The Effect of Very-low-dose Warfarin on Markers of Hypercoagulation in Metastatic Breast Cancer: Results from a Randomized Trial

Summary

Malignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of ‘in vivo’ clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients’ hemostatic parameters were evaluated before entry into the study and after starting chemotherapy ± prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p <0.001), F1+2 (p <0.001), D-dimer (p <0.0001) and FVIIa (p <0.05), as well as an increase of FVII proteolysis (p <0.05), whereas plasma PC and AT concentrations were not different from controls. After starting chemotherapy, markers of clotting activation were progressively lower in the group receiving warfarin prophylaxis compared to the group on placebo. Differences between the groups became statistically significant (p <0.01) after the 4th course of chemotherapy. Deep vein thrombosis occurred in two patients in the placebo arm. The results of this study indicate that before therapy, an hypercoagulable state is present in stage IV breast cancer, and after starting chemotherapy, abnormalities of hypercoagulation markers persist, however they are reduced by very-low-dose-warfarin. None of the laboratory variables could predict thrombosis in the single patient.

• References

• 1 Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’ syndrome revisited.. Blood 1983; 62: 14-31.
• 2 Salzman EW, Hirsh J. Prevention of venous tromboembolism. Hemostasis and Thrombosis.. In: Basic principles and clinical pratice.. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. J. B. Lippincott Co; Philadelphia: 1987. p. 1252-65.
• 3 Rickles FR, Levine MN, Edwards RL. Haemostatic alterations in cancer patients.. Cancer Metast Rev 1992; 11: 237-48.
• 4 Falanga A, Barbui T, Rickles FR, Levine MN. Guidelines for clotting studies in cancer patients.. Thromb Haemost 1993; 70: 343-50.
• 5 Falanga A, Ofosu FA, Cortelazzo S, Delaini F, Consonni R, Caccia R, Longatti S, Maran D, Rodeghiero F, Pogliani E, Marassi A, D’Angelo A, Barbui T. Preliminary study to identify cancer patients at high risk of venous thrombosis following major surgery.. Br J Haematol 1993; 85: 745-50.
• 6 Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis in patients who received adjuvant therapy for breast cancer.. J Clin Oncol 1991; 9: 286-94.
• 7 Barbui T, Finazzi G, Donati MB, Falanga A. Antiblastic therapy and Thrombosis.. In: Thrombosis an Update.. Neri Serneri GG, Abbate R, Gensini G, Prisco D. eds. Scientific Press; Florence: 1992. p. 305-14.
• 8 Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MB, Hryniuk W, DePauw S. The thrombogenic effect of anticancer drug therapy in women with Stage II Breast Cancer.. N Engl J Med 1988; 318: 404-7.
• 9 Bartomeu MC, Gallo S, Lauri D, Levine MN, Orr FW, Buchanan MR. Chemotherapy enhances endothelial cell reactivity to platelets.. Clin Expl Metastasis 1990; 8: 511-8.
• 10 Rogers II JS, Murgo AJ, Fontane JA, Raich PC. Chemotherapy for breast cancer decreases plasma levels of Protein C and Protein S.. J Clin Oncol 1988; 6: 276-81.
• 11 Wheeler HR, Geczy CL. Induction of macrophage procoagulant expression by cisplatin, daunorubicin and doxorubicin.. Int J Cancer 1990; 46: 626-32.
• 12 Walsh J, Wheeler HR, Geczy CL. Modulation of tissue factor on human monocytes by cisplatin and adriamycin.. B J Haematol 1992; 81: 480-8.
• 13 Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Stewart D, Goodwin P. Double-blind randomized trial of very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer.. Lancet 1994; 343: 886-9.
• 14 Hirsh J. Oral anticoagulant drugs.. N Engl J Med 1991; 324: 1865-75.
• 15 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: Insights gained from studies using markers of haemostatic system activation.. Blood 1987; 70: 343-50.
• 16 Nemerson Y. Tissue factor and hemostasis.. Blood 1988; 71: 1-8.
• 17 Carson SD, Haire WD, Broze GJ, Novotny WF, Pirrucello SJ, Duggan MJ. Lipoprotein associated coagulation inhibitor, FVII, ATIII and monocyte tissue factor following surgery.. Thromb Haemost 1991; 66: 534-9.
• 18 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated Factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting FVII activation.. Blood 1993; 81: 734-44.
• 19 Ofosu FA, Leclerc J, Delorme F, Craven S, Shafai S, Frewin L, Blajchman MA. The low molecular weight heparin Enoxaparin inhibits the consumption of factor VII and prothrombin activation in vivo associated with elective knee replacement surgery.. Br J Haematol 1992; 82: 391-9.
• 20 Falanga A, Iacoviello L, Evangelista E, Belotti D, Consonni R, Robba L, Donati MB, Barbui T. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-Retinoic Acid.. Blood 1995; 86: 1072-81.
• 21 Feffer SE, Carmosino LS, Fox RL. Acquired protein C deficiency in patients with breast cancer receiving Cyclophosphamide, Metothrexate, and 5-Fluorouracil.. Cancer 1989; 63: 1303-7.
• 22 Millenson MN, Bauer KA, Kistler JP, Barzegar S, Tulin L, Rosenberg RD. Monitoring “mini-intensity” anticoagulation with warfarin: Comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels.. Blood 1992; 79: 2034-8.
• 23 Kistler JP, Singer DE, Millenson MM, Bauer KA, Gress DR, Barzegar S, Hughes RA, Sheehan MA, Maraventano SW, Oertel LB, Rosner B, Rosenberg RD. Effect of low-intensity warfarin anticoagulation on level of activity of the hemostatic system in patients with atrial fibrillation.. Stroke 1993; 24: 1360-5.
• 24 MacCallum PK, Thomson JM, Poller L. Effects of fixed minidose warfarin on coagulation and fibrinolysis following major gynaecological surgery.. Thromb Haemost 1990; 64: 511-5.