Thromb Haemost 1991; 66(05): 515-519
DOI: 10.1055/s-0038-1646451
Original Article
Schattauer GmbH Stuttgart

Thrombin Generation and Fibrinolysis in the Thrombotic Thrombocytopenic Purpura and the Hemolytic-Uremic Syndrome

J Monteagudo
The Service of Hemotherapy and Hemostasis, Hospital Clinico Provincial, Barcelona, Spain
,
A Pereira
The Service of Hemotherapy and Hemostasis, Hospital Clinico Provincial, Barcelona, Spain
,
J C Reverter
The Service of Hemotherapy and Hemostasis, Hospital Clinico Provincial, Barcelona, Spain
,
J Pijoan
The Service of Hemotherapy and Hemostasis, Hospital Clinico Provincial, Barcelona, Spain
,
J Tusell
1   The Service of Pediatric Hematology, Hospital Valle de Hebrón, Barcelona, Spain
,
L Puig
2   The Blood Bank, Hospital de la Cruz Roja, Barcelona, Spain
,
A Ordinas
The Service of Hemotherapy and Hemostasis, Hospital Clinico Provincial, Barcelona, Spain
,
R Castillo
The Service of Hemotherapy and Hemostasis, Hospital Clinico Provincial, Barcelona, Spain
› Author Affiliations
Further Information

Publication History

Received 20 August 1990

Accepted 24 April 1991

Publication Date:
25 July 2018 (online)

Summary

Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes (TAT), as well as other coagulation and fibrinolysis parameters, were studied in a series of 13 patients affected by thrombotic thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS). Fragment F1+2 was found to be increased in all patients at diagnosis (patients' range, 1.21-19.03 nmol/1; normal limits, 0.28-1.08 nmol/1), and remained also higher than normal after treatment with plasma exchange (patients' range, 1.5-4.01 nmol/1). Even though the analysis of fibrinolysis markers did not show a definite state of hypo or hyperfibrinolysis in the systemic circulation, enhanced circulating D-dimer levels (0.53-12.6 ug/ml, normal levels of 0.03-0.29 εg/ml) indicated that a certain grade of fibrin lysis was present at previously formed thrombi. Plasma PAI-1 activities either on admission (9.2-38.2 U/ml) and after plasma exchange therapy (2.6-38.6 U/ml) showed a behavior irrespective of t-PA: Ag changes, and post-plasmapheresis values remained high only in patients with fatal neurological outcome. Nevertheless, no correlations between clinical and laboratory data could be established useful for the TTP/HUS prognosis. We conclude that increased thrombin generation occurring in damaged areas is appropriately inhibited by antithrombin III in the systemic circulation, avoiding consumption coagulopathy to develop in uncomplicated patients. In addition, fibrinolysis data suggest that elevated PAI-1 may decisively favor the development of microvascular thrombi.

 
  • References

  • 1 Lian ECY. Pathogenesis of thrombotic thrombocytopenic purpura. Semin Hematol 1987; 24: 82-100
  • 2 Byrnes JJ, Moake JL. Thrombotic thrombocytopenic purpura and the haemolytic-uraemic syndrome: evolving concepts of pathogenesis and therapy. Clin Haematol 1986; 15: 413-42
  • 3 Jaffe EA, Nachman RL, Merskey C. Thrombotic thrombocytopenic purpura: coagulation parameters in twelve patients. Blood 1973; 42: 499-507
  • 4 Cuttner J. Thrombotic thrombocytopenic purpura: a ten-year experience. Blood 1980; 56: 302-6
  • 5 Takahashi H, Takakuwa E, Yoshino N, Hanano M, Shibata A. Protein C levels in disseminated intravascular coagulation and thrombotic thrombocytopenic purpura: its correlation with other coagulation parameters. Thromb Haemostas 1985; 54: 445-9
  • 6 Rodgers GM, Greenberg CS, Shuman MA. Characterization of the effects of cultured vascular cells on the activation of blood coagulation. Blood 1983; 61: 1155-62
  • 7 Jaffe EA. Cell biology of endothelial cells. Hum Pathol 1987; 18: 234-9
  • 8 Petty RG, Pearson JD. Endothelium: the axis of vascular health and disease. J R Coll Phys London 1989; 23: 92-102
  • 9 Remuzzi G, Zoja C, Rossi EC. Prostacyclin in thrombotic microangiopathy. Semin Hematol 1987; 24: 110-8
  • 10 Remuzzi G, Mecca G, Livio M, De Gaetano G, Donati MB, Pearson JD, Gordon JL. Prostacyclin generation by cultured endothelial cells in haemolytic uremic syndrome. Lancet 1980; 1: 656-7
  • 11 Kwaan HC. Role of fibrinolysis in thrombotic thrombocytopenic purpura. Semin Hematol 1987; 24: 101-9
  • 12 Glas-Greenwalt P, Hall JM, Panke TW, Kant KS, Allen CM, Pollak VE. Fibrinolysis in health and disease: abnormal levels of plasminogen activator, plasminogen activator inhibitor, and protein C in thrombotic thrombocytopenic purpura. J Lab Clin Med 1986; 108: 415-22
  • 13 Kakishita E, Koyama T, Higuchi M, Kunitomi O, Oura Y, Nagai K. Fibrinogenolysis in thrombotic thrombocytopenic purpura. Am J Hematol 1989; 32: 14-9
  • 14 Monteagudo J, Pereira A, Roig S, Reverter JC, Ordinas A, Castillo R. Investigation of plasma von Willebrand factor and circulating platelet aggregating activity in mitomycin C-related hemolytic-uremic syndrome. Am J Hematol 1990; 33: 46-9
  • 15 Armitage P. Statistical Methods in Medical Research. 1st edition, Blackwell Sci. Publ., Oxford: 1971
  • 16 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-47
  • 17 Pelzer H, Schwartz A, Stüber W. Determination of human prothrombin activation fragment 1+2 in plasma with an antibody against a synthetic peptide. Thromb Haemostas 1991; 65: 153-9
  • 18 Pelzer H, Schwartz A, Heimburger N. Determination of human thrombin-antithrombin HI complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemostas 1988; 59: 101-6
  • 19 Abildgaard U, Lie M, Odegard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrates (S-2238 and Chromozyme TH). Thromb Res 1977; 11: 549-53
  • 20 Bertina RM, Broekmans AW, van Es-Krommenhoek C, van Wijngaarden A. The use of a functional and immunological assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency. Thromb Haemostas 1984; 51: 1-5
  • 21 Holvoet P, Cleemput H, Collen D. Assay of human tissue-type plasminogen activator (t-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA. Thromb Haemostas 1985; 54: 684-7
  • 22 Chmielewska J, Ranby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31: 427-36
  • 23 Friberger P. Chromogenic peptide substrates. Their use for the assay factors in the fibrinolytic and plasma kallikrein-kinin systems. Scand J Clin Lab Invest 1982; 42 (Suppl 162) 49-54
  • 24 Büttner J, Borth R, Boutwell JH, Broughton PMG, Bowyer RC. International Federation of Clinical Chemistry. Expert Panel on nomenclature and principles of quality control in clinical chemistry. Approved recommendation (1978) on quality control in clinical chemistry. Part 2. Assessment of analytical methods for routine use. Clin Chim Acta 1979; 98: 145F-162F
  • 25 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50
  • 26 Carroll JJ. Impact of biotechnology on the diagnostics of thrombotic disorders. Semin Thromb Hemostas 1989; 15: 334-40
  • 27 Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1+2 fragment and thrombin-antithrombin complex. Blood 1982; 59: 1086-97
  • 28 Bauer KA, Goodman TL, Kass BL, Rosenberg RD. Elevated factor Xa activity in the blood of asymptomatic patients with congenital antithrombin deficiency. J Clin Invest 1985; 76: 826-36
  • 29 Prowse CV, Cash JD. Physiologic and pharmacologic enhancement of fibrinolysis. Semin Thromb Hemostas 1984; 10: 51-60
  • 30 Declerck PJ, Mombaerts P, Holvoet P, De Mol M, Collen D. Fibrinolytic response and fibrin fragment D-dimer levels in patients with deep vein thrombosis. Thromb Haemostas 1987; 58: 1024-9
  • 31 Kruithof EKO, Tran-Thang C, Ransijn A, Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood 1984; 64: 907-13
  • 32 Sprengers ED, Kluft C. Plasminogen activator inhibitors: a concise review. Blood 1987; 69: 381-7
  • 33 Kruithof EKO. Plasminogen activator inhibitors: a review. Enzyme 1988; 40: 113-21
  • 34 Colucci M, Páramo JA, Collen D. Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 1985; 75: 818-24
  • 35 Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activator after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989; 320: 1165-72
  • 36 Kruithof EKO, Tran-Thang C, Bachmann F. Studies on the release of a plasminogen activator inhibitor by human platelets. Thromb Haemostas 1986; 55: 201-5
  • 37 Sprengers ED, Akkerman JWN, Jansen BG. Blood platelet plasminogen activator inhibitor: two different pools of endothelial cell type plasminogen activator inhibitor in human blood. Thromb Haemostas 1986; 55: 325-9
  • 38 Bergsdorf N, Nilsson T, Wallen P. An enzyme linked immunosorbent assay for determination of tissue plasminogen activator applied to patients with thromboembolic disease. Thromb Haemostas 1983; 50: 740-4