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Phlebologie 2008; 37(03): 142-147
DOI: 10.1055/s-0037-1622224
Original Article
Schattauer GmbH

Tumor-induzierte Thrombophilie

Zellbiologische Grundlagen und klinischer AusblickTumour-induced thrombophiliaBiological basis and clinical outlookThrombophilie induite par un processus tumoralBases biologiques et corrélation clinique
T. Goerge
1   Klinik und Poliklinik für Hautkrankheiten, Universitätsklinikum Münster
,
St. W. Schneider
1   Klinik und Poliklinik für Hautkrankheiten, Universitätsklinikum Münster
› Author Affiliations
Further Information

Publication History

Eingegangen: 14 April 2008

angenommen: 14 April 2008

Publication Date:
04 January 2018 (online)

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Zusammenfassung

Bereits im späten 19. Jahrhundert wurde von Armand Trousseau die klinische Beobachtung beschrieben, dass Tumorpatienten gehäuft thromboembolische Ereignisse erleiden. Allerdings sind die molekularen Mechanismen, die für die Tumor-induzierte Thrombose verantwortlich sind, noch weitgehend unbekannt. Obwohl es einige molekulare Konzepte zur Aktivierung des Gerinnungssystems bei Tumorpatienten gibt, sind die genauen Mechanismen Gegenstand intensiver Forschung. Das Verständnis und die Zusammenhänge dieses Wechselspiels könnten neue therapeutische Optionen eröffnen. Zunehmend wird klar, dass Tumorpatienten, die eine Aktivierung des Gerinnungssystems (z. B. aufgrund einer Thromboembolie) aufweisen, eine verstärkte Tumorprogression zeigen. Daher korreliert eine Aktivierung des Gerinnungssystems mit einer verstärkten Metastasierung und schlechten Prognose unabhängig von weiteren thrombotischen Ereignissen. Um die Mechanismen der Tumor-induzierten Thrombophilie besser zu verstehen, ist es notwendig, Studien zu initiieren, die diese Zusammenhänge und ihre therapeutischen Optionen untersuchen.

Summary

The clinical observation of thrombotic events in cancer patients has been first described in the late 19th century by Armand Trousseau. However, the molecular mechanisms that link tumour and thrombosis are far from being understood. While molecular concepts of how activation of the coagulation system could occur in cancer patients are being proposed, the exact mechanisms underlying this phenomenon that might finally lead to therapeutic options are still matter of intensive research. Interestingly, it is getting more and more recognized, that tumour patients showing activation of the coagulation system are at a greater risk of tumour progression than those without signs of thrombotic activity. Therefore, activation of the coagulation cascade in tumour patients correlates with higher risk of tumour progression and fatality, even without a thrombotic event. Therefore, it is necessary to increase our understanding of tumour-induced thrombophilia and initiate studies that recognize this important fact.

Résumé

L’observation clinique d’événements thrombotiques chez des patients cancéreux a été faite pour la première fois au 19ème siècle par Armand Trousseau. Cependant les mécanismes moléculaires qui relient une tumeur cancéreuse à une thrombose sont loin d’être compris. Alors que des concepts moléculaires sont avancés pour expliquer l’activation de la coagulation chez les patients cancéreux, les mécanismes précis qui puissent expliquer ce phénomène menant finalement à une décision thérapeutique font toujours l’objet d’une recherche intensive. Il est intéressant de noter que l’on admet de plus en plus que les patients cancéreux qui montrent une activation du système de coagulation ont également un risque de progression tumorale plus grand que ceux qui sont dépourvus de signes d’une activité thrombotique. Ainsi, l’activation de la cascade de la coagulation chez des patients cancéreux est en corrélation directe avec un risque augmenté de progression tumorale fatale, même en l’absence d’un événement thrombotique. Ainsi, il est nécessaire d’accroître notre compréhension de la thrombophilie induite par les tumeurs et de développer des études qui reconnaissent cette réalité importante.

Schlüsselwörter

Gerinnung - Thrombophilie - Antikoagulation - Metastasierung

Keywords

Coagulation - thrombophilia - anticoagulation - tumour progression

Mots clés

Coagulation - thrombophilie - anticoagulation - tumeurs malignes métastatiques
 

  • Literatur

  • 1 Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A. et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2004; 2: 1266-1271.
    CrossrefPubMedSearch in Google Scholar
  • 2 Amirkhosravi A, Mousa SA, Amaya M, Francis JL. Antimetastatic effect of tinzaparin, a low-molecular-weight heparin. J Thromb Haemost 2003; 1: 1972-1976.
    CrossrefPubMedSearch in Google Scholar
  • 3 Arora P, Ricks TK, Trejo J. Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J Cell Sci 2007; 120: 921-928.
    CrossrefPubMedSearch in Google Scholar
  • 4 Bastounis EA, Karayiannakis AJ, Makri GG, Alexiou D, Papalambros EL. The incidence of occult cancer in patients with deep venous thrombosis: a prospective study. J Intern Med 1996; 239: 153-156.
    CrossrefPubMedSearch in Google Scholar
  • 5 Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715-722.
    CrossrefPubMedSearch in Google Scholar
  • 6 Boukerche H, Berthier-Vergnes O, Tabone E, Dore JF, Leung LL, McGregor JL. Platelet-melanoma cell interaction is mediated by the glycoprotein IIb-IIIa complex. Blood 1989; 74: 658-663.
    PubMedSearch in Google Scholar
  • 7 Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR. Platelets, proteaseactivated receptors, and fibrinogen in hematogenous metastasis. Blood 2004; 104: 397-401.
    CrossrefPubMedSearch in Google Scholar
  • 8 Depasquale I, Thompson WD. Prognosis in human melanoma: PAR-1 expression is superior to other coagulation components and VEGF. Histopathology 2008; 52: 500-509.
    CrossrefPubMedSearch in Google Scholar
  • 9 Falanga A, Piccioli A. Effect of anticoagulant drugs in cancer. Curr Opin Pulm Med 2005; 11: 403-407.
    CrossrefPubMedSearch in Google Scholar
  • 10 Gasic GJ, Gasic TB, Galanti N, Johnson T, Murphy S. Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease. Int J Cancer 1973; 11: 704-718.
    CrossrefPubMedSearch in Google Scholar
  • 11 Goerge T, Barg A, Schnaeker EM, Poppelmann B, Shpacovitch V, Rattenholl A. et al. Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation. Cancer Res 2006; 66: 7766-7774.
    CrossrefPubMedSearch in Google Scholar
  • 12 Goerge T, Kleineruschkamp F, Barg A, Schnaeker EM, Huck V, Schneider MF. et al. Microfluidic reveals generation of platelet-strings on tumor-activated endothelium. Thromb Haemost 2007; 98: 283-286.
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton 3rd LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809-815.
    CrossrefPubMedSearch in Google Scholar
  • 14 Hostettler N, Naggi A, Torri G, Ishai-Michaeli R, Casu B, Vlodavsky I. et al. P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. Faseb J 2007; 21: 3562-3572.
    CrossrefPubMedSearch in Google Scholar
  • 15 Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 2004; 104: 2746-2751.
    CrossrefPubMedSearch in Google Scholar
  • 16 Humphries MJ, Olden K, Yamada KM. A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells. Science 1986; 233: 467-470.
    CrossrefPubMedSearch in Google Scholar
  • 17 Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Buller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000; 18: 3078-3083.
    CrossrefPubMedSearch in Google Scholar
  • 18 Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK. et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004; 22: 1944-1948.
    CrossrefPubMedSearch in Google Scholar
  • 19 Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F. et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130-2135.
    CrossrefPubMedSearch in Google Scholar
  • 20 Lazo-Langner A, Goss GD, Spaans JN, Rodger MA. The effect of low-molecular-weight heparin on cancer survival. A systematic review and metaanalysis of randomized trials. J Thromb Haemost 2007; 5: 729-737.
    CrossrefPubMedSearch in Google Scholar
  • 21 Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M. et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-153.
    CrossrefPubMedSearch in Google Scholar
  • 22 Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C. et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23: 2123-2129.
    CrossrefPubMedSearch in Google Scholar
  • 23 Li JJ, Huang YQ, Basch R, Karpatkin S. Thrombin induces the release of angiopoietin-1 from platelets. Thromb Haemost 2001; 85: 204-206.
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Ludwig RJ, Alban S, Bistrian R, Boehncke WH, Kaufmann R, Henschler R. et al. The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Thromb Haemost 2006; 95: 535-540.
    Thieme ConnectPubMedSearch in Google Scholar
  • 25 Ludwig RJ, Boehme B, Podda M, Henschler R, Jager E, Tandi C. et al. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res 2004; 64: 2743-2750.
    CrossrefPubMedSearch in Google Scholar
  • 26 Luxembourg B, Bauersachs R. Malignancy and thrombosis: a double-sided clinical relationship. Vasa 2005; 34: 225-234.
    CrossrefPubMedSearch in Google Scholar
  • 27 McCarty OJ, Mousa SA, Bray PF, Konstantopoulos K. Immobilized platelets support human colon carcinoma cell tethering, rolling, and firm adhesion under dynamic flow conditions. Blood 2000; 96: 1789-1797.
    PubMedSearch in Google Scholar
  • 28 McGregor BC, McGregor JL, Weiss LM, Wood GS, Hu CH, Boukerche H. et al. Presence of cytoadhesins (IIb-IIIa-like glycoproteins) on human metastatic melanomas but not on benign melanocytes. Am J Clin Pathol 1989; 92: 495-499.
    CrossrefPubMedSearch in Google Scholar
  • 29 Miller GJ, Bauer KA, Howarth DJ, Cooper JA, Humphries SE, Rosenberg RD. Increased incidence of neoplasia of the digestive tract in men with persistent activation of the coagulant pathway. J Thromb Haemost 2004; 2: 2107-2114.
    CrossrefPubMedSearch in Google Scholar
  • 30 Monreal M, Lafoz E, Casals A, Inaraja L, Montserrat E, Callejas JM. et al. Occult cancer in patients with deep venous thrombosis. A systematic approach. Cancer 1991; 67: 541-545.
    CrossrefPubMedSearch in Google Scholar
  • 31 Mousa SA. Antithrombotics in thrombosis and cancer. Hamostaseologie 2005; 25: 380-386.
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Nierodzik ML, Chen K, Takeshita K, Li JJ, Huang YQ, Feng XS. et al. Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. Blood 1998; 92: 3694-3700.
    PubMedSearch in Google Scholar
  • 33 Nierodzik ML, Kajumo F, Karpatkin S. Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. Cancer Res 1992; 52: 3267-3272.
    PubMedSearch in Google Scholar
  • 34 Nierodzik ML, Plotkin A, Kajumo F, Karpatkin S. Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo. J Clin Invest 1991; 87: 229-236.
    CrossrefPubMedSearch in Google Scholar
  • 35 Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59: 1295-1300.
    PubMedSearch in Google Scholar
  • 36 Otten HM, Mathijssen J, ten Cate H, Soesan M, Inghels M, Richel DJ. et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: an underestimated phenomenon. Arch Intern Med 2004; 164: 190-194.
    CrossrefPubMedSearch in Google Scholar
  • 37 Prandoni P, Falanga A, Piccioli A. Cancer and venous thromboembolism. Lancet Oncol 2005; 6: 401-410.
    CrossrefPubMedSearch in Google Scholar
  • 38 Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-3488.
    CrossrefPubMedSearch in Google Scholar
  • 39 Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846-1850.
    CrossrefPubMedSearch in Google Scholar
  • 40 Sproul E. Carcinoma and venous thrombosis: the frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Am J Cancer 1938; 34: 566-585.
    Search in Google Scholar
  • 41 Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins – correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
    CrossrefPubMedSearch in Google Scholar
  • 42 Tagalakis V, Blostein M, Robinson-Cohen C, Kahn SR. The effect of anticoagulants on cancer risk and survival: systematic review. Cancer Treat Rev 2007; 33: 358-368.
    CrossrefPubMedSearch in Google Scholar