Prevention of catheter-related venous thrombosis with nadroparin in patients receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled study.

BACKGROUND: Hemato-oncology patients treated with intensive chemotherapy usually require the placement of a central venous catheter (CVC). CVCs are frequently complicated by catheter-related central venous thrombosis (CVT), which has been associated with an increased risk of pulmonary embolism and catheter-related infection. OBJECTIVES: To determine the efficacy and safety of thromboprophylaxis with s.c. low-molecular-weight heparin (nadroparin) administered once daily in a randomized placebo-controlled, double-blind trial in patients with hematologic malignancies. PATIENTS AND METHODS: Consecutive patients with hematologic malignancies requiring intensive chemotherapy including autologous stem cell transplantation were eligible. The patients were randomized to receive nadroparin 2850 antifactor Xa units once daily or placebo s.c. for 3 weeks. Venography was performed on day 21 after CVC insertion. Secondary outcomes were bleeding and catheter-related infection. RESULTS: In total, 113 patients were randomized to nadroparin or placebo, and 87 patients (77%) underwent venography. In total, 11 venographically proven catheter-related CVTs were diagnosed. The frequency of catheter-related CVT was not significantly different between study groups, namely four catheter-related CVTs in the placebo group [9%; 95% CI: 0.002-0.16] vs. seven catheter-related CVTs in the nadroparin group (17%; 95% CI: 0.06-0.28). In addition, no difference in the incidence of catheter-related infection or bleeding was observed between the groups. CONCLUSION: This study showed that the actual risk for catheter-related CVT in patients with hematologic malignancies is lower than suggested in earlier studies in cancer patients. Although prophylactic administration of nadroparin appeared to be safe in this group of patients with a high risk of bleeding, it cannot be recommended for the prevention of catheter-related CVT or catheter-related infection in patients with hematologic malignancies.

Colon cancer metastasis in mouse liver is not affected by hypercoagulability due to Factor V Leiden mutation.

Clinical trials have shown life-prolonging effects of antithrombotics in cancer patients, but the molecular mechanisms remain unknown due to the multitude of their effects. We investigated in a mouse model whether one of the targets of antithrombotic therapy, fibrin deposition, stimulates tumour development. Fibrin may provide either protection of cancer cells in the circulation against mechanical stress and the immune system, or form a matrix for tumours and/or angiogenesis in tumours to develop. Mice homozygous for Factor V Leiden (FVL), a mutation in one of the coagulation factors that facilitates fibrin formation, were used to investigate whether hypercoagulability affects tumour development in an experimental metastasis model. Liver metastases of colon cancer were induced in mice with the FVL mutation and wild-type littermates. At day 21, number and size of tumours at the liver surface, fibrin/fibrinogen distribution, vessel density and the presence of newly formed vessels in tumours were analysed. Number and size of tumours did not differ between mice with and without the FVL mutation. Fibrin/fibrinogen was found in the cytoplasm of hepatocytes and cancer cells, in blood vessels in liver and tumour tissue and diffusely distributed outside vessels in tumours, indicating leaky vessels. Vessel density and angiogenesis varied widely between tumours, but a pre-dominance for vessel-rich or vessel-poor tumours or vessel formation could not be found in either genotype. In conclusion, the FVL mutation has no effect on the development of secondary tumours of colon cancer in livers of mice. Fibrin deposition and thus inhibition of fibrin formation by anticoagulants do not seem to affect tumour development in this model.

Mechanisms of heparin induced anti-cancer activity in experimental cancer models.

BACKGROUND: Retrospective analyses of clinical trials and prospective clinical studies have suggested that heparins may have an effect on cancer survival. This putative anti-cancer activity of heparins is supported by data from studies in animal tumour models. OBJECTIVE: To clarify the various potential mechanisms of heparin anti-cancer activity we evaluated the data from pre-clinical studies in which heparins have been tested as anti-cancer therapy. METHODS: Pre-clinical studies, published between 1960 and 2005 were assessed. Data were collected on the type and dose of heparin used, duration of exposure to heparin, interval between heparin administration and cancer cell inoculation, and the animal tumour model used. In addition, a distinction was made in the analysis between heparin effects on the primary tumour or on established metastases and effects on the metastatic potential of infused cells. RESULTS: Heparins seemed to affect the formation of metastasis rather than the growth of primary tumours. Chemically modified heparins with no or limited anticoagulant activity also showed anti-metastatic properties. Possible mechanisms to explain the effects on the process of metastases include inhibition of blood coagulation, inhibition of cancer cell-platelet and -endothelial interactions by selectin inhibition and inhibition of cell invasion and angiogenesis. CONCLUSION: The anti-cancer activity of heparins depends more on inhibition of metastasis formation than on the effects on primary tumour growth. These effects are probably related to both coagulation and non-coagulation dependent factors. For a definitive proof of the anti-cancer activity of heparins in the clinic, prospective randomized trials especially in patients with early metastatic disease or in the adjuvant setting are urgently needed.