Accelerated thrombus lysis in the blood of plasminogen activator inhibitor deficient mice is inhibited by PAI-1 with a very long half-life.
Patients with defective plasminogen activator inhibitor protein (PAI-1) or with PAI-1 deficiency can experience hemorrhage as a result of a hyperfibrinolysis. In these patients, a normal thrombus forms, but endogenous lysis is unchecked as tissue plasminogen activator is unopposed. Treatment includes anti-fibrinolytic agents, including oral tranexamic acid. Another treatment option is the administration of PAI-1, but this serpin rapidly inactivates itself. We have developed a mutant plasminogen activator inhibitor with a very long half life (VLHL PAI-1, t1/2>700 h). Here we investigate VLHL PAI-1 effects in the blood of PAI-1 deficient mice, as a model of human disease. Using a thrombelastograph, we found that blood clots of PAI-1 knockout mice were lysed much more quickly than wild type mice. Additionally, blood clots had less shear elastic modulus strength than clots of normal animals. VLHL PAI-1 treatment of PAI-1 deficient mice extended or prevented thrombus lysis and increased clot strength in a concentration dependent fashion. These two parameters determine the extent of thrombus growth and regression; thus, further testing is anticipated to confirm the effectiveness of plasminogen activator inhibitor with a very long half life in an in vivo model and we hope that this protein can be effective in human PAI-1 deficiency disorder.
Jankun
Jerzy
J
Urology Research Center, Department of Urology, Health Science Campus, The Univesrsity of Toledo, Toledo, OH 43614, USA. Jerzy.Jankun@utoledo.edu
Aleem
Ansari M
AM
Struniawski
Radosław
R
Lysiak-Szydłowska
Wiesława
W
Selman
Steven H
SH
Skrzypczak-Jankun
Ewa
E
D000818:Animals; D006207:Half-Life; D006801:Humans; D007313:Insecta; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use; D015849:Plasminogen Inactivators / Q000097:blood / Q000172:deficiency / Q000627:therapeutic use; D015912:Thrombolytic Therapy / Q000379:methods; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy
D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators