Systemic or topical application of plasminogen activator inhibitor with extended half-life (VLHL PAI-1) reduces bleeding time and total blood loss

摘要

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 ≈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.