Blood Coagulation and Thrombosis in Patients with Ovarian Malignancy

Summary

Ovarian cancer cells appear to be capable of both thrombin formation and induction of fibrin degradation which may be essential prerequisites for the development of deep vein thrombosis (DVT) as well as the spread of malignancy. To study further this coagulation – cancer interaction in 60 patients with untreated ovarian cancer of FIGO stage I-IV the incidence of DVT was recorded pre-operatively, postoperatively on day 1, 3, 5, 7, 10, before each of six cycles of Cisplati- num/Epirubicin/Cyclophosphamide chemotherapy, during follow-up and in the post-operative period of second look surgery. In addition, blood coagulation tests results were determined prospectively. Two patients were excluded from these calculations due to previous DVT 5 to 6 weeks before the diagnosis of ovarian cancer but all patients were eligible for surgery and randomized to receive either daily low molecular weight heparin (LMWH) (n = 28) or unfractionated heparin (UFH) (n = 32) for perioperative thrombosis prophylaxis until the 7th postoperative day. According to the FIGO stage, patients were equally distributed in the 2 heparin treatment groups. The predictive value of pre-operative coagulation test results, clinical parameters, and type of heparin used were tested in univariate and multivariate analysis for development of post-operative DVT and overall patients survival. Impedance plethysmography for DVT screening was used. The presence of DVT was then confirmed by phlebography. Only D-dimer and fibrinogen levels were correlated significantly with the FIGO stage while antithrombin, protein C, and plasminogen activator inhibitor activity were not. The incidence of DVT was 6.7% (4/60) up to the 7th and 8.3% (5/60) between the 8th and 29th post-operative day. DVT occurred in 10.6 % (5/47) during chemotherapy. Pre-operative coagulation test results, the type of heparin used, and clinical parameters were not significant risk factors for post-operative DVT development in univariate analysis. The D-dimer and fibrinogen levels were significant risk factors for reduced overall survival in univariate analysis but only the FIGO stage was an independent predictor (in multivariate analysis). After a median follow up of 26.5 months (min. 8 months, max. 41 months), 21.4% of LMWH treated and 37.5% of UFH-treated patients died of cancer (p = 0.26). Pre-operative test results were neither predictive for DVT nor the outcome of cancer but patients showed an improved though not statistically significant overall survival after LMWH treatment.

• References

• 1 Rickies FR, Levine M, Edwards RL. Hemostatic alterations in cancer patients. Cancer and Metastasis Reviews 1992; 11: 0237-0248
• 2 Rickies FR, Levine M, Edwards RL, Moritz TE, Zacharski LR. Abnormalities of blood coagulation in patients with cancer. In: Thrombosis an update Scientific Press. Semeri NGG, Gensini GF, Abbate R, Prisco D. Florence 1992. pp 0241-0260
• 3 Gadducci A, Baicchi U, Marrai R, Del BravoB, Fosella PV, Facchini V. Pretreatment plasma levels of Fibrinopeptide A (FPA), D-dimer (DD) and von Willebrand factor (vWF) in patients with ovarian cancinoma. Gynecol Oncol 1994; 03: 0352-0356
• 4 Khoo SK, Rylatt DB, Parsons P, Wilson K, Webb MJ, Dickie G, Kearsley J, Mackay EV. Serial D-dimer levels in the assessment of tumor mass and clinical outcome in ovarian cancer. Gynecol Oncol 1988; 29: 0188-0198
• 5 Rella C, Coviello M, De FrenzaN, Falco G, Chiuri E, Colavito P, Quaranata M, De LeonardisA. Plasma D-dimer measurements as a marker of gynecologic tumors: comparison with Ca 125. Tumori 1993; 79: 0347-0351
• 6 Rӧbel M, Jürgensmeyer R, Schröck R, Wilhelm O, Babic H, Graeff H. Relation of fibrin and tumor-associated antigens to the spread of ovarian cancer. Fibrinolysis 1987; 01: 0143-0148
• 7 Rose PG, Terrien JM, Baker S. Plasma D-dimer and peritoneal Ca 125 levels as predictors of disease status in ovarian carcinoma. J Surg Oncol 1994; 56: 0168-0171
• 8 Wilhelm O, Hafter R, Henschen A, Schmitt M, Graeff H. Role of plasmin in the degradation of the stroma-derived fibrin in human ovarian carcinoma. Blood 1990; 75: 1675-1678
• 9 Kanayma N. The role of D-dimer in diagnosis of ovarian cancer. Nippon Sanka Fujinka Gakkai Zasshi 1991; 43: 0485 (Abstract).
• 10 Clarke-Pearson DL, Coleman RD, Synan IS, Hinshaw W, Creasman WT. Venous thromboembolism prophylaxis in gynecologic oncolog: A prospective, controlled trial of low-dose heparin. Am J Obstet Gynecol 1983; 145: 0606-0613
• 11 Crandon AJ, Koutts J. Incidence of postoperative deep vein thrombosis in gynecologic oncology. Aust N Z J. Obstet Gynaecol 1983; 23: 0216-0219
• 12 Gore M, Miller KE, Soong SJ. Vascular plasminogen activator levels and thromboembolic disease in patients with gynecologic malignancies. Am J Obstet Gynecol 1984; 149: 0830-0834
• 13 Prandoni P, Lensing AWA, Büller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, Ten CateJ. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. New Eng J Med 1992; 327: 1128-1133
• 14 Zacharski LR, Memoli VA, Ornstein DL, Rousseau SM, Kisiel W, Kudryk BJ. Tumor cell procoagulant and urokinase expression in carcinoma of the ovary. J Natl Cancer Inst 1993; 85: 1225-1230
• 15 Costantini V, Zacharski LR. Fibrin and cancer. Thromb Haemost 1993; 69: 0406-0414
• 16 Costantini V, Zacharski LR. The role of fibrin in tumor metastasis. Cancer and Metastasis Reviews 1992; 11: 0283-0290
• 17 Zacharski LR, Costantini V. Blood coagulation activation in cancer: Challenges for cancer treatment. Haemostaseology 1995; 15: 0014-0020
• 18 Chahinian P, Prupert KJ, Ware JH, Zimmer B, Perry MC, Hirsh V, Skarin A, Kopel S, Holland JF, Comis RL, Green MR. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group. Brit J Clin Oncol 1989; 07: 0993-1002
• 19 Kakkar AK, Hedges AR, Williamson RCN, Kakkar VV. Perioperative heparin therapy inhibits late death from metastatic cancer. Int J Oncol 1995; 06: 0885-0888
• 20 Lebeau B, Chastang CL, Brechot JM, Capron F, Dautzenberg B, Delaisement C, Mornet M, Brun J, Hurdebourcq J-P, Lemarie E. Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer 1994; 74: 0038-0045
• 21 Maurer HL, Herndon J, Aisner J, Perry M, Eaton W, Zacharski LR, Green M. A randomized trail of warfarin (W) plus combined modality chemotherapy (CT) and radiation therapy (RT) in limited disease (LD) small cell lung cancer (SCLC). Proc ASCO 1993; 12: 0335
• 22 Zacharski LR, Henderson WG, Rickies FR, Forman WB, Cornell CJ, Forcier RJ, Hedley E, Kim S-H, O’Donnell J-F, O’Dell R, Tornyos K, Kwaan HC. Effect of sodium Warfarin on survival in small carcinoma of the lung. JAMA 1981; 245: 0831-0835
• 23 Pettersson F. Annual report on the results of treatment in gynecological cancer-international Federation of Gynecology and Obstetrics 1994 Volume 22. Stockholm. Sweden: 1994
• 24 Wheeler HB, Anderson FA. Diagnostic methods for deep vein thrombosis. Haemostasis 1995; 25: 0006-0026
• 25 Pineo FP, Hull RD. Classical anticoagulant therapy for venous thromboembolism. Progress in Cariovascular Diseases 1994; 37: 0059-0070
• 26 Thomson JM. Blood collection and preparation pre-analytical varation. In: ECTAT Assay Procedures. Ed Jespersen I, Bertina II JRM. Kluwer Academic Publishers; Dordrecht/Boston/London: 1992: 0013-0020
• 27 Semeraro N, Montemurro P, Conese M, Giordano D, Stella M, Restaino A, Gagnazzo G, Colucci M. Procoagulant activity of mononuclear phagocytes from different anatomical sites in patients with gynecologic malignancies. Int J Cancer 1990; 45: 0251-0254
• 28 Rao VM. Tissue factor as a tumor procoagulant. Cancer and Metastasis Reviews 1992; 11: 0249-0266
• 29 Duffy MJ. The role of proteolytic encymes in cancer invasion and metastasis. Clin Exp Mestasis 1992; 10: 0145-0155
• 30 Casslén B, Bossmar T, Lecander I, Astedt B. Plasminogen activators and plasminogen activator inhibitors in blood and tumour fluids of patients with ovarian cancer. Eur J Cancer 1994; 30A: 1302-1309
• 31 Falanga A, Ofosu FA, Cortelazzo F, Delaini R, Consonni R, Longatti S, Maran D, Rodeghiero F, Pogliani E, Marassi A, D’Angelo A, Barbiu T. Preliminary study to identify cancer patients at high risk of venous thrombosis following major surgery. Brit J Haematol 1993; 85: 0730-0745
• 32 Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Harymink W, de PauerS. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. New Engl J Med 1988; 318: 0404-0407
• 33 Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer. J Clin Oncol 1991; 09: 0286-0294
• 34 Clahsen PC, Cornelis JH, van cerVelde, Julien JP, Floiras J-L, Mignolet FY. Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: A European Organization for Research and Treatment of Cancer Breast Cooperative Group Study. J Clin Oncol 1994; 12: 1266-1271
• 35 Tempelhoff vG-F, Dietrich M, Hommel G, Heilmann L. Blood Coagulation during adjuvant Epirubicin/Cyclophosphamide Chemotherapy in patients with primary operable Breast Cancer. J Clin Oncol 1996; 14: 2560-2568
• 36 Rogers JS, Murgo AJ, Fontana JA, Raich PC. Chemotherapy for breast cancer decreases plasma protein C and protein S. J Clin Oncol 1988; 06: 0276-0281
• 37 Doll DC, Ringenberg QS, Jarbro JW. Vascular toxicity associated with antineoplastic agents. Seminars in Oncology 1992; 19: 0580-0596
• 38 Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Steward D, Goodwin P. Double-blind randomised trial of very-low-dose Warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 1994; 343: 0886-0889
• 39 Honn KV, Tang DG, Crissmann JD. Platelets and cancer metastasis: A causal relationchip?. Cancer Met Rev 1992; 11: 0325-0351
• 40 Wojtukiewicz MZ, Tang DG, Ciarelli JJ, Nelson KK, Walz DA, Diglio CA, Mammen EF, Honn KV. Thrombin increases the metastatic potential of tumor cells. Int J Cancer 1993; 54: 0793-0806
• 41 Zacharski LR, Memoli VA, Morain WD, Schlaeppi JM, Rousseau SM. Cellular localization of enzymatically active thrombin in intact human tissues by hirudin binding. Thromb Haemost 1995; 73: 0793-0797