Very long half-life plasminogen activator inhibitor type 1 reduces bleeding in a mouse model.
OBJECTIVE
To investigate the potential for the future clinical use of a very long half-life plasminogen activator inhibitor type 1 (VLHL PAI-1) as a haemostatic agent.


METHODS
We developed a VLHL PAI-1 (half-life >700 h) recombinant mutant of PAI-1 and assessed VLHL PAI-1 for its ability to inhibit fibrinolysis in vitro using human, rabbit, mouse and rat blood. Fibrin clot lysis time, monitored by thromboelastometry, was determined at various concentrations of VLHL PAI-1. Also, we determined total bleeding time and total blood loss of control, VLHL PAI-1-, tissue-type plasminogen activator (tPA)- and tPA + VLHL PAI-1-treated mice.


RESULTS
Using a thromboelastometer, mouse blood was most similar to human blood in its coagulation and fibrinolytic characteristics. We evaluated the affect of VLHL PAI-1 on haemostasis using the mouse model and showed that VLHL PAI-1 is an effective inhibitor of fibrin clot degradation. It reduced time of bleeding and total blood loss.


CONCLUSIONS
VLHL PAI-1 may provide an important physiological mechanism to protect clots from premature dissolution in surgical and trauma settings.
Jankun
Jerzy
J
Urology Research Center, Department of Urology, Health Science Campus, The University of Toledo, Toledo, OH 43614, USA. Jerzy.Jankun@utoledo.edu
Selman
Steven H
SH
Keck
Rick W
RW
Łysiak-Szydłowska
Wiesława
W
Skrzypczak-Jankun
Ewa
E
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D006470:Hemorrhage / Q000517:prevention & control*; D006490:Hemostatics / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000627:therapeutic use*
D006490:Hemostatics; D017395:Plasminogen Activator Inhibitor 1