Download PDF
Semin Thromb Hemost 2002; 28(1): 45-52
DOI: 10.1055/s-2002-20559
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Anticoagulants in Thrombosis and Cancer: The Missing Link

Shaker A. Mousa
  • Albany College of Pharmacy, Albany, New York
Further Information

Publication History

Publication Date:
05 March 2002 (online)

    Permissions and Reprints

ABSTRACT

Many cancer patients reportedly have a hypercoagulable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) interferes with various processes involved in tumor growth and metastasis. These processes might include fibrin formation, binding of heparin to angiogenic growth factors such as basic fibroblast growth factor and vascular endothelial growth factor, modulation of tissue factor, and other mechanisms. Clinical trials have indicated a clinically relevant effect of LMWH as compared with 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. Recent studies from our laboratory defined the role of an LMWH (tinzaparin), warfarin, anti-factor VIIa, and recombinant tissue factor pathway inhibitor in the modulation of angiogenesis, tumor growth, and tumor metastasis.

KEYWORD

Heparin - LMWH - warfarin - TF/VIIa - TFPI - FGF2 - VEGF - cancer - coagulation - platelet - angiogenesis - venous thrombosis

REFERENCES

  • 1 Weitz J I. Low-molecular-weight heparin.  N Engl J Med . 1997;  337 688-698
    CrossrefPubMedSearch in Google Scholar
  • 2 Aguilar D, Goldhaber S Z. Clinical uses of low molecular weight heparin.  Chest . 1999;  115 1418-1423
    CrossrefPubMedSearch in Google Scholar
  • 3 Linhardt R J, Gunay N S. Production and chemical processing of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25 5-16
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Mousa S A, Fareed J W. Advances in anticoagulant, antithrombotic and thrombolytic drugs.  Exp Opin Invest Drugs . 2001;  10 157-162
    CrossrefPubMedSearch in Google Scholar
  • 5 Nader H B, Walenga J M, Berkowitz S D. Preclinical differentiation of low molecular weight heparins.  Semin Thromb Hemost . 1999;  25 63-72
    PubMedSearch in Google Scholar
  • 6 Mousa S A. Comparative efficacy among different low molecular weight heparins (LMWHs) and drug interaction: implications in the management of vascular disorders.  Thromb Haemost . 2000;  26(Suppl 1) 39-46
    PubMedSearch in Google Scholar
  • 7 Hull R D, Raskob G E, Pineo G F. 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
    CrossrefPubMedSearch in Google Scholar
  • 8 Simonneau G, Sors H, Charbonnier B. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism.  N Engl J Med . 1997;  337 663-669
    CrossrefPubMedSearch in Google Scholar
  • 9 Hull R D, Raskob G E, Pineo G F. A comparison of subcutaneous low-molecular weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation.  N Engl J Med . 1993;  329 1370-1376
    CrossrefPubMedSearch in Google Scholar
  • 10 Leizorovicz A, Picolet H, Peyrieux J C, Boissel J P, and the HBPM research group. Prevention of perioperative deep vein thrombosis in general surgery: a multicenter double blind study comparing two doses of logiparin and standard heparin.  Br J Surg . 1991;  78 412-416
    PubMedSearch in Google Scholar
  • 11 Ryan K E, Lane D A, Flynn A. Dose finding study of a low molecular weight heparin, Innohep, in haemodialysis.  Thromb Haemost . 1991;  66 277-282
    PubMedSearch in Google Scholar
  • 12 Troy S, Fruncillo R, Ozawa T. Absolute and comparative subcutaneous bioavailability of ardeparin sodium, a low molecular weight heparin.  Thromb Haemost . 1997;  78 871-875
    PubMedSearch in Google Scholar
  • 13 Pedersen P C, ;cFstergaard P B, Hedner U, Bergqvist D, Mätzsch T. Pharmacokinetics of low molecular weight heparin, logiparin, after intravenous and subcutaneous administration to healthy volunteers.  Thromb Res . 1991;  61 477-487
    CrossrefPubMedSearch in Google Scholar
  • 14 Mätzsch T, Bergqvist D, Hedner U, ;cFstergaard P B. Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers.  Thromb Haemost . 1987;  57 97-101
    PubMedSearch in Google Scholar
  • 15 Bara L, Planes A, Samama M-M. Occurrence of thrombosis and haemorrhage, relationship with anti-Xa, anti-IIa activities, and D-dimer plasma levels in patients receiving low molecular weight heparin, enoxaparin or tinzaparin, to prevent deep vein thrombosis after hip surgery.  Br J Haematol . 1999;  104 230-240
    PubMedSearch in Google Scholar
  • 16 Emmanuele R M, Fareed J. The effect of molecular weight on the bioavailability of heparin.  Thromb Res . 1987;  48 591-596
    CrossrefPubMedSearch in Google Scholar
  • 17 Brieger D, Dawes J. Production method affects the pharmacokinetic and ex vivo biological properties of low molecular weight heparins.  Thromb Haemost . 1997;  77 317-322
    PubMedSearch in Google Scholar
  • 18 Mousa S A, Bozarth J, Larnkjaer A, Johanson K. Vascular effects of heparin molecular weight fractions and LMWH on the release of TFPI from human endothelial cells.  Blood . 2000;  16 59,3928
    PubMedSearch in Google Scholar
  • 19 Mousa S A, Mohamed S. Anti-angiogenesis efficacy of the low molecular weight heparin (LMWH), tinzaparin and tissue factor pathway inhibitor (TFPI).  Blood . 1999;  94(Suppl 1) 22a,-22a, 82 Abst
    PubMedSearch in Google Scholar
  • 20 GoldbergRJ, Seneff M, Gore J M. Occult malignant neoplasm in patients with deep venous thrombosis.  Ann Intern Med . 1987;  147 251-253
    CrossrefPubMedSearch in Google Scholar
  • 21 Baron J A, Gridley G, Weiderpass E, Nyren O, Linet M. Venous thromboembolism and cancer.  Lancet . 1998;  351 1077-1080
    CrossrefPubMedSearch in Google Scholar
  • 22 Rickles F R, Edwards R L. Activation of blood coagulation in cancer: Trousseau's syndrome revisited.  Blood . 1982;  62 14-31
    PubMedSearch in Google Scholar
  • 23 Levine M N. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy.  Thromb Haemost . 1997;  78 133-136
    PubMedSearch in Google Scholar
  • 24 Levine M N, Gent M, Hirsh J. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer.  N Engl J Med . 1998;  318 404-407
    PubMedSearch in Google Scholar
  • 25 Kakkar A J, De Ruvo N, Tebbutt S, Williamson R CN. Extrinsic pathway activation with elevated tissue factor and factor VIIa in patients with cancer.  Lancet . 1995;  346 1004-1005
    CrossrefPubMedSearch in Google Scholar
  • 26 Kakkar A J, Williamson R C. Prevention of venous thromboembolism in cancer using low molecular weight heparin.  Haemostasis . 1997;  27(Suppl 1) 32-37
    PubMedSearch in Google Scholar
  • 27 Trousseau A. Plegmasia alba dolens. In: Baillier JB, ed. Clinique de l'Hotel-Dieu de Paris, 2nd ed 1865 3: 654-712
    Search in Google Scholar
  • 28 Zacharski L R, Ornstein D L. Heparin and cancer.  Thromb Haemost . 1998;  80 10-23
    PubMedSearch in Google Scholar
  • 29 Gillis S, Dann E J, Eldor A. A low molecular weight heparin in the prophylaxis and treatment of disseminated intravascular coagulation in acute leukemia.  Eur J Haematol . 1995;  54 59-60
    PubMedSearch in Google Scholar
  • 30 Haward W. Phlebitis and thrombosis.  Lancet . 1960;  1 650-655
    PubMedSearch in Google Scholar
  • 31 Dvorak H F. Thrombosis and cancer.  Hum Pathol . 1987;  18 275-284
    Search in Google Scholar
  • 32 Dvorak H F, Senger D R, Dvorak A M. Fibrin as a component of the tumor stroma: origins and biological significance.  Cancer Metastasis Rev . 1983;  2 41-73
    CrossrefPubMedSearch in Google Scholar
  • 33 Falanga A. Mechanisms of hypercoagulation in malignancy and during chemotherapy.  Haemostasis . 1998;  28 50-55
    CrossrefPubMedSearch in Google Scholar
  • 34 Mousa S A. Mechanisms of angiogenesis in vascular disorders: potential therapeutic targets. In: Mousa S, Landes RG, eds. Angiogenesis Inhibitors and Stimulators: Potential Therapeutic Implications Gorgtown, TX: Landes Bioscience 2000: 1-12
    Search in Google Scholar
  • 35 Zhang H-T, Harris A L. Anti-angiogenic therapies in cancer clinical trials.  Exp Opin Invest Drugs . 1998;  7 1629-1655
    CrossrefPubMedSearch in Google Scholar
  • 36 Mousa S A, Mohamed S, Smallheer J, Jadhav P K, Varner J. Anti-angiogenesis efficacy of small molecule a5b1 integrin antagonists, SJ749.  Blood . 1999;  94(Suppl 1) 620a,-620a, 2755 Abst
    PubMedSearch in Google Scholar
  • 37 Colman R W, Jameson B A, Lin Y, Mousa S A. Inhibition of angiogenesis by kininogen domain 5.  Blood . 2000;  95 543-550
    PubMedSearch in Google Scholar
  • 38 Mousa S A, Mohamed S. Anti-angiogenesis efficacy of the low molecular weight heparin (LMWH) tinzaparin and tissue factor pathway inhibitor (TFPI).  Blood . 1999;  94(Suppl 1) 22a,-22a, 82-I Abst
    PubMedSearch in Google Scholar
  • 39 Browder T, Folkman J, Pirie-Shepherd S. The hemostasis system as a regulator of angiogenesis.  J Biol Chem . 2000;  275 1521-1524
    CrossrefPubMedSearch in Google Scholar
  • 40 Brooks P C, Clark R AF, Cheresh D A. Requirement of vascular integrin αvβ3 for angiogenesis.  Science . 1994;  264 569-571
    CrossrefPubMedSearch in Google Scholar
  • 41 Bell W R. The fibrinolytic system in neoplasia.  Semin Thromb Haemost . 1996;  22 459-478
    PubMedSearch in Google Scholar
  • 42 Ruf W, Mueller B M. Tissue factor in cancer angiogenesis and metastasis.  Curr Opin Hematol . 1996;  3 379-384
    CrossrefPubMedSearch in Google Scholar
  • 43 Shoji M, Hancock W W, Abe K. Activation of coagulation and angiogenesis in cancer: immunohistochemical localization in situ of clotting proteins and VEGF in human cancer.  Am J Pathol . 1998;  152 399-411
    PubMedSearch in Google Scholar
  • 44 Mousa S A, Mohamed S. Anti-angiogenesis efficacy and anti-tumor effects of warfarin: potential mechanisms.  FASEB . 2001;  15 A118,-A118, 149
    PubMedSearch in Google Scholar
  • 45 Amirkhosravi A, Francis J, Mousa S A. Anti-metastatic effect of low molecular weight heparin (LMWH) tinzaparin and tissue factor pathway inhibitor (TFPI).  Thromb Haemost . 2001;  Suppl P1409-P1409 Abst
    PubMedSearch in Google Scholar
  • 46 Maloney J P, Silliman C C, Ambruso D R. In vitro release of VEGF during platelet aggregation.  Am J Physiol . 1998;  275 H1054-H1061
    PubMedSearch in Google Scholar
  • 47 Francis J L. Haemostasis and cancer.  Med Lab Sci . 1989;  46 331-346
    PubMedSearch in Google Scholar
  • 48 Brower V. Tumor angiogenesis-new drugs on the block.  Nature Biotechnol . 1999;  17 963-968
    CrossrefPubMedSearch in Google Scholar
  • 49 Paku S. Current concepts of tumor-induced angiogenesis.  Pathol Oncol Res . 1998;  4 62-75
    PubMedSearch in Google Scholar
  • 50 Hassan A R, Hing Y K, Catey B. Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy: results from a randomized, double-blind, controlled clinical trial.  Ophthalmology . 2001;  108 1179-1183
    CrossrefPubMedSearch in Google Scholar
  • 51 Osman K, Comenzo R, Rajkumar S V. Deep vein thrombosis and thalidomide therapy for multiple myeloma.  N Engl J Med . 2001;  344 1951-1952
    CrossrefPubMedSearch in Google Scholar