Tumorwachstum und Hämostase

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

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