Chemotherapy-Induced Activation of Hemostasis: Dalteparin Suppresses Both Thrombin and Interleukin-6 Expression in Breast Cancer Patients Receiving Adjuvant Chemotherapy.

Thrombotic events are well documented in patients with cancer and have frequently been described in the setting of systemic chemotherapy. We have previously reported (Thromb Haemost2002; 88:213–220) that patients treated for breast and lung cancer demonstrate significant hemostatic activation, as documented by increases in thrombin-antithrombin (TAT) complexes and D-dimers, within 1 hour of receiving chemotherapy. The hemostatic effects appear to be cumulative with baseline pretreatment levels of TAT increasing with progressive cycles of chemotherapy. In the same study, we demonstrated that a single injection of dalteparin, a LMW heparin, administered prior to therapy could suppress hemostatic activation. We proposed that the progressive increases in basal thrombin generation resulted from chemotherapy-induced increases in inflammatory cytokines. We measured plasma levels of Il-6 in the 10 women with early stage breast cancer from this study who were receiving cyclophosphamide-doxorubicin adjuvant chemotherapy. Patients had plasma samples drawn prior to each cycle of chemotherapy, and at 1 hour, 24 and 48 hours after treatment. Prior to 2nd cycle of chemotherapy the patients received 2500 U dalteparin, prior to the 4th cycle of treatment, the patients received 5000 U dalteparin. No LMW heparin was given with the 1st and 3rd cycles. There were statistically significant increases in plasma TAT and D-dimers after chemotherapy in cycles 1 and 3. There was a significant increase in basal thrombin generation as measured over the four cycles of treatment unrelated to the presence of active cancer. Both pretreatment doses of dalteparin effectively prevented increases in markers of hemostatic activation after receiving chemotherapy. With each cyle of chemotherapy the 1 hour Il-6 levels were slightly lower than the pretreatment levels, but this was not statistically significant and could reflect a direct effect of the chemotherapeutic regimen on cytokine production. However, in cycle 1 and 3 the Il-6 levels increased to greater than pretreatment levels by 48 hours. There was a statistically significant increase in plasma Il-6 levels measured prior to the 4th cycle of chemotherapy when compared to the plasma Il-6 measured prior to the 1st cycle (4.976pg/ml± 1.620 vs 3.30 pg/ml±1.005 ; P<0.05). There was a trend for the pretreatment Il-6 levels measured prior to the 3rd cycle and 21 days after receiving 2500 U dalteparin to be lower than the levels measured prior to cycle 2, although not statistically significant (4.032±2.415 vs. 6.203±3.862; p=0.072). A 21 day sample was not obtained following the fourth cycle in which 5000U dalteparin was given and therefore the effect of this dose on basal thrombin generation and Il-6 expression could not be determined. We conclude; 1) the progressively increasing basal generation of thrombin associated with systemic chemotherapy in patients with breast cancer is associated with increases in the inflammatory cytokine, Il-6. 2) The increased expression of Il-6 and possibly other cytokines may be responsible for the progressive increases in hemostatic activation with repeated cycles of chemotherapy. In our study, there is a suggestion that a LMW heparin, dalteparin, not only prevented chemotherapy-induced hemostatic activation, but may also suppress chemotherapy-related cytokine expression. However, the optimal dose of dalteparin necessary for suppression of chemotherapy-induced cytokine expression is unknown and may vary with different malignancies and chemotherapy agents.