Comparison Between the Clot-protecting Activity of a Mutant Plasminogen Activator Inhibitor-1 with a Very Long Half-life and 6-aminocaproic Acid

Overview

Journal Exp Ther Med

Specialty Pathology

Date 2015 Jul 3

PMID 26136983

Citations 5

Authors

Daniel Glenn Kindell

Rick Wayne Keck

Jerzy Jankun

Affiliations

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Abstract

Plasminogen activator inhibitor (PAI)-1 is a serpin glycoprotein that can stabilize blood clots by inhibiting fibrinolysis. However, wild-type PAI-1 has the disadvantage of a short half-life of ∼2 h. A very long half-life (VLHL) PAI-1 mutant was developed previously with an active-form half-life of >700 h, making it a possible candidate for use in hemorrhagic therapy. Current treatments for mitigating hemorrhage, other than inducers of blood clotting, are limited to lysine analog antifibrinolytics, including 6-aminocaproic acid and tranexamic acid. VLHL PAI-1 has been previously demonstrated to limit bleeding; however, the efficacy of this protein compared with lysine analog antifibrinolytics has not been investigated. The aim of the current study was to compare the clot stabilizing properties of the novel antifibrinolytic VLHL PAI-1 with those of 6-aminocaproic acid in reference plasma. Using thromboelastographic analysis, VLHL PAI-1 exhibited an IC (half maximal inhibitory concentration) of 8.8×10 mol/l, while 6-aminocaproic acid showed an IC of 1.6×10 mol/l. However, at doses of >9.0×10 mol/l, VLHL PAI-1 exhibited a delay in the onset of clot formation, which may be attributed to thrombin inhibition by excess PAI-1. The inhibition of tissue plasminogen activator by VLHL PAI-1 demonstrated improved efficacy over 6-aminocaproic acid in mitigating hemorrhage. In addition, patients with a PAI-1 deficiency, which causes blood clots to lyse rapidly resulting in profuse bleeding, may benefit from the application of VLHL PAI-1 as an antihemorrhagic therapy.

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References

Jankun J, Skrzypczak-Jankun E . Yin and yang of the plasminogen activator inhibitor. Pol Arch Med Wewn. 2009; 119(6):410-7. View

Zorio E, Gilabert-Estelles J, Espana F, Ramon L, Cosin R, Estelles A . Fibrinolysis: the key to new pathogenetic mechanisms. Curr Med Chem. 2008; 15(9):923-9. DOI: 10.2174/092986708783955455. View

Genet G, Ostrowski S, Sorensen A, Johansson P . Detection of tPA-induced hyperfibrinolysis in whole blood by RapidTEG, KaolinTEG, and functional fibrinogenTEG in healthy individuals. Clin Appl Thromb Hemost. 2012; 18(6):638-44. DOI: 10.1177/1076029611434527. View

Jankun J, Aleem A, Selman S, Skrzypczak-Jankun E, Lysiak-Szydlowska W, Grafos N . Highly stable plasminogen activator inhibitor type one (VLHL PAI-1) protects fibrin clots from tissue plasminogen activator-mediated fibrinolysis. Int J Mol Med. 2007; 20(5):683-7. View

Schulman S . Pharmacologic tools to reduce bleeding in surgery. Hematology Am Soc Hematol Educ Program. 2012; 2012:517-21. DOI: 10.1182/asheducation-2012.1.517. View

Jankun J, Skrzypczak-Jankun E . Bleeding diathesis is associated with an A15T heterozygous mutation in exon 2 of the plasminogen activator inhibitor type 1. Exp Ther Med. 2012; 1(4):575-577. PMC: 3445900. DOI: 10.3892/etm_00000090. View

Morimoto Y, Yoshioka A, Imai Y, Takahashi Y, Minowa H, Kirita T . Haemostatic management of intraoral bleeding in patients with congenital deficiency of alpha2-plasmin inhibitor or plasminogen activator inhibitor-1. Haemophilia. 2004; 10(5):669-74. DOI: 10.1111/j.1365-2516.2004.00914.x. View

Mosesson M . Fibrinogen and fibrin structure and functions. J Thromb Haemost. 2005; 3(8):1894-904. DOI: 10.1111/j.1538-7836.2005.01365.x. View

Jankun J, Selman S, Keck R, Lysiak-Szydlowska W, Skrzypczak-Jankun E . Very long half-life plasminogen activator inhibitor type 1 reduces bleeding in a mouse model. BJU Int. 2009; 105(10):1469-76. DOI: 10.1111/j.1464-410X.2009.08962.x. View

10.

Jankun J, Aleem A, Struniawski R, Lysiak-Szydlowska W, Selman S, Skrzypczak-Jankun E . Accelerated thrombus lysis in the blood of plasminogen activator inhibitor deficient mice is inhibited by PAI-1 with a very long half-life. Pharmacol Rep. 2009; 61(4):673-80. DOI: 10.1016/s1734-1140(09)70119-7. View

11.

Sharp A, Stein P, Pannu N, Carrell R, Berkenpas M, Ginsburg D . The active conformation of plasminogen activator inhibitor 1, a target for drugs to control fibrinolysis and cell adhesion. Structure. 1999; 7(2):111-8. DOI: 10.1016/S0969-2126(99)80018-5. View

12.

Fergusson D, Hebert P, Mazer C, Fremes S, MacAdams C, Murkin J . A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008; 358(22):2319-31. DOI: 10.1056/NEJMoa0802395. View

13.

Mehta R, Shapiro A . Plasminogen activator inhibitor type 1 deficiency. Haemophilia. 2009; 14(6):1255-60. DOI: 10.1111/j.1365-2516.2008.01834.x. View

14.

Rau J, Beaulieu L, Huntington J, Church F . Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost. 2007; 5 Suppl 1:102-15. PMC: 2670448. DOI: 10.1111/j.1538-7836.2007.02516.x. View

15.

Chorostowska-Wynimko J, Swiercz R, Skrzypczak-Jankun E, Wojtowicz A, Selman S, Jankun J . A novel form of the plasminogen activator inhibitor created by cysteine mutations extends its half-life: relevance to cancer and angiogenesis. Mol Cancer Ther. 2003; 2(1):19-28. View

16.

Harrop S, Jankova L, Coles M, Jardine D, Whittaker J, Gould A . The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function. Structure. 1999; 7(1):43-54. DOI: 10.1016/s0969-2126(99)80008-2. View

17.

Iribarren J, Jimenez J, Hernandez D, Brouard M, Riverol D, Lorente L . Postoperative bleeding in cardiac surgery: the role of tranexamic acid in patients homozygous for the 5G polymorphism of the plasminogen activator inhibitor-1 gene. Anesthesiology. 2008; 108(4):596-602. DOI: 10.1097/ALN.0b013e318167aecc. View

18.

Jankun J, Skrzypczak-Jankun E . Plasminogen activator inhibitor with very long half-life (VLHL PAI-1) can reduce bleeding in PAI-1-deficient patients. Cardiovasc Hematol Disord Drug Targets. 2013; 13(2):144-50. DOI: 10.2174/1871529x11313020007. View

19.

Jankun J, Yang J, Zheng H, Han F, Al-Senaidy A, Skrzypczak-Jankun E . Remarkable extension of PAI-1 half-life surprisingly brings no changes to its structure. Int J Mol Med. 2011; 29(1):61-4. DOI: 10.3892/ijmm.2011.798. View

20.

Schleef R, Higgins D, Pillemer E, Levitt L . Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest. 1989; 83(5):1747-52. PMC: 303885. DOI: 10.1172/JCI114076. View