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.
Ohri
S K
SK
Cardiothoracic Unit, Department of Surgery, Royal Postgraduate Medical School, Hammersmith Hospital, London, England.
Paratt
R
R
Becket
J M
JM
Brannan
J
J
Hunt
B J
BJ
Taylor
K M
KM
D000818:Animals; D007611:Aprotinin / Q000627:therapeutic use*; D016063:Blood Loss, Surgical / Q000517:prevention & control; D002315:Cardiopulmonary Bypass; D004353:Drug Evaluation, Preclinical; D006487:Hemostasis / Q000187:drug effects; D006490:Hemostatics / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D011446:Prospective Studies; D011897:Random Allocation; D011994:Recombinant Proteins / Q000627:therapeutic use; D017385:Sequence Homology; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D012756:Sheep; D013997:Time Factors
D006490:Hemostatics; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; C098973:recombinant Kunitz protease inhibitor; D007611:Aprotinin