA) with sequence homology to the protease nexin II-amyloid precursor protein molecule has been manufactured. METHODS: Recombinant Kunitz protease inhibitor was assessed in an ovine model of CPB as a hemostatic agent after CPB. Sheep (n = 22) underwent CPB for 90 minutes. Two thoracic drains were sited and drain losses collected for a period of 3 hours after CPB. Wounds were subjectively assessed before closure for "dryness" using a visual analogue 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 aprotinin (1.25 +/- 0.16; p < 0.05) and rKPI (1.17 +/- 0.17; p < 0.05) animals to score significantly lower than control animals (2.63 +/- 0.42). CONCLUSIONS: On the basis of these in vivo findings, genetic modification may yield a more efficacious serine protease inhibitor with the inherent advantages of using a human-based protein.