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PO-52 Heparins inhibit lung cancer cells proliferation in vitro
Abstracts / Thrombosis Research 120 Suppl. 2 (2007) S145–S178 FM determination followed by the use of F.XIII in high risk patients holds promises for patients. Further clinical studies are warranted. PO-50 Management practices of Connecticut physicians for treatment of cancer patients with venous thrombosis R. Dhami1 *, A. Bulgaru2 , K. Jagathambal2 , S.C. Johnson2 , D. Kapur2 , D.E. Slater2 , M.S. Dhami2 . 1 Stonehill College, Easton Massachussets and 2 Eastern Connecticut Hematology & Oncology, Norwich, Connecticut, USA The superiority of the efficacy and equivalence in safety of Low Molecular Weight Heparin (LMWH) over warfarin for treatment of cancer associated venous thromboembolism (VTE) is well established. CLOT investigators demonstrated a statistically significant reduction in risk of recurrent thromboembolism with dalteparin over warfarin at six months (9% versus 16%, respectively) without increasing the risk of bleeding. We surveyed the management practices of hematologists and oncologists in the state of Connecticut regarding their treatment of cancer patients with VTE. A brief questionnaire was mailed to all 265 current members of American Society of Hematology and/or American Society of Clinical Oncology practicing in Connecticut. Physicians were asked to report the percentage of cancer patients with VTE treated with warfarin versus LMWH. They were also queried regarding their awareness of results of the CLOT study. Additionally, we requested the reasons for not using LMWH. A list of potential barriers was provided and the responders were requested to select the most appropriate response(s). To date responses have been obtained from sixty-one physicians (23%). Paired Student’s t-tests were performed to analyze the data. The results for warfarin utilization demonstrated a mean of 72.3% (95% CI 64.61 79.9) with a standard deviation of 27.2. The results for LMWH utilization demonstrated a mean of 27.7% (95% CI 20.1 35.39) with a standard deviation of 27.2. Nearly all (94%) of physicians are aware of results of CLOT study. Barriers to use of LMWH included: patients’ reluctance with accepting daily injections (67%), problems with LMWH insurance reimbursement by third party payers (46%), and difficulty setting up home services (28%). Only two percent of physicians reported that they do not agree with the results of the CLOT study. We conclude that in this era of evidence based medicine, despite robust data regarding the superior efficacy of LMWH over warfarin, physicians in the United States continue to use warfarin for the treatment of the majority of cancer patients with VTE. This choice is based primarily on socioeconomic reasons and not due to the physician’s lack of awareness of the scientific evidence. PO-51 Thrombosis and central venous catheters in cancer patients A.M. Young *, S. Anderson, A. Ashton, G. Begum, D. Hunter, S. Wronski. WARP Collaborative Group, UK Background: Central venous catheters present a stress test to the coagulation system in cancer patients. Novel catheter types and materials are revolutionising patient care and are alleged to lessen thrombosis. As part of a prospective RCT to determine the utility of warfarin in thrombosis prophylaxis, we examined the catheterspecific risk factors for thrombosis. Methods: Patients with cancer receiving chemotherapy via CVCs, and randomised to no warfarin, warfarin 1mg and warfarin to maintain the INR between 1.5 and 2.0 were stratified according to site of catheter placement PICC (peripherally inserted central catheters) or centrally placed. Catheter types and complications of devices were collected in 1549 patients. All catheters were checked radiographically to be positioned correctly and were flushed as per manufacturer’s recommendations. The primary outcome measure was the number of radiologically proven CVC-related (CVCr),
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symptomatic thrombotic events (STEs). A multivariate analysis of catheter-specific thrombotic risk factors was performed. Results: Of the 1590 patients randomised from 68 UK centres, CVCr STEs were found to be 5.3% with warfarin demonstrating no apparent benefit over no warfarin (5.9% vs 5.9%, p = 0.98). 916 (58%) were PICC and 662 (42%) were centrally placed. No fully implantable catheters (port-o-caths) were utilised. 78% of catheters were single lumen, 92% were silicone, 40% were greater than 4 mm, 56% with non-return valve with 32% of catheters requiring heparin flushes. 21% of patients had catheter complications, 37% of whom had CVCr infection. Median time to thrombosis was 32 days; IQR 13 76 days. STEs: Patients with double lumen CVCs were more likely to suffer a primary thrombotic event than patients with single lumen (8% vs 5% respectively, p = 0.03). CVC insertion site, CVC type, CVC size (FF) and CVC material were found to be unrelated to the occurrence of primary thrombotic events. Of the 84 patients who had a CVCr thrombosis, only 8 (9%) also acquired CVCr infection. Conclusions: Overall, CVCr thrombosis rates are small in keeping with recently published evidence. Warfarin did not demonstrate any advantage in comparison to no warfarin. This large patient sample demonstrates that double lumen catheters are the only independent catheter-specific risk factor for thrombosis.
Poster session V: Anticancer effects of antithrombotics PO-52 Heparins inhibit lung cancer cells proliferation in vitro Y. Carmazzi1 , T. Neri1 , M. Iorio2 , R. Vanacore2 , A. Celi1 *. 1 Dipartimento Cardiotoracico e Vascolare, Universit` a di Pisa; 2 UO Immunoematologia II, Centro Trasfusionale, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy Introduction: Numerous clinical data suggest that heparin treatment improves survival in cancer patients.The mechanisms for this effect are not fully understood. Aim: To investigate whether heparin directly affects lung cancer cells growth. Materials and Methods: Two established lung cancer cell lines were used, A549 and Calu-6. Cells were cultured in the presence of various concentrations of unfractionated heparin, of two different preparations of low-molecular-weight heparin, i.e. nadroparin and enoxaparin, and of the synthetic pentasaccharide, fondaparinux. Cell proliferation was assessed by a standard MTT assay. In selected experiments, cell proliferation was also assessed by bromodeoxyuridine (BrdU) incorporation followed by flow cytometry. Apoptosis was assessed by flow cytometry using annexin V and propidium iodide binding, as well as by DNA fragmentation analysis followed by visualization on agarose gels. Results: All heparin preparations, as well as fondaparinux, induced a dose-dependent, significant decrease in cell proliferation in both cell lines. The effects were similar at comparable anti-Xa activities. The effect was not due to a pro-apoptotic mechanism, as neither DNA fragmentation nor annexin V binding were affected by incubation with heparins. When BrdU incorporation was analyzed, Nadroparin treatment induced a decrease of the number of cells in the S phase of the cell cycle, paralleled by an increase of the number of cells in an aneuploid state. Conclusions: Different heparin preparations, as well as fondaparinux, directly inhibit lung cancer cell proliferation. This observation contributes to the understanding of the basis for the beneficial effect of heparin treatment in cancer patients.
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symptomatic thrombotic events (STEs). A multivariate analysis of catheter-specific thrombotic risk factors was performed. Results: Of the 1590 patients randomised from 68 UK centres, CVCr STEs were found to be 5.3% with warfarin demonstrating no apparent benefit over no warfarin (5.9% vs 5.9%, p = 0.98). 916 (58%) were PICC and 662 (42%) were centrally placed. No fully implantable catheters (port-o-caths) were utilised. 78% of catheters were single lumen, 92% were silicone, 40% were greater than 4 mm, 56% with non-return valve with 32% of catheters requiring heparin flushes. 21% of patients had catheter complications, 37% of whom had CVCr infection. Median time to thrombosis was 32 days; IQR 13 76 days. STEs: Patients with double lumen CVCs were more likely to suffer a primary thrombotic event than patients with single lumen (8% vs 5% respectively, p = 0.03). CVC insertion site, CVC type, CVC size (FF) and CVC material were found to be unrelated to the occurrence of primary thrombotic events. Of the 84 patients who had a CVCr thrombosis, only 8 (9%) also acquired CVCr infection. Conclusions: Overall, CVCr thrombosis rates are small in keeping with recently published evidence. Warfarin did not demonstrate any advantage in comparison to no warfarin. This large patient sample demonstrates that double lumen catheters are the only independent catheter-specific risk factor for thrombosis.
Poster session V: Anticancer effects of antithrombotics PO-52 Heparins inhibit lung cancer cells proliferation in vitro Y. Carmazzi1 , T. Neri1 , M. Iorio2 , R. Vanacore2 , A. Celi1 *. 1 Dipartimento Cardiotoracico e Vascolare, Universit` a di Pisa; 2 UO Immunoematologia II, Centro Trasfusionale, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy Introduction: Numerous clinical data suggest that heparin treatment improves survival in cancer patients.The mechanisms for this effect are not fully understood. Aim: To investigate whether heparin directly affects lung cancer cells growth. Materials and Methods: Two established lung cancer cell lines were used, A549 and Calu-6. Cells were cultured in the presence of various concentrations of unfractionated heparin, of two different preparations of low-molecular-weight heparin, i.e. nadroparin and enoxaparin, and of the synthetic pentasaccharide, fondaparinux. Cell proliferation was assessed by a standard MTT assay. In selected experiments, cell proliferation was also assessed by bromodeoxyuridine (BrdU) incorporation followed by flow cytometry. Apoptosis was assessed by flow cytometry using annexin V and propidium iodide binding, as well as by DNA fragmentation analysis followed by visualization on agarose gels. Results: All heparin preparations, as well as fondaparinux, induced a dose-dependent, significant decrease in cell proliferation in both cell lines. The effects were similar at comparable anti-Xa activities. The effect was not due to a pro-apoptotic mechanism, as neither DNA fragmentation nor annexin V binding were affected by incubation with heparins. When BrdU incorporation was analyzed, Nadroparin treatment induced a decrease of the number of cells in the S phase of the cell cycle, paralleled by an increase of the number of cells in an aneuploid state. Conclusions: Different heparin preparations, as well as fondaparinux, directly inhibit lung cancer cell proliferation. This observation contributes to the understanding of the basis for the beneficial effect of heparin treatment in cancer patients.