Accelerated thrombus lysis in the blood of plasminogen activator inhibitor deficient mice is inhibited by PAI-1 with a very long half-life

Abstract

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.

Behçet’s disease: new insight into the relationship between procoagulant state, endothelial activation/damage and disease activity

“…These mechanisms may explain, at least in part, the increased plasma levels of PAI-1 in BD patients because they show systemic activation of coagulation and increased thrombin production in response to stimulus. Increased levels of PAI-1 can increase the clot formation speed and clot stability [47,48] due to the rapid and irreversible blockage of the protease activity of tPA, the main plasminogen activator [49]. Our results agree with this observation given that we found a significant correlation between antigenic levels of PAI-1 and INTEM-CFT, INTEM-α and INTEM-MCF, which points to PAI-1 as a key factor in the procoagulant state observed in BD patients by this test.…”

Can inactivators of plasminogen activator inhibitor alleviate the burden of obesity and diabetes? (Review)

“…It is tightly controlled at the level of expression, activation and inhibition. The PAS is involved in many of the biological processes and depending on disease its overexpression or underexpression can sometimes lead to surprising outcomes (6)(7)(8)(9).…”

“…For example, the Arg369Ala substitution in active site of PAI-1 results in nonactive PAI-1 (7,8,27). Several mutants with extended half-life have been produced in the past (t ½ , 6-170 h) (8,17,20,(28)(29)(30).…”

Immunohistochemical detection of uPA, tPA, and PAI-1 in a stasis-induced deep vein thrombosis model and its application to thrombus age estimation

“…Both uPA and tPA are responsible for cleaving plasminogen, a large serum β-globulin that is deposited on the fibrin strands within a thrombus. On the other hand, plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor family, has been shown to regulate uPA and tPA, resulting in the inhibition of proteolytic activity [28][29][30][31].…”