Civilian and military
trauma patients consist of a disproportional number of young people, causing a considerable burden to society in terms of disability and premature death.
Hemorrhage is a leading cause of mortality in this group of patients and the novel methods to reduce
bleeding would be welcomed. Management of
bleeding following major
trauma includes
hemostatic agents that offer effective clotting. However a very limited number of agents control secondary
bleeding triggered by lysis of the clot. Fibrinolysis depends on the balance between
tissue plasminogen activator (tPA), activating
plasminogen to
plasmin initiating fibrinolysis, and
plasminogen activator inhibitor type 1 (PAI-1) inhibiting tPA and preventing lysis. The drugs available on the market that prevent the activation of
plasminogen have been used successfully, but have some side effects and limited efficacy for the control of localized
bleeding in the surgical setting. Inhibitors of tPA, initiator of clot fibrinolysis, have not yet found their way into the clinical arena.
Plasminogen activator inhibitor-1, the major specific inhibitor of tPA, can be used to limit fibrinolysis. Unfortunately,
PAI-1 has a short half-life of approximately 2 h and is rapidly converted to the latent form. A recombinant
PAI-1 with very long half-life developed in our laboratory (a two-point mutant, VLHL PAI-1, half-life over 700 h) has clinical potential as an agent to promote hemostasis in several scenarios including
surgical injury,
trauma, and
PAI-1 deficiency. Here we report testing of VLHL
PAI-1 as a potent inactivator of fibrinolysis reducing total blood loss while applied systemically or topically in experimental animals. The very long half-life of VLHL
PAI-1 may provide an advantage in the important physiological mechanism to protect clots from premature dissolution, when applied topically or systemically to prevent excessive
bleeding in the surgical and
trauma setting and possibly in
PAI-1 deficient patients.