Download PDF
Thromb Haemost 1989; 62(02): 673-680
DOI: 10.1055/s-0038-1646881
Original Article
Schattauer GmbH Stuttgart

Elevated Plasminogen Activator Inhibitor (PAI), a Cause of Thrombophilia? – A Study in 203 Patients with Familial or Sporadic Venous Thrombophilia

L Engesser
1   The Gaubius Institute TNO, Leiden, The Netherlands
2   The Department of Hematology, University Hospital Leiden, The Netherlands
,
E J P Brommer
1   The Gaubius Institute TNO, Leiden, The Netherlands
,
C Kluft
1   The Gaubius Institute TNO, Leiden, The Netherlands
,
E Briët
2   The Department of Hematology, University Hospital Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 07 September 1988

Accepted after revision 03 April 1989

Publication Date:
30 June 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Two hundred and three patients with venous thrombophilia were investigated in order to find out whether an elevated plasma concentration of plasminogen activator inhibitor (PAI) could be a cause of their tendency to thrombosis. The patients were studied in an asymptomatic period about 3 months after their last thromboembolic episode. PAI activity was found to be elevated in 19 patients (9%), and a corresponding elevation of PAI-1 antigen was observed.

In 16 out of the 19 patients with elevated PAI activity, followup could be performed after an additional asymptomatic period of about 1 year: in eight patients the elevation of PAI was transient and in eight it was persistent. Out of the eight patients with a persistent elevation of PAI, seven had a positive family history of thrombosis. Investigation of these families excluded a hereditary elevation of PAI activity in two families. In only two other families was elevated PAI activity also found among family members. The occurrence of elevated PAI activity, however, did not coincide with the occurrence of thrombosis in these individuals: except for the probands, all investigated family members who had a history of thrombosis had a normal PAI activity.

We therefore conclude that, at least in our material, familial thrombophilia can not be attributed to an inherited, persistent elevation of the blood level of PAI.

Keywords

Plasminogen activator inhibitor - Venous thrombosis - Thrombophilia
 

  • References

  • 1 Egeberg O. Inherited antithrombin III deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-530
    PubMedGoogle Scholar
  • 2 Griffin JH, Evatt B, Zimmermann TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68: 1370-1373
    CrossrefPubMedGoogle Scholar
  • 3 Comp PC, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-2088
    CrossrefPubMedGoogle Scholar
  • 4 Aoki N, Moroi M, Sakata Y, Yoshida N. Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 1978; 61: 1186-1195
    CrossrefPubMedGoogle Scholar
  • 5 Soria J, Soria C, Caen JP. A new type of congenital dysfibrinogenaemia with defective fibrin lysis - Dusard Syndrome: possible relation to thrombosis. Br J Haematol 1983; 53: 575-586
    CrossrefPubMedGoogle Scholar
  • 6 Wun TC, Capuano A. Spontaneous fibrinolysis in whole human plasma. Identification of tissue activator-related protein as the major plasminogen activator causing spontaneous activity in vitro. J Biol Chem 1985; 260: 5061-5066
    PubMedGoogle Scholar
  • 7 Brommer EJ P. The level of extrinsic plasminogen activator (t-PA) during clotting as a determinant of the rate of fibrinolysis; inefficiency of activators added afterwards. Thromb Res 1984; 34: 109-115
    CrossrefPubMedGoogle Scholar
  • 8 Verheijen JH, Chang GT G, Kluft C. Evidence for the occurrence of a fast-acting inhibitor for tissue-type plasminogen activator in human plasma. Thromb Haemostas 1984; 51: 392-395
    PubMedGoogle Scholar
  • 9 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
    CrossrefPubMedGoogle Scholar
  • 10 Stalder M, Hauert J, Kruithof EK O, Bachmann F. Release of vascular plasminogen activator (v-PA) after venous stasis: electrophoretic-zymographic analysis of free and complexed v-PA. Br J Haematol 1985; 61: 169-176
    CrossrefPubMedGoogle Scholar
  • 11 Hamsten A, Wiman B, De Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-1563
    CrossrefPubMedGoogle Scholar
  • 12 Páramo JA, Alfaro MJ, Rocha E. Postoperative changes in the plasmatic levels 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
    PubMedGoogle Scholar
  • 13 Nilsson IM, Ljungner 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
    CrossrefPubMedGoogle Scholar
  • 14 Juhan-Vague I, Valadier J, Alessi MC, Aillaud MF, Ansaldi J, Philip-Joet C, Holvoet P, Serradimigni A, Collen D. Deficient t-PA release and elevated PA inhibitor levels in patients with spontaneous or recurrent deep venous thrombosis. Thromb Haemostas 1987; 57: 67-72
    PubMedGoogle Scholar
  • 15 Jørgensen M, Bonnevie-Nielsen V. Increased concentration of the fast-acting plasminogen activator inhibitor in plasma associated with familial venous thrombosis. Br J Haematol 1987; 65: 175-180
    CrossrefPubMedGoogle Scholar
  • 16 Nilsson IM, Tengborn L. Impaired fibrinolysis. New evidence in relation to thrombosis. In: Clinical Aspects of Fibrinolysis and Thrombosis. Jespersen J, Kluft C, Korsgaard O. (eds) South Jutland University Press; Esbjerg: 1983: 273-291
    Google Scholar
  • 17 Pizzo SV, Fuchs HE, Doman KA, Petruska DB, Berger jr H. Release of tissue plasminogen activator and its fast-acting inhibitor in defective fibrinolysis. Arch Intern Med 1986; 146: 188
    CrossrefPubMedGoogle Scholar
  • 18 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. Davidson JF, Donati MB, Coccheri S. (eds) Churchill Livingstone; Edinburgh: 1985. (; VII). 146-149
    Google Scholar
  • 19 Kluft C, Verheijen JH, Jie AF H, Rijken DC, Preston FE, Sue-Ling HM, Jespersen J, Aasen AO. 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 Lab Invest 1985; 45: 605-610
    CrossrefPubMedGoogle Scholar
  • 20 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
    CrossrefPubMedGoogle Scholar
  • 21 Engebretsen LF, Kierulf P, Brandtzag P. Extreme plasminogen activator inhibitor and endotoxin values in patients with meningococcal disease. Thromb Res 1986; 42: 713-716
    CrossrefPubMedGoogle Scholar
  • 22 Brommer EJ P, Gevers Leuven JA, Barrett-Bergshoeff MM, Schouten JA. Response of fibrinolytic activity and factor VIII related antigen with desmopressin in hyperlipoproteinemia. J Lab Clin Med 1982; 100: 105-114
    PubMedGoogle Scholar
  • 23 Ahmad M, Saku K, Glas-Greenwalt P, Kashyap ML. Inhibitor and activator of plasminogen in patients with hyperlipoproteinemia. Thromb Haemostas 1985; 54: 266 (Abstr)
    PubMedGoogle Scholar
  • 24 Aillaud MF, Pignol F, Alessi MC, Harle JR, Escande M, Mongin M, Juhan-Vague I. Increase in plasma concentration of plasminogen activator inhibitor, fibrinogen, von Willebrand factor, factor VIII: C and in erythrocyte sedimentation rate with age. Thromb Haemostas 1986; 55: 330-332
    PubMedGoogle Scholar
  • 25 Åstedt B, Holmberg L, Nilsson IM. An inhibitor of plasminogen activator in pregnancy plasma. In: Progress in fibrinolysis. Davidson JF, Donati MB, Coccheri S. (eds) Churchill Livingstone; Edinburgh: 1985. (; VII). 122-125
    Google Scholar
  • 26 Wiman B, Csemiczky G, Marsk L, Robbe H. The fast inhibitor of tissue plasminogen activator in plasma during pregnancy. Thromb Haemostas 1984; 52: 124-126
    PubMedGoogle Scholar
  • 27 Kluft C, Verheijen JH, Rijken DC, Chang GT G, Jie AF H, Onkelinx C. Diurnal fluctuations in the activity of the fast-acting t-PA inhibitor. In: Progress in Fibrinolysis. Davidson JF, Donati MB, Coccheri S. (eds) Churchill Livingstone; Edinburgh: 1985. (; VII). 117-119
    Google Scholar
  • 28 Gaffney PJ, Curtis AD. A collaborative study of a proposed international standard for tissue-type plasminogen activator (t-PA). Thromb Haemostas 1985; 53: 134-136
    PubMedGoogle Scholar
  • 29 Rijken DC, Sprengers ED, Van der Hoeven RJ, Jansen BG. An enzyme immunoassay for endothelial cell-type plasminogen activator inhibitor (PAI). Fibrinolysis 1986; suppl (Suppl. 01) abstract 141
    PubMedGoogle Scholar
  • 30 Sprengers ED, Van Hinsbergh VW M, Jansen BG. The active and inactive plasminogen activator inhibitor from human endothelial cell conditioned medium are immunologically and functionally related to each other. Biochim Biophys Acta 1986; 878: 223-241
    PubMedGoogle Scholar
  • 31 Verheijen JH, Mullaart E, Chang GT G, Kluft C, Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurements in plasma. Thromb Haemostas 1982; 48: 266-269
    PubMedGoogle Scholar
  • 32 Rijken DC, Van Hinsbergh VW M, Sens EH C. Quantitation of tissue-type plasminogen activator in human endothelial cell cultures by use of an enzyme immunoassay. Thromb Res 1984; 33: 145-153
    CrossrefPubMedGoogle Scholar
  • 33 Bertina RM, Broekmans AW, Van der Linden IK, Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemostas 1982; 48: 1-5
    PubMedGoogle Scholar
  • 34 Bertina RM, Van Wijngaarden A, Reinalda-Poot J, Poort SR, Bom VJ J. Determination of plasma protein S - the protein cofactor of activated protein C. Thromb Haemostas 1985; 53: 268-272
    PubMedGoogle Scholar
  • 35 Abildgaard U, Lie N, Odegaard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrates. Thromb Res 1977; 11: 549-553
    CrossrefPubMedGoogle Scholar
  • 36 Chew V. Confidence, prediction, and tolerance of regions for the multivariate normal distribution. J Am Stat Assoc 1966; 61: 605-617
    CrossrefPubMedGoogle Scholar
  • 37 Wiman B, Ljungberg B, Chmielewska J, Urden G, Blomback M, Johnsson H. The role of the fibrinolytic system in deep vein thrombosis. J Lab Clin Med 1985; 105: 265-270
    PubMedGoogle Scholar
  • 38 Brommer EJ P, Barrett-Bergshoeff MM, Allen RA, Schicht I, Bertina RM, Schalekamp MADH. The use of desmopressin acetate (DDAVP) as a test of the fibrinolytic capacity of patients - analysis of responders and non-responders. Thromb Haemostas 1982; 48: 156-161
    PubMedGoogle Scholar
  • 39 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
    PubMedGoogle Scholar
  • 40 Vague P, Juhan Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Metabolism 1986; 35: 250-253
    CrossrefPubMedGoogle Scholar
  • 41 Juhan-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationship between plasma insulin, triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabete Metabolisme 1987; 13: 331-336
    PubMedGoogle Scholar