Antithrombotics in thrombosis and cancer

Summary

Many cancer patients have a hypercoagulable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumour growth and metastasis. These include fibrin formation; binding of heparin to angiogenic growth factors, such as basic fibroblast growth factor (FGF2) and vascular endothelial growth factor (VEGF); modulation of tissue factor; and perhaps other more important modulatory mechanisms, such as enhanced tissue factor pathway inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of low molecular weight heparin (LMWH), as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Studies from our laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa, and LMWH-releasable TFPI on the regulation of angiogenesis, tumour growth, and tumour metastasis. Thus, modulation of tissue factor/VIIa non-coagulant activities by LMWH, warfarin, anti-VIIa, or TFPI might be a useful therapeutic method for the inhibition of angiogenesis associated with human tumour growth and metastasis. Additionally, antiplatelet drugs could have an impact on tumour metastasis, and the combination of antiplatelets and anticoagulants at adjusted doses might provide greater benefits to cancer patients.

Zusammenfassung

Bei vielen Krebspatienten besteht eine erhöhte Gerinnbarkeit mit rezidivierenden Thrombosen, da sich Krebszellen und Chemo- oder Strahlentherapie in die Gerinnung eingreifen. Studien zeigten, dass unfraktioniertes und niedermolekulares Heparin mehrere Vorgänge beeinträchtigen, die an Tumorwachstum und Metastasierung beteiligt sind. Hierzu gehören Fibrinbildung, Bindung von Heparin an angiogene Wachstumsfaktoren wie z. B. der basische Fibroblastenwachstumsfaktor (FGF2) und der vaskuläre endotheliale Wachstumsfaktor (VEGF), Modulation des Gewebefaktors und evtl. andere modulatorische Mechanismen, z. B. vermehrte Freisetzung des Tissue Factor Pathway Inhibitors (TFPI) und Hemmung Matrix-abbauender Enzyme. Studien lassen auf einen klinisch relevanten Effekt von niedermolekularem (LMWH) im Vergleich zu unfraktioniertem Heparin (UFH) auf das Überleben von Krebspatienten mit tiefer Venenthrombose schließen. In gleicher Weise wurden die Auswirkungen von Warfarin auf das Überleben von Krebspatienten mit thromboembolischen Störungen nachgewiesen. Studien aus unserem Labor zeigten eine maßgebliche Rolle von LMWH, Warfarin, anti-VIIa und durch LMWH freisetzbarem TFPI auf die Regulation der Angiogenese, des Tumorwachstums und der Metastasierung. Die Modulation der nicht-koagulativen Aktivitäten von Gewebefaktor/ VIIa durch LMWH, Warfarin, anti-VIIa und TFPI könnte eine nützliche therapeutische Methode zur Hemmung der mit dem Tumorwachstum und der Metastasierung verbundenen Angiogenese sein. Außerdem wirken Thrombozytenfunktionshemmer möglicherweise auf die Metastasierung, und die Kombination aus Thrombozytenfunktionshemmern und Antikoagulanzien in angepasster Dosierung könnte Krebspatienten größere Vorteile bringen.

Keywords

Acetylsalicylic acid - GPIIb/IIIa antagonists - heparin - LMWH - TF/VIIa - TFPI - FGF2 - VEGF - cancer - angiogenesis - thrombosis

Schlüsselwörter

Azetylsalizylsäure - GPIIb/IIIa-Antagonisten - Heparin - LMWH - TF/VIIa - TFPI - FGF2 - VEGF - Krebs - Angiogenese - Thrombose

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