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. 1989 May;83(5):1747–1752. doi: 10.1172/JCI114076

Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor.

R R Schleef 1, D L Higgins 1, E Pillemer 1, L J Levitt 1
PMCID: PMC303885  PMID: 2496147

Abstract

We evaluated an elderly patient with a lifelong history of severe bleeding after surgery or trauma and with evidence of persistent hyperfibrinolysis. Routine coagulation studies were normal. Serum plasminogen (40%, normal 72-128%) and alpha 2-antiplasmin (55%, normal 70-145%) activities were decreased. Euglobulin clot lysis was abnormally shortened (50 min) and normalized in vitro with epsilon-aminocaproic acid (EACA). The patient was treated with EACA with prompt cessation of bleeding. Patient tissue-plasminogen activator (t-PA) levels in serum were normal (4.7 ng/ml, control 3.5-7.2) as detected by a two-site immunoradiometric assay (IRMA). Patient fibrinolytic inhibitor activities were assessed by incubating 125I-labeled t-PA with either whole blood or serum followed by SDS-PAGE and autoradiography to identify the resultant protease/protease inhibitor complexes. In comparison to blood samples obtained from normal donors, patient plasma and serum demonstrated reduced binding of a fast-acting plasminogen activator inhibitor to 125I-labeled t-PA. Immunoprecipitation experiments indicated diminished complex formation between type 1 plasminogen activator inhibitor (PAI-1) in patient serum and 125I-labeled t-PA. Low patient PAI-1 activity was confirmed in serum (0.36 U/ml, control 0.87-1.81; n = 3) and in platelet lysates using a functional IRMA to quantitate PAI-1 binding to immobilized t-PA. However, patient serum PAI-1 antigen was within the normal range when analyzed by IRMA (31.8 ng/ml, control 19.6-42.2); this result was confirmed in both serum and platelets by Western blot (n = 3). Mixing experiments using purified PAI-1 as well as patient and control sera did not show evidence for an inhibitor against PAI-1. We conclude that this patient's bleeding diathesis was due to hyperfibrinolysis and defective PAI-1. This patient provides the first demonstration of a link between decreased in vivo PAI-1 activity and disordered hemostasis, and supports a role for PAI-1 in control of vivo fibrinolysis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoki N., Saito H., Kamiya T., Koie K., Sakata Y., Kobakura M. Congenital deficiency of alpha 2-plasmin inhibitor associated with severe hemorrhagic tendency. J Clin Invest. 1979 May;63(5):877–884. doi: 10.1172/JCI109387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aznar J., Estellés A., Vila V., Regañn E., España F., Villa P. Inherited fibrinolytic disorder due to an enhanced plasminogen activator level. Thromb Haemost. 1984 Oct 31;52(2):196–200. [PubMed] [Google Scholar]
  3. Bauer K. A., Rosenberg R. D. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood. 1987 Aug;70(2):343–350. [PubMed] [Google Scholar]
  4. Bevilacqua M. P., Schleef R. R., Gimbrone M. A., Jr, Loskutoff D. J. Regulation of the fibrinolytic system of cultured human vascular endothelium by interleukin 1. J Clin Invest. 1986 Aug;78(2):587–591. doi: 10.1172/JCI112613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Booth N. A., Bennett B., Wijngaards G., Grieve J. H. A new life-long hemorrhagic disorder due to excess plasminogen activator. Blood. 1983 Feb;61(2):267–275. [PubMed] [Google Scholar]
  6. Colucci M., Paramo J. A., Collen D. Inhibition of one-chain and two-chain forms of human tissue-type plasminogen activator by the fast-acting inhibitor of plasminogen activator in vitro and in vivo. J Lab Clin Med. 1986 Jul;108(1):53–59. [PubMed] [Google Scholar]
  7. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  8. Erickson L. A., Hekman C. M., Loskutoff D. J. The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8710–8714. doi: 10.1073/pnas.82.24.8710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Erickson L. A., Schleef R. R., Ny T., Loskutoff D. J. The fibrinolytic system of the vascular wall. Clin Haematol. 1985 Jun;14(2):513–530. [PubMed] [Google Scholar]
  10. Francis C. W., Marder V. J. Concepts of clot lysis. Annu Rev Med. 1986;37:187–204. doi: 10.1146/annurev.me.37.020186.001155. [DOI] [PubMed] [Google Scholar]
  11. Ginsburg D., Zeheb R., Yang A. Y., Rafferty U. M., Andreasen P. A., Nielsen L., Dano K., Lebo R. V., Gelehrter T. D. cDNA cloning of human plasminogen activator-inhibitor from endothelial cells. J Clin Invest. 1986 Dec;78(6):1673–1680. doi: 10.1172/JCI112761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hamsten A., Wiman B., de Faire U., Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med. 1985 Dec 19;313(25):1557–1563. doi: 10.1056/NEJM198512193132501. [DOI] [PubMed] [Google Scholar]
  13. Hekman C. M., Loskutoff D. J. Kinetic analysis of the interactions between plasminogen activator inhibitor 1 and both urokinase and tissue plasminogen activator. Arch Biochem Biophys. 1988 Apr;262(1):199–210. doi: 10.1016/0003-9861(88)90182-8. [DOI] [PubMed] [Google Scholar]
  14. Kluft C., Vellenga E., Brommer E. J., Wijngaards G. A familial hemorrhagic diathesis in a Dutch family: an inherited deficiency of alpha 2-antiplasmin. Blood. 1982 Jun;59(6):1169–1180. [PubMed] [Google Scholar]
  15. Loskutoff D. J., Sawdey M., Mimuro J. Type 1 plasminogen activator inhibitor. Prog Hemost Thromb. 1989;9:87–115. [PubMed] [Google Scholar]
  16. Miles L. A., Plow E. F., Donnelly K. J., Hougie C., Griffin J. H. A bleeding disorder due to deficiency of alpha 2-antiplasmin. Blood. 1982 Jun;59(6):1246–1251. [PubMed] [Google Scholar]
  17. Nilsson I. M., Ljungnér H., Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J (Clin Res Ed) 1985 May 18;290(6480):1453–1456. doi: 10.1136/bmj.290.6480.1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rheinwald J. G., Jorgensen J. L., Hahn W. C., Terpstra A. J., O'Connell T. M., Plummer K. K. Mesosecrin: a secreted glycoprotein produced in abundance by human mesothelial, endothelial, and kidney epithelial cells in culture. J Cell Biol. 1987 Feb;104(2):263–275. doi: 10.1083/jcb.104.2.263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sakata Y., Loskutoff D. J., Gladson C. L., Hekman C. M., Griffin J. H. Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood. 1986 Dec;68(6):1218–1223. [PubMed] [Google Scholar]
  20. Schleef R. R., Bevilacqua M. P., Sawdey M., Gimbrone M. A., Jr, Loskutoff D. J. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. J Biol Chem. 1988 Apr 25;263(12):5797–5803. [PubMed] [Google Scholar]
  21. Schleef R. R., Sinha M., Loskutoff D. J. Characterization of two monoclonal antibodies against human tissue-type plasminogen activator. Thromb Haemost. 1985 Apr 22;53(2):170–175. [PubMed] [Google Scholar]
  22. Schleef R. R., Sinha M., Loskutoff D. J. Immunoradiometric assay to measure the binding of a specific inhibitor to tissue-type plasminogen activator. J Lab Clin Med. 1985 Oct;106(4):408–415. [PubMed] [Google Scholar]
  23. Sprengers E. D., Kluft C. Plasminogen activator inhibitors. Blood. 1987 Feb;69(2):381–387. [PubMed] [Google Scholar]
  24. Tate K. M., Higgins D. L., Holmes W. E., Winkler M. E., Heyneker H. L., Vehar G. A. Functional role of proteolytic cleavage at arginine-275 of human tissue plasminogen activator as assessed by site-directed mutagenesis. Biochemistry. 1987 Jan 27;26(2):338–343. doi: 10.1021/bi00376a002. [DOI] [PubMed] [Google Scholar]
  25. van Mourik J. A., Lawrence D. A., Loskutoff D. J. Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J Biol Chem. 1984 Dec 10;259(23):14914–14921. [PubMed] [Google Scholar]

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