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Thromb Haemost 1997; 77(01): 062-070
DOI: 10.1055/s-0038-1655908
Clinical Studies
Schattauer GmbH Stuttgart

Tissue Factor (TF) and Urokinase Plasminogen Activator Receptor (uPAR) and Bleeding Complications in Leukemic Patients

Chary López-Pedrera
,
Merce Jardí
,
Maria del Mar Malagón
The Servicio de Hematología Hospital Reina Sofia, Córdoba, Spain
,
Julia Inglés-Esteve
1   Institut Recerca Oncològica (IRO), Hospital Duran i Reynals, Barcelona, Spain
,
Gabriel Dorado
The Servicio de Hematología Hospital Reina Sofia, Córdoba, Spain
,
Antonio Torres
The Servicio de Hematología Hospital Reina Sofia, Córdoba, Spain
,
Jordi Félez
1   Institut Recerca Oncològica (IRO), Hospital Duran i Reynals, Barcelona, Spain
,
Francisco Velasco
The Servicio de Hematología Hospital Reina Sofia, Córdoba, Spain
› Author Affiliations
Further Information

Publication History

Received 22 January 1996

Accepted after resubmisssion 09 September 1996

Publication Date:
11 July 2018 (online)

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Summary

Tissue factor (TF) and urokinase receptor (uPAR) are key cellular receptors triggering, respectively, coagulation and fibrinolysis. Bleeding complications among leukemic patients have been related to an abnormal expression of TF by blast cells and/or to an abnormal fibrinolytic response. In this study the expression of TF and uPAR has been assessed in 18 acute non-lymphoblastic and 8 lymphoblastic leukemic blast cells using several methodological approaches. TF mRNA was evaluated by in situ hybridization and TF and uPAR antigen were evaluated immunologically in cell lysates and on the cell surface by flow cytometry. In addition, TF-procoagulant activity was measured in coagulation-based assays. The reliability of these methods was corroborated in six leukemic cell lines of different lineages and states of maturation. Disseminated intravascular coagulation was detected in two M3 leukemia patients whose blast cells expressed high amounts of TF. Hyperfibrinolysis was detected in one M1 and two M2 patients, whose blast cells displayed a high content of uPAR antigen, but no TF. Furthermore, M5 leukemia blast cells expressed both TF and uPAR, although no hemostatic defects or bleeding complications were detected in these patients. Taken together, although a limited number of patients was included in this study, these data suggest that in leukemia patients exhibiting bleeding, either TF or uPAR are expressed by their blast cells. However, the presence of these receptors does not necessarily imply the existence of a hemostatic disorder.

 

  • References

  • 1 Ruf W, Edgington TS. Structural biology of tissue factor, the initiator of thrombogenesis in vivo. FASEB J 1994; 08: 385-390
    CrossrefPubMedSearch in Google Scholar
  • 2 Mackman N. Regulation of the Tissue Factor Gene. FASEB J 1995; 09 (10) 883-889
    CrossrefPubMedSearch in Google Scholar
  • 3 Carmeliet P, Mackman N, Wyns S, Kieckens L, Edgington TS, Collen D. Inactivation of the tissue factor gene in embryonic stem cells. Thromb Hae-most 1995; 73: 1177 (1059, Abstract)
    PubMedSearch in Google Scholar
  • 4 Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues: implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134: 1087-1097
    PubMedSearch in Google Scholar
  • 5 Drake TA, Ruf W, Morrissey JH, Edgington TS. Functional tissue factor is entirely cell surface expressed on lipopolysaccharide-stimulated human blood monocytes and a constitutively tissue factor-producing neoplastic cell line. J Cell Biol 1989; 109: 389-395
    CrossrefPubMedSearch in Google Scholar
  • 6 Drake TA, Cheng J, Chang A, Taylor Jr FB. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol 1993; 142: 1458-1470
    PubMedSearch in Google Scholar
  • 7 Flössel C, Luther T, Müller M, Albrecht S, Kasper M. Immunohistochemi-cal detection of tissue factor (TF) on paraffin sections of routinely fixed human tissue. Histochemistry 1994; 101: 449-453
    CrossrefPubMedSearch in Google Scholar
  • 8 Branch DW, Rodgers GM. Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: A possible mechanism of thrombosis. Am J Obstet Gynecol 1993; 168: 206-210
    CrossrefPubMedSearch in Google Scholar
  • 9 Del Prete G, De Carli M, Lammel RM, D’ Elios MM, Daniel KC, Giusti B, Abbate R, Romagnani S. Thl and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes. Blood 1995; 86: 250-257
    PubMedSearch in Google Scholar
  • 10 Callander NS, Varki N, Mohan Rao LV. Immunohistochemical identification of tissue factor in solid tumors. Cancer 1992; 70: 1194-1201
    CrossrefPubMedSearch in Google Scholar
  • 11 Rao LVM. Tissue factor as a tumor procoagulant Cancer Metastasis Rev. 1992; 11: 249-266
    PubMedSearch in Google Scholar
  • 12 Silverstein RL, Nachman RL. Cancer and clotting – Trousseau’s warning. 2019; N Engl J Med 1992; 327: 1163-1164
    CrossrefPubMedSearch in Google Scholar
  • 13 Prandoni P, Lensing AWA, Büller HR. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. The New England Journal of Medicine 1992; 327: 1128-1133
    CrossrefPubMedSearch in Google Scholar
  • 14 Mueller BM, Reisfeld RA, Edgington TS, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proc Natl Acad Sci USA 1992; 89: 11832-11836
    CrossrefPubMedSearch in Google Scholar
  • 15 Tallman MS, Hakimian D, Kwann HC, Rickies FR. New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukemia. Leukemia and Lymphoma 1993; 11: 27-36
    PubMedSearch in Google Scholar
  • 16 Grignani F, Fagioli M, Alcalay M, Longo L, Donti E, Biondi A, LoCoco F, Pelicci G. Acute promyelocytic leukemia: From genetics to treatment. Blood 1994; 83: 10-25
    PubMedSearch in Google Scholar
  • 17 Hair GA, Padula S, Zeff R, Schmeizl M, Contrino J, Kreutzer DL, De Moerloose P, Boyds AW, Stanley I, Burgess AW, Rickies FR. Tissue Factor Expression in Human Leukemic Cells. Leukemia Res 1996; 20 (01) 1-11
    CrossrefPubMedSearch in Google Scholar
  • 18 Takahashi H, Satoh N, Wada K, Takakuwa E, Seki Y, Shibata A. Tissue factor in plasma of patients with disseminated intravascular coagulation. Am JHematol 1994; 46: 333-337
    PubMedSearch in Google Scholar
  • 19 Wada H, Nakase T, Nakaya R, Minamikawa K, Wakita Y, Kaneko T, Ohi-wa M, Deguchi K, Shirakawa S. Elevated plasma tissue factor antigen level in patients with disseminated intravascular coagulation. Am J Hematol 1994; 45: 232-236
    CrossrefPubMedSearch in Google Scholar
  • 20 Iijima K, Fukuda C, Nakamura K. Measurements of tissue factor-like activity in plasma of patients with DIC. Thromb Res 1991; 61: 29-238
    PubMedSearch in Google Scholar
  • 21 Koyama T, Nishida K, Ohdama S, Sawada M, Murakami N, Hirosawa S, Kuriyama R, Matsuzawa K, Hasegawa R, Aoki N. Determination of plasma tissue factor antigen and its clinical significance. Br J Haematol 1994; 87: 343-347
    CrossrefPubMedSearch in Google Scholar
  • 22 Andoh K, Kubota T, Takada M, Tanaka H, Kobayashi N, Mackawa T. Tissue factor activity in leukemia cells. Special reference to disseminated intravascular coagulation. Cancer 1987; 59: 748-754
    CrossrefPubMedSearch in Google Scholar
  • 23 Velasco F, Torres A, Rojas R, Alvarez MA, Gomez P, Castillo D. Increase in the D-Dimer levels during treatment in patients with acute myelogenous leukemia. Haemostasis 1992; 22: 117-123
    PubMedSearch in Google Scholar
  • 24 García Frade LJ, Sureda A, Torrado MC, García Avello A. High plasma urokinase-type plasminogen activator levels are present in patients with acute nonlymphoblastic leukemia. Acta Haematol 1992; 88: 7-10
    CrossrefPubMedSearch in Google Scholar
  • 25 Tapiovaara H, Stephens RW, Vahteri A. Persistence of plasmin-mediated pro-urokinase activation on the surface of human monocytoid leukemia cells in vitro. Int J Cancer 1993; 53: 499-505
    CrossrefPubMedSearch in Google Scholar
  • 26 Gruneiro AJ, Montesanti DP, Corasanti JG, Markus G. The induction of the plasminogen activator system during phorbol ester (PMA)-induced differentiation in HL-60 leukemic cells. Fibrinolysis 1995; 09: 71-78
    PubMedSearch in Google Scholar
  • 27 Plesner T, Ralfkiaer E, Wittrup M, Johnsen H, Pyke C, Pedersen Hansen NE, Dano K. Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue. Am J Clin Pathol 1994; 102: 835-841
    CrossrefPubMedSearch in Google Scholar
  • 28 Plesner T, Ploug M, Ellis V, Ronne E, Hoyer-Hansen G, Wittrup M, Lindhardt Pedersen T, Tscheming T, Dano K, Hansen NE. The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils. Blood 1994; 83: 808-815
    PubMedSearch in Google Scholar
  • 29 Nykjaer A, Moller B, Todd RF, Christensen III T, Andreasen PA, Gliemann J, Petersen CM. Urokinase receptor: An activation antigen in human T lymphocytes. J Immunol 1994; 152: 505-516
    PubMedSearch in Google Scholar
  • 30 Jardí M, Inglés-Esteve J, Fabregas P, Félez J. Different expression of urokinase receptors (uPAR) among leukemic cells. Thromb Haemost 1993; 69: 608 (231, Abstract)
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Vassalli J. The urokinase receptor. Fibrinolysis 1994; 08: 172-181
    PubMedSearch in Google Scholar
  • 32 Blasi F, Conese M, Moller LB, Pedersen N, Cavallaro U, Cubellis MV, Fazioli F, Hemandez-Marrero L, Limongi P, Munoz-Canoves P, Resnati M, Riitinen L, Sidenius N, Soravia E, Soria MR, Stoppelli MP, Talarico D, Teesalu T, Valcamonica S. The Urokinase Receptor: Structure, Regulation and Inhibitor-mediated Internalization. Fibrinolysis 1994; 08: 182-188
    PubMedSearch in Google Scholar
  • 33 Danø K, Behrendt N, Brunner N, Ellis V, Ploug M, Pyke C. The urokinase receptor: Protein structure and role in plasminogen activation and cancer invasion. Fibrinolysis 1994; 08: 189-203
    PubMedSearch in Google Scholar
  • 34 Conese M, Blasi F. Urokinase/urokinase receptor system: Internalization/degradation of urokinase-serpin complexes: Mechanism and regulation. Biol Chem Hoppe Seyler 1995; 376: 143-155
    PubMedSearch in Google Scholar
  • 35 Ellis V, Behrendt N, Danø K. Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated. J Biol Chem 1991; 266: 12752-12758
    PubMedSearch in Google Scholar
  • 36 Ellis V, Pyke C, Eriksen J, Solberg H, Danø K. The urokinase receptor: Involvement in cell surface proteolysis and cancer invasion. Ann NY Acad Sci 1992; 667: 13-31
    CrossrefPubMedSearch in Google Scholar
  • 37 Bennett JM, Catovsky D, Daniel MT. Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103: 626-629
    CrossrefPubMedSearch in Google Scholar
  • 38 Velasco F, Torres A, Andres P, Martinez F, Gomez P. Changes in plasma levels of protease and fibrinolytic inhibitors induced by treatment in acute myeloid leukemia. Thromb Haemost 1984; 52 (01) 81-4
    PubMedSearch in Google Scholar
  • 39 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-254
    CrossrefPubMedSearch in Google Scholar
  • 40 Granelli-Piperno A, Vassalli J, Reich E. Secretion of plasminogen activator by human polymorphonuclear leukocytes. J Exp Med 1989; 146: 1693-1705
    PubMedSearch in Google Scholar
  • 41 Carson S. Continous chromogenic tissue factor assay comparison to clot-based assays and sensitivity established using pure tissue factor. Br J Haematol 1987; 47: 379-387
    PubMedSearch in Google Scholar
  • 42 Haire WD, Pirruccello SJ, Carson SD. Monocyte tissue factor in treated Hodgkin’s disease. 2019; Leuk Lymphoma 1994; 12: 259-263
    CrossrefPubMedSearch in Google Scholar
  • 43 Kubota T, Andoh K, Sadakata H, Tanaka H, Kobayashi N. Tissue Factor Released from Leukemic Cells. Thromb Haemost 1991; 65: 59-63
    Thieme ConnectPubMedSearch in Google Scholar
  • 44 Bauer KA, Conway EM, Bach R, Konigsberg WH, Griffin JD, Demetri G. Tissue factor gene expression in acute myeloblastic leukemia. Thromb Res 1989; 56: 425-430
    CrossrefPubMedSearch in Google Scholar
  • 45 Carson SD, Pirrucello SJ, Haire WD. Tissue factor antigen and activity are not expressed on the surface of intact cells isolated from an acute promyelocytic leukemia patient. Thromb Res 1990; 59: 159-170
    CrossrefPubMedSearch in Google Scholar
  • 46 Tanaka M, Yamanishi H. The expression of tissue factor antigen and activity on the surface of leukemic cells. Leuk Res 1993; 17: 103-111
    CrossrefPubMedSearch in Google Scholar
  • 47 Dickinson JL, Antalis TM. Tissue factor and plasminogen activator inhibitor expression in the differentiation of myeloid leukemic cells. Leukemia 1993; 07 (06) 864-871
    PubMedSearch in Google Scholar
  • 48 Rickies FR, Hair GA, Zeff RA, Lee E, Bona RD. Tissue factor expression in human leukocytes and tumor cells. Thromb Haemost 1995; 74 (01) 391-5
    Thieme ConnectPubMedSearch in Google Scholar
  • 49 Parry GCN, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb 1995; 15: 612-621
    CrossrefPubMedSearch in Google Scholar
  • 50 Jardí M, Inglés-Esteve J, Burgal M, Azqueta C, Velasco F, Miles LA, Félez J. Distinct patterns of urokinase receptor (uPAR) expression by leukemic cells and peripheral blood cells. Thromb Haemost 1996; 76: 1009-1019
    Thieme ConnectPubMedSearch in Google Scholar
  • 51 Claxton DF, Reading CL, Nagarajan L, Tsujimoto Y, Andersson BS, Estev E, Cork A, Huh YO, Trujillo J, Deisseroth AB. Correlation of CD2 Expression with PML Gene Breakpoints in patients with acute promyelocytic leukemia. Blood 1992; 80: 582-586
    PubMedSearch in Google Scholar
  • 52 Van der Logt CPE, Reitsma PH, Bertina RM. Alternative splicing is responsible for the presence of two tissue factor mRNA species in LPS stimulated human monocytes. Thromb Haemost 1992; 67: 272-276
    Thieme ConnectPubMedSearch in Google Scholar
  • 53 Edgington TS, Mackman N, Brand K, Ruf W. The structural biology of expression and function of tissue factor. Thromb Haemost 1991; 66: 67-79
    Thieme ConnectPubMedSearch in Google Scholar
  • 54 Mohri M, Oka M, Aoki Y, Gonda Y, Hirata S, Gomi K, Kiyoata T, Sugihara T, Yamamoto S, Ishida T, Maruyama I. Intravenous extended infusion of recombinant human soluble thrombomodulin prevented tissue factor-induced disseminated intravascular coagulation in rats. Am J Hematol 1994; 45: 298-303
    CrossrefPubMedSearch in Google Scholar
  • 55 Warr TA, Rao VM, Rapaport SI. Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: Effect of anti-tissue factor antibodies and measurement of plasma extrinsic inhibitor activity. Blood 1990; 7: 1481-1489
    PubMedSearch in Google Scholar
  • 56 Jang I-K, Gold HK, Leinbach RC, Fallon JT, Collen D, Wilcox JN. Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis. Arterioscler Thromb 1992; 12: 948-954
    CrossrefPubMedSearch in Google Scholar
  • 57 Sakata Y, Murakami T, Noro A, Mori K, Matsuda M. The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia. Blood 1991; 77: 1949-1957
    PubMedSearch in Google Scholar
  • 58 Ellis V, Scully MF, Kakkar VV. Plasminogen activation initiated by singlechain urokinase-type plasminogen activator. J Biol Chem 1989; 264: 2185-2188
    PubMedSearch in Google Scholar
  • 59 Ellis V, Behrendt N, Danø K. Plasminogen activation by-receptor-bound urokinase: A kinetic study with both cell-associated and isolated receptor. J Biol Chem 1991; 266: 12752-12758
    PubMedSearch in Google Scholar
  • 60 Plow EF, Felez J, Miles LA. Cellular Regulation of Fibrinolysis. Thromb Haemost 1991; 66: 32-36
    Thieme ConnectPubMedSearch in Google Scholar
  • 61 Ploug M, Eriksen J, Plesner T, Hansen NE, Danø K. A soluble form of the glycolipid-anchored receptor for urokinase-type plasminogen activator is secreted from peripheral blood leukocytes from patients with paroxysmal nocturnal hemoglobinuria. Eur J Biochem 1992; 208: 397-404
    CrossrefPubMedSearch in Google Scholar
  • 62 Chapman HA, Stone OL. Characterization of a macrophage-derived plas-minogen-activator inhibitor. Biochem J 1985; 230: 109-116
    CrossrefPubMedSearch in Google Scholar
  • 63 Vassalli J, Dayer J, Wohlwend A, Belin D. Concomitant secretion of prourokinase and of a plasminogen activator specific inhibitor by cultured human monocytes-macrophages. J Exp Med 1984; 159: 1653
    CrossrefPubMedSearch in Google Scholar
  • 64 Hart PH, Burgess DR, Vitti GF, Hamilton JA. Interleukin-4 stimulates human monocytes to produce tissue-type plasminogen activator. Blood 1989; 74: 1222-1225
    PubMedSearch in Google Scholar
  • 65 Hart PH, Vitti GF, Burgess DR, Singleton DK, Hamilton JA. Human monocytes can produce tissue-type plasminogen activator. J Exp Med 1989; 169: 1509-1514
    CrossrefPubMedSearch in Google Scholar
  • 66 Broze GJ. Tissue factor pathway inhibitor and the revised theory of coagulation. Annu Rev Med 1995; 46: 103-112
    CrossrefPubMedSearch in Google Scholar
  • 67 Falanga A, Alessio MG, Donati MB, Barbui T. A new procoagulant in acute leukemia. Blood 1988; 71 (04) 870-875
    CrossrefPubMedSearch in Google Scholar
  • 68 Cozzolino F, Torcia M, Miliani A, Carossino AM, Giordani R, Cinotti S, Filimberti E, Saccardi R, Bemabei P, Guidi G, Di Guglielmo R, Pistoia V, Ferrarini M, Nawroth PP, Stern D. Potential role of interleukine-1 as the trigger for diffuse intravascular coagulation in acute nonlymphoblastic leukemia. The American Journal of Medicine 1988; 84: 240-250
    CrossrefPubMedSearch in Google Scholar
  • 69 Cozzolino F, Rubartelli A, Aldinucci D, Sitia R, Torcia M, Shaw A, Di Guglielmo R. Interleukin 1 as an autocrine growth factor for acute myeloid leukemia cells. Proc Natl Acad Sci USA 1989; 86: 2369-2373
    CrossrefPubMedSearch in Google Scholar