Aprotinin is a protein-based inhibitor of plasmin and is used in the clinic to stop bleeding during various surgical procedures. It has several drawbacks however, including renal toxicity, thrombic complications, immunogenicity and sometimes mortality. These shortcomings arise because the low specificity and affinity of aprotinin towards plasmin requires large doses and more recent evidence indicates that aprotinin inhibits kallikrein. The inhibitor can also interfere with other metabolic pathways and can invoke an immune response because of its bovine origin. Thus an ideal plasmin inhibitor would be more potent than aprotinin and be of human origin so as to decrease antigenicity.

INNOVATION:  Scientists at UCLA have developed an improved plasmin inhibitor. The enhanced inhibitor is based on the human protein Tissue Factor Pathway Inhibitor-2 (TFPI-2). TFPI-2 contains a Kunitz-type domain (KD1) that is similar to aprotinin and specifically inhibits plasmin. The researchers used computational modeling to introduce specific mutations in the KD1 domain that improve its affinity for plasmin. In vitro experiments show the mutant KD1 binds plasmin 50X tighter than the wild-type molecule.

POTENTIAL APPLICATIONS 

• The improved KD1 domain can replace aprotinin during surgical procedures to prevent excessive bleeding.
• It could also be of benefit to other clinical conditions that have been associated with the plasmin pathway.

ADVANTAGES

• Significantly improved potency versus aprotinin.
• Does not act on kallikrein.
• Humanized protein presents less risk of immunogenicity thereby improving safety compared to aprotinin.

Reference: UCLA Case No. 2006-064