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Thromb Haemost 1999; 82(02): 947-952
DOI: 10.1055/s-0037-1615937
Research Article
Schattauer GmbH

Do Heparins Do More than Just Treat Thrombosis? The Influence of Heparins on Cancer Spread

Rohan J.K. Hettiarachchi
1   Department of Clinical Epidemiology & Biostatistics, Academic Medical Center, University of Amsterdam, THE NETHERLANDS
,
Susanne M. Smorenburg
2   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, THE NETHERLANDS
3   Departments of Clinical Oncology and Cell Biology and Histology, Academic Medical Center, University of Amsterdam, THE NETHERLANDS
,
Jeffrey Ginsberg
4   Hamilton Civic Hospitals Research Center and the Hamilton Regional Cancer Center, McMaster University, Hamilton, Ontario, CANADA
,
Mark Levine
4   Hamilton Civic Hospitals Research Center and the Hamilton Regional Cancer Center, McMaster University, Hamilton, Ontario, CANADA
,
Martin H. Prins
1   Department of Clinical Epidemiology & Biostatistics, Academic Medical Center, University of Amsterdam, THE NETHERLANDS
,
Harry R. Büller
2   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, THE NETHERLANDS
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

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Introduction

The influence of unfractionated heparin (UFH) and other anticoagulants on the spread of cancer has been reported since the early 1960s.1 However, clinical studies investigating the use of heparins in cancer patients have not produced consistent results.2 Intravenous, adjusted-dose UFH for 5 to 10 days has been the standard initial treatment for venous thrombosis. More recently, subcutaneous, fixed-dose, low molecular weight heparins (LMWHs), which are fractions of the parent compound, have been shown to be safe and effective alternatives to UFH in the initial treatment for venous thromboembolism.3-5

In one of our randomized clinical trials comparing LMWH and UFH in the initial treatment of deep vein thrombosis (DVT), we observed an unexpected difference in 6-month mortality among cancer patients in favor of LMWH, which could not be attributed to a difference in the incidence of thrombotic or bleeding complications.6 A similar observation in favor of LMWH was reported in a subsequent study and in a meta-analysis of trials.7,8 The number of cancer patients included in these studies was small, and adjustment of the observed effect for the baseline characteristics of the cancer patients was not possible. However, these findings suggested an inhibitory effect of LMWH on tumor growth or metastasis, which is less apparent or absent for UFH, resulting in a beneficial effect on the survival of cancer patients. This hypothesis is supported by the observations, in experimental studies, that LMWH and low molecular weight heparan sulfate, in comparison to UFH, effectively suppressed angiogenesis, a process necessary for tumor growth and metastasis.9,10

On the other hand, animal studies that investigated the effect of chemically-modified heparins on the spread of cancer did not detect a superior anti-tumor effect of LMWH compared to UFH; both were found to inhibit metastasis.11,12 To date, the effect of LMWH on cancer survival in humans has not been investigated as a primary objective. If a consistent and beneficial effect of LMWH on mortality is indeed present, such a study would be warranted.

We performed a meta-analysis of all available randomized clinical trials where LMWH was compared with UFH in the treatment of venous thromboembolism (VTE) to estimate the crude treatment effect of LMWH on mortality in cancer patients compared to UFH. Subsequently, we adjusted this treatment effect for age, gender, and primary malignancy site by reanalyzing data from three of those trials.3-5 This effect was further adjusted for other prognostic factors, including cancer histology, tumor stage, presence of metastases, duration of cancer, and concomitant use of cancer treatment, by analyzing individual patient data from the largest randomized trial.5

 

  • References

  • 1 Agostino D, Grossi CE, Cliffton EE. Effect of heparin on circulating walker carcinoma 256 cells. J Nat Cancer Inst 1961; 27: 17-24.
    PubMedGoogle Scholar
  • 2 Zacharski LR, Meehan KR, Algarra SM, Calvo FA. Clinical trials with anticoagulant and antiplatelet therapies. Cancer Metastasis Rev 1992; 11: 421-431.
    CrossrefPubMedGoogle Scholar
  • 3 Koopman MMW, Prandoni P, Piovella F, Ockelford PA, Brandjes DPM, van der Meer J, Gallus AS, Simonneau G, Chesterman CH, Prins MH, Bossuyt PMM, de Haes H, van den Belt AGM, Sagnard L, d’Azemar P, Buller HR. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682-687.
    CrossrefPubMedGoogle Scholar
  • 4 Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-681.
    CrossrefPubMedGoogle Scholar
  • 5 The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337: 657-662.
    CrossrefPubMedGoogle Scholar
  • 6 Prandoni P, Lensing AWA, Büller HR, Carta M, Cogo A, Vigo M, Casara D, Ruol A, ten Cate JW. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-445.
    CrossrefPubMedGoogle Scholar
  • 7 Green D, Hull RD, Brant R, Pineo GF. Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin. Lancet 1992; 339: 1476.
    PubMedGoogle Scholar
  • 8 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results results of a meta-analysis. Am J Med 1996; 100: 269-277.
    CrossrefPubMedGoogle Scholar
  • 9 Norrby K. Heparin and angiogenesis: A a low molecular weight fraction inhibits and a high molecular weight fraction stimulates angiogenesis systemically. Haemostasis 1993; 23 (01) 141-149.
    PubMedGoogle Scholar
  • 10 Lepri A, Benelli U, Bernardini N, Bianchi F, Lupetti M, Danesi R, Del Tacca M, Nardi M. Effect of low molecular weight heparan sulphate on angiogenesis in the rat cornea after chemical cauterization. J Ocular Pharmacol 1994; 10: 273-280.
    CrossrefPubMedGoogle Scholar
  • 11 Sciumbatta T, Caretto P, Pirovano P, Pozzi P, Cremonesi P, Galimberti G, Leoni F, Marcucci F. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long term survival. Invas Metast 1996; 16: 132-143.
    PubMedGoogle Scholar
  • 12 Vlodavsky I, Mohsen M, Lider O, Svahn CM, Ekre HP, Vigoda M, Ishai-Michaeli R, Peretz T. Inhibition of tumour metastasis by heparanase inhibiting species of heparin. Invas Metast 1994; 14: 290-302.
    PubMedGoogle Scholar
  • 13 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Canc Inst 1959; 22: 719-748.
    PubMedGoogle Scholar
  • 14 Kleinbaum DG, Kupper LL, Chambless LE. Logistic regression analysis of epidemiologic data: Theory theory and practice. Commun Stat 1982; 11 (05) 485-547.
    PubMedGoogle Scholar
  • 15 TNM Classification of Malignant Tumours. fifth edition5th ed.. Sobin LH L.H., Wittekind C C.. (Eds). New York: John Wiley & Sons, Inc.; New York 1997: 227.
    Google Scholar
  • 16 Duroux P. A randomized trial of subcutaneous low molecular weight heparin (CY216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. A Collaborative collaborative European Multimulti-centre Studystudy:. Thromb Haemost 1991; 65: 251-256.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Hull RD, Raskob GL, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lerner RG, Hall J, Sparling T, Brettell HR. et al. Subcutaneous low molecular weight heparin compared with continuous intravenous heparin in the treatment of proximal vein thrombosis. N Engl J Med 1992; 326: 975-982.
    CrossrefPubMedGoogle Scholar
  • 18 Lopaciuk S, Meissner J, Filipecki S, Zawilska K, Sowier J, Ciesielski L, Bielawiec M, Glowinski S, Czestochowska E. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thromb Haemost 1992; 68: 14-18.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Simonneau G, Charbonnier B, Decousus H, Planchon B, Ninet J, Sie P, Silsiguen M, Combe S. Subcutaneous fixed dose of enoxaparine versus intravenous adjusted dose of unfractionated heparin in the treatment of deep vein thrombosis. Arch Intern Med 1993; 153: 1541-1546.
    CrossrefPubMedGoogle Scholar
  • 20 Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, Laurent M, Hirsch JL, Ferrari E, Bosson JL, Mottier D, Beau B. A comparison of low-molecular weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337: 663-669.
    CrossrefPubMedGoogle Scholar
  • 21 Bratt G, Aberg W, Johansson M, Tornebohm E, Granqvist S, Lockner D. Two daily subcutaneous injections of Fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis. Thromb Haemost 1990; 64: 506-510.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Holm HA, Ly B, Handeland GF, Abildgaard U, Arnesen KE, Gottschalk P, Hoeg V, Aandahl M, Haugen K, Laerum F. et al. Subcutaneous heparin treatment of deep vein thrombosis: a comparison of unfractionated and low molecular weight heparin. Haemostasis 1986; 16 (suppl) 30-37.
    PubMedGoogle Scholar
  • 23 Bratt G, Tornebohm E, Granqvist S, Aberg W, Lockner D. A comparison between low molecular weight heparin Kabi 2165 and standard heparin in the intravenous treatment of deep vein thrombosis. Thromb Haemost 1985; 54 (04) 813-817.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Circulation 1989; 80: 935-940.
    CrossrefPubMedGoogle Scholar
  • 25 Harenberg J, Huck K, Bratsch H, Stehle G, Dempfle CE, Mall K, Blauth M, Usadel KH, Heene DL. Therapeutic application of subcutaneous low-molecular-weight heparin in acute venous thrombosis. Haemostasis 1990; 20: 205-219.
    PubMedGoogle Scholar
  • 26 Fiessinger JN, Lopez-Fernandez M, Gatterer E, Granqvist S, Kher A, Olsson CG, Soderberg K. Once-daily Subcutaneous subcutaneous Dalteparindalteparin, a Low low Molecular molecular Weight weight Heparinheparin, for the Initial initial Treatment treatment of Acute acute Deep deep Vein vein Thrombosisthrombosis. Thromb Haemost 1996; 76: 195-199.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Lindmarker P, Holmström M, Granqvist S, Johnson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemost 1994; 72: 186-190.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Notarbartolo A, Salanitri G, Davi G, Averna M, Barbagallo C, Catalano I. Low molecular weight heparin in the short and long-term treatment of deep vein thrombosis in diabetic subjects. Med Prax 1988; 9: 393-405.
    PubMedGoogle Scholar
  • 29 Zanghi M, Morici V, Costanzo M, Astuto L, Salanitri G. Deep vein thrombosis of the legs: new therapy by means of low molecular weight heparins. J Intern Med Res 1988; 16: 474-484.
    PubMedGoogle Scholar
  • 30 Tedoldi A, Botticella F, Maloberti MR. Antithrombophilic effect of low molecular weight heparins in patients with deep vein thrombosis. Clin Trials Meta-analysis 1993; 28: 215-225.
    PubMedGoogle Scholar
  • 31 Lockner D, Bratt G, Tornebohm E, Aberg W, Granqvist S. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis. Haemostasis 1986; 16 (suppl) 25-29.
    PubMedGoogle Scholar
  • 32 Handeland GF, Abildgaard U, Holm HA, Arnesen KE. Dose adjusted heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin. Eur J Clin Pharmacol 1990; 39: 107-112.
    CrossrefPubMedGoogle Scholar
  • 33 Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, Laporte S, Faivre R, Charbonnier B, Barral FG, Huet Y, Simonneau G. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 1998; 338: 409-415.
    CrossrefPubMedGoogle Scholar