Download PDF
Semin Thromb Hemost 2003; 29(5): 499-514
DOI: 10.1055/s-2003-44641
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Impact of Rheological Variables in Cancer

Georg-Friedrich von Tempelhoff1,2 , Lothar Heilmann2 , Gerhard Hommel3 , Kunhard Pollow4
  • 1Specialist for Gynecology and Obstetrics, City Hospital of Ruesselsheim, Ruesselsheim, Germany
  • 2City Hospital of Ruesselsheim, Ruesselsheim, Germany
  • 3Institute for Medical Statistics and Documentation, University of Mainz, Johannes Gutenberg University and
  • 4Institute for Experimental Endocrinology, University of Mainz, Johannes Gutenberg University, Mainz, Germany
Further Information

Publication History

Publication Date:
21 November 2003 (online)

    Permissions and Reprints

ABSTRACT

Rheological alterations are commonly found in malignant disease and are most pronounced in advanced-stage cancer. Although most of these changes are caused by cancer-unspecific mechanisms, it has been shown that the extent of these changes in some cancer types is related with the stage of cancer, prognosis of disease, and the patient's risk for thrombosis. Monitoring of rheological variables during follow-up of patients has been useful in gynecologic cancer; a significant increase in the main determinants of blood viscosity was found when metastasis became clinically apparent. The most frequent constellation in newly diagnosed cancer is an increase in plasma viscosity (PV) and red blood cell (RBC) aggregation that produces hyperviscosity and is compensated for by anemia. Unconditional elevation of the hematocrit in cancer can deteriorate microcirculatory flow properties and may plunge the patient into an undesirable hemorheological condition that limits effectiveness of cytoreductive treatment and favors dissemination of cancer cells and the development of thrombosis. Modification of hyperviscosity, most likely at the plasma level, may represent a concept for cancer treatment and prevention of thrombosis. Anticoagulants and anti-inflammatory substances seem most suitable at this point, because high fibrinogen turnover is an important determinant of hyperviscosity in malignancy.

KEYWORDS

Hyperviscosity - cancer prognosis - anemia - thrombosis - plasma viscosity

REFERENCES

  • 1 Rickles F R, Levine M, Edwards R L, Moritz T E, Zacharski L R. Abnormalities of blood coagulation in patients with cancer. In: Serneri GGN, Gensini GF, Abbate R, Prisco D, eds. Thrombosis An Update Scientific Press 1992 : 241-260
    Google Scholar
  • 2 von Tempelhoff G-F, Heilmann L. Thrombosis and hemorheology in patients with breast cancer and adjuvant chemotherapy.  Clin Hemorheol . 1995;  15 311-323
    PubMedGoogle Scholar
  • 3 Riley V. Erythrocyte sedimentation rate in breast cancer.  Science . 1976;  191 86-88
    PubMedGoogle Scholar
  • 4 Miller B, Heilmann L. Hemorheologic variables in breast cancer patients at the time of diagnosis and during treatment.  Cancer . 1988;  62 350-354
    PubMedGoogle Scholar
  • 5 Laffargue F, Brun J F, Boulet P, Elbouhmadi A, Orsetti A. Blood rheology in ovarian cancer (Abst).  Clin Hemorheol . 1995;  15 550
    PubMedGoogle Scholar
  • 6 El Bouhmadi A, Laffargue F, Brun J F. Aggregability and disaggregability of erythrocytes in women suffering from ovarian cancer: evidence for an increased disaggregation threshold.  Clin Hemorheol Microcirc . 2000;  22 91-97
    PubMedGoogle Scholar
  • 7 von Tempelhoff G-F, Heilmann L, Hommel G. et al . Hyperviscosity syndrome in ovarian malignancy.  Cancer . 1998;  82 1104-1111
    CrossrefPubMedGoogle Scholar
  • 8 Miller B, Heilmann L. Hemorheological parameters in patients with gynecologic malignancies.  Gynecol Oncol . 1989;  33 177-181
    CrossrefPubMedGoogle Scholar
  • 9 Chen H, Yunpeng W, Shaoxi C, Mian L A. Research on rheological properties of erythrocyte of lung cancer patients.  Clin Hemorheol . 1996;  16 135-141
    PubMedGoogle Scholar
  • 10 Khan M M, Puniyani R R, Huilgol N G, Hussain M A, Ranade G G. Hemorheological profiles in cancer patients.  Clin Hemorheol . 1995;  15 37-44
    PubMedGoogle Scholar
  • 11 Ranade G G, Puniyana R R, Huilgol N G, Khan M M. Application of PV to assess the status of cancer patients.  Clin Hemorheol . 1995;  15 755-761
    PubMedGoogle Scholar
  • 12 Beshara S, Letocha H, Linde T. et al . Anemia associated with advanced prostatic adenocarcinoma: effects of recombinant human erythropoietin.  Prostate . 1997;  31 153-160
    CrossrefPubMedGoogle Scholar
  • 13 Dintenfass L. Elevation of PV and of aggregation of red cells in melanoma metastasis.  Biorheology . 1978;  15 99-110
    PubMedGoogle Scholar
  • 14 Dintenfass L. Hemorheology of cancer metastases: an example of malignant melanoma. Survival times and abnormality of blood viscosity factors.  Clin Hemorheol . 1982;  2 259-271
    PubMedGoogle Scholar
  • 15 Humphreys W V, Walker A, Charlesworth D. Altered viscosity and yield stress in patients with abdominal malignancy: relationship to deep venous thrombosis.  Br J Surg . 1976;  63 559-561
    PubMedGoogle Scholar
  • 16 Tietjen G W, Chien S, Scholz P, Gump F E, Kinney J M. Changes in blood viscosity and plasma proteins in carcinoma.  J Surg Oncol . 1977;  9 53-59
    PubMedGoogle Scholar
  • 17 Lowe G DO. Rheological influences on thrombosis.  Baillieres Clin Haematol . 1994;  7 573-589
    PubMedGoogle Scholar
  • 18 Lip G Y, Chin B S, Blann A D. Cancer and the prothrombotic state.  Lancet Oncol . 2002;  3 27-34
    CrossrefPubMedGoogle Scholar
  • 19 Dintenfass L. Hemorheology of cancer metastasis-an example of malignant melanoma, survival times and abnormality of blood viscosity factors.  Clin Hemorheol . 1982;  2 259-271
    PubMedGoogle Scholar
  • 20 von Tempelhoff G-F, Schönmann N, Pollow K, Hommel G, Heilmann L. Prognostic role of PV in breast cancer.  Clin Hemorheol Microcirc Blood Flow Vessels . 2002;  26 55-61
    PubMedGoogle Scholar
  • 21 Weiss L. The hemodynamic destruction of circulating cancer cells.  Biorheology . 1987;  24 105-115
    PubMedGoogle Scholar
  • 22 Dong C, Slattery M J, Rank B M, You J. In vitro characterization and micromechanics of tumor cell chemotatic protrusion, locomotion, and extravasation.  Ann Biomed Eng . 2002;  30 344-355
    CrossrefPubMedGoogle Scholar
  • 23 Singh A, Eckardt K U, Zimmermann A. et al . Increased PV as a reason for inappropriate erythropoietin formation.  J Clin Invest . 1993;  91 251-256
    CrossrefPubMedGoogle Scholar
  • 24 Baish J W, Gazit Y, Berk D A. et al . Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model.  Microvasc Res . 1996;  51 327-346
    PubMedGoogle Scholar
  • 25 Chahwala S B, Hickmann J A. Effect of the antitumor drug adriamycin on human blood cell discocyte-echinocyte transitions.  Cancer Res . 1985;  45 4986-4989
    PubMedGoogle Scholar
  • 26 Vasigara-Singh W, Subramaniam S, Shyama S, JagadeEsan M, Sshyamala-Devi C S. Changes in erythrocyte membrane lipids in breast cancer patients after radiotherapy and chemotherapy.  Chemotherapy . 1996;  42 65-70
    PubMedGoogle Scholar
  • 27 Levine M N. Prevention of thrombotic disorders in cancer patients undergoing chemotherapy.  Thromb Haemost . 1999;  78 133-136
    PubMedGoogle Scholar
  • 28 Denko N C, Giaccia A J. Tumor hypoxia, the physiological link between Trousseaus's syndrome (carcinoma induced coagulopathy) and metastasis.  Cancer Res . 2001;  61 795-798
    PubMedGoogle Scholar
  • 29 Keller D K, Nauth C, Thews O, Krueger W, Vaupel P. Localized hypothermia: impact on oxygenation, microregional perfusion, metabolic and bioenergetic status of subcutaneous rat tumours.  Br J Cancer . 1998;  78 56-61
    PubMedGoogle Scholar
  • 30 Baron J A, Cole B F, Sandler R S. et al . Randomized trial of aspirin to prevent colorectal adenomas.  N Engl J Med . 2003;  348 891-899
    CrossrefPubMedGoogle Scholar
  • 31 Zacharski L R. Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy.  Cancer Lett . 2002;  186 1-9
    CrossrefPubMedGoogle Scholar
  • 32 Konerding M A, van Ackern A C, Fait E, Steinberg F, Streffer C. Morphologic aspects of tumor angiogenesis and microcirculation. In: Molls M, Vaupel P, eds. Blood Perfusion and Microenvironment of Human Tumors Berlin: Springer-Verlag 1998: 5-18
    Google Scholar
  • 33 Less J R, Posner M C, Boucher Y. et al . Interstitial hypertension in human tumors.  Cancer Res . 1992;  52 6371
    PubMedGoogle Scholar
  • 34 Milosevic M F, Fyles A W, Hill R P. The relationship between elevated interstitial fluid pressure and blood flow in tumors: a bioengineering analysis.  Int J Radiat Oncol Biol Phys . 1999;  43 1111-1112
    CrossrefPubMedGoogle Scholar
  • 35 Jain R K. Determinants of tumor blood flow: a review.  Cancer Res . 1988;  48 2641-2658
    PubMedGoogle Scholar
  • 36 Sevick E M, Jain R K. Blood flow and venous pH of tissue-isolated Walker 256 carcinoma during hyperglycemia.  Cancer Res . 1988;  48 1201-1207
    PubMedGoogle Scholar
  • 37 Lowe G DO. Blood rheology, haemostasis and vascular disease. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD, eds. Haemostasis and Thrombosis London: Churchill Livingstone 1994: 1169-1188
    Google Scholar
  • 38 Butler T P, Grantham F H, Gullino P M. Bulk transfer of fluid in the interstitial compartment of mammary tumors.  Cancer Res . 1975;  35 512-516
    PubMedGoogle Scholar
  • 39 Funakoshi N, Onizuka M, Yanagi K. et al . A new model of lung metastasis for intravital studies.  Microvasc Res . 2000;  59 361-367
    PubMedGoogle Scholar
  • 40 Lane D W, L'Anson S. Viscosimetric effect of fibrinogen.  J Clin Pathol . 1994;  47 1004-1005
    PubMedGoogle Scholar
  • 41 Dintenfass L, Kammer S. PV in 615 subjects. Effect of fibrinogen, globulin, and cholesterol in normals, peripheral vascular disease retinopathy, and melanoma.  Biorheology . 1977;  14 247-251
    PubMedGoogle Scholar
  • 42 Dintenfass L. Criteria and values in diagnosis and treatment, and prevention of metastasis in neoplastic disease. In: Dintenfass L, ed. Rheology of Blood in Diagnostic and Preventive Medicine London: Butterworths 1976: 137-162
    Google Scholar
  • 43 von Tempelhoff G-F, Nieman F, Hommel G, Heilmann L. Association between blood rheology, thrombosis, and cancer survival in patients with gynecologic malignancy.  Clin Hemorheol Microcirc Blood Flow Vessels . 2000;  22 107-130
    PubMedGoogle Scholar
  • 44 Thompson D K, Haddow J E, Smithe D E, Ritchi R F. Elevated serum acute phase protein levels as predictors of disseminated breast cancer.  Cancer . 1983;  51 2100-2104
    PubMedGoogle Scholar
  • 45 Jung F, Kieseweter H, Roggenkamp H G, Nüttgens H P, Ringelstein E B. Bestimmung der Referenzbereiche rheologischer Parameter: Studie an 653 zufällig ausgewählten Probanden im Kreis Aachen.  Klin Wochenschr . 1986;  64 375-381
    CrossrefPubMedGoogle Scholar
  • 46 von Tempelhoff G-F, Heilmann L. Coagulation disorders in gynecologic malignancy. In: Rath W, Heilmann L, eds. Coagulation Disorders in Obstetrics and Gynecology New York: Thieme 1999: 66-88
    Google Scholar
  • 47 Zacharski L R, Memoli V A, Ornstein D L. et al . Tumor cell procoagulant and urokinase expression in carcinoma of the ovary.  J Natl Cancer Inst . 1993;  85 1225-1230
    CrossrefPubMedGoogle Scholar
  • 48 Moradi M M, Carson L F, Weinberg B. et al . Serum and ascitic fluid levels of interleukin-1, interleukin-6, and tumor necrosis factor alpha in patients with ovarian epithelial cancer.  Cancer . 1993;  72 2433-2440
    PubMedGoogle Scholar
  • 49 Semeraro N, Montemurro P, Conese M. et al . Procoagulant activity of mononuclear phagocytes from different anatomical sites in patients with gynecological malignancies.  Int J Cancer . 1990;  45 251-254
    CrossrefPubMedGoogle Scholar
  • 50 Zacharski L R, Howell A L, Memoli V A. The coagulation biology of cancer.  Fibrinolysis . 1992;  6(suppl) 39-42
    PubMedGoogle Scholar
  • 51 Sorensen H T, Mellemkjaer L, Olsen J, Baron J A. Prognosis of cancers associated with venous thromboembolism.  N Engl J Med . 2000;  343 1846-1850
    CrossrefPubMedGoogle Scholar
  • 52 Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. Duration of anticoagulation trial.  N Engl J Med . 2000;  342 1953-1958
    CrossrefPubMedGoogle Scholar
  • 53 von Tempelhoff G-F, Heilmann L, Hommel G. Thrombosis-a clue of poor prognosis in primary non-metastatic breast cancer.  Breast Cancer Res Treatment . 2002;  73 275-277
    PubMedGoogle Scholar
  • 54 Zacharski L R, Henderson W G, Rickles F R. et al . Effect of sodium warfarin on survival in small carcinoma of the lung.  JAMA . 1981;  245 831-835
    CrossrefPubMedGoogle Scholar
  • 55 Hettiarachchi R JK, Smorenburg S M, Ginsberg J. et al . Do heparins do more than just treat thrombosis?.  <~>The influence of heparins on cancer spread. Thromb Haemost . 1999;  82 947-952
    PubMedGoogle Scholar
  • 56 Goldhaber S Z. Epidemiology of pulmonary embolism and deep vein thrombosis. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD, eds. Haemostasis and Thrombosis London: Churchill Livingstone 1994: 1327-1333
    Google Scholar
  • 57 Balendra R, Rumley A, Orr M. et al . Blood lipids, coagulation, fibrinolysis and rheology in spontaneous proven deep vein thrombosis (Abst).  Br J Haematol . 1991;  77 (suppl 1) 83-(Abst)
    PubMedGoogle Scholar
  • 58 Chabanel A, Horellou M H, Conrad J, Samama M M. Red blood cell aggregability in patients with a history of leg vein thrombosis: influence of postthrombotic treatment.  Br J Haematol . 1994;  88 174-179
    PubMedGoogle Scholar
  • 59 Mercke C E. Anemia in patients with solid tumours and the role of erythrocyte deformability.  Br J Cancer . 1981;  44 425-432
    PubMedGoogle Scholar
  • 60 Thomas D P. Pathogenesis of venous thrombosis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis Philadelphia: JB Lippincott 1982: 820-830
    Google Scholar
  • 61 Patterson W P, Caldwell C W, Doll D C. Hyperviscosity syndromes and coagulopathies.  Semin Oncol . 1990;  17 210-216
    PubMedGoogle Scholar
  • 62 von Tempelhoff G-F, Pollow K, Schneider D M, Heilmann L. State of the art: Chemotherapy and thrombosis in gynaecological malignancy.  Clin Appl Thromb Hemost . 1999;  5 92-104
    PubMedGoogle Scholar
  • 63 Subramaniam S, Subramaniam S, Aagadeesan M, Devi S SC. Alterations in erythrocyte membrane structure of breast cancer patients treated with CMF-a lipid profile.  Chemotherapy . 1994;  40 427-430
    PubMedGoogle Scholar
  • 64 Vasigara-Singh W, Subramaniam S, Shyama S, Jagade Esan M, Shyamala-Devi C S. Changes in erythrocyte membrane lipids in breast cancer patients after radiotherapy and chemotherapy.  Chemotherapy . 1996;  42 65-70
    PubMedGoogle Scholar
  • 65 Baerlocher G M, Beer J H, Owen G R, Meiselman H J, Reinhart W H. The anti-neoplastic drug 5-fluorouracil produces echinocytosis and affects blood rheology.  Br J Haematol . 1997;  99 426-432
    CrossrefPubMedGoogle Scholar
  • 66 Chahwala S B, Hickmann J A. Effect of the antitumor drug adriamycin on human blood cell discocyte-echinocyte transitions.  Cancer Res . 1985;  45 4986-4989
    PubMedGoogle Scholar
  • 67 Mark M, Walter R, Meredith D O, Reinhart W H. Commercial taxane formulations induce stomatocytosis and increase blood viscosity.  Br J Pharmacol . 2001;  134 1207-1214
    CrossrefPubMedGoogle Scholar
  • 68 von Tempelhoff G-F, Heilmann L. Thrombosis and hemorheology in patients with breast cancer and adjuvant chemotherapy.  Clin Hemorheol . 1995;  15 311-323
    PubMedGoogle Scholar
  • 69 Cwikiel M, Persson S U, Larsson H, Albertsson M, Eskilsson J. Changes of blood viscosity in patients treated with 5-fluorouracil-a link to cardiotoxicity?.  Acta Oncol . 1995;  34 83-85
    PubMedGoogle Scholar
  • 70 von Tempelhoff G-F, Niemann F, Schneider D. et al . Blood rheology during chemotherapy in patients with ovarian cancer.  Thromb Res . 1998;  90 73-82
    PubMedGoogle Scholar
  • 71 Rapp S. Hemorheology in Cervical and Endometrial Cancer Patients. Mainz, Germany: Johannes Gutenberg Universität Mainz; 2001. Inaugural dissertation
    Google Scholar
  • 72 Höckel M, Schlenger K, Aral B. et al . Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix.  Cancer Res . 1996;  56 4509-4515
    PubMedGoogle Scholar
  • 73 Vaupel P, Schlenger K, Knoop C, Höckel M. Oxygenation of human tumors: elevation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements.  Cancer Res . 1991;  51 3316-3322
    PubMedGoogle Scholar
  • 74 Vaupel P, Briest S, Hockel M. Hypoxia in breast cancer: pathogenesis, characterization and biological/therapeutic implications.  Wien Med Wochenschr . 2002;  152 334-342
    CrossrefPubMedGoogle Scholar
  • 75 von Tempelhoff G-F, Hommel G, Heilmann L Tumor hypoxia, the physiological link between Trousseau's syndrome (carcinoma induced coagulopathy) and metastasis. Cancer Res .  2001;  61 7697-7698
    PubMedGoogle Scholar
  • 76 Akhtar N, Thompson J, Durrant S T. et al . The clinical relevance of plasma viscosity in Hodgkin's disease.  Clin Lab Haematol . 1991;  13 1-8
    PubMedGoogle Scholar
  • 77 Koenig W, Sund M, Lowel H, Doring A, Ernst E. Association between PV and all-cause mortality results from the MONICA-Augsburg Cohort Study 1984-92.  Br J Haematol . 2000;  109 453-458
    CrossrefPubMedGoogle Scholar
  • 78 Grau C, Overgaard J. Significance of hemoglobin concentration for treatment outcome. In: Molls M, Vaupel P, eds. Blood Perfusion and Microenvironment of Human Tumors Berlin: Springer-Verlag 1998: 101-112
    Google Scholar
  • 79 Obermair A, Handisurya A, Kaider A. et al . The relation of pretreatment serum hemoglobin level to the survival of epithelial ovarian carcinoma patients.  Cancer . 1998;  83 726-731
    CrossrefPubMedGoogle Scholar
  • 80 Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsburg 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
    CrossrefPubMedGoogle Scholar
  • 81 Vaupel P, Menke H. Blood flow, vascular resistance and oxygen availability in malignant tumors upon intravenous flunaritine.  Adv Exp Med Biol . 1987;  215 393-398
    PubMedGoogle Scholar