Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin
Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE r...
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| Veröffentlicht in: | PloS one 2018-11, Vol.13 (11), p.e0207387-e0207387 |
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| creator | Gezelius, E Flou Kristensen, A Bendahl, P O Hisada, Y Risom Kristensen, S Ek, L Bergman, B Wallberg, M Falkmer, U Mackman, N Pedersen, S Belting, M |
| description | Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness. |
| doi_str_mv | 10.1371/journal.pone.0207387 |
| format | Article |
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The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0207387</identifier><identifier>PMID: 30412630</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Aged ; Anticoagulants ; Biochemistry ; Biology and Life Sciences ; Biomarkers ; Biomarkers, Tumor - blood ; Cancer ; Cancer and Oncology ; Cancer och onkologi ; Cancer therapies ; Cell adhesion & migration ; Cell survival ; Chemotherapy ; Clinical Medicine ; Clinical trials ; Coagulation ; Disease-Free Survival ; Extracellular Vesicles - metabolism ; Female ; Health risks ; Hematology ; Heparin ; Heparin, Low-Molecular-Weight - administration & dosage ; Humans ; Incidence ; Klinisk medicin ; Low molecular weights ; Lung cancer ; Lung diseases ; Lung Neoplasms - blood ; Lung Neoplasms - drug therapy ; Lung Neoplasms - mortality ; Male ; Medical and Health Sciences ; Medicin och hälsovetenskap ; Medicine ; Medicine and Health Sciences ; Metastasis ; Middle Aged ; Molecular weight ; Oncology ; Pathology ; Patients ; Phospholipids ; Phospholipids - blood ; Predictions ; Small cell lung carcinoma ; Small Cell Lung Carcinoma - blood ; Small Cell Lung Carcinoma - drug therapy ; Small Cell Lung Carcinoma - mortality ; Survival ; Survival Rate ; Thrombin ; Thromboembolism ; Thromboplastin - metabolism ; Thrombosis ; Tissue factor ; Venous Thromboembolism - blood ; Venous Thromboembolism - drug therapy ; Venous Thromboembolism - mortality</subject><ispartof>PloS one, 2018-11, Vol.13 (11), p.e0207387-e0207387</ispartof><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 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The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.</description><subject>Activation</subject><subject>Aged</subject><subject>Anticoagulants</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - blood</subject><subject>Cancer</subject><subject>Cancer and Oncology</subject><subject>Cancer och onkologi</subject><subject>Cancer therapies</subject><subject>Cell adhesion & migration</subject><subject>Cell survival</subject><subject>Chemotherapy</subject><subject>Clinical Medicine</subject><subject>Clinical trials</subject><subject>Coagulation</subject><subject>Disease-Free Survival</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Female</subject><subject>Health risks</subject><subject>Hematology</subject><subject>Heparin</subject><subject>Heparin, Low-Molecular-Weight - 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mortality</subject><subject>Survival</subject><subject>Survival Rate</subject><subject>Thrombin</subject><subject>Thromboembolism</subject><subject>Thromboplastin - metabolism</subject><subject>Thrombosis</subject><subject>Tissue factor</subject><subject>Venous Thromboembolism - blood</subject><subject>Venous Thromboembolism - drug therapy</subject><subject>Venous Thromboembolism - mortality</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNptks9u1DAQxiMEoqXwBggsceGyxX8SJ-GAVFUFKlUgQTlbE3u86-LEwU52VZ6LB8Tb3VYt4jC2ZX_z08z4K4qXjB4zUbN3V2GOA_jjMQx4TDmtRVM_Kg5ZK_hCcioe3zsfFM9SuqK0Eo2UT4sDQUvGpaCHxZ_TAMvZw-TCQDoXeog_MSYCgyFjROP0zUuwZI1DmBOZVjH0XcAc3qX-RpjmuHZr8MQNJPXgPdGYFz8PS6Jh0Bjfk5Os6hZpms31lvbt5Pvl2ReyyPcxI0LvfqMhU3SZsnHTiviwIX3wqHNxkWzQLVcTWeEI0Q3PiycWfMIX-_2o-PHx7PL08-Li66fz05OLha7aalpYUSG0WoMwFhprqsZYWUMpG8a6SnArK2FoXQPwtuXMVDxLylrLqtOaoRFHxesdd_Qhqf3Ak-JMsKptyqrMivOdwgS4UmN0eX7XKoBTNxchLhXEyWmPyuqSMURbU2ZKabHhUHYtGM65sUbYzLrYsdIGx7l7QPPzmKPLoRIqMLkbwaRqgVJVsqZRbWdqJXO3rTaG0nZb2od98XPXo9E4TBH8A-rDl8Gt1DKsleRcckYz4O0eEMOvGdOkepe2HwsDZidsx8B5SetWZumbf6T_H1a5U-kYUopo74phVG09fZultp5We0_ntFf3G7lLujWx-AtRQPla</recordid><startdate>20181109</startdate><enddate>20181109</enddate><creator>Gezelius, E</creator><creator>Flou Kristensen, A</creator><creator>Bendahl, P O</creator><creator>Hisada, Y</creator><creator>Risom Kristensen, S</creator><creator>Ek, L</creator><creator>Bergman, B</creator><creator>Wallberg, M</creator><creator>Falkmer, U</creator><creator>Mackman, N</creator><creator>Pedersen, S</creator><creator>Belting, M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AGCHP</scope><scope>AOWAS</scope><scope>D8T</scope><scope>D95</scope><scope>ZZAVC</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-9157-0524</orcidid><orcidid>https://orcid.org/0000-0001-6636-0293</orcidid><orcidid>https://orcid.org/0000-0002-9245-7678</orcidid><orcidid>https://orcid.org/0000-0003-1585-5434</orcidid></search><sort><creationdate>20181109</creationdate><title>Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin</title><author>Gezelius, E ; Flou Kristensen, A ; Bendahl, P O ; Hisada, Y ; Risom Kristensen, S ; Ek, L ; Bergman, B ; Wallberg, M ; Falkmer, U ; Mackman, N ; Pedersen, S ; Belting, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c595t-f35ea9cca3dfa8fd58df67a46811b532f653d077aa29921d52d5847c65bcc1ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Activation</topic><topic>Aged</topic><topic>Anticoagulants</topic><topic>Biochemistry</topic><topic>Biology and Life Sciences</topic><topic>Biomarkers</topic><topic>Biomarkers, Tumor - blood</topic><topic>Cancer</topic><topic>Cancer and Oncology</topic><topic>Cancer och onkologi</topic><topic>Cancer therapies</topic><topic>Cell adhesion & migration</topic><topic>Cell survival</topic><topic>Chemotherapy</topic><topic>Clinical Medicine</topic><topic>Clinical trials</topic><topic>Coagulation</topic><topic>Disease-Free Survival</topic><topic>Extracellular Vesicles - 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drug therapy</topic><topic>Small Cell Lung Carcinoma - mortality</topic><topic>Survival</topic><topic>Survival Rate</topic><topic>Thrombin</topic><topic>Thromboembolism</topic><topic>Thromboplastin - metabolism</topic><topic>Thrombosis</topic><topic>Tissue factor</topic><topic>Venous Thromboembolism - blood</topic><topic>Venous Thromboembolism - drug therapy</topic><topic>Venous Thromboembolism - mortality</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gezelius, E</creatorcontrib><creatorcontrib>Flou Kristensen, A</creatorcontrib><creatorcontrib>Bendahl, P O</creatorcontrib><creatorcontrib>Hisada, Y</creatorcontrib><creatorcontrib>Risom Kristensen, S</creatorcontrib><creatorcontrib>Ek, L</creatorcontrib><creatorcontrib>Bergman, B</creatorcontrib><creatorcontrib>Wallberg, M</creatorcontrib><creatorcontrib>Falkmer, U</creatorcontrib><creatorcontrib>Mackman, N</creatorcontrib><creatorcontrib>Pedersen, S</creatorcontrib><creatorcontrib>Belting, M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SWEPUB Lunds universitet full text</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Lunds universitet</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gezelius, E</au><au>Flou Kristensen, A</au><au>Bendahl, P O</au><au>Hisada, Y</au><au>Risom Kristensen, S</au><au>Ek, L</au><au>Bergman, B</au><au>Wallberg, M</au><au>Falkmer, U</au><au>Mackman, N</au><au>Pedersen, S</au><au>Belting, M</au><au>Karamanos, Nikos K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-11-09</date><risdate>2018</risdate><volume>13</volume><issue>11</issue><spage>e0207387</spage><epage>e0207387</epage><pages>e0207387-e0207387</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04-1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30412630</pmid><doi>10.1371/journal.pone.0207387</doi><orcidid>https://orcid.org/0000-0001-9157-0524</orcidid><orcidid>https://orcid.org/0000-0001-6636-0293</orcidid><orcidid>https://orcid.org/0000-0002-9245-7678</orcidid><orcidid>https://orcid.org/0000-0003-1585-5434</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2018-11, Vol.13 (11), p.e0207387-e0207387 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2131598454 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; SWEPUB Freely available online; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Aged Anticoagulants Biochemistry Biology and Life Sciences Biomarkers Biomarkers, Tumor - blood Cancer Cancer and Oncology Cancer och onkologi Cancer therapies Cell adhesion & migration Cell survival Chemotherapy Clinical Medicine Clinical trials Coagulation Disease-Free Survival Extracellular Vesicles - metabolism Female Health risks Hematology Heparin Heparin, Low-Molecular-Weight - administration & dosage Humans Incidence Klinisk medicin Low molecular weights Lung cancer Lung diseases Lung Neoplasms - blood Lung Neoplasms - drug therapy Lung Neoplasms - mortality Male Medical and Health Sciences Medicin och hälsovetenskap Medicine Medicine and Health Sciences Metastasis Middle Aged Molecular weight Oncology Pathology Patients Phospholipids Phospholipids - blood Predictions Small cell lung carcinoma Small Cell Lung Carcinoma - blood Small Cell Lung Carcinoma - drug therapy Small Cell Lung Carcinoma - mortality Survival Survival Rate Thrombin Thromboembolism Thromboplastin - metabolism Thrombosis Tissue factor Venous Thromboembolism - blood Venous Thromboembolism - drug therapy Venous Thromboembolism - mortality |
| title | Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin |
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