Download PDF
Semin Thromb Hemost 2009; 35(7): 644-653
DOI: 10.1055/s-0029-1242718
© Thieme Medical Publishers

The Bidirectional Relationship of Cancer and Hemostasis and the Potential Role of Anticoagulant Therapy in Moderating Thrombosis and Cancer Spread

Massimo Franchini1 , Martina Montagnana2 , Emmanuel J. Favaloro3 , Giuseppe Lippi4
  • 1Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine University Hospital of Parma, Parma
  • 2Section of Clinical Chemistry, Department of Biomedical and Morphological Sciences, University of Verona, Verona; Italy
  • 3Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia
  • 4U.O. Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospadaliero-Universitaria di Parma, Parma, Italy
Further Information

Publication History

Publication Date:
09 December 2009 (online)

    Permissions and Reprints

ABSTRACT

The relationship between hemostasis and malignancy is well recognized, with both elements interacting in a “vicious cycle” where cancers overexpress procoagulants and thrombin, which in turn promote both prothrombotic potential and tumor growth, invasion, and spread. Indeed, venous thromboembolism, particularly idiopathic venous thrombosis, occurs frequently as a paraneoplastic phenomenon, and in turn several components of primary and secondary hemostasis (namely platelets, tissue factor, and thrombin) play an important role in primary tumor growth and metastasization. Despite the many and various mechanisms involved in this multifaceted relationship, anticoagulants might represent an attractive anticancer therapy, in that current research supports the hypothesis that such drugs may offer a better control of cancer progression. The main biological and clinical evidence on the relationship between cancer and hemostasis are briefly summarized in this review, as is the potential benefits of anticoagulant therapy in this setting.

KEYWORDS

Cancer - hemostasis - anticoagulant therapy

REFERENCES

  • 1 De Bouillaud S. L'oblitération des veines et de son influence sur la formation des hydropisies partielles: considération sur la hydropisies passive et général.  Arch Gen Med. 1823;  1 188-204
    PubMedGoogle Scholar
  • 2 Trousseau A. Phlegmasia alba dolens. In: Trousseau A Clinique médicinale de l'Hôtel-Dieu de Paris. Paris, France; JB Bailliere et fils 1865: 645-712
    PubMedGoogle Scholar
  • 3 Otten H M, Prins M H. Venous thromboembolism and occult malignancy.  Thromb Res. 2001;  102 V187-194
    CrossrefPubMedGoogle Scholar
  • 4 Nierodzik M L, Plotkin A, Kajumo F, Karpatkin S. Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo.  J Clin Invest. 1991;  87(1) 229-236
    CrossrefPubMedGoogle Scholar
  • 5 Buller H R, van Doormaal F F, van Sluis G L, Kamphuisen P W. Cancer and thrombosis: from molecular mechanisms to clinical presentations.  J Thromb Haemost. 2007;  5(Suppl 1) 246-254
    CrossrefPubMedGoogle Scholar
  • 6 Tsopanoglou N E, Maragoudakis M E. Role of thrombin in angiogenesis and tumor progression.  Semin Thromb Hemost. 2004;  30(1) 63-69
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 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(9) 2746-2751
    CrossrefPubMedGoogle Scholar
  • 8 Zain J, Huang Y Q, Feng X, Nierodzik M L, Li J J, Karpatkin S. Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells.  Blood. 2000;  95(10) 3133-3138
    PubMedGoogle Scholar
  • 9 Versteeg H H, Ruf W. Emerging insights in tissue factor-dependent signaling events.  Semin Thromb Hemost. 2006;  32(1) 24-32
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Østerud B, Bjørklid E. Sources of tissue factor.  Semin Thromb Hemost. 2006;  32(1) 11-23
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Rao L V. Tissue factor as a tumor procoagulant.  Cancer Metastasis Rev. 1992;  11(3-4) 249-266
    CrossrefPubMedGoogle Scholar
  • 12 Rak J, Milsom C, May L, Klement P, Yu J. Tissue factor in cancer and angiogenesis: the molecular link between genetic tumor progression, tumor neovascularization, and cancer coagulopathy.  Semin Thromb Hemost. 2006;  32(1) 54-70
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Kataoka H, Uchino H, Asada Y et al.. Analysis of tissue factor and tissue factor pathway inhibitor expression in human colorectal carcinoma cell lines and metastatic sublines to the liver.  Int J Cancer. 1997;  72(5) 878-884
    CrossrefPubMedGoogle Scholar
  • 14 Signaevsky M, Hobbs J, Doll J, Liu N, Soff G A. Role of alternatively spliced tissue factor in pancreatic cancer growth and angiogenesis.  Semin Thromb Hemost. 2008;  34(2) 161-169
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Zwicker J I. Tissue factor-bearing microparticles and cancer.  Semin Thromb Hemost. 2008;  34(2) 195-198
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Milsom C, Yu J, May L, Magnus N, Rak J. Diverse roles of tissue factor-expressing cell subsets in tumor progression.  Semin Thromb Hemost. 2008;  34(2) 170-181
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Falanga A, Barbui T, Rickles F R. Hypercoagulability and tissue factor gene upregulation in hematologic malignancies.  Semin Thromb Hemost. 2008;  34(2) 204-210
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Zhang Y, Deng Y, Luther T et al.. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.  J Clin Invest. 1994;  94(3) 1320-1327
    Google Scholar
  • 19 Rickles F R, Patierno S, Fernandez P M. Tissue factor, thrombin, and cancer.  Chest. 2003;  124(3, Suppl) 58S-68S
    CrossrefPubMedGoogle Scholar
  • 20 Ruf W, Mueller B M. Tissue factor in cancer angiogenesis and metastasis.  Curr Opin Hematol. 1996;  3(5) 379-384
    CrossrefPubMedGoogle Scholar
  • 21 Franchini M, Montagnana M, Targher G, Manzato F, Lippi G. Pathogenesis, clinical and laboratory aspects of thrombosis in cancer.  J Thromb Thrombolysis. 2007;  24(1) 29-38
    CrossrefPubMedGoogle Scholar
  • 22 Yu J, May L, Milsom C et al.. Contribution of host-derived tissue factor to tumor neovascularization.  Arterioscler Thromb Vasc Biol. 2008;  28(11) 1975-1981
    CrossrefPubMedGoogle Scholar
  • 23 Amirkhosravi A, Amaya M, Desai H, Francis J L. Platelet-CD40 ligand interaction with melanoma cell and monocyte CD40 enhances cellular procoagulant activity.  Blood Coagul Fibrinolysis. 2002;  13(6) 505-512
    CrossrefPubMedGoogle Scholar
  • 24 Schaffner F, Ruf W. Tissue factor and protease-activated receptor signaling in cancer.  Semin Thromb Hemost. 2008;  34(2) 147-153
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Palumbo J S, Talmage K E, Massari J V et al.. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms.  Blood. 2007;  110(1) 133-141
    CrossrefPubMedGoogle Scholar
  • 26 Hembrough T A, Swartz G M, Papathanassiu A et al.. Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism.  Cancer Res. 2003;  63(11) 2997-3000
    Google Scholar
  • 27 Ngo C V, Picha K, McCabe F et al.. CNTO 859, a humanized anti-tissue factor monoclonal antibody, is a potent inhibitor of breast cancer metastasis and tumor growth in xenograft models.  Int J Cancer. 2007;  120(6) 1261-1267
    CrossrefPubMedGoogle Scholar
  • 28 Versteeg H H, Schaffner F, Kerver M et al.. Inhibition of tissue factor signaling suppresses tumor growth.  Blood. 2008;  111(1) 190-199
    CrossrefPubMedGoogle Scholar
  • 29 Amarzguioui M, Peng Q, Wiiger M T et al.. Ex vivo and in vivo delivery of anti-tissue factor short interfering RNA inhibits mouse pulmonary metastasis of B16 melanoma cells.  Clin Cancer Res. 2006;  12(13) 4055-4061
    CrossrefPubMedGoogle Scholar
  • 30 Kondraganti S, Gondi C S, Gujrati M et al.. Restoration of tissue factor pathway inhibitor inhibits invasion and tumor growth in vitro and in vivo in a malignant meningioma cell line.  Int J Oncol. 2006;  29(1) 25-32
    Google Scholar
  • 31 Borsig L. The role of platelet activation in tumor metastasis.  Expert Rev Anticancer Ther. 2008;  8(8) 1247-1255
    CrossrefPubMedGoogle Scholar
  • 32 Sierko E, Wojtukiewicz M Z. Inhibition of platelet function: does it offer a chance of better cancer progression control?.  Semin Thromb Hemost. 2007;  33(7) 712-721
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Enjeti A K, Lincz L F, Seldon M. Microparticles in health and disease.  Semin Thromb Hemost. 2008;  34(7) 683-691
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Toth B, Liebhardt S, Steinig K et al.. Platelet-derived microparticles and coagulation activation in breast cancer patients.  Thromb Haemost. 2008;  100(4) 663-669
    PubMedGoogle Scholar
  • 35 Sierko E, Wojtukiewicz M Z. Platelets and angiogenesis in malignancy.  Semin Thromb Hemost. 2004;  30(1) 95-108
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 McNicol A, Israels S J. Beyond hemostasis: the role of platelets in inflammation, malignancy and infection.  Cardiovasc Hematol Disord Drug Targets. 2008;  8(2) 99-117
    PubMedGoogle Scholar
  • 37 Chen M, Geng J G. P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis.  Arch Immunol Ther Exp (Warsz). 2006;  54(2) 75-84
    CrossrefPubMedGoogle Scholar
  • 38 Lowenstein C J, Morrell C N, Yamakuchi M. Regulation of Weibel-Palade body exocytosis.  Trends Cardiovasc Med. 2005;  15(8) 302-308
    CrossrefPubMedGoogle Scholar
  • 39 Vestweber D, Blanks J E. Mechanisms that regulate the function of the selectins and their ligands.  Physiol Rev. 1999;  79(1) 181-213
    PubMedGoogle Scholar
  • 40 Kim Y J, Borsig L, Han H L, Varki N M, Varki A. Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium.  Am J Pathol. 1999;  155(2) 461-472
    PubMedGoogle Scholar
  • 41 Borsig L, Wong R, Feramisco J, Nadeau D R, Varki N M, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis.  Proc Natl Acad Sci U S A. 2001;  98(6) 3352-3357
    CrossrefPubMedGoogle Scholar
  • 42 Robak P, Smolewski P, Robak T. The role of non-steroidal anti-inflammatory drugs in the risk of development and treatment of hematologic malignancies.  Leuk Lymphoma. 2008;  49(8) 1452-1462
    CrossrefPubMedGoogle Scholar
  • 43 Kast R E. Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications.  Med Oncol. 2007;  24(1) 1-6
    CrossrefPubMedGoogle Scholar
  • 44 Smith C J, McKay G A, Fisher M. Diabetes, colorectal cancer and cyclooxygenase 2 inhibition.  Int J Clin Pract. 2008;  62(5) 810-815
    CrossrefPubMedGoogle Scholar
  • 45 Hart A R, Kennedy H, Harvey I. Pancreatic cancer: a review of the evidence on causation.  Clin Gastroenterol Hepatol. 2008;  6(3) 275-282
    CrossrefPubMedGoogle Scholar
  • 46 Agrawal A, Fentiman I S. NSAIDs and breast cancer: a possible prevention and treatment strategy.  Int J Clin Pract. 2008;  62(3) 444-449
    CrossrefPubMedGoogle Scholar
  • 47 Harris R E. Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer.  Subcell Biochem. 2007;  42 93-126
    PubMedGoogle Scholar
  • 48 Jana N R. NSAIDs and apoptosis.  Cell Mol Life Sci. 2008;  65(9) 1295-1301
    CrossrefPubMedGoogle Scholar
  • 49 Shureiqi I, Chen D, Lee J J et al.. 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells.  J Natl Cancer Inst. 2000;  92(14) 1136-1142
    CrossrefPubMedGoogle Scholar
  • 50 Ulrich C M, Bigler J, Potter J D. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics.  Nat Rev Cancer. 2006;  6(2) 130-140
    CrossrefPubMedGoogle Scholar
  • 51 Palumbo J S, Talmage K E, Massari J V et al.. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.  Blood. 2005;  105(1) 178-185
    CrossrefPubMedGoogle Scholar
  • 52 Pietras K, Sjöblom T, Rubin K, Heldin C H, Ostman A. PDGF receptors as cancer drug targets.  Cancer Cell. 2003;  3(5) 439-443
    CrossrefPubMedGoogle Scholar
  • 53 Östman A, Heldin C H. Involvement of platelet-derived growth factor in disease: development of specific antagonists.  Adv Cancer Res. 2001;  80 1-38
    PubMedGoogle Scholar
  • 54 Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug.  Nat Rev Drug Discov. 2002;  1(7) 493-502
    CrossrefPubMedGoogle Scholar
  • 55 Baranowska-Kortylewicz J, Abe M, Nearman J, Enke C A. Emerging role of platelet-derived growth factor receptor-beta inhibition in radioimmunotherapy of experimental pancreatic cancer.  Clin Cancer Res. 2007;  13(1) 299-306
    CrossrefPubMedGoogle Scholar
  • 56 Wu W B, Chiang H S, Fang J Y, Hung C F. Inhibitory effect of lycopene on PDGF-BB-induced signalling and migration in human dermal fibroblasts: a possible target for cancer.  Biochem Soc Trans. 2007;  35(Pt 5) 1377-1378
    CrossrefPubMedGoogle Scholar
  • 57 Felding-Habermann B, O'Toole T E, Smith J W et al.. Integrin activation controls metastasis in human breast cancer.  Proc Natl Acad Sci U S A. 2001;  98(4) 1853-1858
    CrossrefPubMedGoogle Scholar
  • 58 Mehta P, Lawson D, Ward M B, Lee-Ambrose L, Kimura A. Effects of thromboxane A2 inhibition on osteogenic sarcoma cell-induced platelet aggregation.  Cancer Res. 1986;  46(10) 5061-5063
    PubMedGoogle Scholar
  • 59 Nelson R M, Cecconi O, Roberts W G, Aruffo A, Linhardt R J, Bevilacqua M P. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation.  Blood. 1993;  82(11) 3253-3258
    PubMedGoogle Scholar
  • 60 Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.  J Clin Invest. 1998;  101(4) 877-889
    CrossrefPubMedGoogle Scholar
  • 61 Ludwig R J, Boehme B, Podda M et al.. Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis.  Cancer Res. 2004;  64(8) 2743-2750
    CrossrefPubMedGoogle Scholar
  • 62 Hostettler N, Naggi A, Torri G et al.. P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins.  FASEB J. 2007;  21(13) 3562-3572
    CrossrefPubMedGoogle Scholar
  • 63 Lee D Y, Park K, Kim S K et al.. Antimetastatic effect of an orally active heparin derivative on experimentally induced metastasis.  Clin Cancer Res. 2008;  14(9) 2841-2849
    CrossrefPubMedGoogle Scholar
  • 64 Lippi G, Franchini M, Guidi G C. Diagnostic approach to inherited bleeding disorders.  Clin Chem Lab Med. 2007;  45(1) 2-12
    CrossrefPubMedGoogle Scholar
  • 65 Ruf W, Mueller B M. Thrombin generation and the pathogenesis of cancer.  Semin Thromb Hemost. 2006;  32(Suppl 1) 61-68
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 O'Reilly M S. Antiangiogenic antithrombin.  Semin Thromb Hemost. 2007;  33(7) 660-666
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Huang Y Q, Li J J, Hu L, Lee M, Karpatkin S. Thrombin induces increased expression and secretion of VEGF from human FS4 fibroblasts, DU145 prostate cells and CHRF megakaryocytes.  Thromb Haemost. 2001;  86(4) 1094-1098
    PubMedGoogle Scholar
  • 68 Wang J, Morita I, Onodera M, Murota S I. Induction of KDR expression in bovine arterial endothelial cells by thrombin: involvement of nitric oxide.  J Cell Physiol. 2002;  190(2) 238-250
    CrossrefPubMedGoogle Scholar
  • 69 Caunt M, Hu L, Tang T, Brooks P C, Ibrahim S, Karpatkin S. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis.  Cancer Res. 2006;  66(8) 4125-4132
    CrossrefPubMedGoogle Scholar
  • 70 Huang Y Q, Li J J, Hu L, Lee M, Karpatkin S. Thrombin induces increased expression and secretion of angiopoietin-2 from human umbilical vein endothelial cells.  Blood. 2002;  99(5) 1646-1650
    CrossrefPubMedGoogle Scholar
  • 71 Duhamel-Clérin E, Orvain C, Lanza F, Cazenave J P, Klein-Soyer C. Thrombin receptor-mediated increase of two matrix metalloproteinases, MMP-1 and MMP-3, in human endothelial cells.  Arterioscler Thromb Vasc Biol. 1997;  17(10) 1931-1938
    PubMedGoogle Scholar
  • 72 Hu L, Roth J M, Brooks P, Luty J, Karpatkin S. Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis.  Cancer Res. 2008;  68(12) 4666-4673
    CrossrefPubMedGoogle Scholar
  • 73 Snyder K M, Kessler C M. The pivotal role of thrombin in cancer biology and tumorigenesis.  Semin Thromb Hemost. 2008;  34(8) 734-741
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Falanga A, Marchetti M. Heparin in tumor progression and metastatic dissemination.  Semin Thromb Hemost. 2007;  33(7) 688-694
    Article in Thieme ConnectPubMedGoogle Scholar
  • 75 Mousa S A. Anti-thrombotics in thrombosis and cancer.  Future Oncol. 2005;  1(3) 395-403
    CrossrefPubMedGoogle Scholar
  • 76 Smorenburg S M, Van Noorden C J. The complex effects of heparins on cancer progression and metastasis in experimental studies.  Pharmacol Rev. 2001;  53(1) 93-105
    PubMedGoogle Scholar
  • 77 Bobek V, Kovarík J. Antitumor and antimetastatic effect of warfarin and heparins.  Biomed Pharmacother. 2004;  58(4) 213-219
    CrossrefPubMedGoogle Scholar
  • 78 Guo R R, Liu Y, Lu W L et al.. A recombinant peptide, hirudin, potentiates the inhibitory effects of stealthy liposomal vinblastine on the growth and metastasis of melanoma.  Biol Pharm Bull. 2008;  31(4) 696-702
    CrossrefPubMedGoogle Scholar
  • 79 Weitz I C, Liebman H A. The role of oral anticoagulants in tumor biology.  Semin Thromb Hemost. 2007;  33(7) 695-698
    Article in Thieme ConnectPubMedGoogle Scholar
  • 80 Sciumbata T, Caretto P, Pirovano P et al.. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival.  Invasion Metastasis. 1996;  16(3) 132-143
    PubMedGoogle Scholar
  • 81 Onaran I, Sencan S, Demirtaş H, Aydemir B, Ulutin T, Okutan M. Toxic-dose warfarin-induced apoptosis and its enhancement by gamma ionizing radiation in leukemia K562 and HL-60 cells is not mediated by induction of oxidative stress.  Naunyn Schmiedebergs Arch Pharmacol. 2008;  378(5) 471-481
    CrossrefPubMedGoogle Scholar
  • 82 Association of Surgeons of Great Britain and Ireland Annual Meeting. Glasgow, United Kingdom, 13–15 April 2005. Abstracts.  Br J Surg. 2005;  92(Suppl 1) 1-159
    PubMedGoogle Scholar
  • 83 Franchini M, Tagliaferri A, Mannucci P M. The management of hemophilia in elderly patients.  Clin Interv Aging. 2007;  2(3) 361-368
    PubMedGoogle Scholar
  • 84 Walker I R, Julian J A. Association of Hemophilia Clinic Directors of Canada . Causes of death in Canadians with haemophilia 1980–1995.  Haemophilia. 1998;  4(5) 714-720
    CrossrefPubMedGoogle Scholar
  • 85 Darby S C, Kan S W, Spooner R J et al.. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV.  Blood. 2007;  110(3) 815-825
    CrossrefPubMedGoogle Scholar
  • 86 Brüggemann L W, Versteeg H H, Niers T M, Reitsma P H, Spek C A. Experimental melanoma metastasis in lungs of mice with congenital coagulation disorders.  J Cell Mol Med. 2008;  12(6B) 2622-2627
    CrossrefPubMedGoogle Scholar
  • 87 Langer F, Amirkhosravi A, Ingersoll S B et al.. Experimental metastasis and primary tumor growth in mice with hemophilia A.  J Thromb Haemost. 2006;  4 1056-1062
    Google Scholar
  • 88 Lee A Y. The effects of low molecular weight heparins on venous thromboembolism and survival in patients with cancer.  Thromb Res. 2007;  120(Suppl 2) S121-S127
    CrossrefPubMedGoogle Scholar
  • 89 Lemoine N R. Antithrombotic therapy in cancer.  J Clin Oncol. 2005;  23(10) 2119-2120
    CrossrefPubMedGoogle Scholar
  • 90 Falanga A. The effect of anticoagulant drugs on cancer.  J Thromb Haemost. 2004;  2(8) 1263-1265
    CrossrefPubMedGoogle Scholar
  • 91 Tagalakis V, Blostein M, Robinson-Cohen C, Kahn S R. The effect of anticoagulants on cancer risk and survival: systematic review.  Cancer Treat Rev. 2007;  33(4) 358-368
    CrossrefPubMedGoogle Scholar
  • 92 Zacharski L R, Henderson W G, Rickles F R et al.. Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75.  JAMA. 1981;  245(8) 831-835
    CrossrefPubMedGoogle Scholar
  • 93 Smorenburg S M, Vink R, Otten H M, Swaneveld F, Büller H R. The effects of vitamin K-antagonists on survival of patients with malignancy: a systematic analysis.  Thromb Haemost. 2001;  86(6) 1586-1587
    PubMedGoogle Scholar
  • 94 Kakkar A K, Hedges A R, Williamson R CN et al.. Perioperative heparin therapy inhibits late deaths from metastatic cancer.  Int J Oncol. 1995;  6 885-888
    PubMedGoogle Scholar
  • 95 Lebeau B, Chastang C, Brechot J M et al.. Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” Group.  Cancer. 1994;  74(1) 38-45
    CrossrefPubMedGoogle Scholar
  • 96 Altinbas M, Coskun H S, Er O 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(8) 1266-1271
    CrossrefPubMedGoogle Scholar
  • 97 Smorenburg S M, Hettiarachchi R J, Vink R, Büller H R. The effects of unfractionated heparin on survival in patients with malignancy—a systematic review.  Thromb Haemost. 1999;  82(6) 1600-1604
    PubMedGoogle Scholar
  • 98 Kakkar A K, Levine M N, Kadziola Z 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(10) 1944-1948
    CrossrefPubMedGoogle Scholar
  • 99 Klerk C P, Smorenburg S M, Otten H M et al.. The effect of low molecular weight heparin on survival in patients with advanced malignancy.  J Clin Oncol. 2005;  23(10) 2130-2135
    CrossrefPubMedGoogle Scholar
  • 100 Lee A Y, Rickles F R, Julian J A 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(10) 2123-2129
    Google Scholar
  • 101 Lazo-Langner A, Goss G D, Spaans J N, Rodger M A. The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials.  J Thromb Haemost. 2007;  5(4) 729-737
    CrossrefPubMedGoogle Scholar
  • 102 Sandler R S, Halabi S, Baron J A et al.. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.  N Engl J Med. 2003;  348(10) 883-890
    CrossrefPubMedGoogle Scholar
  • 103 Baron J A, Cole B F, Sandler R S et al.. A randomized trial of aspirin to prevent colorectal adenomas.  N Engl J Med. 2003;  348(10) 891-899
    CrossrefPubMedGoogle Scholar
  • 104 Bertagnolli M M, Eagle C J, Zauber A G APC Study Investigators et al. Celecoxib for the prevention of sporadic colorectal adenomas.  N Engl J Med. 2006;  355(9) 873-884
    CrossrefPubMedGoogle Scholar
  • 105 Baron J A, Sandler R S, Bresalier R S APPROVe Trial Investigators et al. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas.  Gastroenterology. 2006;  131(6) 1674-1682
    CrossrefPubMedGoogle Scholar
  • 106 Thun M J, Henley S J, Patrono C. Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues.  J Natl Cancer Inst. 2002;  94(4) 252-266
    PubMedGoogle Scholar
  • 107 Chan A T, Ogino S, Fuchs C S. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.  N Engl J Med. 2007;  356(21) 2131-2142
    CrossrefPubMedGoogle Scholar
  • 108 Hejna M, Raderer M, Zielinski C C. Inhibition of metastases by anticoagulants.  J Natl Cancer Inst. 1999;  91(1) 22-36
    CrossrefPubMedGoogle Scholar
  • 109 Franchini M, Lippi G. Antagonists of activated factor X and thrombin: innovative antithrombotic agents.  Curr Vasc Pharmacol. 2007;  5(2) 121-128
    CrossrefPubMedGoogle Scholar
  • 110 Harenberg J. Development of new anticoagulants: present and future.  Semin Thromb Hemost. 2008;  34(8) 779-793
    Article in Thieme ConnectPubMedGoogle Scholar

Massimo FranchiniM.D. 

Immunohematology and Transfusion Center, Department of Pathology and Laboratory Medicine

University Hospital of Parma, Parma, Italy

Email: massimo.franchini@azosp.vr.it

      >