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PO-14 Diagnostic characteristics in patients with clinically suspected deep venous thrombosis with and without malignancy
Abstracts / Thrombosis Research 120 Suppl. 2 (2007) S145–S178 Results: MDA.MB.231 CM induced a significant increase in EC TF activity. This increase was dose-dependently inhibited by LMWH. In particular, a 75% and 97% mean inhibition was obtained with 1 IU/ml and 10 IU/ml dalteparin, respectively (p < 0.05 for both vs tumor CM alone). In addition, dalteparin dose-dependently increased the release of TFPI by EC exposed to tumor CM. In the same setting, dalteparin significantly (p < 0.05) inhibited the capillary tube formation induced by tumor CM, as well as by standard FGF-2, giving >70% inhibition at 1 IU/ml and >90% inhibition at 10 IU/ml LMWH concentration against both stimuli. Conclusion: Dalteparin simultaneously counteracts the prothrombotic features and the angiogenic response of microvascular endothelium stimulated by tumor cells. These results support the strict relationship between the coagulation system and the biology of tumor progression. Our in vitro model can be a valuable tool to further study and clarify the mechanisms underlying this asssociation. PO-13 Low-molecular weight heparin (LMWH) bemiparin and ultra-low-MWH RO-14 inhibit lung, breast and leukemia cancer cell-induced endothelial angiogenesis A. Vignoli *, M. Marchetti, E. Cantalino, L. Russo, D. Balducci, A. Falanga. Department of Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy Introduction: Besides their role as antithrombotics, heparins may have a beneficial effect on survival in cancer patients, with a major role of LMWHs over unfractionated heparin. Mechanisms by which LWMH might interfere with cancer biology are under investigation. Aim: In this study we evaluated the effects of LMWH Bemiparin (BMP) and of a novel type of heparin, i.e. the Ultra-LowMWH RO-14, on tumor cell-induced endothelial angiogenesis, compared to unfractionated heparin (UFH). Methods: Angiogenesis was evaluated by the in vitro capillary-like tube formation assay in Matrigel. Tumor cell conditioned medium (TCM) was obtained from the following human tumor cell lines: 1. small cell lung cancer cell line H69, 2. breast cancer cell line MDA.MB.231, 3. leukemia cell line NB4. Human microvascular endothelial cells (HMEC-1) were incubated in 96-well plates pre-coated with Matrigel with the different TCM, or purified proangiogenic factors (VEGF, bFGF), in the absence or presence of increasing concentrations (i.e. 0.01, 0.1, 1.0, and 10 IU/ml) of BMP, RO-14, UFH or vehicle (control). After 24 h incubation, tubule formation was examined under phasecontrast microscopy and tube length determined by an image analysis software. The content of the main pro-angiogenic factors (i.e. bFGF, VEGF, and IL-8) in TCM was quantified by ELISA. Results: TCM from all 3 tumor cell lines induced a significant (p < 0.05) increase in total tube length (23 69% mean increase) vs control growth medium. All TCM-induced tube formation was dose-dependently counteracted by BMP, RO-14 and UFH (82 100% mean inhibition at 10 IU/ml heparin). Similarly, BMP, RO-14 and UFH inhibited capillary formation induced by purified angiogenic factors (i.e. VEGF and bFGF), reaching 100% mean inhibition at the highest dose of heparin utilized. The evaluation of proangiogenic cytokine content in TCM show that all three cancer lines released bFGF and IL-8 in their medium. Differently, significant quantities of VEGF were found in the TCM from MDA.MB.231 breast cancer cells and NB4 leukemic cells, but not in the small cell lung cancer H69 cells. Conclusions: These data show that LMWH Bemiparin and the UltraLowMWH RO-14 can counteract the proangiogenic stimulus of tumor cells and of purified angiogenic factors on microvascular endothelium. Interestingly, the Ultra-low molecular weight heparin RO-14 presents an anti-angiogenic activity similar to that of LMWH. This study has been supported by Laboratorios Farmaceuticos Rovi S.A. (Madrid, Spain).
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Poster Session II: Thrombotic markers PO-14 Diagnostic characteristics in patients with clinically suspected deep venous thrombosis with and without malignancy G.L. van Sluis *, P.W. Kamphuisen, H.R. B¨ uller. Academic Medical Center, Amsterdam, The Netherlands Introduction: Clinical prediction of deep venous thrombosis (DVT) in patients with malignancy is difficult. We analyzed the positive predictive value of the modified clinical decision rule (CDR) according to Wells in patients with and without active malignancy. In addition, the clinical characteristics that potentially better predict DVT in patients with malignancy were investigated. Methods: Consecutive patients with a suspicion for DVT were included. CDR was used according to the modified Wells score, in which patients are categorised in DVT unlikely (<2) and likely (2). Compression ultrasounds were performed blinded to the diagnosis of malignancy. Multivariate logistic regression was performed to identify independent risk factors. Results: Of 826 patients with suspected DVT, in 224 (27%) the diagnosis was confirmed. Sixty-seven patients with malignancy (8%) significantly more often had a likely CDR (75% versus 37%). Patients with malignancy had a 2.6-fold (95% CI 1.6 4.3) increased prevalence of DVT compared to other patients. The positive predictive value of a likely CDR in both patients groups was 50%. Compared to patients without cancer, patients with malignancy had less often previous VTE, recent trauma or an alternative diagnosis. Strong family history of VTE ( two first degree relatives) (OR 12.9; 95% CI 1.02 163) and hospitalization (OR 4.9; 95% CI 1.3 17) were independent risk factors for DVT in patients with active malignancy. Conclusion: Patients with malignancy and clinically suspected DVT had twice as much a likely clinical decision rule compared to patients without cancer. The positive predictive value of this test is low and does not effectively discriminate which patients should be additionally tested. Clinical characteristics that are currently not included in the Wells score, such as strong family history for VTE and hospitalization might help to better predict DVT in patients with malignancy. PO-15 Should common inherited thrombophilic abnormalities be tested in cancer patients with central venous catheter? F. Dentali1 *, M. Gianni, G. Agnelli2 , W. Ageno1 . 1 Department of Clinical Medicine, University of Insubria, Varese; 2 Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy Background: Venous thromboembolism (VTE) is a common complication and one of the leading causes of death in patients with cancer. The risk of deep vein thrombosis (DVT) is further increased in cancer patients with central venous catheters (CVC). Factor V Leiden (FVL) and the G20210A prothrombin mutation (PTM) are the most common inherited thrombophilic abnormalities and these mutations may have a role in causing catheter-related DVT in patients with advanced cancer. However, information on the association between these inherited thrombophilic abnormalities and CVCrelated thrombosis are scarce and are only based on small studies. Purpose: To obtain the most reliable estimates of the prevalence of FVL and PTM in patients with CVC and to assess the risk of CVC-related thrombosis associated with these two inherited thrombophilic disorders. Data sources: The MEDLINE and EMBASE databases were searched up to March 2007; research was supplemented searching reference lists of retrieved articles and contacting content experts.
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Poster Session II: Thrombotic markers PO-14 Diagnostic characteristics in patients with clinically suspected deep venous thrombosis with and without malignancy G.L. van Sluis *, P.W. Kamphuisen, H.R. B¨ uller. Academic Medical Center, Amsterdam, The Netherlands Introduction: Clinical prediction of deep venous thrombosis (DVT) in patients with malignancy is difficult. We analyzed the positive predictive value of the modified clinical decision rule (CDR) according to Wells in patients with and without active malignancy. In addition, the clinical characteristics that potentially better predict DVT in patients with malignancy were investigated. Methods: Consecutive patients with a suspicion for DVT were included. CDR was used according to the modified Wells score, in which patients are categorised in DVT unlikely (<2) and likely (2). Compression ultrasounds were performed blinded to the diagnosis of malignancy. Multivariate logistic regression was performed to identify independent risk factors. Results: Of 826 patients with suspected DVT, in 224 (27%) the diagnosis was confirmed. Sixty-seven patients with malignancy (8%) significantly more often had a likely CDR (75% versus 37%). Patients with malignancy had a 2.6-fold (95% CI 1.6 4.3) increased prevalence of DVT compared to other patients. The positive predictive value of a likely CDR in both patients groups was 50%. Compared to patients without cancer, patients with malignancy had less often previous VTE, recent trauma or an alternative diagnosis. Strong family history of VTE ( two first degree relatives) (OR 12.9; 95% CI 1.02 163) and hospitalization (OR 4.9; 95% CI 1.3 17) were independent risk factors for DVT in patients with active malignancy. Conclusion: Patients with malignancy and clinically suspected DVT had twice as much a likely clinical decision rule compared to patients without cancer. The positive predictive value of this test is low and does not effectively discriminate which patients should be additionally tested. Clinical characteristics that are currently not included in the Wells score, such as strong family history for VTE and hospitalization might help to better predict DVT in patients with malignancy. PO-15 Should common inherited thrombophilic abnormalities be tested in cancer patients with central venous catheter? F. Dentali1 *, M. Gianni, G. Agnelli2 , W. Ageno1 . 1 Department of Clinical Medicine, University of Insubria, Varese; 2 Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy Background: Venous thromboembolism (VTE) is a common complication and one of the leading causes of death in patients with cancer. The risk of deep vein thrombosis (DVT) is further increased in cancer patients with central venous catheters (CVC). Factor V Leiden (FVL) and the G20210A prothrombin mutation (PTM) are the most common inherited thrombophilic abnormalities and these mutations may have a role in causing catheter-related DVT in patients with advanced cancer. However, information on the association between these inherited thrombophilic abnormalities and CVCrelated thrombosis are scarce and are only based on small studies. Purpose: To obtain the most reliable estimates of the prevalence of FVL and PTM in patients with CVC and to assess the risk of CVC-related thrombosis associated with these two inherited thrombophilic disorders. Data sources: The MEDLINE and EMBASE databases were searched up to March 2007; research was supplemented searching reference lists of retrieved articles and contacting content experts.