Physiological Functions of Plasminogen Activation: Effects of Gene Deficiencies in Humans and Mice

Abstract

Exhaustive analysis of humans and mice with genetic deficiencies in plasminogen, plasminogen activators, plasmin inhibitor, and plasminogen activator inhibitors have yielded fundamental new insights into both the mechanisms of activation and the physiological functions of the plasminogen activation system. At least five different pathways for the activation of plasminogen are operative in vivo, and these five pathways display a remarkable functional redundancy. Plasminogen as well as the components that govern the activation and inhibition of the plasminogen activation system are dispensable for development. However, the cleavage of fibrin and other extracellular substrates by plasmin is critical for postnatal remodeling and repair of multiple epithelial and mesenchymal tissues. As a consequence, life without plasminogen is associated with high morbidity and mortality due to progressive multiorgan damage. Conversely, genetic deficiencies in inhibitors of plasmin and plasminogen activators not only markedly accelerate tissue repair but also result in a lifelong bleeding predisposition due to premature fibrin dissolution.