Download PDF
Thromb Haemost 1993; 70(05): 736-742
DOI: 10.1055/s-0038-1649661
Clinical Studies
Schattauer GmbH Stuttgart

Platelet Hyperactivation in Patients with Essential Thrombocythemia Is not Associated with Vascular Endothelial Cell Damage as Judged by the Level of Plasma Thrombomodulin, Protein S, PAI-1, t-PA and vWF

S Bellucci
1   Laboratory of Hematology, Hôpital Lariboisière, Paris, France
,
E Ignatova
1   Laboratory of Hematology, Hôpital Lariboisière, Paris, France
,
N Jaillet
1   Laboratory of Hematology, Hôpital Lariboisière, Paris, France
,
M C Boffa
2   INSERM U 353, Hôpital Saint-Louis, Paris, France
› Author Affiliations
Further Information

Publication History

Received 28 October 1992

Accepted after revision 22 June 1993

Publication Date:
05 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

The occurrence of thrombotic events remains an important clinical problem in Essential Thrombocythemias (ET). Thus, hemostatic, fibrinolytic and vascular status was investigated in 16 patients (5 males and 11 females) with ET. Among them five presented thromboses in their past history. Platelet hyperactivation, as evidenced by a mean three-fold increase in plasma betathromboglobulin (βTG), was observed in 13 among 16 patients; surprisingly this activation was present even when the platelet count was normal (in two patients) or subnormal, below 600 x 109/1 (in 11 patients). The mean value was 104 ± 57 IU/ml significantly different from that of normal controls (35 ± 16.5 IU/ ml) (p <0.001). An artefactual in vitro platelet activation was ruled out by the concomitant measurement of platelet factor, 4 (PF4). D-dimers fibrin degradation products (D-Di FDP) were normal in all patients. Vascular endothelial cell function parameters were not markedly modified. The mean value of plasma thrombomodulin ™ was found slightly but not significantly increased (60.1 ±4.9 ng/ml versus 49.1 ± 10.0 ng/ml in controls). The values of plasma TM correlated neither with that of the platelet count nor with that of plasma βTG or plasma PF4. The mean values of plasma protein S, von Willebrand factor (vWF), plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (tPA) were normal and were not correlated neither with that of plasma TM nor with that of plasma βTG. In spite of a significant increase in vWF in two patients who presented peripheral thromboses, the markers of vascular endothelial cell function were not significantly different in patients having presented or not thromboses. Thus, in ET, these data showed the presence of platelet hyperactivation, even in patients in remission; it was not associated with vascular endothelial cell damage which might account for a greater risk of thrombosis.

 

  • References

  • 1 Bellucci S, Janvier M, Tobelem G, Flandrin G, Charpak Y, Berger R, Boiron M. Essential thrombocythemia. Clinical evolutionary and biological data. Cancer 1986; 58: 2440-2447
    CrossrefPubMedGoogle Scholar
  • 2 Rozman C, Girart M, Feliu E, Rubio D, Cortes MT. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Lancet 1991; 67: 2658-2663
    PubMedGoogle Scholar
  • 3 Lahuerta-Palacios JJ, Bornstein R, Fernandez-Debora FJ. et al. Controlled and uncontrolled thrombocytosis. Its clinical role in essential thrombocythemia. Cancer 1988; 61: 1207-1212
    CrossrefPubMedGoogle Scholar
  • 4 Hehlmann R, Jahn M, Baumann B, Kopcke W. Essential thrombocythemia. Clinical characteristics and course of 61 cases. Cancer 1988; 61: 2487-2496
    CrossrefPubMedGoogle Scholar
  • 5 Fenaux P, Simon M, Caulier MT, Lai JL, Goudemand J, Bauters F. Clinical course of essential thrombocythemia in 147 cases. Cancer 1990; 66: 549-556
    CrossrefPubMedGoogle Scholar
  • 6 Mitus AJ, Barbui T, Shulman LN, Rosenthal DS, Viero P, Cortelazzo S, Schafer AI. Hemostatic complications in young patients with essential thrombocythemia. Am J Med 1990; 88: 371-375
    CrossrefPubMedGoogle Scholar
  • 7 Chistolini A, Mazzucconi MG, Ferrari A, La VerdeG, Ferrazza G, Dragoni F, Vitale A, Arcieri R, Mandelli F. Essential thrombocythemia: a retrospective study on the clinical course of 100 patients. Haematologica 1990; 75: 537-540
    PubMedGoogle Scholar
  • 8 Cortelazzo S, Viero P, Finazzi G, D’Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990; 8: 556-562
    CrossrefPubMedGoogle Scholar
  • 9 Colombi M, Radaelli F, Zocchi L, Maiolo AT. Thrombotic and hemorrhagic complications in essential thrombocythemia. A retrospective study of 103 patients. Cancer 1991; 67: 2926-2930
    CrossrefPubMedGoogle Scholar
  • 10 Jabaily J, Iland HJ, Laszlo J, Massey EW, Faguet GB, Briere J, Landaw SA, Pisciotta AV. Neurologic manifestations of essential thrombocythemia. Ann Intern Med 1983; 99: 513-518
    CrossrefPubMedGoogle Scholar
  • 11 Preston FE, Martin JF, Stewart RW, Davies-Jones GAB. Thrombocytosis, circulating platelet aggregates and neurological dysfunction. Br Med J 1979; 2: 1561-1563
    CrossrefPubMedGoogle Scholar
  • 12 Cortelazzo S, Barbui T, Bassian R, Dini E. Abnormal aggregation and increased size of platelets in myeloproliferative disorders. Thromb Haemostas 1980; 43: 127-130
    PubMedGoogle Scholar
  • 13 Boughton BJ, Allington MJ, King A. Platelet and plasma β thromboglobulin in myeloproliferative syndromes and secondary thrombocytosis. Br J Haematol 1978; 40: 125-132
    CrossrefPubMedGoogle Scholar
  • 14 Berild D, Hasselbalch H, Bjerreknudsen J. Platelet survival, plateletfactor 4 and bleeding time in myeloproliferative disorders. Scand J Clin Lab Invest 1987; 47: 497-501
    CrossrefPubMedGoogle Scholar
  • 15 Wehmeier A, Scharf RE, Fricke S, Schneider V. Bleeding and thrombosis in chronic myeloproliferative disorders: relation of platelet disorders to clinical aspects of the disease. Haemostasis 1989; 19: 251-259
    PubMedGoogle Scholar
  • 16 Grossi A, Vannucchi A, Rafanelli D, Filimberti E, Ferrini P. Betathromboglobulin content in megakaryocytes of patients with myeloproliferative disorders. Thromb Res 1986; 19: 367-374
    PubMedGoogle Scholar
  • 17 Legrand C, Bellucci S, Disdier M, Edelman L, Tobelem G. Platelet thrombospondin and glycoprotein IV anbnormalities in patients with essential thrombocythaemia. Effect of alpha interferon treatment. Am J Hematol 1991; 38: 307-313
    CrossrefPubMedGoogle Scholar
  • 18 Murphy S, Iland H, Rosenthal D, Lazio J. Essential thrombocythemia: an interim report from the Polycythemia Vera Study Group. Semin Haematol 1986; 23: 177-182
    PubMedGoogle Scholar
  • 19 Amiral J, Canton M, Larrivaz I, Adam M, Boffa MC. A two site monoclonal ELISA for soluble forms of thrombomodulin in plasma. Blood 1991; 78 (Suppl. 01) 69A
    PubMedGoogle Scholar
  • 20 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76: 2024-2029
    PubMedGoogle Scholar
  • 21 Soria C, Tron P, Boffa MC. et al. Increased plasma thrombomodulin level in patients with Wegener’s disease. Thromb Haemostas 1991; 65: 1122 (1537 Abstr).
    PubMedGoogle Scholar
  • 22 Contant G, Martinoli JL. Determination of plasminogen activator inhibitor (PAI) activity of human plasma after dilution in a PAI-depleted plasma. Thromb Res 1989; 56: 377-386
    CrossrefPubMedGoogle Scholar
  • 23 Kaplan KL, Owen J. Plasma levels of β-thromboglobulin and platelet factor 4 as indices of platelet activation in vivo. Blood 1981; 57: 199-202
    PubMedGoogle Scholar
  • 24 Dittman WA, Majerus PW. Structure and function of thrombomodulin: a natural anticoagulant. Blood 1990; 75: 329-336
    CrossrefPubMedGoogle Scholar
  • 25 Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemostas 1991; 65: 618-623
    PubMedGoogle Scholar
  • 26 Ishii H, Nakano M, Tsuboucchi J. et al. Establishment of enzyme immunoassay of human thrombomodulin in plasma and urine using monoclonal antibodies. Thromb Haemostas 1990; 63: 157-162
    PubMedGoogle Scholar
  • 27 Boffa MC, Karochkme M, Berard M. Plasma thrombomodulin as a marker of endothelium damage. Nouv Rev Fr Hematol 1991; 33: 529-530
    PubMedGoogle Scholar
  • 28 Suzuki K, Nishioka J, Hayashi T, Kosaka Y. Functionally active thrombomodulin is present in human platelets. J Biochem 1988; 104: 628-632
    CrossrefPubMedGoogle Scholar
  • 29 Wada H, Ohiwa M, Kaneko T. et al. Plasma thrombomodulin as a marker of vascular disorders in thrombotic thrombocytopenic purpura and disseminated intravascular coagulation. Am J Hematol 1992; 39: 20-24
    CrossrefPubMedGoogle Scholar
  • 30 Tanaka A, Ishii H, Hiraishi S, Kazama M, Mazewa H. Increased thrombomodulin values in plasma of diabetic men with microangiopathy. Clin Chem 1991; 37: 269-272
    PubMedGoogle Scholar
  • 31 Karmochkine M, Boffa MC, Piette JC, Cacoub P, Wechsler B, Godeau P, Juhan I, Weiller PJ. Increase in plasma thrombomodulin in lupus erythematosus with antiphospholipid antibodies. Blood 1992; 79: 837-838
    Google Scholar
  • 32 Juhan-Vague I, Moerman B, De CockF, 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
  • 33 Juhan-Vague I, Alessi MC, Fossat C, Declerck PJ, Kruithof EKO. Plasma determination of plasminogen activator inhibitor 1 must be performed in blood collected on antiplatelet-antiaggregant mixture. Thromb Haemostas 1987; 58: 1096-2002
    PubMedGoogle Scholar
  • 34 Lambers JWJ, Cannenga M, Konig BW, Mertens K, Pannekoek H, Van MourikJA. JA. Activation of human endothelial cell type plasminogen activator inhibitor (PAI-1) by negatively charged phospholipids. J Biol Chem 1987; 262: 17492-17496
    PubMedGoogle Scholar
  • 35 Friedenberg WR, Roberts RC, David DE. Relationship of thrombohemorrhagic complications to endothelial cell function in patients with chronic myeloproliferative disorders. Am J Hematol 1992; 40: 283-289
    CrossrefPubMedGoogle Scholar
  • 36 Cohen AM, Gelvan A, Kadouri A, Creter D, Djaldetti M. Tissue plasminogen activator levels in different types of polycythemia. Eur J Haematol 1990; 45: 48-51
    PubMedGoogle Scholar
  • 37 Moake JL, Rudy CK, Troll JH. Unusually large plasma factor VIII von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435
    CrossrefPubMedGoogle Scholar
  • 38 Scrobohaci ML, Drouet L, Monem-Mansi A, Devergie A, Baudin B, D’Agay MF, Gluckman E. Liver venoocclusive disease after bone marrow transplantation: changes in coagulation parameters and endothelial markers. Thromb Res 1991; 63: 509-519
    CrossrefPubMedGoogle Scholar
  • 39 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-2088
    CrossrefPubMedGoogle Scholar
  • 40 Bissuel F, Berruyer M, Causse X, Dechavanne M, Trepo C. Acquired protein S deficiency: correlation with advanced disease in HIV-1 infected patients. J Acquired Immune Defic Syndr 1992; 51: 484-489
    PubMedGoogle Scholar
  • 41 Mitchell CA, Salem HH. Cleavage of protein S by a platelet membrane protease. J Clin Invest 1987; 79: 374-379
    CrossrefPubMedGoogle Scholar
  • 42 Conlan MG, Haire WD. Low protein S in essential thrombocythemia with thrombosis. Am J Hematol 1989; 32: 88-93
    CrossrefPubMedGoogle Scholar
  • 43 Mazzucconi MG, Chistolini A, Ferrari A, Arcieri P, Mandelli F. Level of protein S and essential thrombocythemia. Comment. Am J Hematol 1991; 36: 73 (Letter).
    CrossrefPubMedGoogle Scholar
  • 44 Marcus AJ, Weksler BB, Jaffe EA, Broekman MJ. Synthesis of prostacyclin from platelet-derived endoperoxydes by cultured human endothelial cells. J Clin Invest 1980; 66: 979-986
    CrossrefPubMedGoogle Scholar
  • 45 Johnsen ULH, Lyberg T, Galdal KS, Prydz H. Platelets stimulate thromboplastin synthesis in human endothelial cells. Thromb Haemostas 1983; 49: 69-72
    PubMedGoogle Scholar
  • 46 Menashi S, He L, Soria C, Soria J, Thomaidis A, Legrand Y. Modulation of endothelial cells fibrinolytic activity by platelets. Thromb Haemostas 1991; 65: 77-81
    PubMedGoogle Scholar
  • 47 Slivka SR, Loskutoff DJ. Platelets stimulate endothelial cells to synthesize type I, plasminogen activator inhibitor. Evaluation of the role of transforming growth factor β. Blood 1991; 77: 1013-1019
    PubMedGoogle Scholar