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

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
• 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
• 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
• 4 Hehlmann R, Jahn M, Baumann B, Kopcke W. Essential thrombocythemia. Clinical characteristics and course of 61 cases. Cancer 1988; 61: 2487-2496
• 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
• 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
• 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
• 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
• 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
• 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
• 11 Preston FE, Martin JF, Stewart RW, Davies-Jones GAB. Thrombocytosis, circulating platelet aggregates and neurological dysfunction. Br Med J 1979; 2: 1561-1563
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 20 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76: 2024-2029
• 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).
• 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
• 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
• 24 Dittman WA, Majerus PW. Structure and function of thrombomodulin: a natural anticoagulant. Blood 1990; 75: 329-336
• 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
• 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
• 27 Boffa MC, Karochkme M, Berard M. Plasma thrombomodulin as a marker of endothelium damage. Nouv Rev Fr Hematol 1991; 33: 529-530
• 28 Suzuki K, Nishioka J, Hayashi T, Kosaka Y. Functionally active thrombomodulin is present in human platelets. J Biochem 1988; 104: 628-632
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 41 Mitchell CA, Salem HH. Cleavage of protein S by a platelet membrane protease. J Clin Invest 1987; 79: 374-379
• 42 Conlan MG, Haire WD. Low protein S in essential thrombocythemia with thrombosis. Am J Hematol 1989; 32: 88-93
• 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).
• 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
• 45 Johnsen ULH, Lyberg T, Galdal KS, Prydz H. Platelets stimulate thromboplastin synthesis in human endothelial cells. Thromb Haemostas 1983; 49: 69-72
• 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
• 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