Pathophysiologie, Diagnostik und aktuelle Therapie der tumorinduzierten Hämostasestörung

Zusammenfassung

Neuere Erkenntnisse zur Pathophysiologie der Tumorthrombophilie verdeutlichen zunehmend die Komplexität. Verschiedene Tumoren unterscheiden sich deutlich bezüglich der Expression von Tumorprokoagulanzien, Komponenten des Fibrinolysesystems, Zytokin-vermittelter Beeinflussung von Entzündungszellen und Endothel und der plättchenaktivierenden Eigenschaften. Die Gerinnungsaktivierung mit Thrombinbildung geht über ein Epiphänomen deutlich hinaus. Dies wird durch zahlreiche tierexperimentelle und klinische Daten zur Beeinflussung des Tumorwachstums mit antithrombotischen Maßnahmen belegt. Darüber hinaus besteht eine autokrine mitogene Stimulation der Tumorzelle selbst durch das von ihr induzierte Thrombin, das auf diese Weise Tumorwachstum unterhalten kann. Auf diesem Boden werden aktuelle Therapiestrategien für ganz bestimmte Tumorarten einschließlich spezieller Probleme der Therapie mit Antikoagulanzien und Plättchenfunktionshemmern beim Tumorpatienten aufgezeigt.

Schlüsselwörter

Neoplasma - Tumorprokoagulanz - Thrombophilie - Akute-Phase-Reaktion - antithrombotische Therapie

• LITERATUR

• 1 Al-Mondhiry H. Disseminated intravascular coagulation experience in a major cancer center. Throm Diath Haemorrh 1975; 34: 181-93.
• 2 Ambrus JL, Ambrus CM. Blood coagulation in neoplastic disease. In: Onkohämostaseologie. Gastpar H. Hrsg. Stuttgart, New York: Schattauer; 1976: 167-93.
• 3 Andoh K, Kubota T, Takada M. et al. Tissue, factor activity in leukemic cells. Special reference to disseminated intravascular coagulation. Cancer 1987; 59: 748-54.
• 4 Avvisati G, Ten Cate JW, Böller HR, Mandelli F. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet 1989; i: 122-4.
• 5 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.
• 6 Bern MM, Lokich JJ, Wallach SR. et al. Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Int Med 1990; 112: 423-8.
• 7 Bertomeu MC, Gallo S, Lauri D. et al. Chemotherapy enhances endothelial cell reactivity to platelets. Clin Exp Metastasis 1990; 08: 511-8.
• 8 Bick RL. Alterations of hemostasis associated with malignancy: etiology, pathophysiology, diagnosis and management. Semin Thromb Hemost 1978; 05: 1-26.
• 9 Brain MC, Azzopardi JG, Baker LRI. Microangiopathic hemolytic anaemia in mucin-forming adenocarcinoma. Br J Haematol 1970; 18: 183-93.
• 10 Bruhn HD, Knapp S, Senger H, Werner H, Zurborn KH. Auswirkungen einer Strahlenoder Zytostatikatherapie auf das Hämostasesystem. In: Blutgerinnung und Onkologie. XXXI. Hamburger Symposion über Blutgerinnung. Tilsner V, Matthias FR. Hrsg. Basel: Editiones Roche; 1988: 171.
• 11 Bruhn HD, Zurborn K-H. Influences of clotting factors (thrombin, factor XIII) and of fibrinonectin on the growth of tumor cells and leukemic cells in vitro. Blut 1983; 46: 85-8.
• 12 Chahinian AP, Propert KJ, Ware JH. et al. 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; 07: 993-1002.
• 13 Clarke-Pearson DL, Synan IS, Creasman WT. Anticoagulation therapy for venous thromboembolism in patients with gynecologic malignancy. Am J Obstet Gynecol 1983; 147: 369-75.
• 14 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.
• 15 Costantini V, Zacharski LR. Fibrin and cancer. Thromb Haemost 1993; 69: 406-14.
• 16 de Jong E, Knot EAR, Piket D. et al. Increased plasminogen activator inhibition levels in malignancy. Thromb Haemost 1987; 57: 771-82.
• 17 Donati MB, Falanga A, Consonni R. et al. Cancer procoagulant in acute non lymphoid leukemia: Relationship of enzyme detection to disease activity. Thromb Haemost 1990; 64: 11-6.
• 18 Duffy MJ, O’Grady P. Plasminogen activator and cancer. Perspectives and commentaries. Eur J Cancer Clin Oncol 1984; 20: 577-82.
• 19 Dvorak HF. Thrombosis and cancer. Hum Pathol 1987; 18: 275-84.
• 20 Drapkin RL, Gee TS, Dowling MD. et al. Prophylactic heparin therapy in acute promyelocytic leukemia. Cancer 1978; 41: 2484-90.
• 21 Edwards RL, Silver J, Rickies 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.
• 22 Falanga A, Alessio MG, Donati MB, Barbui T. A new procoagulant in acute leukemia. Blood 1988; 71: 870-5.
• 23 Francis JL. Haemostasis and cancer. Med Lab Sci 1989; 46: 331-46.
• 24 Gabazza EC, Taguchi O, Yamakami T. et al. Evaluating prethrombotic state in lung cancer using molecular markers. Chest 1993; 103: 196-200.
• 25 Gasic GJ, Gasic TB, Galanti N. et al. Platelet-tumor-cell interactions in mice. Int J Cancer 1973; 11: 704-18.
• 26 Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci USA 1968; 61: 46-52.
• 27 Gastpar H. Beeinflussung der Metastasierung durch Hemmung der Thrombozytenaggregation. Beitr Onkol 1982; 13: 290-306.
• 27a Gastpar H. Platelet-cancer cell interaction in metastasis formation: A possible therapeutic approach to metastasis prophylaxis. J Med 1977; 08: 103-14.
• 28 Goerner A. The influence of anticlotting agents on transplantation and growth of tumor tissue. J Lab Clin Med 1930; 16: 369-72.
• 29 Goldberg RJ, Seneff M, Gore JM. et al. Occult malignant neoplasm in patients with deep venous thrombosis. Arch Intern Med 1987; 147: 251-3.
• 30 Goodnight SH. Bleeding and intravascular clotting in malignancy: a review. Ann NY Acad Sci 1974; 230: 271-88.
• 31 Gordon SG. Tumorprokoagulans, Gerinnung und Fibrinolyse bei malignen Erkrankungen. Hämostaseologie 1985; 05: 160-5.
• 32 Gralnick HR, Abrell H. Studies of the procoagulant and fibrinolytic activity of promyelocytic leukaemia. Br J Haematol 1973; 24: 89-99.
• 33 Guarini A, Gugliotta L, Timoncini C. et al. Procoagulant cellular activity and disseminated intravascular coagulation in acute nonlymphoid leukaemia. Scand J Haematol 1985; 34: 152-6.
• 34 Hafter R, Schröck R, Von Hugo R, Graeff I. Measurement of crosslinked fibrin derivatives in plasma and ascitic fluid with monoclonal antibodies against D Dimer using EIA and Latex test. Scand J Clin Invest 1985; 45: 137-44.
• 35 Hagedorn AB, Bowie EJW, Elveback LR, Owen CA. Coagulation abnormalities in patients with inoperable lung cancer. Mayo Clin Proc 1974; 49: 649-53.
• 36 Harker LA, Slichter SJ. Platelet and fibrinogen consumption in man. N Engl J Med 1972; 287: 999-1003.
• 37 Hilgard P. Tumorausbreitung und Metastasierung als Indikation für Antikoagulation und Fibrinolysetherapie. In: Onkohämostaseologie. Gastpar H. Hrsg. Stuttgart, New York: Schattauer; 1976: 107-9.
• 38 Honn KV, Cicone B, Skoff A. Prostacyclin: a potent antimetastatic agent. Science 1981; 212: 1270-2.
• 39 Kemkes-Matthes B. Das Trousseausche Syndrom. Hämostaseologie 1993; 13: 132-7.
• 40 Kies MS, Posch JJ, Giolma JP, Rubin RN. Hemostatic function in cancer patients. Cancer 1980; 46: 831-7.
• 41 Kutti J. The management of thrombocytosis. Eur J Haematol 1990; 44: 81-8.
• 42 Kwaan HC, Keer HN. Fibrinolysis in cancer. Semin Thromb Hemost 1990; 16: 230-5.
• 43 Levine MN, Gent M, Hirsh J. et al. The thrombogenic effect of anticancer drug therapy in women with stage III breast cancer. N Engl J Med 1988; 318: 404-7.
• 44 Levine MN, Hirsh J, Gent M. et al. Doubleblind randomised trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: 886-9.
• 45 Licciardello JTW, Moake JL, Rudy ChK. et al. Elevated plasma von Willebrand factor levels and arterial occlusive complications associated with cisplatin-based chemotherapy. Oncology 1985; 42: 296-300.
• 46 Ludwig H. Anticoagulantien beim fortgeschrittenen Carcinom. Gynäkologe 1974; 07: 204-12.
• 47 Luzzatto G, Schafer AI. The prethrombotic state of cancer. Sem Oncol 1990; 17: 147-59.
• 48 Markus G. The role of haemostasis and fibrinolysis in the metastatic spread of cancer. Semin Thromb Haemost 1984; 10: 61-70.
• 49 Moore FD, Osteen RT, Karp DD. et al. Anticoagulants, venous thromboembolism, and the cancer patient. Arch Surg 1981; 116: 405-7.
• 50 Myers TJ, Rickies FR, Barb C, Cronlund M. Fibrinopeptide A in acute leukemia: relationship of activation of blood coagulation to disease activity. Blood 1981; 57: 518-25.
• 51 Nanninga PB, van Teunenbroek A, Veenhof CHN. et al. Low prevalence of coagulation and fibrinolytic activation in patients with primary untreated cancer. Thromb Haemost 1990; 64: 361-4.
• 52 Nordstrom M, Lindblad B, Anderson H, Kjellström T. Deep venous thrombosis and occult malignancy: an epidemiological study. Br Med J 1994; 308: 891-4.
• 53 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.
• 54 Peuscher FW, Cleton FJ, Armstrong L. et al. Significance of plasma fibrinopeptide A (fpA) in patients with malignancy. J Lab Clin Med 1980; 96: 5-14.
• 55 Poller L, McKernan A, Thomson JM. et al. Fixed mini-dose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery. Br Med J 1987; 295: 1309-12.
• 56 Prandoni P, Lensing AWA, Büller HR. et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327: 1128-33.
• 57 Preston FE, Emmanuel IG, Winfield DA, Malia RG. Essential thrombocythaemia and peripheral gangrene. Br Med J 1974; 03: 548-52.
• 58 Rasche H, Dietrich M. Hemostatic abnormalities associated with malignant diseases. Europ J Cancer 1977; 13: 1053-64.
• 59 Rickies FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983; 62: 14-31.
• 60 Rickies FR, Levine M, Edwards RL. Hemostatic alterations in cancer patients. Cancer Metast Rev 1992; 11: 237-48.
• 61 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; 08: 476-86.
• 62 Schafer AI. Bleeding and thrombosis in myeloproliferative disorders. Blood 1984; 64: 1.
• 63 Schmidt MB. Die Verbreitungswege der Karzinome und die Beziehungen generalisierter Sarkome zu den leukämischen Neubildungen. Jena: Fischer. 1903
• 64 Schneider W. Bedeutung von Hämostasestörungen für Diagnostik und Therapie von Tumorkrankheiten. Hämostaseologie 1988; 08: 34-6.
• 65 Schöndorf TH, Witt I. Protein C in patients under L-asparaginase treatment. In: Protein C Biochemical and Medical Aspects. Witt J. ed. Berlin, New York: Walter de Gruyter; 1985: 125-34.
• 66 Seitz R, Heidtmann H-H, Maasberg M. et al. Activation of coagulation in cultured human lung-tumor cells. Int J Cancer 1993; 53: 514-20.
• 67 Speiser W, Pabinger-Fasching I, Kyrie PA. et al. Blut. 1990; 61: 298-302.
• 68 Südhoff T, Schneider W. Fibrinolytic mechanisms in tumor growth and spreading. Clin Invest 1992; 70: 631-5.
• 69 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.
• 70 Sutor AH, Ritter J. Thrombosen bei Kindern mit akuter lymphatischer Leukämie. Hämostaseologie 1992; 12: 107-15.
• 71 Tanaka H, Narahara N, Kurabayashi H. et al. Studies on leukemic cell tissue factor. Thromb Res 1989; 53: 535-49.
• 72 Terranova T, Chiossone F. II fattore coagulazione neH’attecchimento delle cellule neoplastiche immesse in circolo. Boll Soc Ital Biol Sper 1952; 28: 1224-5.
• 73 Trousseau A. Phlegmasia alba dolens. Clinique médicale de l’hôtel-dieu de Paris. London: The New Sydenham Society; 1865: 3-94.
• 74 Wehmeier A, Scharf RE, Schneider W. Thrombose und Blutungsneigung bei myeloproliferativen Erkrankungen. Hämostaseologie 1985; 05: 185-92.
• 75 Weiss RB, Tormey DC, Holland JF, Weinberg VE. Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat Rep 1981; 65: 677-9.
• 76 Yoda Y, Abe T. Fibrinopeptide A (FPA) level and fibrinogen kinetics in patients with malignant disease. Thromb Haemost 1981; 46: 706-9.
• 77 Zacharski LR, Henderson WG, Ricles 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.
• 78 Zacharski LR, Costantini V, Wojtukiewicz MZ. et al. Anticoagulants as cancer therapy. Sem Oncol 1990; 17: 217-27.
• 79 Zacharski LR, Donati MB, Rickies FR. Registry of clinical trials of antithrombotic drugs in cancer: second report. Thromb Haemost 1993; 70: 357-60.
• 80 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.
• 81 Zurborn K-H, Gram J, Glander K. et al. 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.
• 82 Zurborn K-H. Hemostasis and hormonal tumor therapy: epidemiology and clinical studies. Gynecol Endocrinol 1993; 07 (Suppl): 1-5.