Skip to main content
SpringerLink
Log in

Hemostatic alterations in cancer patients

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Summary

Nearly all patients with cancer manifest laboratory evidence of hypercoagulability and some develop clinical thromboembolic disease (TED). Routine laboratory studies of blood coagulation have been performed in several large, prospective trials of the use of anticoagulant drugs in cancer treatment. The results of these studies, as well as data from several smaller studies of more sensitive tests of hypercoagulability [e.g. fibrinopeptide A (FPA); thrombin-antithrombin (TAT) complexes; prothrombin fragment F1+2)], indicate that the levels of some clotting proteins parallel disease activity. However, no studies of sound methodologic design have yet been performed to indicate that any of these tests of blood coagulation can serve as adequate predictors of TED in patients with cancer.

In addition to the important role played by tumor-related procoagulants, several other mechanisms may be involved in the pathogenesis of thromboembolic events in patients with cancer, including stasis and endothelial damage. Considerable variability in the relative importance of these mechanisms in the pathogenesis of TED may exist among patients with different types of cancer.

The risk for TED associated with surgical procedures in cancer patients is substantial and prophylactic antithrombotic therapy should be considered for most of these patients. Chemotherapy and hormonal therapy of cancer probably increases the likelihood of TED, particularly in those subjects with indwelling venous catheters. This risk has been particularly well-studied in patients with breast cancer treated with tamoxifen plus cytotoxic drugs. The pathogenic mechanisms may be complex but vascular injury is likely as a proximate cause of venous access catheter thrombosis and can be prevented with low dose coumadin therapy. The utility of low dose coumadin anticoagulation in reducing the risk for TED during breast cancer treatment is unknown but is currently being tested in a large, multiinstitutional study. Since chronic coumadin anticoagulation of cancer patients, and single pulse dose heparin prior to intravenous chemotherapy, both prevent thrombin generation, these agents may be of use in reducing the risk of chemotherapy-associated thrombosis. Prophylactic anticoagulation should be considered for high risk patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. TrousseauA: Phlegmasia alba dolens. In: Clinique Medicale de l'Hotel-Dieu de Paris. JB Balliere et Fils, Paris, vol 3, pp 654–712, 1865

    Google Scholar 

  2. RicklesFR, EdwardsRL: Leukocytes and tumor cells in thrombosis. In: ColmanRW, HirshJ, MarderVJ, SalzmanEW (eds) Hemostasis and thrombosis, 3rd Edition. J.B. Lippincott Co, Philadelphia, 1992, in press

    Google Scholar 

  3. RicklesFR, HancockWW, EdwardsRL, ZacharskiLR: Antimetastatic agents. I. Role of cellular procoagulants in the pathogenesis of fibrin deposition in cancer and the use of anticoagulants and/or antiplatelet drugs in cancer treatment. Sem Thromb Hem 14: 88–94, 1988

    Google Scholar 

  4. SunNC, McAfeeWM, HumGH, WeinerJM: Hemostatic abnormalities in malignancy, a prospective study in one hundred eight patients. Part I. Coagulation studies. Am J Clin Pathol 71: 10–16, 1979

    PubMed  Google Scholar 

  5. EdwardsRL, RicklesFR, MoritzTE, HendersonWG, ZacharskiLR, FormanWB, CornellCJ, ForcierRJ, O'DonnellJF, HeadleyE, KimSH, O'DellR, TornyosK, KwaanHC: Abnormalities of blood coagulation tests in patients with cancer. Am J Clin Pathol 88: 596–602, 1987

    PubMed  Google Scholar 

  6. CarlssonS: Fibrinogen degradation products in serum from patients with cancer. Acta Chir Scand 139: 499–502, 1973

    PubMed  Google Scholar 

  7. OkajimaK, OkabeH, InoueM, TakasukiK: Characterization of the fibrinolytic state by measuring stable crosslinked fibrin degradation products in disseminated intravascular coagulation associated with acute promyelocytic leukemia. Acta Haematologica 81: 15–18, 1989

    PubMed  Google Scholar 

  8. RicklesFR, EdwardsRL: Activation of blood coagulation in cancer: Trousseau's syndrome revisited. Blood 62: 14–31, 1983

    PubMed  Google Scholar 

  9. WajimaT, MukhopadhyayP: Serial coagulation profiles in patients with small cell carcinoma of the lung. Thromb Haemostas Suppl 62: 136, 1989 (Abstract)

    Google Scholar 

  10. ZacharskiLR, MoritzTE, BaczekLA, RicklesFR EdwardsRL, FormanWB, ForcierRJ, CornellCJ, HaakensonCM, BallardHS, CrumED, JohnsonGJ, LevineJ, HongWK, O'DonnellJF, SchilskyRL, RingenbergQS, RobertF, SpauldingMB, TornyosK, WilliamsC, ZuckerS, FaulknerCS, EatonWL, HoppelCL: Effect of Mopidamol on survival in carcinoma of the lung and colon: final report of Veterans Administration Cooperative Study No. 188. J Nat Ca Instit 80: 90–97, 1988

    Google Scholar 

  11. Al-MondhiryH, LawlorBA, SadulaD: Fibrinogen survival and fibrinolysis in acute leukemia. Cancer 35: 432–435, 1975

    PubMed  Google Scholar 

  12. LymanGH, BettigoleRE, RobsonE, AmbrusJL, UrbanH: Fibrinogen kinetics in patients with neoplastic disease. Cancer 41: 1113–1122, 1978

    PubMed  Google Scholar 

  13. YodaY, AbeT: Fibrinopeptide A (FPA) level and fibrinogen kinetics in patients with malignant disease. Thromb Haemostas 46: 706–709, 1981

    Google Scholar 

  14. MombelliG, RouxA, HaeberliA, StraubPW: Comparison of125I-fibrinogen kinetics and fibrinopeptide A in patients with disseminated neoplasia. Blood 60: 381–388, 1982

    PubMed  Google Scholar 

  15. PeuscherFW, CletonFJ, ArmstrongL, Stoepman-van DalenEA, vanMourikJA, vanAkenWG: Significance of plasma fibrinopeptide A (FPA) in patients with malignancy. J Lab Clin Med 96: 5–14, 1980

    PubMed  Google Scholar 

  16. MyersTJ, RicklesFR, BarbC, CronlundM: Activation of blood coagulation in acute leukemia — fibrinopeptide A (FPA) generation as an indicator of disease activity. Blood 57: 518–525, 1981

    PubMed  Google Scholar 

  17. RicklesFR, EdwardsRL, BarbC, CronlundM: Abnormalities of blood coagulation in patients with cancer: Fibrinopeptide A generation and tumor growth. Cancer 51: 301–307, 1983

    PubMed  Google Scholar 

  18. BauerKA, RosenbergRD: Thrombin generation in acute promyelocytic leukemia. Blood 64: 791–796, 1984

    PubMed  Google Scholar 

  19. NandS, FisherSG, SalgiaR, FisherRI: Hemostatic abnormalities in untreated cancer: incidence and correlation with thrombotic and hemorrhagic complications. J Clin Oncol 12: 1998–2003, 1987

    Google Scholar 

  20. AugerMJ, GallowayMJ, LeinsterSJ, McVerryBA, MackieMJ: Elevated fibrinopeptide A levels in patients with clinically localized breast carcinoma. Haemostasis 17: 336–339, 1987

    PubMed  Google Scholar 

  21. LindahlAK, SandsetPM, AbildgaardU: Indices of hypercoagulation in cancer as compared with those in acute inflammation and acute infarction. Haemostasis 20: 253–262, 1990

    PubMed  Google Scholar 

  22. GadducciA, BaicchiU, delBravoB: The assessment of the hemostasis system in patients with ovarian and cervical carcinoma. The Cancer J 4: 183–187, 1991

    Google Scholar 

  23. UchiyamaT, MatsumotoM, KobayashiN: Studies of the pathogenesis of coagulopathy in patients with arterial thromboembolism and malignancy. Thromb Res 59: 955–965, 1990

    PubMed  Google Scholar 

  24. AbshireTC, GoldSH, OdomLF, CarsonSD, HathawayWE: The coagulopathy of childhood leukemia. Thrombin activation or primary fibrinolysis? Cancer 66: 716–721, 1990

    PubMed  Google Scholar 

  25. BickRL: Disseminated intravascular coagulation and related syndromes: a clinical review. Sem Thromb Hem 14: 65–81, 1988

    Google Scholar 

  26. RubinRN, KiesMS, PoschJJ: Measurements of antithrombin III in solid tumor patients with and without hepatic metastases. Thromb Res 18: 353–360, 1980

    PubMed  Google Scholar 

  27. HoneggerH, AndersonN, HewittLA, TullisJL: Antithrombin III profiles in malignancy, relationship to primary tumors and metastatic sites. Thromb Haem 46: 500–503, 1981

    Google Scholar 

  28. RodeghieroF, MannucciPM, ViganoS, BarbuiT, GugliottaL, CortellaroM, DiniE: Liver dysfunction rather than intravascular coagulations as the main cause of low protein C and antithrombin III in acute leukemia. Blood 63: 969–969, 1984

    Google Scholar 

  29. TroyK, EssexD, RandJ, LemaM, CuttnerJ: Protein C and S levels in acute leukemia. Am J Hematol 37: 159–162, 1991

    PubMed  Google Scholar 

  30. SweeneyJD, KillionKM, PruetCF, SpauldingMB: von Willebrand factor in head and neck cancer. Cancer 66: 2387–2389, 1990

    PubMed  Google Scholar 

  31. Falanga A, Levine M, Edwards RL, Moritz TE, Zacharski LR, Rickles FR: Clotting studies in cancer patients. Report from the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee, International Society of Thrombosis and Haemostasis. In preparation, 1992

  32. EdwardsRL, MorganDL, RicklesFR: Animal tumor procoagulants: Resistry of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee, International Society on Thrombosis and Haemostasis. Thromb Haem 63: 133–138, 1990; Edwards RL, Silver J, Rickles FR: Human tumor procoagulants. Registry of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Subcommittee, International Society on Thrombosis and Haemostasis. Thromb Haem, Submitted for Publication

    Google Scholar 

  33. EdwardsRL, RicklesFR: The role of leukocytes in the activation of blood coagulation. Sem Hematol 29: 202–212, 1992

    Google Scholar 

  34. TallmanM and KwaanHC: Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood 79: 543–553, 1992

    PubMed  Google Scholar 

  35. AndohK, KkubotaT, TakadaM, TanakaH, KobayashiN, MaekawaT: Tissue factor activity in leukemic cells. Special reference to disseminated intravascular coagulation. Cancer 59: 748–754, 1987

    PubMed  Google Scholar 

  36. KubotaT, AndohK, SadakataH, TanakaH, KobayashiN: Tissue factor released from leukemic cells. Thromb Haem 65: 59–63, 1991

    Google Scholar 

  37. FalangaA, AlessioMG, DonatiMB, BarbuiT: A new procoagulant in acute leukemia. Blood 71: 870–875, 1988

    PubMed  Google Scholar 

  38. DonatiMB, FalangaA, ConsonniR, AlessioG, BassanR, BuelliM, BorinL, CataniL, PoglianiE, GugliottaL, MaseraG, BarbuiT: Cancer procoagulant in acute non lymphoid leukemia: relationship of enzyme detection to disease activity. Thromb Haem 64: 11–16, 1990

    Google Scholar 

  39. CozzolinoF, TorciaM, MilianiA, CarossinoAM, GiordaniR, CinottiS, FilimbertiE, SaccardiR, BernabeiP, GuidiG, DiGuglielmoR, PistoiaV, FerrariniM, NawrothPP, SternD: Potential role of interleukin-1 as the trigger for diffuse intravascular coagulation in acute nonlymphoblastic leukemia. Am J Med 84: 240–250, 1988

    PubMed  Google Scholar 

  40. WijermansPW, RebelVI, OssenkoppeleGJ, HuijgensPC, LangenhujsenMMAC: Combined procoagulant activity and proteolytic activity of acute promyelocytic leukemic cells: Reversal of the bleeding disorder by cell differentiation. Blood 73: 800–805, 1989

    PubMed  Google Scholar 

  41. TakahashiH, TatewakiW, WadaK, HananoM, ShibataA: Thrombin vs. plasmin generation in disseminated intravascular coagulation associated with various underlying disorders. Am J Hematol 33: 90–95, 1990

    PubMed  Google Scholar 

  42. BennettB, BoothNA, CrollA, DawsonAA: The bleeding disorder in acute promyelocytic leukemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol 71: 511–515, 1989

    PubMed  Google Scholar 

  43. SchwartzBS, WilliamsEC, ConlanMG, MosherDF: Epsilon amino caproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency. Ann Int Med 105: 873–877, 1986

    PubMed  Google Scholar 

  44. SalzmanEW, HirshJ: Prevention of venous thromboembolism In: ColmanRW, HirshJ, MarderVJ, SalzmanEW (eds) Hemostasis and Thrombosis: Basic principles and clinical practice. Lippincott, Philadelphia, pp 1252–1265, 1987

    Google Scholar 

  45. FraschiniG, JadejaJ, LawsonM, HolmesFA, CarrascoHC, WallaceS: Local infusion of urokinase for the lysis of thrombosis associated with permanent central venous catheters in cancer patients. J Clin Oncol 5: 672–678, 1987

    PubMed  Google Scholar 

  46. ClagettGP, ReischJS: Prevention of venous thromboembolism in general surgical patients. Ann Surg 208: 227–240, 1988

    PubMed  Google Scholar 

  47. Clarke-PearsonDL, ColemanRE, SynanIS, HinshawW, CreasmanWT: Venous thromboembolism prophylaxis in gynecologic oncology: a prospective controlled trial of low dose heparin. Am J Obstet Gynecol 145: 606–613, 1983

    PubMed  Google Scholar 

  48. Clarke-PearsonDL, SynanIS, HinshawWM, ColemanE, CreasmanWT: Prevention of postoperative venous thromboembolism by external pneumatic calf compression in patients with gynecologic malignancy. Obstet Gynecol 63: 92–98, 1984

    PubMed  Google Scholar 

  49. Clarke-PearsonDL, CreasmanWT, ColemanRE, SynanIS, HinshawWM: Perioperative external pneumatic calf compression as thromboembolism prophylaxis in gynecologic oncology: report of a randomized controlled trial. Gynecol Oncol 18: 222–232, 1984

    Google Scholar 

  50. Clarke-PearsonDL, DelongE, SynanIS, HinshawWM: A controlled trial of two low-dose heparin regimens for the prevention of postoperative deep vein thrombosis. Obstet Gynecol 75: 684–689, 1990

    PubMed  Google Scholar 

  51. CoeNP, CollinsREC, KleinLA, BettmannMA, SkillmanJJ, ShapiroRM, SalzmanEW: Prevention of deep vein thrombosis in urological patients: a controlled randomized trial of low dose heparin and external pneumatic compression boots. Surgery 83: 230–234, 1978

    PubMed  Google Scholar 

  52. KutnowskiM, VandendrisM, SteinbergerR, KraytmanM: Prevention of postoperative deep vein thrombosis by low dose heparin in urologic surgery. Urolog Res 5: 123–125, 1977

    Google Scholar 

  53. TurpieAGG, GallusAS, BeattieWS, HirshJ: Prevention of venous thrombosis in patients with intracranial disease by intermittent pneumatic compression of the calf. Neurology 27: 435–438, 1977

    PubMed  Google Scholar 

  54. CerratoD, ArianoC, FiacchinoF: Deep vein thrombosis and low dose heparin prophylaxis in neurosurgical patients. J Neurosurg 49: 378–381, 1978

    PubMed  Google Scholar 

  55. SkillmanJJ, CollinsREC, CoeNP, GoldsteinBS, ShapiroRM, ZervesNT, BettmannMA, SalzmanEW: Prevention of deep vein thrombosis in neurosurgical patients: a controlled, randomized trial of external pneumatic compression boots. Surgery 83: 354–358, 1978

    PubMed  Google Scholar 

  56. TurpieAGG, DoyleDJ, SaerensE, deBoerAC, TalbotC, McNameeJ, HirshJ: An evaluation of suloctidil in the prevention of deep vein thrombosis in neurosurgical patients. Thromb Res 39: 173–181, 1985

    PubMed  Google Scholar 

  57. TurpieAGG, DelmoreT, HirshJ, HullR, GentonE, HiscoeC, GentM: Prevention of venous thrombosis by intermittent sequential calf compression in patients with intracranial disease. Thromb Res 15: 611–616, 1979

    PubMed  Google Scholar 

  58. WeissRB, TormeyDC, HollandJF, WeinbergVE: Venous thrombosis during multimodal treatment of primary breast carcinoma. Cancer Treat Rep 65: 677–679, 1981

    PubMed  Google Scholar 

  59. LevineM, GentM, HirshJ, ArnoldA, GoodyearMD, HryniukW, DePauwS: The thrombogenic effect of anticancer drug therapy in women with Stage II breast cancer. N Engl J Med 318: 404–407, 1988

    PubMed  Google Scholar 

  60. PritchardKI, PaterJ, PatersonAHJ, FineS: Thromboembolic complications related to chemotherapy. Proc Amer Soc Clin Oncol 8: 25, 1989 (Abstract)

    Google Scholar 

  61. WallJG, WeissRB, NortonL, PerloffM, RiceMA, KorzunAH, WoodWC: Arterial thrombosis associated with adjuvant chemotherapy for breast carcinoma: a Cancer and Leukemia Group B study. Amer J Med 87: 501–504, 1989

    PubMed  Google Scholar 

  62. SaphnerT, TormeyDC, GrayR: Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 9: 286–294, 1991

    PubMed  Google Scholar 

  63. FisherB, ConstantinoJ, RedmondC, PoissonR, BowmanD, CoutureJ: A randomized clinical trial evaluating Tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen receptor positive tumors. N Engl J Med 320: 479–484, 1989

    PubMed  Google Scholar 

  64. GoodnoughLT, SaitoH, ManniA, JonesPK, PearsonOH: Increased incidence of thromboembolism in Stage IV breast cancer patients treated with five-drug chemotherapy regimen: a study of 159 patients. Cancer 54: 1264–1268, 1984

    PubMed  Google Scholar 

  65. BernMM, LokichJJ, WallachSR, BotheA, BenottiPN, ArkinCF, GrecoFA, HubermanM, MooreC: Very low doses of warfarin can prevent thrombosis in central venous catheters. A randomized prospective trial. Ann Int Med 112: 423–428, 1990

    PubMed  Google Scholar 

  66. EdwardsRL, KlausM, MatthewsE, McCullenC, BonaRD, RicklesFR: Heparin abolishes the chemotherapy-induced increases in plasma fibrinopeptide A levels. Am J Med 89: 25–28, 1990

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Connecticut School of Medicine, Farmington, CT

    Frederick R. Rickles, Mark Levine & Richard L. Edwards

  2. American Red Cross Connecticut Region Blood Services, Farmington, CT

    Frederick R. Rickles, Mark Levine & Richard L. Edwards

  3. the Veterans Administration (VA) Medical Center, Newington, CT, USA

    Frederick R. Rickles, Mark Levine & Richard L. Edwards

  4. the Ontario Cancer Foundation, McMaster University, L8V 1C3, Hamilton, Ontario, Canada

    Frederick R. Rickles, Mark Levine & Richard L. Edwards

  5. the Hamilton Regional Cancer Centre, McMaster University, L8V 1C3, Hamilton, Ontario, Canada

    Frederick R. Rickles, Mark Levine & Richard L. Edwards

  6. the Department of Medicine, McMaster University, L8V 1C3, Hamilton, Ontario, Canada

    Frederick R. Rickles, Mark Levine & Richard L. Edwards

Authors
  1. Frederick R. Rickles
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard L. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rickles, F.R., Levine, M. & Edwards, R.L. Hemostatic alterations in cancer patients. Cancer Metast Rev 11, 237–248 (1992). https://doi.org/10.1007/BF01307180

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01307180

Key words

Search

Navigation