Plasminogen Activator Inhibitor 1 and Plasminogen Activator Inhibitor 2 in Various Disease States

Summary

The association of increased PA-inhibitor (PAI) activity and of PAI-1 and PAI-2 antigen levels with different pathological conditions was studied in a collective of over 300 patients. PAI-1 and PAI-2 levels were measured by specific radioimmunoassays. A good correlation was observed of PAI activity with PAI-1 antigen (r = 0.718; p <0.0001) but not with PAI-2 (r = 0.070; n.s.). Both in the controls and in the patients, PAI activity and PAI-1 antigen showed an extremely large range of values. PAI activity ranged from 0.5 to 68 U/ml and PAI-1 antigen from 6 to 600 ng/ml. Increased PAI activity and PAI-1 antigen was observed in patients with malignant tumors, cardiovascular or thromboembolic disease, in the postoperative phase, with hepatic insufficiency, after trauma and after extracorporeal circulation. The large spectrum of disease states with increased PAI activity and PAI-1 antigen reinforces previous suggestions that PAI-1 is an acute phase reactant. After extracorporeal circulation, PAI activity and PAI-1 concentrations strongly increased within one hour, remained elevated for at least one week and returned to preoperation values within 7 days.

PAI-2 values ranged from below detection limit (15 ng/ml), observed in half of the plasmas, to 485 ng/ml in a pregnant woman. High values of PAI-2 were only observed in pregnancy.

Key words

Tissue-type plasminogen activator - Urokinase - Plasminogen activator inhibition - Plasminogen activator inhibitor type 1 and 2

• References

• 1 Chmielewska J, Ranby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31: 427-436
• 2 Kruithof EK O, Tran-Thang C, Ransijn A, Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood 1984; 64: 907-913
• 3 Juhan-Vague I, Moerman B, De Cock F, Aillaud MF, Collen D. Plasma levels of a specific inhibitor of tissue-type plasminogen activator (and urokinase) in normal and pathological conditions. Thromb Res 1984; 33: 523-530
• 4 Verheijen JH, Chang GT G, Kluft C. Evidence of the occurrence of a fast-acting inhibitor for tissue-type plasminogen activator in human plasma. Thromb Haemostas 1984; 51: 392-395
• 5 Thorsen S, Philips M. Isolation of tissue-type plasminogen activator-inhibitor complexes from human plasma. Evidence for a rapid plasminogen activator inhibitor. Biochim Biophys Acta 1984; 802: 111-118
• 6 Kruithof EK O. Inhibitors of plasminogen activators. In: Tissue-type plasminogen activator: Physiological and clinical aspects. Kluft C. (ed.) CRC Press; Boca Raton: 1988. (in press)
• 7 Van Mourik JA, Lawrence DA, Loskutoff DJ. Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J Biol Chem 1984; 259: 14914-14921
• 8 Andreasen PA, Nielsen LS, Kristensen P, Grøndahl-Hansen J, Skriver L, Danø K. Plasminogen activator inhibitor from human fibrosarcoma cells binds urokinase-type plasminogen activator but not its proenzyme. J Biol Chem 1986; 261: 7644-7651
• 9 Astedt B, Lecander I, Brodin T, Lundblad A, Low K. Purification of a specific placental plasminogen activator inhibitor by monoclonal antibody and its complex formation with plasminogen activator. Thromb Haemostas 1985; 53: 122-125
• 10 Kopitar M, Rozman B, Babnik J, Turk V, Mullins DE, Wun TC. Human leukocyte urokinase inhibitor – Purification, characterization and comparative studies against different plasminogen activators. Thromb Haemostas 1985; 54: 750-755
• 11 Kruithof EK O, Vassalli J-D, Schleuning W-D, Mattaliano RJ, Bachmann F. Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937. J Biol Chem 1986; 261: 11207-11213
• 12 Kruithof EK O, Tran-Thang C, Bachmann F. The fast-acting inhibitor of tissue-type plasminogen activator in plasma is also the primary plasma inhibitor of urokinase. Thromb Haemostas 1986; 55: 65-69
• 13 Erickson LA, Hekman CM, Loskutoff DJ. The primary plasminogen activator inhibitors in endothelial cells, platelets, serum and plasma are immunologically related. Proc Natl Acad Sci USA 1985; 82: 8710-8714
• 14 Kruithof EK O, Tran-Thang C, Bachmann F. Studies on the release of a plasminogen activator inhibitor from human platelets. Thromb Haemostas 1986; 55: 201-205
• 15 Sprengers ED, Akkerman JW N, Jansen BG. Blood platelet plasminogen activator inhibitor: two different pools of endothelial cell type plasminogen activator inhibitor in human blood. Thromb Haemostas 1986; 55: 325-329
• 16 Booth NA, Anderson JA, Bennett B. Platelets release protein which inhibits plasminogen activators. J Clin Pathol 1985; 38: 825-830
• 17 Kawano X, Morimoto K, Uemura Y. Partial purification and properties of urokinase inhibitor from human placenta. J Biochem 1970; 67: 333-342
• 18 Kopitar M. Isolation and some characteristics of urokinase inhibitors isolated from pig leukocytes. Haemostasis 1981; 10: 215-232
• 19 Chapman HA, Vavrin Z, Hibbs JB. Macrophage fibrinolytic activity: identification of two pathways of plasmin formation by intact cells and of a plasminogen activator inhibitor. Cell 1982; 28: 653-662
• 20 Golder JP, Stephens RW. Minactivin: a human monocyte product which specifically inactivates urokinase-type plasminogen activator. Eur J Biochem 1983; 136: 517-522
• 21 Vassalli J-D, Dayer J-M, Wohlwend A, Belin D. Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages. J Exp Med 1984; 159: 1653-1668
• 22 Saksela O, Hovi T, Vaheri A. Urokinase-tvpe plasminogen activator and its inhibitor secreted by cultured human monocytes-macrophages. J Cell Physiol 1985; 122: 123-132
• 23 Hisazumi H, Naito K, Misaki T, Kosaka S. Urokinase inhibitor in patients with bladder cancer. Urol Res 1974; 2: 137
• 24 Páramo JA, Colucci M, Colen D. Plasminogen activator inhibitor in the blood of patients with coronary artery disease. Br Med J 1985; 291: 573-574
• 25 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. New Engl J Med 1985; 313: 1557-1563
• 26 Páramo JA, De Boer A, Colucci M, Jonker JJ C, Collen D. Plasminogen activator inhibitor activity in the blood of patients with deep vein thrombosis. Thrombos Haemostas 1985; 54: 725
• 27 Wiman B, Ljungberg J, Chmielewska J, Urden G, Blombáck M, Johnsson H. The role of the fibrinolytic system in deep vein thrombosis. J Lab Clin Med 1985; 105: 265-270
• 28 Brommer EJ P, Verheijen JH, Chang GT G, Rijken DC. Masking of fibrinolytic response to stimulation by an inhibitor of tissue-type plasminogen activator in plasma. Thromb Haemostas 1984; 52: 154-156
• 29 Nilsson IM, 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 1985; 290: 1453-1456
• 30 Colucci M, Páramo JA, Collen D. Generation in plasma of a fastacting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 1985; 75: 818-824
• 31 Engebretsen LF, Kierulf P, Brandtzaeg P. Extreme plasminogen activator inhibitor and endotoxin values in patients with meningococcal disease. Thromb Res 1986; 42: 713-716
• 32 Juhan-Vague I, Aillaud MF, De Cock F, Philip-Joet C, Arnaud C, Serradimigni A, Collen D. The fast-acting inhibitor of tissue-type plasminogen activator is an acute phase reactant protein. In: Progress in Fibrinolysis Vol 7. Davidson JF, Donati MB, Coccheri S. (eds.) Churchill Livingstone; Edinburgh: 1985: 146-149
• 33 Kluft C, Verheijen JH, Jie AF H, Rijken DC, Preston FE, Sue-Ling HM, Jespersen J, Aasen O. The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Invest 1985; 45: 605-610
• 34 Aillaud MF, Juhan-Vague I, Alessi MC, Marecal M, Vinson MF, Arnaud C, Vague P, Collen D. Increased PA-inhibitor levels in the postoperative period – no cause-effect relation with increased cortisol. Thromb Haemostas 1985; 54: 466-468
• 35 Páramo JA, Alfaro MJ, Rocha E. Postoperative changes in the plasma level of tissue-type plasminogen activator and its fast-acting inhibitor. Relationship to deep vein thrombosis and influence of prophylaxis. Thromb Haemostas 1985; 54: 713-716
• 36 Sue-Ling HM, Davies JA, Prentice CR M, Verheijen JH, Kluft C. Effects of oral stanozolol used in the prevention of postoperative deep vein thrombosis on fibrinolytic activity. Thromb Haemostas 1985; 53: 141-142
• 37 Mcllbring G, Dahlgren S, Wiman B, Surregardh O. Relationship between preoperative status of the fibrinolytic system and occurrence of deep vein thrombosis after major abdominal surgery. Thromb Res 1985; 39: 157-163
• 38 D’Angelo A, Kluft C, Verheijen JH, Rijken DC, Mozzi E, Mannucci PM. Fibrinolytic shutdown after surgery: impairment of the balance between tissue-type plasminogen activator and its specific inhibitor. Eur J Clin Invest 1985; 15: 308-312
• 39 Lecander L, Åstedt B. Isolation of a new specific plasminogen activator inhibitor from pregnancy plasma. Br J Haematol 1986; 62: 221-228
• 40 Kruithof EK O, Tran-Thang C, Gudinchet A, Hauert J, Nicoloso G, Genton C, Welti H, Bachmann F. Fibrinolysis in pregnancy. A study on plasminogen activator inhibitors. Blood 1987; 69: 460-466
• 41 Kruithof EK O, Schleuning WD, Bachmann F. Human tissue-type plasminogen activator. Production in continuous serum-free cell culture and rapid purification. Biochem J 1985; 226: 631-636
• 42 Kruithof EK O, Nicoloso G, Bachmann F. Plasminogen activator inhibitor 1: development of a radioimmunoassay and observations on its plasma concentration after venous occlusion and platelet aggregation. Blood 1987; 70: 1645-1653
• 43 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254
• 44 Fraker PJ, Speck JC. Protein and cell membrane iodinations with a sparingly soluble chloramide, 1, 2,4,6, tetrachloro-3a-6a-diphenyl glycoluril. Biochem Biophys Res Commun 1978; 80: 849-857
• 45 Wissenschaftliche Tabellen Geigy. Vol 3. Statistik. 8. Auflage, Ciba Geigy, Basel 1980
• 46 De Jong E, Knot EA R, Piket D, Iburg AH C, Rijken DC, Veenhof KH N, Dooijewaard G, Ten Cate JW. Increased plasminogen activator inhibition levels in malignancy. Thromb Haemostas 1987; 57: 140-143
• 47 Dawes J, Simth RC, Pepper DS. The release, distribution and clearance of human P-thromboglobulin and platelet factor 4. Thromb Res 1978; 12: 851-861
• 48 Åstedt B, Hägerstrand I, Lecander I. Cellular localisation in placenta of placenta type plasminogen activator inhibitor. Thromb Haemostas 1986; 56: 63-65
• 49 Levin EG. Quantitation and properties of the active and latent plasminogen activator inhibitors in cultures of human endothelial cells. Blood 1986; 67: 1309-1313
• 50 Mellbring G, Dahlgren S, Wiman B. Plasma fibrinolytic activity in patients undergoing major abdominal surgery. Acta Chir Scand 1985; 151: 109-114