Low-Molecular-Weight Heparins: Beyond Thrombosis in the Management of the Cancer Patient

ABSTRACT

Thrombosis is a common complication in patients with cancer and large, retrospective population-based studies indicate that cancer patients with clinical venous thromboembolism have a poorer prognosis than those without. The risk of thrombosis appears to differ between different tumor types. Beyond the important impact that fatal pulmonary embolism may have on cancer outcome, the activated coagulation serine proteases generated by cancer cells through the peritumor activation of blood coagulation pathways are able to interact with cell surface protease receptors. These, in turn, mediate several cellular events resulting in important phenotypic alterations in tumor cell behavior.

Low-molecular-weight heparin - thromboembolism - cancer

REFERENCES

• 1 Shen V S, Pollak E W. Fatal pulmonary embolism in cancer patients: is heparin prophylaxis justified?.  South Med J . 1980;  73 841-843
• 2 Levitan N, Dowlati A, Remick S. et al . Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data.  Medicine (Baltimore) . 1999;  78 285-291
• 3 Sorensen H T, Mellemkjaer L, Olsen J H, Baron J A. Prognosis of cancers associated with venous thromboembolism.  N Engl J Med . 2000;  343 1846-1850
• 4 Thodiyil P A, Kakkar A K. Variation in relative risk of venous thromboembolism in different cancers.  Thromb Haemost . 2002;  87 1076-1077
• 5 Kakkar A K, Lemoine N R, Scully M F, Tebbutt S, Williamson R C. Tissue factor expression correlates with histological grade in human pancreatic cancer.  Br J Surg . 1995;  82 1101-1104
• 6 Kakkar A K, Chinswangwatanakul V, Lemoine N R, Tebbutt S, Williamson R C. Role of tissue factor expression on tumour cell invasion and growth of experimental pancreatic adenocarcinoma.  Br J Surg . 1999;  86 890-894
• 7 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 1320-1327
• 8 Mueller B M, Reisfeld R A, Edgington T S, Ruf W. Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis.  Proc Natl Acad Sci USA . 1992;  89 11832-11836
• 9 Taniguchi T, Kakkar A K, Tuddenham E G, Williamson R C, Lemoine N R. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer.  Cancer Res . 1998;  58 4461-4467
• 10 Ott I, Fischer E G, Miyagi Y, Mueller B M, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.  J Cell Biol . 1998;  140 1241-1253
• 11 Riewald M, Kravchenko V V, Petrovan R J. et al . Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1.  Blood . 2001;  97 3109-3116
• 12 Even-Ram S, Uziely B, Cohen P. et al . Thrombin receptor overexpression in malignant and physiological invasion processes.  Nat Med . 1998;  4 909-914
• 13 Sampson M T, Kakkar A K. Coagulation proteases and human cancer.  Biochem Soc Trans . 2002;  30 201-207
• 14 Green D, Hull R D, Brant R, Pineo G F. Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin [letter].  Lancet . 1992;  339 1476
• 15 Siragusa S, Cosmi B, Piovella R, Hirsh J, Ginsberg J S. Low-molecular-weight-heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis.  Am J Med . 1996;  100 269-277
• 16 Hettiarachchi R J, Smorenburg S M, Ginsberg J, Levine M, Prins M H, Büller H R. Do heparins do more than just treat thrombosis?.  <~>The influence of heparins on cancer spread. Thromb Haemost . 1999;  82 947-952
• 17 Gould M K, Dembitzer A D, Doyle R L, Hastie T J, Garber A M. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.  Ann Intern Med . 1999;  130 800-809
• 18 Kakkar A K, Kadziola Z, Williamson R C, Levine M, Low V, Lemoine N R. Low molecular weight heparin (LMWH) therapy and survival in advanced cancer.  Blood . 2002;  100 148A
• 19 Lee A Y, Levine M N, Baker R I. et al . Low-molecular-weight heparin versus coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med . 2003;  349 146-153
• 20 Levine M N, Lee A Y, Kakkar A K. From Trousseau to targeted therapy: new insights and innovations in thrombosis and cancer.  J Thromb Haemost . 2003;  1 1456-1463