Cells regularly invade and migrate through tissues during embryogenesis, angiogenesis, cancer, and a number of other normal and pathological processes (1). Since much of this movement frequently occurs through quite formidable barriers, it is dependent upon the action ofhighly regulated and specific proteinases that can locally digest tissue proteins without the widespread damage associated with, for example, chronic inflamma-tory disease. This" targeted" proteolysis is accomplished in large part by the plasminogen activating system, a versatile, temporally controlled enzymatic cascade that when activated, generates locally expressed extracellular proteolytic activity. Activation ofthis system is initiated by the release ofplasminogen activators (PAs) from cells in response to signals (eg, growth factors, cytokines, hormones) liberated during tissue remodeling, inflammation, and thrombosis, and leads to the formation of plasmin. Remarkably, this same system in blood (ie, the fibrinolytic system) functions to maintain vessel patency by specifically removing fibrin deposits from the vasculature. This diversity of function suggests that the plasminogen activating system is broadly used in human physiology. At the clinical level, excessive plasmin formation is frequently associated with bleeding and/or various destructive conditions (eg, cancer, pemphigus, inflammatory joint disease), empha-sizing that PA activity must be precisely regulated. This regulation is achieved initially at the level of PA biosynthesis, and ultimately at the level of specific PA inhibitors (PAls) that prevent the escape of this potentially destructive protease system. Although four molecules with PAI activity have been described, PAI-I appears to be the primary inhibitor ofplasminogen activation in vivo (2).

Because regulation of the PA system appears to be of such fundamental importance, it has long been suspected that abnormal expression of PAI-I itselfalso would be associated with human disease. In fact, individuals with elevated PAI-I in their blood may be at increased risk to develop thrombotic disease, including myocardial infarction, and transgenic animals expressing excessive PAI-I develop thrombi in their extremities (reviewed in reference 2). Against this background, workers in the field have speculated that plasminogen activation control would be completely compromised in PAI-1-deficient individ-uals, and that the resulting severe hyperfibrinolytic state would be inconsistent with normal development and hemostasis. A number of recent observations suggest that this idea is only partially correct. For example, individuals with low PAI-1 in their blood have been identified (reviewed in reference3), and Fay et al.(4) elegantly demonstrated and characterized a complete PAI-I deficiency in a 9-yr-old girl. None ofthese individ-uals have obvious physical or developmental abnormalities, but all of them present with mild to moderate, life-long bleed-ing problems. Whether the young girl will ultimately develop fertility problems as well (the PA system has been directly im-plicated in ovulation, implantation, and pregnancy [1, 5]) re-mains to be seen.