THE EFFECT OF VERY-LOW-DOSE WARFARIN ON MARKERS OF HYPERCOAGULATION IN METASTATIC BREAST-CANCER - RESULTS FROM A RANDOMIZED TRIAL

Malignancy is a risk factor for thromboembolism and anti-cancer chemot herapy can increase this risk. Prophylaxis of thrombosis with very-low -dose warfarin given concurrently with chemotherapy has a significantl y reduced rate of thromboembolism in a randomized trial in women with stage TV breast cancer. In a group of 32 patients randomized in one ce nter (16 subjects on warfarin and 16 on placebo), we have prospectivel y studied the plasma levels of: 1. Markers of 'in vivo' clotting activ ation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [ F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulant s (protein C [PC] and antithrombin [ATI). The aims of this study were: 1. to examine whether laboratory tests predict ed those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose w arfarin on hemostatic variables. The patients' hemostatic parameters w ere evaluated before entry into the study and after starting chemother apy +/- prophylaxis, before each course for nine courses. Before-treat ment results were compared to those of a sex and age-matched non-cance r 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), wherea s plasma PC and AT concentrations were not different from controls. Af ter starting chemotherapy, markers of clotting activation were progres sively lower in the group receiving warfarin prophylaxis compared to t he group on placebo. Differences between the groups became statistical ly significant (p < 0.01) after the 4th course of chemotherapy. Deep v ein thrombosis occurred in two patients in the placebo arm. The result s 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 co uld predict thrombosis in the single patient.