Plasminogen is an abundant
plasma protein that exists in various zymogenic forms.
Plasmin, the proteolytically active form of
plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote
plasmin generation for thromboembolic conditions or to stop
plasmin to reduce
bleeding. However,
plasmin and
plasminogen serve other important functions, some of which are unrelated to
fibrin removal. Indeed, for >40 years, the
antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties.
Plasmin also plays an important role in the removal of misfolded/aggregated
proteins and can trigger other enzymatic cascades, including
complement. In addition,
plasminogen, via binding to one of its dozen
cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes.
Plasminogen administration itself has been reported to improve thrombolysis and to accelerate
wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of
antifibrinolytic agents to reduce
bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing
infection risk that is independent of its
hemostatic effects. The finding that many viruses harness the host
plasminogen to aid infectivity has suggested that
antifibrinolytic agents may have
antiviral benefits. Here, we review the broadening role of the
plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in
thrombosis and hemostasis.