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Hamostaseologie 2000; 20(03): 124-135
DOI: 10.1055/s-0037-1619485
Original article
Schattauer GmbH

Tumorwachstum und Hämostase

Cancer and haemostasis
H. D. Bruhn
1   I. Medizinische Universitätsklinik, Kiel
,
Chr. Steffens
1   I. Medizinische Universitätsklinik, Kiel
,
K.-H. Zurborn
2   Reha-Klinik Ahrenshoop
,
F. Gieseler
1   I. Medizinische Universitätsklinik, Kiel
› Author Affiliations
Further Information

Publication History

Publication Date:
27 December 2017 (online)

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Zusammenfassung

Hämostaseologische Vorgänge wie Aktivierung von Thrombozyten und von plasmatischer Gerinnung können für das Auftreten von Thromboembolien bei Malignomen entscheidend sein. In klinischen Studien wurden signifikante Korrelationen zwischen zytostatischer Chemotherapie und Strahlentherapie einerseits und dem Auftreten von Thromboembolien andererseits dokumentiert.

Nach neueren klinischen Studien kommt es bei angeborener Thrombophilie zu einer verstärkten Reaktion des Hämostasesystems auf ein Tumorleiden mit der Konsequenz einer erhöhten Thromboemboliefrequenz (bei APC-Resistenz, bei Mutation des Prothrombin-Gens, bei Protein-C-Mangel, bei Protein-S-Mangel, bei Antithrombin-Verminderung und bei erhöhtem Lipoprotein a). Durch eine angemessene Antikoagulation können thromboembolische Komplikationen, zumindest partiell, verhindert werden.

Die vermehrte Freisetzung von Thrombin bei metastasierenden Malignomen hat offensichtlich jedoch noch weitere Konsequenzen: Thrombin wirkt nicht nur als Enzym des Hämostasesystems, sondern auch als Gewebshormon (Wachstumsfaktor), so dass Thrombin bei verschiedenen Tumorzelllinien eine verstärkte Proliferation induzieren kann. In neueren Untersuchungen konnten wir jetzt zusätzlich in Zellkulturen demonstrieren, daß die Vorinkubation von Leukämiezellen (HL-60) mit Thrombin bei bestimmten Konzentrationen zu einer Resistenz dieser Zellen gegenüber Idarubicin führt und damit auch, zumindest partiell, die durch Idarubicin ausgelöste Apoptose beeinträchtigt. Damit wäre eine mögliche Erklärung für die positiven Effekte einer kombinierten Chemotherapie und Antikoagulation gefunden, welche durch weiterführende Zellkulturversuche und klinische Studien erhärtet werden müsste.

Summary

Liberation of tumor cell thromboplastins induces activation of the coagulation system and of thrombocytes with the consequence of an increased rate of thromboembolic complications in malignancies. Chemotherapy and radiation therapy thereby induce also an increased rate of thromboembolic complications. Inherited thrombophilia induces an additional increase of thromboembolism in patients with malignancies and leukemias (inherited APC resistance, mutation of the prothrombin gene, protein C deficiency, protein S deficiency, antithrombin deficiency, increased lipoprotein a). Adequate anticoagulation reduces thromboembolic complications in malignancies at least partially.

The increased liberation of thromboplastins by tumour cells in malignancies has according to our data another consequence: thrombin does not only act as enzyme of the haemostatic system, but also as a tissue hormone (growth factor). Thus, thrombin may induce an increased proliferation of tumour cells. Additionally, we could recently demonstrate that the preincubation of leukemic cells (HL-60) with thrombin induces resistance of these cells against the cytostatic substance idarubicin. The induction of apoptosis by idarubicin thus apparently is counteracted by thrombin. The reduction of thrombin liberation in tumor patients by anticoagulation therefore might increase the effect of idarubicin to induce apoptosis. This combined effect of anticoagulation and chemotherapy on apoptosis has to be investigated in further clinical studies.

Schlüsselwörter

Malignome - Gerinnungsaktivierung - Tumorzellenthromboplastine - Thrombin als Wachstumsfaktor - Apoptosemechanismus

Keywords

Malignancies - activation of coagulation - tumor cell thromboplastins - thrombin as growth factor - apoptosis
 

  • Literatur

  • 1 Ambrus JL, Ambrus CM. Blood Coagulation in Neoplastic Disease. In: Gastpar H. (ed): Onkohämostaseologie. Stuttgart, New York: Schattauer; 1976: 167-93.
    Google Scholar
  • 2 Andoh K, Kubota T, Takada M, Tanaka H, Kobayashi N, Maekawa T. Tissue factor activity in leukemic cells. Special reference to disseminated intravascular coagulation. Cancer 1987; 59: 748-54.
    CrossrefPubMedGoogle Scholar
  • 3 Avvisati G, Ten Cate JW, Boller HR, Mandelli F. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet 1989; i: 122-4.
    PubMedGoogle Scholar
  • 4 Bennett B, Booth NA, Croll A, Dawson AA. The bleeding disorder in acute promyelocytic leukemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol 1989; 71: 511-5.
    CrossrefPubMedGoogle Scholar
  • 5 Berger H, Freudenberg N. Todesursachen bei Malignompatienten. Med Welt 1983; 34: 112-8.
    PubMedGoogle Scholar
  • 6 Bern MM, Lokich JJ, Wallach SR, Bothe A, Benotti PN, Arkin CF, Greco FA, Huberman M, Moore C. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Int Med 1990; 112: 423-8.
    CrossrefPubMedGoogle Scholar
  • 7 Bick RL. Alterations of Hemostasis Associated with Malignancy: Etiology, Pathophysiology, Diagnosis and Management. Semin Thromb Hemost 1978; 5: 1-26.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Bruhn HD, Zurborn KH. Influence of clotting factors (thrombin, factor XIII) and of fibronectin on the growth of tumor cells and leukemic cells in vitro. Bluood 1983; 46: 85-8.
    PubMedGoogle Scholar
  • 9 Bruhn HD, Heimburger N, Wormsbächer S, Zurborn KH. Untersuchungen zum Mechanismus der Thrombin- und Faktor-XIII-Wirkung auf Fibroblasten und Leukämiezellen. In: Beck EA. (Hrsg). Thrombose- und Hämostaseforschung. Berichtsband 3. Kongreß für Thrombose und Blutstillung. Stuttgart: Schattauer; 1984: 375.
    Google Scholar
  • 10 Bruhn HD. Untersuchungen zur Biochemie der Tumorzellenthrombose. Thrombin als Gewebshormon. Behring Inst Mitt 1986; 79: 31-6.
    PubMedGoogle Scholar
  • 11 Bruhn HD, Knapp S, Senger H, Werner H, Zurborn KH. Auswirkungen einer Strahlen- oder Zytostatikatherapie auf das Hämostasesystem. In: Tilsner V, Matthias FR. (eds). Blutgerinnung und Onkologie. XXXI. Hamburger Symposion über Blutgerinnung. Basel: Editiones Roche; 1988: 171.
    Google Scholar
  • 12 Bruhn HD, Zurborn KH. Veränderungen des Hämostasesystems bei malignen Erkrankungen und deren klinische Bedeutung. In: Spanuth E. (ed). Malignome und Hämostase. Berlin, Heidelberg, New York: Springer; 1996: 3-15.
    Google Scholar
  • 13 Chahinlan AP, Propert KJ, Ware JH, Zimmer B, Perry MC, Hirsh V, Skarin A, Kopel S, Holland JF, Comis RL. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group. B J Clin Oncol 1989; 7: 993-1002.
    PubMedGoogle Scholar
  • 14 Clarke-pearson DL, Synan IS, Creasman WT. Anticoagulation therapy for venous thromboembolism in patients with gynecologic malignancy. Am J Ostet Gynecol 1983; 147: 369-75.
    CrossrefPubMedGoogle Scholar
  • 15 Cohen JR, Tenenbaum N, Citron M. Greenfield filter as primary therapy for deep venous thrombosis and/or pulmonary embolism in patients with cancer. Surgery 1991; 109: 12-5.
    PubMedGoogle Scholar
  • 16 Costantini V, Zacharski LR. Fibrin and Cancer. Thromb Haemost 1993; 69: 406-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Debatin KM. Die Rolle von Apoptosesignalwegen bei der Tumorregression. In: Spontanremissionen in der Onkologie. Heim ME, Schwarz R. (Hrsg). Stuttgart, New York: Schattauer; 1998: 76-83.
    Google Scholar
  • 18 de Jong E, Knot EAR, Piket D, Iburg AHC, Rijken DC, Veenhof KHN, Dooijewaard G, ten Cate JW. Increased Plasminogen Activator Inhibition Levels in Malignancy. Thromb Haemostas 1987; 57: 771-82.
    PubMedGoogle Scholar
  • 19 Donate MB, Falanga A, Consonni R, Alessio MG, Bassan R, Buelli M, Borin L, Catani L, Pogliani E, Guliotta L, Masera G, Barbui T. Cancer procoagulant in acute non lymphoid leukemia: Relationship of enzyme detection to disease activity. Thromb Haemostas 1990; 64: 11-6.
    PubMedGoogle Scholar
  • 20 Duffy MJ, O’Grady P. Plasminogen activator and cancer. Perspectives and commentaries. Eur J Cancer Clin Oncol 1984; 20: 577-82.
    CrossrefPubMedGoogle Scholar
  • 21 Dvorak HF. Thrombosis and Cancer. Hum Pathol 1987; 18: 275-84.
    CrossrefPubMedGoogle Scholar
  • 22 Drapkin RL, Gee TS, Dowling MD, Arlin Z, McKenzie S, Kempin S, Clarkson B. Prophylactic Heparin Therapy in Acute Promyelocytic Leukemia. Cancer 1978; 41: 2484-90.
    CrossrefPubMedGoogle Scholar
  • 23 Edwards RL, Silver J, Rickles FR. Human Tumor Procoagulants: Registry of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee, International Society on Thrombosis and Haemostasis. Thromb Haemost 1993; 69: 205-13.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Francis JL. Haemostasis and cancer. Med Lab Sci 1989; 46: 331-46.
    PubMedGoogle Scholar
  • 25 Gasic GJ, Gasic TB, Galanti N, Johnson T, Murphy S. Platelet-tumor-cell interactions in mice. Int J Cancer 1973; 11: 704-18.
    CrossrefPubMedGoogle Scholar
  • 26 Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA 1968; 61: 46-52.
    CrossrefPubMedGoogle Scholar
  • 27 Gastpar H. Beeinflussung der Metastasierung durch Hemmung der Thrombozytenaggregation. Beitr Onkol 1982; 13: 290-306.
    PubMedGoogle Scholar
  • 28 Goerner A. The influence of anticlotting agents on transplantation and growth of tumor tissue. J Lab Clin Med 1930; 16: 369-72.
    PubMedGoogle Scholar
  • 29 Gordon SG. Tumorprokoagulans, Gerinnung und Fibrinolyse bei malignen Erkrankungen. Hämostaseologie 1985; 5: 160-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Gralnick HR, Abrell E. Studies of the Procoagulant and Fibrinolytic Activity of Promyelocytes in Acute Promyelocytic Leukaemia. Brit J Haematol 1973; 24: 89-99.
    CrossrefPubMedGoogle Scholar
  • 31 Guarini A, Gugliotta L, Timoncini C, Chetti L, Catani L, Russo D, Tura S. Procoagulant cellular activity and disseminated intravascular coagulation in acute non-lymphoid leukaemia. Scand J Haematol 1985; 34: 152-6.
    PubMedGoogle Scholar
  • 32 Hagedorn AB, Bowie EJW, Elveback LR, Owen CA. Coagulation abnormalities in patients with inoperable lung cancer. Mayo Clin Proc 1074; 49: 649-53.
    PubMedGoogle Scholar
  • 33 Hilgard P. Tumorausbreitung und Metastasierung als Indikation für Antikoagulation und Fibrinolysetherapie. In: Gastpar H. (ed). Onkohämostaseologie. Stuttgart, New York: Schattauer; 1976: 107-9.
    Google Scholar
  • 34 Honn KV, Cicone B, Skoff A. Prostacyclin: a potent antimetastatic agent. Sience 1981; 212: 1270-2.
    CrossrefPubMedGoogle Scholar
  • 35 Kutti J. The management of thrombocytosis. Eur J Haematol 1990; 44: 81-8.
    PubMedGoogle Scholar
  • 36 Kwaan HC, Keer HN. Fibrinolysis in cancer. Semin Thromb Hemost 1990; 16: 230-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, De Pauw S. The Thrombogenic Effect of Anticancer Drug Therapy in Women With Stage II Breast Cancer. N Engl J Med 1988; 318: 404-7.
    CrossrefPubMedGoogle Scholar
  • 38 Levine MN, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Stewart D, Goodwin P. Double-blind randomised trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: 886-9.
    CrossrefPubMedGoogle Scholar
  • 39 Licciardello JTW, Moake JL, Rudy ChK, Karp DD, Hong K. Elevated Plasma von Willebrand Factor Levels and Arterial Occlusive Complications Associated with Cisplatin-Based Chemotherapy. Oncology 1985; 42: 296-300.
    CrossrefPubMedGoogle Scholar
  • 40 Lohrmann HP, Adam W, Heymer B, Kubanek B. Microangiopathic hemolytic anemia in metastatic carcinoma. Report of eight cases. Ann Intern Med 1973; 79: 368-75.
    CrossrefPubMedGoogle Scholar
  • 41 Ludwig H. Anticoagulantien beim fortgeschrittenen Carcinom. Gynäkologe 1974; 7: 204-12.
    PubMedGoogle Scholar
  • 42 Markus G. The role of haemostasis and fibrinolysis in the metastatic spread of cancer. Semin Thromb Haemost 1984; 10: 61-70.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Moore FD, Osteen RT, Karp DD, Steele G, Wilson RE. Anticoagulants, venous thromboembolism, and the cancer patient. Arch Surg 1981; 116: 405-7.
    CrossrefPubMedGoogle Scholar
  • 44 Nambi P. et al. Stimulation of intracellular topoisomerase I activity by vasopressin and thrombin. Differential regulation by pertussis toxine. Biochem J 1989; 262: 485-9.
    CrossrefPubMedGoogle Scholar
  • 45 Nanninga PB, van Teunenbroek A, Veenhof CHN, Büller HR, ten Cate JW. Low prevalence of coagulation and fibrinolytic activation in patients with primary untreated cancer. Thromb Haemost 1990; 64: 361-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Nordström M, Lindblad B, Anderson H, Kjellström T. Deep venous thrombosis and occult malignancy: an epidemiological study. Br Med J 1994; 308: 891-4.
    CrossrefPubMedGoogle Scholar
  • 47 Nowak-Göttl U. et al. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leucaemia carrying the MTHFRTT 677 Genotype, the prothrombin G 20210 A Variant, and further prothrombotic risk factors. Blatt 1999; 93: 1595-9.
    PubMedGoogle Scholar
  • 48 Nowak-Göttl U. et al. Increased lipoprotein (a) is an important risk factor for venous thromboembolism in childhood. Circulation 1999; 100: 743-8.
    CrossrefPubMedGoogle Scholar
  • 49 Pearlstein E, Salk PL, Yogeeswaran G, Karpatkin S. Correlation between spontaneous metastastic potential platelet aggregating activity of cell surface extracts and cell surface sialylation in 10 metastatic variant derivatives of a rat renal sarcoma cell line. Proc Natl Acad Sci USA 1980; 77: 4336-9.
    CrossrefPubMedGoogle Scholar
  • 50 Peuscher FW, Cleton FJ, Armstrong L, Stoepman-Van Dalen EA, van JA, van WG. Significance of plasma fibrinopeptide A (fpA) in patients with malignancy. J Lab Clin Med 1980; 96: 5-14.
    PubMedGoogle Scholar
  • 51 Poller L, Mckernan A, Thomson JM, Elstein M, Hirsh PJ, Jonbes JB. Fixed mini-dose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery. Br Med J 1987; 295: 1309-12.
    CrossrefPubMedGoogle Scholar
  • 52 Prandoni P, Lensing AWA, Büller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, Ten Cate JW. Deep-Vein Thrombosis and the Incidence of Subsequent Symptomatic Cancer. N Engl J Med 1992; 327: 1128-33.
    CrossrefPubMedGoogle Scholar
  • 53 Rasche H, Dietrich M. Hemostatic abnormalities associated with malignant diseases. Europ J Cancer 1977; 13: 1053-64.
    CrossrefPubMedGoogle Scholar
  • 54 Rickles FR, Edwards RL. Activation of Blood Coagulation in Cancer: Trousseau’s Syndrome Revisited. Blood 1983; 62: 14-31.
    PubMedGoogle Scholar
  • 55 Rickles Fr, Levine M, Edwards RL. Hemostatic alterations in cancer patients. Cancer Metast Rev 1992; 11: 237-48.
    CrossrefPubMedGoogle Scholar
  • 56 Sarasin FP, Eckman MH. Management and prevention of thromboembolic events in patients with cancer-related hypercoagulability states: a risky business. J Gen Intern Med 1993; 8: 476-86.
    CrossrefPubMedGoogle Scholar
  • 57 Schafer AI. Bleeding and thrombosis in myeloproliferative disorders. Blood 1984; 64: 1-22.
    PubMedGoogle Scholar
  • 58 Schmidt MB. Die Verbreitungswege der Karzinome und die Beziehungen generalisierter Sarkome zu den leukämischen Neubildungen. Jena: Fischer; 1903
    Google Scholar
  • 59 Schneider W. Bedeutung von Hämostasestörungen für Diagnostik und Therapie von Tumorkrankheiten. Hämostaseologie 1988; 8: 34-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Schöndorf TH, Witt I. Protein C in patients under L-asparaginase treatment. In: Witt I. (ed). Protein C – Biochemical and Medical Aspects. Berlin, New York: Walter de Gruyter; 1985: 125-34.
    Google Scholar
  • 61 Smirnova IV. et al. Thrombin is an extracellular signal that activates intracellular death protease pathways inducing apoptosis in model motor neurons. J Neurobiol 1998; 36: 64-80.
    CrossrefPubMedGoogle Scholar
  • 62 Südhoff T, Schneider W. Fibrinolytic mechanisms in tumor growth and spreading. Clin Investig 1992; 70: 631-5.
    CrossrefPubMedGoogle Scholar
  • 63 Sun NC, Mcaffee WM, Hum GJ. et al. Hemostatic abnormalities in malignancy, a prospective study of one hundred eight patients. Am J Clin Pathol 1979; 71: 10-9.
    CrossrefPubMedGoogle Scholar
  • 64 Sutor AH, Ritter J. Thrombosen bei Kindern mit akuter lymphatischer Leukämie. Hämostaseologie 1992; 12: 107-15.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 65 Tanaka H, Narahara N, Kurabayashi H, Sadakata H, Andoh K, Uchiyama T, Kobayashi N, Maekawa T. Studies on leukemic cell tissue factor. Thromb Res 1989; 53: 535-49.
    CrossrefPubMedGoogle Scholar
  • 66 Terranova T, Chiossone F. Il fattore coagulazione nell’attecchimento delle cellule neoplastiche immesse in circolo. Boll Soc Ital Biol Sper 1952; 28: 1224-5.
    PubMedGoogle Scholar
  • 67 Trousseau A. Phlegmasia alba dolens. Clinique médicale de l’hotel-dieu de Paris. London: The New Sydenham Society; 1865: 3-94.
    Google Scholar
  • 68 Wehmeier A, Schneider W. Megakaryocytes and platelets as the main cause for vascular events in chronic myeloproliferative disease. Hämostaseologie 1996; 16: 151-63.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Weiss RB, Tormey DC, Holland JF, Weinberg VE. Venous Thrombosis During Multimodal Treatment of Primary Breast Carcinoma. Cancer Treat Rep 1981; 65: 677-9.
    PubMedGoogle Scholar
  • 70 Zacharski LR, Henderson WG, Rickles FE. et al. Effect of warfarin anticoagulation on survival in carcinoma of lung, colon, head and neck and prostate: final report of VA cooperative study #75. Cancer 1984; 53: 2046-52.
    CrossrefPubMedGoogle Scholar
  • 71 Zacharski LR, Costantini V, Wojtukiewicz MZ, Memoli VA, Kududryk BJ. Anticoagulants as Cancer Therapy. Sem Oncol 1990; 17: 217-27.
    PubMedGoogle Scholar
  • 72 Zacharski LR, Donati MB, Rickles FR. Registry of clinical trials of antithrombotic drugs in cancer: second report. Thromb Haemost 1993; 70: 357-60.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 73 Zurborn K-H, Duscha H, Gram J, Bruhn HD. Investigations of Coagulation System and Fibrinolysis in Patients with Disseminated Adenocarcinomas and Non-Hodgkin’s Lymphomas. Oncology 1990; 47: 376-80.
    CrossrefPubMedGoogle Scholar
  • 74 Zurborn K-H, Gram J, Glander K, Delbrück K, Pelzer H, Löffler H, Bruhn HD. Influence of cytostatic treatment on the coagulation system and fibrinolysis in patients with non-Hodgkin’s lymphomas and acute leukemias. Eur J Haematol 1991; 47: 55-9.
    PubMedGoogle Scholar
  • 75 Zurborn K-H. Hemostasis and hormonal tumor therapy: epidemiology and clinical studies. Gynecol Endocrinol 1993; 7 (Suppl.): 1-5.
    PubMedGoogle Scholar