Download PDF
Thromb Haemost 1992; 67(01): 111-116
DOI: 10.1055/s-0038-1648390
Original Articles
Schattauer GmbH Stuttgart

Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

Quantitative Assessment of Plasmin-α2-Antiplasmin Complex with a Novel Monoclonal Antibody Based Radioimmunoassay
Marcel Levi
1   The Center for Thrombosis, Haemostasis and Atherosclerosis Research, Academic Medical Center, Amsterdam, The Netherlands
,
Jan Paul de Boer
2   Dept. of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Bloodtransfusion Service and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands
,
Dorina Roem
2   Dept. of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Bloodtransfusion Service and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands
,
Jan Wouter ten Cate
1   The Center for Thrombosis, Haemostasis and Atherosclerosis Research, Academic Medical Center, Amsterdam, The Netherlands
,
C Erik Hack
2   Dept. of Autoimmune Diseases, Central Laboratory of the Netherlands Red Cross Bloodtransfusion Service and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 09 April 1991

Accepted after revision 24 July 1991

Publication Date:
02 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Infusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.

A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.

Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.

We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

 

  • References

  • 1 Mannucci PM, Rota L. Plasminogen activator response after DDAVP: a clinicopharmacological study. Thromb Res 1980; 20: 69-76
    CrossrefPubMedGoogle Scholar
  • 2 Prowse CV, Farrugia A, Boulton F, Tucker J, Ludlam CA, McLaren M. et al A comparative study using immunological and biological assays of the haemostatic responses to DDAVP infusion, venous occlusion and exercise in normal men. Thromb Haemostas 1984; 51: 110-114
    PubMedGoogle Scholar
  • 3 Levi M, ten Cate JW, Dooijewaard G, Sturk A, Brommer EJP, Agnelli G. DDAVP induces systemic release of urokinase-type plasminogen activator. Thromb Haemostas 1989; 62: 686-689
    PubMedGoogle Scholar
  • 4 Brommer EJP, Barrett-Bergshoeff MM, Allen RA, Schicht J, 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
  • 5 Aoki N, Moroi M, Matsuda M, Tachiyaka K. The behavior of a2 plasmin inhibitor in fibrinolytic states. J Clin Invest 1977; 60: 361-369
    CrossrefPubMedGoogle Scholar
  • 6 Sasahara AA, Hyers TM, Cole CM. et al The urokinase pulmonary embolus trial: A national cooperative study. Circulation 1973; 47 II 33-59
    PubMedGoogle Scholar
  • 7 Harpel PC. a2-plasmin inhibitor and a2-macroglobulin-plasmin complexes in plasma. J Clin Invest 1981; 68: 46-55
    CrossrefPubMedGoogle Scholar
  • 8 Collen D, de Cock F, Cambiaso CL, Masson P. A latex agglutination test for rapid quantitative estimation of the plasmin-antiplasmin complex in human plasma. Eur J Clin Invest 1977; 7: 21-26
    CrossrefPubMedGoogle Scholar
  • 9 Wiman B, Jacobson L, Andersson M, Mellbring G. Determination of plasmin-a2-antiplasmin complex in plasma samples by means of a radioimmunoassay. Scand J Clin Lab Invest 1983; 43: 7
    CrossrefPubMedGoogle Scholar
  • 10 Mimuro J, Koike Y, Sumi Y, Aoki N. Monoclonal antibodies to discrete regions in a2-plasmin inhibitor. Blood 1987; 69: 446-453
    PubMedGoogle Scholar
  • 11 Holvoet P, de Boer A, Verstreken M, Collen D. An enzyme linked immunosorbent assay (ELISA) for the measurement of PAP complexes in human plasma: application to the detection of in vivo activation of the fibrinolytic system. Thromb Haemostas 1986; 56: 124-127
    PubMedGoogle Scholar
  • 12 Nuijens JH, Huijbregts CCM, van Mierlo GM, Hack CE. Inactivation of Cl inhibitor by proteases: demonstration by a monoclonal antibody of a neodeterminant on inactivated, non-complexed Cl inhibitor. Immunology 1987; 61: 387-389
    PubMedGoogle Scholar
  • 13 Hack CE, Paardekooper J, Smeenk RJT, Abbink J, Eerenberg AJM, Nuijens JH. Disruption of the internal thioester bond in the third component of complement (C3) results in the exposure of neodeterminants also present on activation products of C3. J Immunol 1988; 141: 1602-1609
    PubMedGoogle Scholar
  • 14 Peters M, Breederveld C, Kahlé LH, ten Cate JW. Rapid microanalysis of coagulation parameters by automated chromogenic substrate methods application in neonatal patients. Thromb Res 1982; 28: 773-781
    CrossrefPubMedGoogle Scholar
  • 15 Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies on the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1+2 fragment and thrombin antithrombin complex. Blood 1982; 59: 1086-1097
    PubMedGoogle Scholar
  • 16 Hoek J, Sturk A, ten Cate JW, Lamping R, Berends F, Borm JJJ. Laboratory and clinical evaluation of an assay of thrombin-antithrombin III complexes in plasma. Clin Chem 1988; 34: 2058-2062
    PubMedGoogle Scholar
  • 17 Garvey MB, Black JN. The detection of fibrin/fibrinogen degradation products by means of a new antibody-coated latex particle. J Clin Pathol 1972; 25: 680-682
    CrossrefPubMedGoogle Scholar
  • 18 Holvoet P, Cleemput H, Collen D. Assay of human tissue-type plasminogen activator with an enzyme linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA. Thromb Haemostas 1985; 54: 684-687
    PubMedGoogle Scholar
  • 19 Binnema DJ, van Iersel JJL, Dooijewaard G. Quantification of urokinase antigen in plasma and culture media by use of an ELISA. Thromb Res 1986; 43: 569-577
    CrossrefPubMedGoogle Scholar
  • 20 Hoylaerts M, Collen D. Kinetics of activation of plasminogen activation by tissue type plasminogen activator. Role of fibrin. J Biol Chem 1982; 257: 2912-2919
    PubMedGoogle Scholar
  • 21 Panell R, Black J, Gurewich V. Complementary modes of action of tissue-type plasminogen activator and pro-urokinase by which their synergistic effect on clot lysis may be explained. J Clin Invest 1988; 81: 853-859
    CrossrefPubMedGoogle Scholar
  • 22 Collen D, Stump DC, van de Werf F. Coronary thrombolysis in patients with acute myocardial infarction by intravenous infusion of synergic thrombolytic agents. Am Heart J 1986; 112: 1083-1084
    CrossrefPubMedGoogle Scholar
  • 23 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
  • 24 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
  • 25 Levi M, Lensing AWA, Prandoni P, Dooijewaard G, Cano va B, Btiller HR, Cuppini S, ten Cate JW. Absent urokinase-type plasminogen activator (u-PA) release upon DDAVP in patients with deep vein thrombosis. Thromb Haemostas 1989; 62: 392 (Abstr 1239).
    PubMedGoogle Scholar
  • 26 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subject. N Engl J Med 1989; 320: 1165-1172
    CrossrefPubMedGoogle Scholar
  • 27 van Deventer SJH, Biiller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic and complement pathways. Blood 1990; 76: 2520-2527
    PubMedGoogle Scholar
  • 28 Bruch M, Weiss V, Engel J. Plasma serine protease inhibitors (serpins) exhibit major conformational changes and a large increase in conformational stability upon cleavage at their reactive sites. J Biol Chem 1988; 263: 16626-16630
    PubMedGoogle Scholar
  • 29 Abbink JJ, Kamp AM, Roem D, Swaak AJG, de Boer EJP, Hack CE. Monoclonal antibodies against cq-antichymotrypsin and antithrombin III feasible tools to study the state of these inhibitors in biological fluids. Submitted 1990
    PubMedGoogle Scholar
  • 30 Asakura S, Yoshida N, Matsuda M, Murayama H, Soe G. Preparation and characterization of monoclonal antibodies against the human thrombin-antithrombin III complex. Biochim Biophys Acta 1988; 952: 37-47
    CrossrefPubMedGoogle Scholar