|
1
|
Xu DG, Tan J. Interplay of genetic and clinical factors in cancer-associated thrombosis: Deciphering the prothrombotic landscape of colorectal cancer. World J Gastroenterol 2025; 31:103901. [PMID: 40248375 PMCID: PMC12001197 DOI: 10.3748/wjg.v31.i14.103901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/03/2025] [Accepted: 03/25/2025] [Indexed: 04/11/2025] Open
Abstract
Colorectal cancer (CRC), the third most prevalent cancer globally, exhibits a notable association with venous thromboembolism (VTE), significantly impacting patient morbidity and mortality. We delve into the complex pathogenesis of cancer-associated thrombosis (CAT) in CRC, highlighting the interplay of clinical risk factors and tumor-specific mechanisms. Our comprehensive review synthesizes the current understanding of CRC's pro-thrombotic tendencies, examining both general clinical factors (e.g., age, gender, obesity, prior VTE history) and tumor-specific aspects (e.g., tumor location, stage, targeted therapies). Key findings illustrate how CRC cells themselves actively contribute to coagulation cascade activation through various procoagulant elements such as tissue factor, cancer procoagulant, and extracellular vesicles. We also explore how CRC influences host cells to adopt a procoagulant phenotype, thereby exacerbating thrombotic risks. This review underscores the role of genetic mutations in CRC (e.g., KRAS, p53) in modulating coagulation-related protein expression and thrombosis risks. An in-depth understanding of the genetic landscape specific to CRC subtypes is essential for developing targeted anticoagulation strategies and could significantly advance thrombosis prevention while improving the overall management of patients with CRC. This highlights the urgent need for precision in addressing CAT within clinical settings.
Collapse
Affiliation(s)
- Duo-Gang Xu
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, China
| | - Jing Tan
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, China
| |
Collapse
|
|
2
|
Zuin M, Nohria A, Henkin S, Krishnathasan D, Sato A, Piazza G. Pulmonary Embolism-Related Mortality in Patients With Cancer. JAMA Netw Open 2025; 8:e2460315. [PMID: 39964681 PMCID: PMC11836760 DOI: 10.1001/jamanetworkopen.2024.60315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 12/13/2024] [Indexed: 02/21/2025] Open
Abstract
Importance Acute pulmonary embolism (PE) is a major cause of morbidity and mortality in patients with cancer in the US and worldwide. Objectives To assess the trends in PE-related mortality from 2011 to 2020 among US patients with cancer across age, sex, ethnic and racial groups, urbanicity, and regionality. Design, Setting, and Participants This cohort study used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system to determine national trends in age-adjusted mortality rates (AAMRs) due to acute PE among US patients with cancer aged 15 years or older from January 2011 to December 2020. Concomitant trends in cancer mortality and incidence that may have contributed to PE-related mortality were obtained from US Cancer Statistics. Data were analyzed from September to November 2024. Exposure PE-related mortality. Main Outcomes and Measures The primary outcome was PE-related deaths among individuals with cancer. AAMRs and cancer incidence were assessed using joinpoint regression modeling, expressed as an average annual percentage change (AAPC) with relative 95% CIs. Results From 2011 to 2020, a total of 27 280 194 individuals aged 15 years or older (13 897 519 male [50.9%]; 13 382 675 female [49.1%]) died in the US. The AAMR for PE-related mortality in patients with cancer increased during this time period (AAPC, 2.5%; 95% CI, 1.4% to 3.6%; P = .001), without differences between sexes (P for parallelism = .38). The AAMR increased among those aged 15 to 64 years (AAPC, 3.2%; 95% CI, 1.9% to 4.6%; P = .001), non-Hispanic and non-Latinx White individuals (AAPC, 2.7%; 95% CI, 1.52% to 3.94%; P = .001), non-Hispanic and non-Latinx Black or African American individuals (AAPC, 2.2%; 95% CI, 0.7% to 3.7%; P = .001), Hispanic and Latinx individuals (AAPC, 2.6%; 95% CI, 0.7% to 4.5%; P = .006), and among individuals residing in the Southern US (AAPC, 3.7%; 95% CI, 1.3% to 6.2%; P = .003). During the same period, age-adjusted cancer incidence and cancer-related mortality decreased while the absolute number of new cancer diagnoses and cancer-related deaths increased. Conclusions and Relevance This cohort study found that despite decreases in cancer-related mortality rates, age-adjusted PE-related mortality in US patients with cancer increased over the last decade; concerning trends included rising PE-related mortality in younger individuals aged 15 to 64 years, particular ethnic and racial groups, and the Southern region of the US. Recognition of such patterns may inform further research into thromboprophylaxis and treatment of PE as a complication of cancer and cancer-directed therapy.
Collapse
Affiliation(s)
- Marco Zuin
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Department of Cardio-Thoraco-Vascular Sciences and Public Health, University of Padova, Padua, Italy
| | - Anju Nohria
- Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
| | | | - Darsiya Krishnathasan
- Thrombosis Research Group, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Alyssa Sato
- Thrombosis Research Group, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Gregory Piazza
- Thrombosis Research Group, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
- Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| |
Collapse
|
|
3
|
Pestana RM, Duarte RC, Alves MT, de Oliveira AN, Oliveira HH, Soares CE, de P. Sabino A, Silva LM, das Graças Carvalho M, Simões R, Gomes KB. Hemostatic status in women with breast cancer and cardiotoxicity associated to doxorubicin-based chemotherapy – A one-year follow-up study. Thromb Res 2022; 211:56-59. [DOI: 10.1016/j.thromres.2022.01.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/23/2021] [Accepted: 01/10/2022] [Indexed: 11/15/2022]
|
|
4
|
Fioretti AM, Leopizzi T, Puzzovivo A, Giotta F, Lorusso V, Luzzi G, Oliva S. Cancer-Associated Thrombosis: Not All Low-Molecular-Weight Heparins Are the Same, Focus on Tinzaparin, A Narrative Review. Int J Clin Pract 2022; 2022:2582923. [PMID: 35936060 PMCID: PMC9325617 DOI: 10.1155/2022/2582923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/13/2022] [Accepted: 05/25/2022] [Indexed: 12/21/2022] Open
Abstract
Cancer-associated thrombosis (CAT) is the second main cause of cancer death with high related mortality and morbidity, leading to anticancer agent delays and interruptions. The recommended therapy, low-molecular-weight heparin (LMWH), however, is burdensome for patients and costly for society, as treatment should last until cancer is no longer active, even indefinitely. Tinzaparin is a manageable, efficient, safe, and cost-effective option. Compared to the other LMWHs, advantages are single-daily dose and safety in the elderly and those with renal impairment (RI). The purpose of this review is to critically discuss recent data on its efficacy and safety in CAT.
Collapse
Affiliation(s)
- Agnese Maria Fioretti
- Cardio-Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Tiziana Leopizzi
- Cardiology-Intensive Care Unit, Ospedale SS. Annunziata, Via Francesco Bruno 1, 74121 Taranto, Italy
| | - Agata Puzzovivo
- Cardio-Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Francesco Giotta
- Medical Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Vito Lorusso
- Medical Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Giovanni Luzzi
- Cardiology-Intensive Care Unit, Ospedale SS. Annunziata, Via Francesco Bruno 1, 74121 Taranto, Italy
| | - Stefano Oliva
- Cardio-Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| |
Collapse
|
|
5
|
Athanazio RA, Ceresetto JM, Marfil Rivera LJ, Cesarman-Maus G, Galvez K, Marques MA, Tabares AH, Ortiz Santacruz CA, Santini FC, Corrales L, Cohen AT. Direct Oral Anticoagulants for the Treatment of Cancer-Associated Venous Thromboembolism: A Latin American Perspective. Clin Appl Thromb Hemost 2022; 28:10760296221082988. [PMID: 35261295 PMCID: PMC8918974 DOI: 10.1177/10760296221082988] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. On the basis of results from randomized controlled trials, direct oral anticoagulants (DOACs) are now recommended for the treatment of cancer-associated VTE. The decision to use a DOAC requires consideration of bleeding risk, particularly in patients with gastrointestinal (GI) malignancies, the cost-benefit and convenience of oral therapy, and patient preference. While efficacy with apixaban, edoxaban, and rivaroxaban versus dalteparin has been consistent in the treatment of cancer-associated VTE, heterogeneity is evident with respect to major GI bleeding, with an increased risk with edoxaban and rivaroxaban but not apixaban. Although cost and accessibility vary in different countries of Latin America, DOACs should be considered for the long-term treatment of cancer-associated VTE in all patients who are likely to benefit. Apixaban may be the preferred DOAC in patients with GI malignancies and LMWH may be preferred for patients with upper or unresected lower GI tumors. Vitamin K antagonists should only be used for anticoagulation when DOACs and low molecular weight heparin are inaccessible or unsuitable.
Collapse
Affiliation(s)
- Rodrigo Abensur Athanazio
- Pulmonary Division-Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina de São Paulo, São Paulo, Brazil
- Rodrigo Abensur Athanazio, Pulmonary Division-Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina de São Paulo,
Av. Dr. Enéas de Carvalho Aguiar, 44 - 5 andar (pneumologia), 05403-900 - São Paulo/SP – Brazil.
| | | | - Luis Javier Marfil Rivera
- Servicio de Hematología, Hospital Universitario “Dr José E González”, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | | | - Kenny Galvez
- Cancer Unit, Hospital Pablo Tobón Uribe, Medellín, Colombia
| | - Marcos Arêas Marques
- Unit of Angiology, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Aldo Hugo Tabares
- Vascular Medicine and Thrombosis Service, Instituto Universitario de Ciencias Biomedicas de Córdoba (IUCBC), Córdoba, Argentina
| | | | | | - Luis Corrales
- Medical Oncology, Centro de Investigación y Manejo del Cáncer (CIMCA), San José, Costa Rica
| | - Alexander T. Cohen
- Department of Haematological Medicine, Guy's and St Thomas' Hospitals NHS Foundation Trust, King's College London, UK
| |
Collapse
|
|
6
|
Falanga A, Marchetti M, Russo L. Hemostatic Biomarkers and Cancer Prognosis: Where Do We Stand? Semin Thromb Hemost 2021; 47:962-971. [PMID: 34450680 DOI: 10.1055/s-0041-1733925] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cancer patients are characterized by hypercoagulable state and an increased rate of thrombotic events, the most common being venous thromboembolism. Several hemostatic pathways that are significantly implicated in mechanisms of thromboembolic disease are also involved in growth, invasion, and metastatic spread of malignant cells as well in tumor-induced neo-angiogenesis. This close connection between cancer and the hemostatic system has prompted numerous studies on the role of alterations in the level plasma biomarkers of the different compartments of hemostasis in predicting cancer prognosis. In this review, we collect the results of several exemplificative studies that have evaluated clotting activation biomarkers in relation to different cancer outcomes with a final emphasis on current research and forthcoming directions in this field.
Collapse
Affiliation(s)
- Anna Falanga
- Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy.,Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
| | - Marina Marchetti
- Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - Laura Russo
- Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
| |
Collapse
|
|
7
|
Izuegbuna OO, Agodirin OS, Olawumi HO, Olatoke SA. Plasma D-Dimer and Fibrinogen Levels Correlates with Tumor Size and Disease Progression in Nigerian Breast Cancer Patients. Cancer Invest 2021; 39:597-606. [PMID: 33843402 DOI: 10.1080/07357907.2021.1909059] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Fourty-five breast cancer patients and 50 apparently healthy sex-matched controls from the University of Ilorin Teaching Hospital were enrolled in this study. Plasma D-dimer and fibrinogen were found to be significantly higher than controls; APTT was significantly shorter than the controls. D-dimer and fibrinogen were also significantly positively correlated with ECOG, disease stage, lymph node involvement, and tumor size. On multivariate analysis, D-dimer and fibrinogen were found to be independently related to lymph node involvement. This study shows that plasma D-dimer and fibrinogen levels are elevated in breast cancer patients, and both are markers of disease progression.
Collapse
Affiliation(s)
- Ogochukwu O Izuegbuna
- Department of Haematology and Blood Transfusion, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Olayide S Agodirin
- Department of Surgery, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Hannah O Olawumi
- Department of Haematology and Blood Transfusion, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Samuel A Olatoke
- Department of Surgery, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| |
Collapse
|
|
8
|
Clinical characteristics, management, and outcome of incidental pulmonary embolism in cancer patients. Blood Adv 2021; 4:1606-1614. [PMID: 32311012 DOI: 10.1182/bloodadvances.2020001501] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/12/2020] [Indexed: 12/17/2022] Open
Abstract
Incidental pulmonary embolisms (IPEs) are common in cancer patients. Examining the characteristics and outcomes of IPEs in cancer patients can help to ensure proper management, promoting better outcomes. To determine the clinical characteristics, management, and outcomes of IPEs for cancer patients, we conducted a 1:2 ratio case-control study and identified all consecutive patients with IPE who visited the emergency department at The University of Texas MD Anderson Cancer Center between 1 January 2006 and 1 January 2016. Each IPE case was matched with 2 controls using a propensity score obtained using logistic regression for IPE status with other factors affecting overall survival. A total of 904 confirmed cases were included in the analysis. IPE frequently occurred during the first year after cancer diagnosis (odds ratio [OR], 2.79; 95% confidence interval [95% CI], 2.37-3.29; P < .001). Patients receiving cytotoxic chemotherapy had a nearly threefold greater risk of developing IPE (OR, 2.87; 95% CI, 2.42-3.40; P < .001). In-hospital mortality was 1.9%. The 7- and 30-day mortality rates among the cases were 1.8% and 9.9%, respectively, which was significantly higher than in the control groups: 0.2% and 3.1%, respectively (P < .001). IPE was associated with reduced overall survival (hazard ratio [HR], 1.93; 95% CI, 1.74-2.14; P < .001). Concurrent incidental venous thromboembolism was identified in 189 of the patients (20.9%) and was also associated with reduced overall survival (HR, 1.65; 95% CI, 1.21-2.25; P = .001). Our results show that IPE events are associated with poor outcomes in cancer patients. Proper management plans similar to those of symptomatic pulmonary embolisms are essential.
Collapse
|
|
9
|
Thromboembolism in Malignant Musculoskeletal Tumour: A Literature Review. Adv Orthop 2021; 2021:6678167. [PMID: 33688439 PMCID: PMC7910073 DOI: 10.1155/2021/6678167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/22/2021] [Accepted: 02/09/2021] [Indexed: 12/03/2022] Open
Abstract
Malignant musculoskeletal tumour may cause considerable burden to general health. The fast growth combined with the tumour characteristics and its invasion capability resulted in the poor prognosis of malignant musculoskeletal tumour. Malignant musculoskeletal tumour may cause significant disability by destroying normal tissue that plays important role in body kinematics. Thromboembolism, including deep vein thrombosis, pulmonary embolism, and other kinds of venous thromboembolism, is one of the most underestimated complications of musculoskeletal tumour. Normally, thrombosis ensues when pathologic factors overcame the body hemostatic regulatory capabilities, which will predispose the body to the formation of thrombus. Venous thromboembolism in musculoskeletal tumour may develop as a result of interaction between the tumour pathologic capabilities and its interaction with normal bodily functions. In this study, we reviewed the burden of musculoskeletal tumour and its complication on global health. Then, the review will focus on the pathologic and clinical aspect of thromboembolism in malignant musculoskeletal tumour, including pathophysiology, diagnosis, and treatment based on recent findings and literature.
Collapse
|
|
10
|
SARS-CoV-2 and cancer: Are they really partners in crime? Cancer Treat Rev 2020; 89:102068. [PMID: 32731090 PMCID: PMC7351667 DOI: 10.1016/j.ctrv.2020.102068] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/29/2020] [Accepted: 07/01/2020] [Indexed: 12/15/2022]
Abstract
The outbreak of the SARS-CoV-2 pandemic has overwhelmed health care systems in many countries. The clinical presentation of the SARS-CoV-2 varies between a subclinical or flu-like syndrome to that of severe pneumonia with multi-organ failure and death. Initial reports have suggested that cancer patients may have a higher susceptibility to get infected by the SARS-CoV-2 virus but current evidence remains poor as it is biased by important confounders. Patients with ongoing or recent cancer treatment for advanced active disease, metastatic solid tumors and hematological malignancies are at higher risk of developing severe COVID-19 respiratory disease that requires hospitalization and have a poorer disease outcome compared to individuals without cancer. However it is not clear whether these are independent risk factors, or mainly driven by male gender, age, obesity, performance status, uncontrolled diabetes, cardiovascular disease and various other medical conditions. These often have a greater influence on the probability to die due to SARS-CoV-2 then cancer. Delayed diagnosis and suboptimal cancer management due to the pandemic results in disease upstaging and has considerable impact cancer on specific death rates. Surgery during the peak of the pandemic seems to increase mortality, but there is no convincing evidence that adjuvant systemic cancer therapy and radiotherapy are contraindicated, implicating that cancer treatment can be provided safely after individual risk/benefit assessment and some adaptive measures. Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status may fuel the effects of a SARS-CoV-2 in some cancer patients, but have the potential to be used as biomarkers for severe disease and therapeutic targets. The rapidly expanding literature on COVID-19 should be interpreted with care as it is often hampered by methodological and statistical flaws.
Collapse
|
|
11
|
Tavares V, Pinto R, Assis J, Pereira D, Medeiros R. Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: Linkage to ovarian tumour behaviour. Biochim Biophys Acta Rev Cancer 2020; 1873:188331. [DOI: 10.1016/j.bbcan.2019.188331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/01/2019] [Accepted: 11/01/2019] [Indexed: 12/14/2022]
|
|
12
|
Mir Seyed Nazari P, Marosi C, Moik F, Riedl J, Özer Ö, Berghoff AS, Preusser M, Hainfellner JA, Pabinger I, Zlabinger GJ, Ay C. Low Systemic Levels of Chemokine C-C Motif Ligand 3 (CCL3) are Associated with a High Risk of Venous Thromboembolism in Patients with Glioma. Cancers (Basel) 2019; 11:cancers11122020. [PMID: 31847343 PMCID: PMC6966639 DOI: 10.3390/cancers11122020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/05/2019] [Accepted: 12/10/2019] [Indexed: 12/16/2022] Open
Abstract
A tight interplay between inflammation and hemostasis has been described as a potential driver for developing venous thromboembolism (VTE). Here, we investigated the association of systemic cytokine levels and risk of VTE in patients with glioma. This analysis was conducted within the prospective, observational Vienna Cancer and Thrombosis Study. Patients with glioma were included at time of diagnosis or progression and were observed for a maximum of two years. Primary endpoint was objectively confirmed VTE. At study entry, a single blood draw was performed. A panel of nine cytokines was measured in serum samples with the xMAP technology developed by Luminex. Results: Overall, 76 glioma patients were included in this analysis, and 10 (13.2%) of them developed VTE during the follow-up. Chemokine C-C motif ligand 3 (CCL3) levels were inversely associated with risk of VTE (hazard ratio [HR] per double increase, 95% confidence interval [CI]: 0.385, 95% CI: 0.161–0.925, p = 0.033), while there was no association between the risk of VTE and serum levels of interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-11, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF), respectively. In conclusion, low serum levels of CCL3 were associated with an increased risk of VTE. CCL3 might serve as a potential biomarker to predict VTE risk in patients with glioma.
Collapse
Affiliation(s)
- Pegah Mir Seyed Nazari
- Division of Hematology and Hemostaseology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (P.M.S.N.); (F.M.); (J.R.); (Ö.Ö.); (I.P.)
| | - Christine Marosi
- Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (C.M.); (A.S.B.); (M.P.)
| | - Florian Moik
- Division of Hematology and Hemostaseology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (P.M.S.N.); (F.M.); (J.R.); (Ö.Ö.); (I.P.)
| | - Julia Riedl
- Division of Hematology and Hemostaseology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (P.M.S.N.); (F.M.); (J.R.); (Ö.Ö.); (I.P.)
| | - Öykü Özer
- Division of Hematology and Hemostaseology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (P.M.S.N.); (F.M.); (J.R.); (Ö.Ö.); (I.P.)
| | - Anna Sophie Berghoff
- Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (C.M.); (A.S.B.); (M.P.)
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (C.M.); (A.S.B.); (M.P.)
| | - Johannes A. Hainfellner
- Institute of Neurology and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria;
| | - Ingrid Pabinger
- Division of Hematology and Hemostaseology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (P.M.S.N.); (F.M.); (J.R.); (Ö.Ö.); (I.P.)
| | - Gerhard J. Zlabinger
- Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Cihan Ay
- Division of Hematology and Hemostaseology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria; (P.M.S.N.); (F.M.); (J.R.); (Ö.Ö.); (I.P.)
- I.M. Sechenov First Moscow State Medical University (Sechenov University), 119146 Moscow, Russia
- Correspondence:
| |
Collapse
|
|
13
|
AmraneDjedidi R, Rousseau A, Larsen AK, Elalamy I, Van Dreden P, Gerotziafas GT. Extracellular vesicles derived from pancreatic cancer cells BXPC3 or breast cancer cells MCF7 induce a permanent procoagulant shift to endothelial cells. Thromb Res 2019; 187:170-179. [PMID: 32006891 DOI: 10.1016/j.thromres.2019.09.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 08/19/2019] [Accepted: 09/03/2019] [Indexed: 01/28/2023]
Abstract
The endothelium could be a potential target of cancer cell derived extracellular vesicles (CaCe-dEV). We investigated in vitro the effect of CaCe-dEV on the hemostatic balance of endothelial cells. Extracellular vesicles released from pancreas adenocarcinoma cells (BXPC3) or human breast cancer cells (MCF7) were isolated by differential centrifugation. Human umbilical vein endothelial cells (HUVEC) were cultured for 72 h in the presence or absence of CaCe-dEV. Subsequently, they were washed and re-cultivated over three cycles to get daughter cell generations (DG) which were not exposed to CaCe-dEV. Thrombin generation of normal platelet poor plasma (PPP) added in wells carrying HUVEC was assessed by the Calibrated Automated Thrombogram®. Tissue factor activity (TFa) and procoagulant phospholipid clotting time were assessed. Some traces of TFa were displayed by non-exposed HUVEC (0.18 ± 0.03 pM) and their EVs (1.2 ± 1.0 pM). Non-exposed HUVEC did not induce any detectable thrombin generation. BXPC3-dEV displayed significantly higher TFa as compared to MCF7-dEV (45 ± 5 pM versus 4.6 ± 2.3pM respectively; p < 0.05). HUVEC exposed to CaCe-dEV enhanced thrombin generation. BXPC3-dEV induced significantly higher thrombin generation as compared to those exposed to MCF7-dEV. The procoagulant properties of HUVEC, acquired upon exposure to CaCe-dEV were transferred to DG. In conclusion, CaCe-dEV lead to a procoagulant shift of endothelial cells which, upon exposure, display TFa and enhance thrombin generation which is transferred to DG of HUVEC. The potency of CaCe-dEV to induce procoagulant shift of HUVEC depends on the histological type of the cancer cells. The procoagulant shift of endothelial cells which is transferable to DG could be an additional mechanism - together with cancer-induced blood hypercoagulability - in the pathogenesis of cancer associated thrombosis.
Collapse
Affiliation(s)
- Rania AmraneDjedidi
- Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Faculty of Medicine, Sorbonne University, Paris, France
| | - Aurélie Rousseau
- Clinical Research Department, Diagnostica Stago, Gennevilliers, France
| | - Annette K Larsen
- Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Faculty of Medicine, Sorbonne University, Paris, France
| | - Ismail Elalamy
- Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Faculty of Medicine, Sorbonne University, Paris, France; Department of Hematology and Cell Therapy, Saint Antoine Hospital, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris, Sorbonne University, Paris, France
| | | | - Grigoris T Gerotziafas
- Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Faculty of Medicine, Sorbonne University, Paris, France; Department of Hematology and Cell Therapy, Saint Antoine Hospital, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris, Sorbonne University, Paris, France.
| |
Collapse
|
|
14
|
Fernandes CJ, Morinaga LTK, Alves JL, Castro M, Calderaro D, Jardim CV, Souza R. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev 2019; 28:28/151/180119. [PMID: 30918022 PMCID: PMC9488553 DOI: 10.1183/16000617.0119-2018] [Citation(s) in RCA: 186] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 03/01/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer-associated thrombosis (CAT) is a condition in which relevance has been increasingly recognised both for physicians that deal with venous thromboembolism (VTE) and for oncologists. It is currently estimated that the annual incidence of VTE in patients with cancer is 0.5% compared to 0.1% in the general population. Active cancer accounts for 20% of the overall incidence of VTE. Of note, VTE is the second most prevalent cause of death in cancer, second only to the progression of the disease, and cancer is the most prevalent cause of deaths in VTE patients. Nevertheless, CAT presents several peculiarities that distinguish it from other VTE, both in pathophysiology mechanisms, risk factors and especially in treatment, which need to be considered. CAT data will be reviewed in this review. Cancer-associated thrombosis (CAT) presents peculiar features (risk factors and pathophysiology) that distinguish it from common VTE cases. Treatment of CAT requires a different approach, since the patients are more prone to recurrence and bleeding.http://ow.ly/j1Lu30nYmd5
Collapse
|
|
15
|
Abstract
Thrombosis is a major cause of morbidity and mortality in cancer patients. The pathogenesis of blood coagulation activation in oncological patients is complex and involves both clinical and biological factors. Abnormalities in one or more coagulation test are common in cancer patients, even without thrombotic manifestations, indicating an ongoing hypercoagulable condition. Moreover, venous thromboembolism (VTE) can be the first symptom of an occult malignancy in an otherwise healthy individual. The levels of laboratory markers of activation of blood coagulation parallel the development of malignancy, being the coagulant mechanisms important for both thrombogenesis and tumor progression. Besides general clinical risk factors for VTE, also disease-specific clinical factors, i.e., type and stage of the tumor, and anticancer therapies increase the thrombotic risk in these patients. Furthermore, biological factors, including the cancer cell-specific prothrombotic properties together with the host cell inflammatory response to the tumor, are relevant as well as unique players in the pathogenesis of the cancer-associated hypercoagulability. Cancer cells produce and release procoagulant and fibrinolytic proteins, inflammatory cytokines, and procoagulant microparticles. They also express adhesion molecules binding to the receptors of host vascular cells (i.e., endothelial cells, platelets, and leukocytes), thereby stimulating the prothrombotic properties of these normal cells, including the shed of cell-specific microparticles and neutrophil extracellular traps. Of interest, several genes responsible for the cellular neoplastic transformation drive the programs of hemostatic properties expressed by cancer tissues. A better understanding of such mechanisms will help the development of novel strategies to prevent and treat the Trousseau's syndrome (i.e., cancer-associated thrombosis).
Collapse
Affiliation(s)
- Anna Falanga
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy.
- University of Milan Bicocca, School of Medicine and Surgery, Monza, Italy.
| | - Francesca Schieppati
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - Laura Russo
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| |
Collapse
|
|
16
|
Novel isomeric metabolite profiles correlate with warfarin metabolism phenotype during maintenance dosing in a pilot study of 29 patients. Blood Coagul Fibrinolysis 2018; 29:602-612. [PMID: 30334816 DOI: 10.1097/mbc.0000000000000752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
: For this pilot study, we leveraged metabolite patterns for warfarin patients to more accurately assess clinically relevant differences in drug metabolism. We tested our hypothesis that plasma metabolite levels correlate with the influence of clinical factors on R-warfarin and S-warfarin metabolism (warfarin metabolic phenotype). We recruited 29 patients receiving a maintenance dose and testing within targeted therapeutic range. We determined their CYP2C9 and vitamin K epoxide reductase genotype and profiled 14 isomeric forms of warfarin and its metabolites. We employed three novel types of clearance ratios using analyte levels to perform multiple-linear regression analyses with clinical factors impacting drug metabolism and dose-responses. Competitive clearance ratios correlated with seven clinical factors including lifestyle choices (smoking), genetics (CYP2C9 and vitamin K epoxide reductase 1), and drug interactions (omeprazole) along with age, weight, and malignancy. Significant competitive clearance ratio correlations (P = 0.04 to < 0.001) explained 21-95% variability. Their performances surpassed that of oxidative and metabolic clearance ratios based on the number and significance of correlations. Competitive clearance ratios may accurately assess significance of factors on maintaining levels of pharmacologically active forms of the drug and metabolites related to dose-responses and thus provide a strategy to minimize adverse events and improve safety during anticoagulant therapy. This unique capacity could provide a strategy in a future, higher power study with a larger cohort of patients to more accurately assess the significance of clinical factors on active drug levels contributing to warfarin dose-responses.
Collapse
|
|
17
|
Falanga A, Marchetti M. Hemostatic biomarkers in cancer progression. Thromb Res 2018; 164 Suppl 1:S54-S61. [PMID: 29703485 DOI: 10.1016/j.thromres.2018.01.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 02/06/2023]
Abstract
Malignant disease is characterized by a hemostatic imbalance, usually shifted towards a procoagulant direction, and a high incidence of thrombotic complications. The mechanisms of hemostasis that are critically involved in thrombosis are also implicated in tumor progression, angiogenesis, and metastatic spread. As there is a close relationship between cancer and the clotting system, circulating biomarkers of activation of various hemostasis compartments (i.e. coagulation, fibrinolysis, platelets, endothelium, and other blood cells) have been extensively studied to predict cancer outcomes along with predicting the thrombotic risk. In this review, we will summarize the results of published studies and will focus on ongoing research and future directions of clotting activation bioproducts as biomarkers of cancer disease and progression.
Collapse
Affiliation(s)
- Anna Falanga
- Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy.
| | - Marina Marchetti
- Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
| |
Collapse
|
|
18
|
Ünlü B, Versteeg HH. Cancer-associated thrombosis: The search for the holy grail continues. Res Pract Thromb Haemost 2018; 2:622-629. [PMID: 30349879 PMCID: PMC6178660 DOI: 10.1002/rth2.12143] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 06/24/2018] [Indexed: 02/06/2023] Open
Abstract
Cancer patients have an increased risk of developing venous thromboembolism (VTE), a condition that is associated with increased morbidity and mortality. Although risk assessment tools have been developed, it is still very challenging to predict which cancer patients will suffer from VTE. The scope of this review is to summarize and discuss studies focusing on the link between genetic alterations and risk of cancer-associated thrombosis (CAT). Thus far, classical risk factors that contribute to VTE have been tried as risk factors of CAT, with low success. In support, hypercoagulant plasma profiles in patients with CAT differ from those with only VTE, indicating other risk factors that contribute to VTE in cancer. As germline mutations do not significantly contribute to elevated risk of VTE, somatic mutations in tumors may significantly associate with and contribute to CAT. As it is very time-consuming to investigate each and every mutation, an unbiased approach is warranted. In this light we discuss our own recent unbiased proof-of-principle study using RNA sequencing in isolated colorectal cancer cells. Our work has uncovered candidate genes that associate with VTE in colorectal cancer, and these gene profiles associated with VTE more significantly than classical parameters such as platelet counts, D-dimer, and P-selectin levels. Genes associated with VTE could be linked to pathways being involved in coagulation, inflammation and methionine degradation. We conclude that tumor cell-specific gene expression profiles and/or mutational status has superior potential as predictors of VTE in cancer patients.
Collapse
Affiliation(s)
- Betül Ünlü
- Department of Internal MedicineEinthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| | - Henri H. Versteeg
- Department of Internal MedicineEinthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
| |
Collapse
|
|
19
|
Al Saleh HA, Haas-Neill S, Al-Hashimi A, Kapoor A, Shayegan B, Austin RC, Al-Nedawi K. Thrombotic characteristics of extracellular vesicles derived from prostate cancer cells. Prostate 2018; 78:953-961. [PMID: 29761522 DOI: 10.1002/pros.23653] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 05/01/2018] [Indexed: 11/11/2022]
Abstract
BACKGROUND Prostate cancer (PC) patients in advanced stages of the disease have high risk of blood coagulation complications. The procoagulant molecule Tissue factor (TF), and the fibrinolysis inhibitor plasminogen activator inhibitor-1 PAI-1 play important role in this complication. Extracellular vesicles (EV) shed from cancer cells may contribute to the regulation of TF and PAI-1. The procoagulant activity of EV can be associated with the oncogenic and metastatic characteristics of their cells. METHODS We have expressed EGFRvIII in DU145 cells to assess the role of this oncogene in the procoagulant activity of EV. The intercellular exchange of TF via EV was assessed by downregulating its expression in DU145 cells using shRNA vector, and determining the transfer of TF via EV enriched with the protein. Two PC cell lines with different metastatic potential were used to assess the correlation between the procoagulant activity of EV and the metastatic potential of PC cells. Photometric assays were used to determine FXa-activity and thrombin generation as indicators for the procoagulant activity of EV. Double-tagged proteinase-activated receptor 1(PAR-1) expressed in CHO cells to assess its activation by EV. RESULTS The expression of EGFRvIII in DU145 cells led to increased mRNA levels for TF and PAI-1, but the increase in these proteins expression was detected mostly in the EV. EV with enhanced levels of TF protein conferred higher TF procoagulant activity on the acceptor cells by intercellular exchange of this protein. Procoagulant activity of EV, assessed by FXa activity, and thrombin generation, was correlated with the oncogenic and metastatic potential of PC cells. The ability of EV to generate thrombin led to the activation of PAR-1, which was evident by the truncation of tagged-PAR-1. CONCLUSION The active oncogene EGFRvIII increases the concentration of TF and PAI-1 in EV. The procoagulant activity of EV is associated with the oncogenic and metastatic characteristics of their PC cells. Also, EV may contribute to the high procoagulant activity in the tumour microenvironment by the intercellular exchange of TF. Finally, through the generation of thrombin, EV can activate PAR-1, which evidently contributes to cancer progression, linking the coagulation system to tumor progression.
Collapse
Affiliation(s)
- Hassan A Al Saleh
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada
| | - Sandor Haas-Neill
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada
| | - Ali Al-Hashimi
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada
| | - Anil Kapoor
- Division of Urology, Department of Surgery, McMaster University, Hamilton, Canada
| | - Bobby Shayegan
- Division of Urology, Department of Surgery, McMaster University, Hamilton, Canada
| | - Richard C Austin
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada
| | - Khalid Al-Nedawi
- Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Canada
| |
Collapse
|
|
20
|
Muñoz Martín AJ, Ortega I, Font C, Pachón V, Castellón V, Martínez-Marín V, Salgado M, Martínez E, Calzas J, Rupérez A, Souto JC, Martín M, Salas E, Soria JM. Multivariable clinical-genetic risk model for predicting venous thromboembolic events in patients with cancer. Br J Cancer 2018; 118:1056-1061. [PMID: 29588512 PMCID: PMC5931103 DOI: 10.1038/s41416-018-0027-8] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 01/17/2018] [Accepted: 01/22/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. Outpatients with cancer should be periodically assessed for VTE risk, for which the Khorana score is commonly recommended. However, it has been questioned whether this tool is sufficiently accurate at identifying patients who should receive thromboprophylaxis. The present work proposes a new index, TiC-Onco risk score to be calculated at the time of diagnosis of cancer, that examines patients' clinical and genetic risk factors for thrombosis. METHODS We included 391 outpatients with a recent diagnosis of cancer and candidates for systemic outpatient chemotherapy. All were treated according to standard guidelines. The study population was monitored for 6 months, and VTEs were recorded. The Khorana and the TiC-Onco scores were calculated for each patient and their VTE predictive accuracy VTEs was compared. RESULTS We recorded 71 VTEs. The TiC-Onco risk score was significantly better at predicting VTE than the Khorana score (AUC 0.73 vs. 0.58, sensitivity 49 vs. 22%, specificity 81 vs. 82%, PPV 37 vs. 22%, and NPV 88 vs. 82%). CONCLUSIONS TiC-Onco risk score performed significantly better than Khorana score at identifying cancer patients at high risk of VTE who would benefit from personalised thromboprophylaxis.
Collapse
Affiliation(s)
- Andrés J Muñoz Martín
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo, 46, 28007, Madrid, Spain.
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain.
| | - Israel Ortega
- Scientific Department, Gendiag, Joan XXIII, 10, 08950, Esplugues de Llobregat, Spain
| | - Carme Font
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Hospital Clínic, c/ Villarroel, 170, 08036, Barcelona, Spain
| | - Vanesa Pachón
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Hospital Universitario Ramón y Cajal Madrid, Ctra. Colmenar Viejo, Km. 9,100, 28034, Madrid, Spain
| | - Victoria Castellón
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Complejo Hospitalario de Torrecárdenas, c/ Hermandad de Donantes de Sangre, 04009, Almería, Spain
| | - Virginia Martínez-Marín
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Hospital Universitario la Paz, Paseo de la Castellana, 261, 28046, Madrid, Spain
| | - Mercedes Salgado
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Complejo Hospitalario Universitario de Ourense, c/ Ramon Puga Noguerol, 54, 32005, Ourense, Spain
| | - Eva Martínez
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Hospital Universitario Marqués de Valdecilla, Av. Valdecilla, 25, 39008, Santander, Spain
| | - Julia Calzas
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Hospital Universitario de Fuenlabrada, Camino del Molino, 2, 28942, Madrid, Spain
| | - Ana Rupérez
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
- Medical Oncology, Fundación Jiménez Díaz, Av. Reyes Católicos, 2, 28040, Madrid, Spain
| | - Juan C Souto
- Thrombosis and Haemostasia, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08041, Barcelona, Spain
| | - Miguel Martín
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo, 46, 28007, Madrid, Spain
- Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM), C/ de Velázquez, 7, 28001, Madrid, Spain
| | - Eduardo Salas
- Scientific Department, Gendiag, Joan XXIII, 10, 08950, Esplugues de Llobregat, Spain
| | - Jose M Soria
- Genomic of complex diseases, Institut d'Investigació Sant Pau (IIB-Sant Pau), Carrer de Sant Quintí, 89, 08041, Barcelona, Spain
| |
Collapse
|
|
21
|
Abdel-Razeq H, Mansour A, Saadeh SS, Abu-Nasser M, Makoseh M, Salam M, Abufara A, Ismael Y, Ibrahim A, Khirfan G, Ibrahim M. The Application of Current Proposed Venous Thromboembolism Risk Assessment Model for Ambulatory Patients With Cancer. Clin Appl Thromb Hemost 2018; 24:429-433. [PMID: 28183196 PMCID: PMC6714656 DOI: 10.1177/1076029617692880] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Venous thromboembolism (VTE) is a commonly encountered problem in patients with cancer. In recent years, cancer treatment paradigm has shifted with most therapy offered in ambulatory outpatient settings. Excess of half VTEs in patients with cancer occur in outpatient settings without prior hospitalization, where current practice guidelines do not recommend routine prophylaxis. Risk assessment models (RAMs) for VTE in such patients were recently introduced. This study aims to assess the practical application of one of these models in clinical practice. Medical records and hospital electronic database were searched for patients with cancer having VTE. Known risk factors were collected, and risk assessment was done using the Khorana RAM. Over a 10-year period, 346 patients developed VTE in ambulatory settings. Median age was 57 and 59.0% were females. Lower extremities were involved in 196 (56.6%), while 96 (27.7%) had pulmonary embolism. Most (76.6%) patients had stage IV disease, only 9.0% had stage I or II disease. Only 156 (45.1%) patients were on active chemotherapy, for whom Khorana risk assessment score was calculated. In these patients, high risk was identified in 31 (19.9%) patients, while 81 (51.9%) had intermediate risk and 44 (28.2%) had low risk. No patients were on prophylaxis prior to VTE. Most ambulatory patients with cancer who developed VTE were not on chemotherapy, and many of those who were on active treatment had low Khorana risk scores. This illustrates the need to modify the model or develop a new one that takes into consideration this group of patients.
Collapse
Affiliation(s)
- Hikmat Abdel-Razeq
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Asem Mansour
- Department of Radiology, King Hussein Cancer Center, Amman, Jordan
| | - Salwa S. Saadeh
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Mahmoud Abu-Nasser
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Mohammad Makoseh
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Murad Salam
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Alaa Abufara
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Yousef Ismael
- Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan
| | - Alaa Ibrahim
- Department of Radiology, King Hussein Cancer Center, Amman, Jordan
| | - Ghaleb Khirfan
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Mohammad Ibrahim
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| |
Collapse
|
|
22
|
Date K, Ettelaie C, Maraveyas A. Tissue factor-bearing microparticles and inflammation: a potential mechanism for the development of venous thromboembolism in cancer. J Thromb Haemost 2017; 15:2289-2299. [PMID: 29028284 DOI: 10.1111/jth.13871] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Indexed: 12/31/2022]
Abstract
Cancer is associated with an increased risk of venous thromboembolism (VTE); the exact mechanisms for the induction of VTE remain to be fully elucidated, but it is widely acknowledged that tissue factor (TF)-bearing microparticles (TF-MPs) may play a significant role. However, TF-MPs have yet to be accepted as a genuine biomarker for cancer-associated VTE, as the presence of elevated TF-MP levels is not always accompanied by thrombosis; interestingly, in certain cases, particularly in pancreatic cancer, VTE seems to be more likely in the context of acute inflammation. Although several potential mechanisms for the development of VTE in cancer have been postulated, this review explores the homeostatic disruption of TF-MPs, as the main reservoir of bloodborne TF, in the context of cancer and inflammation, and considers the abrogated responses of the activated endothelium and mononuclear phagocyte system in mediating this disruption.
Collapse
Affiliation(s)
- K Date
- Hull York Medical School, University of Hull, Hull, UK
| | - C Ettelaie
- School of Life Sciences, University of Hull, Hull, UK
| | - A Maraveyas
- Hull York Medical School, University of Hull, Hull, UK
- Queen's Centre for Oncology and Haematology, Castle Hill Hospital, Cottingham, UK
| |
Collapse
|
|
23
|
Antic D, Jelicic J, Vukovic V, Nikolovski S, Mihaljevic B. Venous thromboembolic events in lymphoma patients: Actual relationships between epidemiology, mechanisms, clinical profile and treatment. Blood Rev 2017; 32:144-158. [PMID: 29126566 DOI: 10.1016/j.blre.2017.10.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 10/15/2017] [Accepted: 10/27/2017] [Indexed: 02/08/2023]
Abstract
Venous thromboembolic events (VTE) are an underestimated health problem in patients with lymphoma. Many factors contribute to the pathogenesis of thromboembolism and the interplay between various mechanisms that provoke VTE is still poorly understood. The identification of parameters that are associated with an increased risk of VTE in lymphoma patients led to the creation of several risk-assessment models. The models that evaluate potential VTE risk in lymphoma patients in particular are quite limited, and have to be validated in larger study populations. Furthermore, the VTE prophylaxis in lymphoma patients is largely underused, despite the incidence of VTE. The lack of adequate guidelines for the prophylaxis and treatment of VTE in lymphoma patients, together with a cautious approach due to an increased risk of bleeding, demands great efforts to ensure the implementation of current knowledge in order to reduce the incidence and complications of VTE in lymphoma patients.
Collapse
Affiliation(s)
- Darko Antic
- Clinic for Hematology, Clinical Centre Serbia, Belgrade, Serbia; Medical Faculty, University of Belgrade, Belgrade, Serbia.
| | - Jelena Jelicic
- Clinic for Hematology, Clinical Centre Serbia, Belgrade, Serbia
| | - Vojin Vukovic
- Clinic for Hematology, Clinical Centre Serbia, Belgrade, Serbia
| | | | - Biljana Mihaljevic
- Clinic for Hematology, Clinical Centre Serbia, Belgrade, Serbia; Medical Faculty, University of Belgrade, Belgrade, Serbia
| |
Collapse
|
|
24
|
Rousseau A, Van Dreden P, Khaterchi A, Larsen AK, Elalamy I, Gerotziafas GT. Procoagulant microparticles derived from cancer cells have determinant role in the hypercoagulable state associated with cancer. Int J Oncol 2017; 51:1793-1800. [PMID: 29075792 DOI: 10.3892/ijo.2017.4170] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/25/2017] [Indexed: 11/05/2022] Open
Abstract
Hypercoagulablity is a common alteration of blood coagulation in cancer patients. However, the procoagulant activity of cancer cells is not sufficient to induce hypercoagulability. The present study was aimed to identify the mechanism with which hypercoagulabilty is produced in the presence of cancer cells. We focused on the analysis of the procoagulant elements carried by cancer cell-derived microparticles (CaCe-dMP) and we evaluated the impact of microparticles associated with the cancer cells from which they stem on thrombin generation. CaCe-dMP from the cancer cells were isolated from the conditioned medium and analyzed for tissue factor (TF) and procoagulant phospholipid expression. Thrombin generation of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of pancreas adeno-carcinoma cells (BXPC3) or breast cancer MCF7 cells supplemented with the respective CaCe-dMP. Both BXPC3 and MCF7 cells express abundant amounts of active TF. Phosphatidylserine was identified on the surface of CaCe-dMP, unlike the cancer cells themselves. The expression of TFa by the microparticles was significantly higher to that observed on the cancer cells. Culture of the cancer cells with their microparticles resulted in thrombin generation significantly higher as compared to the upper normal limit. In conclusion, cancer cells 'enrich' the microenvironment with procoagulant elements, especially procoagulant micro-particles which express TF and procoagulant phospholipids. The association of cancer cells with procoagulant microparticles is necessary for a state of hypercoagulability, at the level of the tumoral microenvironment. The intensity of the hypercoagulability depends on the histological type of the cancer cells.
Collapse
Affiliation(s)
- Aurélie Rousseau
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938, Institut Universitaire de Cancérologie, Faculty of Medicine Pierre and Marie Curie (UPMC), Sorbonne Universities, Paris, France
| | | | - Amir Khaterchi
- Department of Biological Hematology, Tenon Hospital, University Hospitals of the East Paris, Paris, France
| | - Annette K Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938, Institut Universitaire de Cancérologie, Faculty of Medicine Pierre and Marie Curie (UPMC), Sorbonne Universities, Paris, France
| | - Ismail Elalamy
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938, Institut Universitaire de Cancérologie, Faculty of Medicine Pierre and Marie Curie (UPMC), Sorbonne Universities, Paris, France
| | - Grigoris T Gerotziafas
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938, Institut Universitaire de Cancérologie, Faculty of Medicine Pierre and Marie Curie (UPMC), Sorbonne Universities, Paris, France
| |
Collapse
|
|
25
|
Mechanisms and risk factors of thrombosis in cancer. Crit Rev Oncol Hematol 2017; 118:79-83. [DOI: 10.1016/j.critrevonc.2017.08.003] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 08/16/2017] [Indexed: 12/21/2022] Open
|
|
26
|
Elmoamly S, Afif A. Can biomarkers of coagulation, platelet activation, and inflammation predict mortality in patients with hematological malignancies? ACTA ACUST UNITED AC 2017; 23:89-95. [PMID: 28823228 DOI: 10.1080/10245332.2017.1365458] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND Patients with cancer commonly demonstrate laboratory evidence for hypercoagulability. Coagulation and inflammation play a role in the pathophysiology of hematological malignancies and the correlation between hypercoagulability and inflammation with tumor outcomes and the patient's prognosis are well studied. OBJECTIVE To identify an association between hemostasis activation, fibrinolysis and inflammation with mortality in patients with hematological malignancies to determine their prognostic significance. METHODS This study is a prospective observational cohort study; Hypercoagulability and inflammatory biomarkers including:(1) Coagulation and fibrinolysis activation Markers (D-dimer, Fibrinogen, Antithrombin, plasminogen activator inhibitor 1 [PAI-1]);(2) Endothelium and platelet activation Markers (von Willebrand Factor [vWF], soluble P-selectin); and (3) Inflammation Markers (Tumor necrosis factor alpha [TNF-α], Interleukin-6 [IL-6]) were assayed on a group of 171 patients with hematological malignancies at time of diagnosis. They have been followed up for an average period of 416.8 days with an endpoint of mortality. RESULTS Sixty patients died during follow up. There were statistically significant associations between Plasma cell dyscrasias mortality and ECOG performance status (P value:<0.005), Hemoglobin level (P value: 0.04), serum Albumin level (P value: 0.001), vWF (P value: 0.006) and IL-6 (P value 0.015), and between lymphoproliferative disorders mortality and presence of B symptoms (P value: 0.02), ECOG performance status (P value:<0.02), serum Albumin level (P value: 0.038), Antithrombin (P value: 0.004). CONCLUSION Some biomarkers of coagulation and inflammation showed statistically significant associations with plasma cell dyscrasias mortality (vWF and IL-6) and lymphoproliferative disorders mortality (Antithrombin) and potentially could be used as prognostic markers.
Collapse
Affiliation(s)
- Shereef Elmoamly
- a Department of Internal Medicine and Clinical Hematology, Faculty of Medicine , Cairo University , Cairo , Egypt
| | - Alaa Afif
- b Department of Chemical Pathology, Faculty of Medicine , Cairo University , Cairo , Egypt
| |
Collapse
|
|
27
|
D'Alessio A, Marchetti M, Tartari CJ, Russo L, Cecchini S, Lambregts KWFM, di Mauro D, Falanga A. Long Term Low Molecular Weight Heparin Anticoagulant Therapy Modulates Thrombin Generation and D-dimer in Patients with Cancer and Venous Thromboembolism. Cancer Invest 2017; 35:490-499. [PMID: 28692314 DOI: 10.1080/07357907.2017.1340480] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
We enrolled 62 consecutive patients with advanced stage cancers and venous thromboembolism (VTE), prospectively followed until 1 year. All patients received 6 month low-molecular-weight heparin (LMWH) therapy. We evaluated thrombin generation (TG) and D-dimer levels at different time points, to determine whether they were sensitive to LMWH and explore a possible association with VTE recurrence, bleeding, and overall survival. During LMWH, levels of TG and D-dimer significantly dropped. No VTE recurrences occurred, one patient had cancer-related intestinal hemorrhage. LMWH treatment was effective in controlling patient hypercoagulation. No VTE recurrences were detected. High D-dimer concentration was an independent predictor of poor survival.
Collapse
Affiliation(s)
- Andrea D'Alessio
- a Medical Oncology and Internal Medicine , Policlinico San Marco-Istituti Ospedalieri Bergamaschi , Bergamo , Italy
| | - Marina Marchetti
- b Department of Immunohematology and Transfusion Medicine , Hospital Papa Giovanni XXIII , Bergamo , Italy
| | - Carmen Julia Tartari
- b Department of Immunohematology and Transfusion Medicine , Hospital Papa Giovanni XXIII , Bergamo , Italy
| | - Laura Russo
- b Department of Immunohematology and Transfusion Medicine , Hospital Papa Giovanni XXIII , Bergamo , Italy
| | - Sara Cecchini
- a Medical Oncology and Internal Medicine , Policlinico San Marco-Istituti Ospedalieri Bergamaschi , Bergamo , Italy
| | | | - Daniela di Mauro
- a Medical Oncology and Internal Medicine , Policlinico San Marco-Istituti Ospedalieri Bergamaschi , Bergamo , Italy
| | - Anna Falanga
- b Department of Immunohematology and Transfusion Medicine , Hospital Papa Giovanni XXIII , Bergamo , Italy
| |
Collapse
|
|
28
|
Wen S, Duan Q, Yang F, Li G, Wang L. Early diagnosis of venous thromboembolism as a clinical primary symptom of occult cancer: Core proteins of a venous thrombus. Oncol Lett 2017; 14:491-496. [PMID: 28693196 DOI: 10.3892/ol.2017.6175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Accepted: 03/03/2017] [Indexed: 11/05/2022] Open
Abstract
Malignancy is one of the risk factors of venous thromboembolism (VTE). As a common accompanying factor of malignant tumors, almost 20% of idiopathic VTEs are identified in patients with occult types of cancer as the primary symptom. The type of internal association that exists between malignant tumors and VTE has not yet been determined. The present review discusses the following: i) Reversible combinations between core proteins of venous thrombi and their ligand proteins. With the condition of immune cell balancing function collapse, which is characterized as dysfunction immune cells and impaired immune functions, the human body loses the function of eliminating infectious/malignant cells quickly and effectively. Thus, integrins β2 and β3 on the membrane of platelets and white blood cells are activated to combine with fibrinogen ligands to form an intravenous mesh-like structure, which acts as an intravenous biological filter that prevents infectious/malignant cells from flowing back into the circulatory system. During the defense process, blood cells (mainly red blood cells) stagnate and fill the filter, which results in venous thrombotic diseases. ii) Tumor cells, which cannot be eliminated quickly, proliferate and invade; or ischemic necrosis destroys peripheral tissues and vessels (veins and arteries), resulting in the formation of a biological filter in injured veins. The filter is filled with stranded tumor cells, which prevents the hemorrhagic metastasis of malignant cells. The formation of an intravenous biological filter results from the transition of the body's own defense capabilities, which is also a physical/histopathological phenomenon. iii) An increase in the number of core proteins in a venous thrombus is a basic molecular step in the formation of intravenous biological filters, which is also defined as a marker of the newly initiated defensive barrier. Increased levels of integrins β1, β2 and β3 are useful in not only the specific diagnosis of VTE, but also in the early recognition of occult malignant tumors in idiopathic VTE patients.
Collapse
Affiliation(s)
- Siwan Wen
- Department of Cardiology, Tongji University Affiliated to Tongji Hospital, Shanghai 200065, P.R. China
| | - Qianglin Duan
- Department of Cardiology, Tongji University Affiliated to Tongji Hospital, Shanghai 200065, P.R. China
| | - Fan Yang
- Department of Clinical Laboratory, Tongji University Affiliated to Tongji Hospital, Shanghai 200065, P.R. China
| | - Guiyuan Li
- Department of Oncology, Tongji University Affiliated to Tongji Hospital, Shanghai 200065, P.R. China
| | - Lemin Wang
- Department of Cardiology, Tongji University Affiliated to Tongji Hospital, Shanghai 200065, P.R. China
| |
Collapse
|
|
29
|
Deng C, Wu S, Zhang L, Yang M, Lin Q, Xie Q, Ding H, Lian N, Gao S, Huang Y, Jin Y. Role of monocyte tissue factor on patients with non-small cell lung cancer. CLINICAL RESPIRATORY JOURNAL 2017; 12:1125-1133. [PMID: 28419722 DOI: 10.1111/crj.12640] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 02/28/2017] [Accepted: 03/20/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND To examine the expression of D-dimer, fibrinogen (FIB), leukocyte, C-reactive protein (CRP) and tissue factor (TF) released from monocyte in non-small cell lung cancer (NSCLC) patients with or without venous thromboembolism (VTE) and analyse the correlation, to explore the possible mechanisms. METHODS Seventy-two patients confirmed the diagnosis of lung cancer, among whom 10 with VTE were enrolled into the study from November 2012 to January 2014 in the First Affiliated Hospital of Fujian Medical University and 30 healthy subjects were also enrolled as the control group. Ficoll and Percoll density gradient centrifugation separated of peripheral blood monocyte. Monocyte TF mRNA expression was detected using reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS There were significant differences in different stages of the cancer (P < .05) and no significance among the histopathologic types (P > .05) for the expression of monocyte TF mRNA in NSCLC patients, its expression was significantly higher in cancer with lymph node metastasis than those without lymph node metastasis (P < .01). Meanwhile, in NSCLC patients with VTE, the expression of monocyte TF mRNA was significantly higher than that in patients without VTE (P < .01). Difference of the survival curves between the low monocyte TF mRNA expression and the high monocyte TF mRNA expression was significant (Log-rank x2 = 4.923, P < .05). CONCLUSIONS Monocyte TF may be a relevant source of TF-mediated thrombogenicity in NSCLC patients and may be associated with prognosis in NSCLC.
Collapse
Affiliation(s)
- Chaosheng Deng
- Division of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Shuang Wu
- Division of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Lina Zhang
- Department of Respiratory Disease, the Chinese People's Liberation Army 155 Central Hospital, Luoyang, Henan Province, China
| | - Minxia Yang
- Department of Critical Care Medicine, First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Qichang Lin
- Division of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Qiang Xie
- Fuzhou Pulmonary Hospital in Fujian Province, Fuzhou, Fujian Province, China
| | - Haibo Ding
- Division of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Ningfang Lian
- Division of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Shaoyong Gao
- Division of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yunjian Huang
- Fujian Provincial Tumor hospital, Fuzhou, Fujian Province, China
| | - Yongxu Jin
- Division of Respiratory and Critical Care Medicine, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| |
Collapse
|
|
30
|
Tumor-Derived Tissue Factor Aberrantly Activates Complement and Facilitates Lung Tumor Progression via Recruitment of Myeloid-Derived Suppressor Cells. Int J Mol Sci 2017; 18:ijms18010022. [PMID: 28106852 PMCID: PMC5297657 DOI: 10.3390/ijms18010022] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 12/09/2016] [Accepted: 12/15/2016] [Indexed: 12/31/2022] Open
Abstract
The initiator of extrinsic coagulation, tissue factor (TF), and its non-coagulant isoform alternatively spliced TF (asTF) are closely associated with tumor development. In the tumor microenvironment, the role of TF-induced coagulation in tumor progression remains to be fully elucidated. Using TF-knockdown lung tumor cells, we showed that TF is the dominant component of procoagulant activity but is dispensable in the cellular biology of tumor cells. In a xenograft model, using immunohistochemical analysis and flow cytometry analysis of the tumor microenvironment, we demonstrated that TF-induced fibrin deposition, which is correlated with complement activation and myeloid-derived suppressor cell (MDSC) recruitment, is positively associated with tumor progression. C5aR antagonism blunted the effect of TF on tumor progression and decreased MDSC recruitment. In conclusion, our data suggested that in tumor microenvironment, TF-induced coagulation activated the complement system and subsequently recruited myeloid-derived suppressor cells to promote tumor growth, which brings new insights into the coagulation-induced complement activation within the tumor microenvironment during tumor progression.
Collapse
|
|
31
|
Abstract
Cancer patients have a significantly higher risk of developing venous thromboembolism (VTE) compared to non-cancer patients and several studies suggest that VTE risk among ambulatory cancer patients varies widely. Recently, predictive models capable of risk-stratifying a broad range of ambulatory cancer outpatients have been developed and validated; using the Khorana model a score of 2 is associated with an intermediate-high risk for VTE. However, the use of VTE prophylaxis in ambulatory patients who have cancer remains controversial. Even if important randomized clinical trials showed decreased rates of VTE events among patients who were receiving chemotherapy, the effect of prophylaxis on morbidity, mortality, and costs has not been rigorously studied. Outpatients with active cancer should be assessed for thrombosis risk and although most do not routinely require thromboprophylaxis, it should be considered for high risk patients.
Collapse
Affiliation(s)
- Davide Imberti
- Haemostasis and Thrombosis Center, Department of Internal Medicine, Hospital of Piacenza, Piacenza, Italy.
| | - Raffaella Benedetti
- Haemostasis and Thrombosis Center, Department of Internal Medicine, Hospital of Piacenza, Piacenza, Italy
| |
Collapse
|
|
32
|
Alexander ET, Minton AR, Hayes CS, Goss A, Van Ryn J, Gilmour SK. Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis. Cancer Biol Ther 2016; 16:1802-11. [PMID: 26383051 DOI: 10.1080/15384047.2015.1078025] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Cancer is often associated with an increased risk of thrombotic events which are exacerbated by treatment with chemotherapeutics such as cyclosphosphamide (CP). Evidence suggests that thrombin can stimulate tumor progression via formation of fibrin and activation of protease-activated receptors (PARs) and platelets. We examined the effect of co-treatment with CP and dabigatran etexilate, a direct inhibitor of thrombin, using the murine orthotopic 4T1 tumor model. Mice receiving co-treatment with both low dose CP and dabigatran etexilate had significantly smaller mammary tumors and fewer lung metastases than mice treated with CP or dabigratran etexilate alone. Co-treatment with dabigatran etexilate and low dose CP also significantly decreased the number of arginase(+)Gr-1(+)CD11b(+) myeloid derived suppressor cells as well as levels of TGF-β in spleens from tumor bearing mice. 4T1 tumors express procoagulant tissue factor (TF) and spontaneously release TF(+) microparticles which are potent procoagulant factors that promote thrombin generation. Treatment with dabigatran etexilate alone prevented tumor-induced increases in circulating TF(+) microparticles and also decreased the numbers of tumor-induced activated platelets by 40%. These results show that co-treatment with dabigatran etexilate and CP synergistically inhibits growth and metastasis of mammary tumors, suggesting that oral administration of the thrombin inhibitor dabigatran etexilate may be beneficial in not only preventing thrombotic events in cancer patients but also in treating malignant tumors themselves.
Collapse
Affiliation(s)
| | | | - Candace S Hayes
- a Lankenau Institute for Medical Research ; Wynnewood , PA USA
| | - Ashley Goss
- b Boehringer Ingelheim Pharmaceuticals Inc. ; Ridgefield , CT USA
| | - Joanne Van Ryn
- c Boehringer Ingelheim Pharma GmbH & Co. KG ; Biberach an der Riss , Germany
| | - Susan K Gilmour
- a Lankenau Institute for Medical Research ; Wynnewood , PA USA
| |
Collapse
|
|
33
|
Fotiou D, Gerotziafas G, Kastritis E, Dimopoulos MA, Terpos E. A review of the venous thrombotic issues associated with multiple myeloma. Expert Rev Hematol 2016; 9:695-706. [DOI: 10.1080/17474086.2016.1194750] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Despina Fotiou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Grigoris Gerotziafas
- INSERM U938, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris, France
- Thrombosis Center, Service d’Hématologie Biologique Hôpital Tenon, Hôpitaux Universitaires de l’Est Parisien, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Meletios A. Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Evangelos Terpos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| |
Collapse
|
|
34
|
Reitter EM, Kaider A, Ay C, Quehenberger P, Marosi C, Zielinski C, Pabinger I. Longitudinal analysis of hemostasis biomarkers in cancer patients during antitumor treatment. J Thromb Haemost 2016; 14:294-305. [PMID: 26662117 DOI: 10.1111/jth.13218] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 11/24/2015] [Indexed: 12/21/2022]
Abstract
UNLABELLED ESSENTIALS: Hemostasis biomarkers impact thrombosis occurrence and survival in cancer patients. We performed a longitudinal analysis of hemostatic parameters in 112 cancer patients. Hemostatic parameters are associated with disease state, patients' prognosis, and the risk of VTE. The procoagulant state exists not only at diagnosis, but also during the course of disease. BACKGROUND Hemostasis biomarkers are known to have an impact on venous thromboembolism (VTE) occurrence and survival in cancer patients. OBJECTIVES As there are almost no data on longitudinal changes, we aimed to evaluate those in the present prospective observational study during chemotherapy and the course of disease. PATIENTS/METHODS Patients with cancer of the brain (n = 39), lung (n = 41), colon (n = 15) or pancreas (n = 17) were included before initiation of antitumor therapy. Blood samples for determination of factor VIII, thrombin peak height, D-dimer, F1 + 2 , fibrinogen and soluble P-selectin (sP-selectin) were drawn on a monthly basis. The study endpoints were death, VTE occurrence, or completion of the study period. RESULTS Overall, 546 blood samples of 112 patients were analyzed. D-dimer and sP-selectin levels were significantly higher in patients with distant metastasis than in those without. Patients with complete remission had significantly lower levels of F1 + 2 , D-dimer and fibrinogen. Peak height thrombin levels showed a decrease over time in all tumor types. Levels of biomarkers behaved differently in the various tumor types. Patients who developed VTE (n = 14) showed increasing levels of FVIII, sP-selectin, and D-dimer. At the last blood sampling time-point before VTE occurrence, in 13 patients the D-dimer level was above the median, and in seven of these patients it was even above the 75th percentile; however, the individual course was highly variable. Regarding survival, steadily increased FVIII, sP-selectin and D-dimer levels were associated with higher mortality. CONCLUSIONS Hemostatic parameters show an association with disease state, prognosis, and the risk of VTE, not only at diagnosis, but also during the course of antineoplastic treatment.
Collapse
Affiliation(s)
- E-M Reitter
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - A Kaider
- Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - C Ay
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - P Quehenberger
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - C Marosi
- Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - C Zielinski
- Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - I Pabinger
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
35
|
Lee H, Lee SE, Byun SS, Kim HH, Kwak C, Hong SK. Preoperative Plasma Fibrinogen Level as a Significant Prognostic Factor in Patients With Localized Renal Cell Carcinoma After Surgical Treatment. Medicine (Baltimore) 2016; 95:e2626. [PMID: 26825920 PMCID: PMC5291590 DOI: 10.1097/md.0000000000002626] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
We sought to investigate the association of preoperative fibrinogen levels with clinicopathologic outcomes after surgical treatment of nonmetastatic renal cell carcinoma. We reviewed the records of 1511 patients who had their fibrinogen levels measured preceding surgery. The associations between preoperative fibrinogen level and risk of adverse clinicopathologic outcomes were tested using the multivariate logistic regression and multiple Cox-proportional hazards model, respectively. Based on plasma fibrinogen levels, we stratified the patients into 2 groups with a cut-off value of 328 mg/dL. Kaplan-Meier analysis showed significantly inferior survival outcomes in progression-free (P < 0.001), cancer-specific (P < 0.001), and overall survival (P < 0.001). In multivariate analyses, a high fibrinogen level (≥328 mg/dL) was significantly related to a higher Fuhrman grade (hazard ratio [HR] 1.374, P = 0.006) and a larger tumor size (≥7 cm) (HR 2.364, P < 0.001). Multivariate Cox analysis also revealed that a high preoperative fibrinogen level is a significant predictor for poor disease progression (HR 1.857, P < 0.001), cancer-specific survival (HR 3.608, P = 0.003), and overall survival (HR 1.647, P = 0.027). Increased plasma fibrinogen levels were significantly associated with poor pathological features and worse survival outcomes in patients with nonmetastatic renal cell carcinoma after surgical treatment. Further evaluations such as prospective randomized trials are needed to understand the underlying mechanism for these associations.
Collapse
Affiliation(s)
- Hakmin Lee
- From the Department of Urology, Seoul National University Bundang Hospital, Seongnam (HL, SEL, S-SB, SKH); and Department of Urology, Seoul National University Hospital, Seoul, Korea (HHK, CK)
| | | | | | | | | | | |
Collapse
|
|
36
|
Surov A, Bach AG, Schramm D. Clinically Relevant Cardiovascular Findings Detected on Staging Computed Tomography in Patients with Several Malignancies. Angiology 2015; 67:630-7. [DOI: 10.1177/0003319715605971] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
We evaluated the frequency and subtypes of clinically relevant cardiovascular (CV) findings identified on staging computed tomography (CT) in a large sample. Patients (n = 5026) with different malignant diseases were staged by CT. Clinically relevant CV findings (CRCFs) were included into the study. The CRCFs were defined as cardiac aneurysm, cardiac thrombus, venous thrombosis, arterial thrombosis, arterial dissection, pulmonary thromboembolism, arterial dissection, and dislocation of venous ports/central venous catheters. The CRCFs were identified in 342 patients (6.8% of all patients). Overall, 491 CRCFs were identified in the patients (1.4 per patient). In 203 (59.4%) patients, 1 CRCF; in 129, 2 (37.7%) CRCFs; and in 10 (2.9%) cases, 3 CRCFs were detected. There were incidental venous thrombosis (n = 298, 60.7% of all CRCFs), pulmonary thromboembolism (n = 84, 17.1%), arterial aneurysms (n = 44, 8.9%), arterial thrombosis (n = 43, 8.8%), heart thrombus (n = 15, 3.1%), arterial dissection (n = 3, 0.6%), heart aneurysms (n = 2, 0.4%), and port catheter dislocation (n = 2, 0.4%). The identified CRCF can be associated with potential hazardous complications. The CV system should be carefully evaluated in staging CT investigations.
Collapse
Affiliation(s)
- Alexey Surov
- Department of Radiology, Martin-Luther-University Hale-Wittenberg, Halle, Germany
| | - Andreas Gunter Bach
- Department of Radiology, Martin-Luther-University Hale-Wittenberg, Halle, Germany
| | - Dominik Schramm
- Department of Radiology, Martin-Luther-University Hale-Wittenberg, Halle, Germany
| |
Collapse
|
|
37
|
Keller K, Geyer M, Beule J, Coldewey M, Balzer JO, Dippold W. Impact of cancer on the effectiveness of cardiac Troponin I to predict right ventricular dysfunction in acute pulmonary embolism. Thorac Cancer 2015; 6:584-8. [PMID: 26443088 PMCID: PMC4567003 DOI: 10.1111/1759-7714.12226] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 12/11/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Deep vein thrombosis (DVT) and pulmonary embolism (PE) are connected with a poor outcome in cancer patients. We aimed to investigate the impact of cancer on the effectiveness of cardiac Troponin I (cTnI) to predict right ventricular dysfunction (RVD) in acute PE. METHODS We retrospectively analyzed the data of 182 patients with confirmed PE. PE patients were subdivided into two groups: (i) with concomitant active cancer disease or history of cancer, and (ii) without known cancer. Receiver operating characteristic (ROC) curves with area under the curve (AUC) was calculated for cTnI predicting RVD and related cut-off levels for both groups. RESULTS Thirty-seven PE patients (20.3%) had an active cancer disease or a history of cancer. In contrast, 145 (79.7%) of the included PE patients did not have a known cancer disease or a history of cancer. In the PE group with cancer, analysis of the ROC curve showed an AUC of 0.76 for cTnI predicting RVD with an optimal cut-off value of 0.04 ng/mL; the risk of misclassification was 25.0%. In the PE group without cancer, AUC was 0.81 for cTnI predicting RVD with an optimal cut-off value of 0.015 ng/mL; the risk of misclassification was 24.9%. CONCLUSIONS cTnI is effective for predicting RVD in PE patients with and without cancer. However, the effectiveness of cTnI to predict RVD was higher in PE patients without cancer than in those with cancer or a history of cancer.
Collapse
Affiliation(s)
- Karsten Keller
- Department of Medicine II, University Medical Center Mainz, Johannes Gutenberg-University MainzMainz, Germany
- Center for thrombosis and hemostasis, University Medical Center Mainz, Johannes Gutenberg-University MainzMainz, Germany
| | - Martin Geyer
- Department of Medicine II, University Medical Center Mainz, Johannes Gutenberg-University MainzMainz, Germany
| | - Johannes Beule
- Department of internal medicine, St. Vincenz and Elisabeth Hospital Mainz (KKM)Mainz, Germany
| | - Meike Coldewey
- Department of Medicine II, University Medical Center Mainz, Johannes Gutenberg-University MainzMainz, Germany
- Center for thrombosis and hemostasis, University Medical Center Mainz, Johannes Gutenberg-University MainzMainz, Germany
| | - Jörn Oliver Balzer
- Department of Radiology and Nuclear medicine, Catholic Clinic Mainz (KKM)Mainz, Germany
- Department of Diagnostic and Interventional Radiology, University Clinic, Johann Wolfgang Goethe-University Frankfurt/MainMainz, Germany
| | - Wolfgang Dippold
- Department of internal medicine, St. Vincenz and Elisabeth Hospital Mainz (KKM)Mainz, Germany
| |
Collapse
|
|
38
|
Day RW, Aloia TA. Clinical Care Pathways in Cancer Surgery. CURRENT ANESTHESIOLOGY REPORTS 2015. [DOI: 10.1007/s40140-015-0115-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
|
|
39
|
Ay C, Pabinger I. VTE risk assessment in cancer. Who needs prophylaxis and who does not? Hamostaseologie 2015; 35:319-24. [PMID: 25740182 DOI: 10.5482/hamo-14-11-0066] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 01/13/2015] [Indexed: 12/21/2022] Open
Abstract
Venous thromboembolism (VTE) in patients with cancer is associated with an increased morbidity and mortality, and its prevention is of major clinical importance. However, the VTE rates in the cancer population vary between 0.5% - 20%, depending on cancer-, treatment- and patient-related factors. The most important contributors to VTE risk are the tumor entity, stage and certain anti-cancer treatments. Cancer surgery represents a strong risk factor for VTE, and medical oncology patients are at increased risk of developing VTE, especially when receiving chemotherapy or immunomodulatory drugs. Also biomarkers have been investigated for their usefulness to predict risk of VTE (e.g. elevated leukocyte and platelet counts, soluble P-selectin, D-dimer, etc.). In order to identify cancer patients at high risk of VTE and to improve risk stratification, risk assessment models have been developed, which contain both clinical parameters and biomarkers. While primary thromboprophylaxis with low-molecular-weight-heparin (LMWH) is recommended postoperatively for a period of up to 4 weeks after major cancer surgery, the evidence is less clear for medical oncology patients. Thromboprophylaxis in hospitalized medical oncology patients is advocated, and is based on results of randomized controlled trials which evaluated the efficacy and safety of LMWH for prevention of VTE in hospitalized medically ill patients. In recent trials the benefit of primary thromboprophylaxis in cancer patients receiving chemotherapy in the ambulatory setting has been investigated. However, at the present stage primary thromboprophylaxis for prevention of VTE in these patients is still a matter of debate and cannot be recommended for all cancer outpatients.
Collapse
Affiliation(s)
- C Ay
- Priv.-Doz. Dr. Cihan Ay, Medical University, Department of Medicine I, Clinical Division of Haematology and Haemostaseology, Waehringer Guertel 18-20, 1090 Vienna, Austria, Tel. +43/1/40 40 04-41 00, Fax -03 00, E-mail:
| | | |
Collapse
|
|
40
|
Abstract
PURPOSE OF REVIEW To provide an updated overview of the complex coagulopathy associated with malignancy, together with the advances in our knowledge of the interactions of cancer with the hemostatic system. Also, to offer an update of the recent progresses in the risk assessment, prevention, and treatment of thrombohemorrhagic complications in cancer patients. RECENT FINDINGS Mechanisms underlying the hemostatic derangement caused by cancer include many prothrombotic properties of tumor tissues. Of extreme interest are the most recent findings that the regulation of tumor cell hemostatic protein expression is driven by oncogenes, the tumor-derived tissue factor-positive microparticles are an important player in thrombosis, and the changes in the tumor microenvironment in the presence of tissue factor affect 'dormant' cells to shift to a malignant phenotype.On the clinical side, risk assessment models, based on clinical and biological risk factors, are becoming very attractive to identify categories of cancer patients at different thrombotic risk. Unsuspected pulmonary embolism, incidentally discovered, is also opening an intensive area of research. Finally, new updates of the guidelines to help clinicians in the management of venous thromboembolism in cancer patient have been recently released. SUMMARY The coagulopathy of cancer is complex. Thrombotic and bleeding complications significantly contribute to morbidity and mortality in this disease. The accrued knowledge of the underlying mechanisms is helping establish more accurate and appropriate interventions for the management of the thrombotic risk in these patients.
Collapse
|
|
41
|
|
|
42
|
Han X, Guo B, Li Y, Zhu B. Tissue factor in tumor microenvironment: a systematic review. J Hematol Oncol 2014; 7:54. [PMID: 25084809 PMCID: PMC4237870 DOI: 10.1186/s13045-014-0054-8] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 07/09/2014] [Indexed: 01/01/2023] Open
Abstract
The aberrant hemostasis is a common manifestation of cancer, and venous thromboembolism (VTE) is the second leading cause of cancer patients’ mortality. Tissue factor (TF), comprising of a 47-kDa transmembrane protein that presents in subendothelial tissues and leukocytes and a soluble isoform, have distinct roles in the initiation of extrinsic coagulation cascade and thrombosis. Laboratory and clinical evidence showed the deviant expression of TF in several cancer systems and its tumor-promoting effects. TF contributes to myeloid cell recruitment in tumor stroma, thereby remodeling of tumor microenvironment. Additionally, the number of TF-positive-microparticles (TF+MP) from tumor origins correlates with the VTE rates in cancer patients. In this review, we summarize our current understanding of the TF regulation and roles in tumor progression and clinical complications.
Collapse
|
|
43
|
Bouvy C, Gheldof D, Chatelain C, Mullier F, Dogné JM. Contributing role of extracellular vesicles on vascular endothelium haemostatic balance in cancer. J Extracell Vesicles 2014; 3:24400. [PMID: 25045423 PMCID: PMC4095764 DOI: 10.3402/jev.v3.24400] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/13/2014] [Accepted: 06/13/2014] [Indexed: 12/21/2022] Open
Abstract
Extracellular vesicles (EVs) generated during tumourigenesis are thought to play a major role in the hypercoagulant state observed in cancer patients. They exhibit negatively charged phospholipids and tissue factor (TF) that promote coagulation cascade activation. In addition, they contain surface proteins and cytoplasmic molecules, both originating from the producing cell that can impact target cells’ expression. By targeting endothelial cells of blood vessels, these EVs could disturb the physiological anticoagulant properties of these cells and be partly responsible for the vascular endothelium activation observed in cancer patients. Indeed, vascular endothelium naturally exhibits heparin-like proteoglycan, TF pathway inhibitor and protein C anticoagulant pathway that prevent thrombosis in physiological condition. An overexpression of TF and a decreased expression of coagulation cascade inhibitors have been reported after EVs’ treatment of endothelial cells. The induction of apoptosis and an increased expression of platelet adhesion molecules have also been highlighted. These events may promote thrombus formation in cancer. The aim of this paper is to provide a targeted review on the current evidence and knowledge of roles and impact of EVs on endothelial surface anticoagulant and procoagulant factors and cellular adhesion molecules expression.
Collapse
Affiliation(s)
- Céline Bouvy
- Department of Pharmacy, Namur Research Institute of Life Sciences (NARILIS), Namur Thrombosis and Hemostasis Center (NTHC), University of Namur, Namur, Belgium
| | - Damien Gheldof
- Department of Hematology, Namur Thrombosis and Hemostasis Center (NTHC), CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium
| | - Christian Chatelain
- Department of Hematology, Namur Thrombosis and Hemostasis Center (NTHC), CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium
| | - François Mullier
- Department of Hematology, Namur Thrombosis and Hemostasis Center (NTHC), CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium
| | - Jean-Michel Dogné
- Department of Pharmacy, Namur Research Institute of Life Sciences (NARILIS), Namur Thrombosis and Hemostasis Center (NTHC), University of Namur, Namur, Belgium
| |
Collapse
|
|
44
|
Liang Z, Han R, Qu Y, Cao W, Cui J. Role of prophylactic filter placement in the endovascular treatment of symptomatic thrombosis in the central veins. Thromb Res 2014; 134:57-62. [DOI: 10.1016/j.thromres.2014.04.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 03/24/2014] [Accepted: 04/11/2014] [Indexed: 10/25/2022]
|
|
45
|
Tanasanvimon S, Garg N, Viswanathan C, Truong M, Kaur H, Kee BK, Sahin IH, Javle MM, Garrett CR. High prevalence of recurrent thrombosis in subsets of cancer patients with isolated gonadal vein thrombosis: A single center retrospective study. Thromb Res 2014; 133:154-7. [DOI: 10.1016/j.thromres.2013.10.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 08/06/2013] [Accepted: 10/17/2013] [Indexed: 12/01/2022]
|
|
46
|
Bach AG, Schmoll HJ, Beckel C, Behrmann C, Spielmann RP, Wienke A, Abbas J, Surov A. Pulmonary embolism in oncologic patients: frequency and embolus burden of symptomatic and unsuspected events. Acta Radiol 2014; 55:45-53. [PMID: 23864061 DOI: 10.1177/0284185113491569] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Pulmonary embolism (PE) is a common cause of morbidity and mortality in oncologic patients. Furthermore, PE is an unsuspected finding in many cases. PURPOSE To determine the frequency and embolus burden of PE in a consecutive oncologic patient group including symptomatic as well as incidental and initially unreported events. MATERIAL AND METHODS In a retrospective, single-center study from June 2005 to January 2010 all patients with an oncologic disease (ICD-10 code C00 to C96) that received at least one contrast-enhanced computed tomography (CT) examination of the chest were reviewed. The study group included 3270 patients with 6780 examinations. A validated pulmonary artery obstruction index (Mastora score) was used to assess embolus burden. RESULTS PE was found in 240 of 3270 (7.3%) oncologic patients. The frequency was highly variable among different malignancies ranging from 0% to 25%. In the present study about half of all PE were unsuspected. The mean embolus burden was significantly higher in symptomatic PE than in unsuspected PE (P <0.001). The risk of developing a PE was 1.5 times higher in patients with metastases compared to patients without metastases (P <0.005). Age and sex had no influence on PE risk and embolus burden. CONCLUSION PE is a frequent unsuspected finding in staging examinations: particularly in patients with malignancies of the ovary, brain, and pancreas, and in patients with metastases. Therefore, the status of the pulmonary vasculature should be assessed in every staging examination that includes the chest. The effect of therapeutic actions on PE events and the unsuspected finding of PE in follow-up CT examinations require further prospective studies.
Collapse
Affiliation(s)
- Andreas Gunter Bach
- Department of Radiology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Hans-Joachim Schmoll
- Department of Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Christoph Beckel
- Department of Radiology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Curd Behrmann
- Department of Radiology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Rolf Peter Spielmann
- Department of Radiology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Andreas Wienke
- Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Jasmin Abbas
- Department of Radiology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Alexey Surov
- Department of Radiology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| |
Collapse
|
|
47
|
Abstract
Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, are common problems experienced by patients with lung cancer that can impact treatment plans, prognoses, and survival. Patients with lung cancer are at greatest risk for development of VTE in the ambulatory care treatment setting. Literature does exist on VTE management for medical and surgical oncology inpatients, as well as clinical guidelines for inpatient prophylaxis; however, published evidence is lacking on outpatient risk and thromboprophylaxis in medical oncology outpatients, particularly patients with lung cancer. Because patients with lung cancer treated in the ambulatory setting have established risks for VTE, they may benefit from thromboprophylaxis. Clinical guidelines for outpatient thromboprophylaxis direct the clinical practice for thromboprophylaxis in lung cancer treatment. The purpose of the current article is to explore the VTE risks associated with ambulatory lung cancer treatment and to review the recommended guidelines for thromboprophylaxis to guide clinical decision making for patients with lung cancer.
Collapse
Affiliation(s)
- Loretta Cavaliere
- Jefferson School of Nursing, Thomas Jefferson University, Philadelphia, PA, USA.
| |
Collapse
|
|
48
|
Falanga A, Marchetti M, Vignoli A. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013; 11:223-33. [PMID: 23279708 DOI: 10.1111/jth.12075] [Citation(s) in RCA: 355] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Malignancy affects the hemostatic system and the hemostatic system affects malignancy. In cancer patients there are a number of coagulation abnormalities which provide the background for an increased tendency of these patients to both thrombosis and hemorrhage. The causes of this coagulation impairment rely on general risk factors which are common to other categories of patients, and other factors which are specific to cancer, such as tumor type and disease stage. In addition, data from basic research indicate that the hemostatic components and the cancer biology are interconnected in multiple ways. Notably, while cancer cells are able to activate the coagulation system, the hemostatic factors play a role in tumor progression. This opens the way to the development of bifunctional therapeutic approaches that are both capable of attacking the malignant process and resolving the coagulation impairment. On the other hand, the management of thrombosis and hemorrhages in cancer patients can be different. To approach these problems, some guidelines have been released by prominent international scientific societies. Also actively investigated is the issue of identifying new biomarkers to classify the subjects at a higher risk, thus improving the prevention of thrombohemorrhagic events in these patients. Finally, novel prophylactic and therapeutic approaches are currently under development. This review provides an overview of the hemostatic complications in cancer, together with new insights into the interaction between hemostasis and cancer biology. We also review the assessment of the risk of thrombohemorrhagic events in cancer patients, and the prophylaxis and treatment of such manifestations.
Collapse
Affiliation(s)
- A Falanga
- Division of Immunohematology and Transfusion Medicine, Ospedali Riuniti, Bergamo, Italy.
| | | | | |
Collapse
|
|
49
|
Date K, Hall J, Greenman J, Maraveyas A, Madden LA. Tumour and microparticle tissue factor expression and cancer thrombosis. Thromb Res 2012; 131:109-15. [PMID: 23237339 DOI: 10.1016/j.thromres.2012.11.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Revised: 11/12/2012] [Accepted: 11/15/2012] [Indexed: 12/22/2022]
Abstract
Cancer is frequently complicated by venous thromboembolic events (VTE), which pose a significant health burden due to the associated high morbidity and mortality rates, yet the exact details of the pathophysiological mechanisms underlying their development are yet to be fully elucidated. Tissue factor (TF), the primary initiator of coagulation, is often overexpressed in malignancy and as such is a prime candidate in predicting the hypercoagulable state. Further exploration of this potential role has identified increases in the number of TF-expressing microparticles (MP) in the circulation of cancer patients, in particular in those known to have high incidences of thromboembolic complications. The risk of VTE in cancer is found to be further elevated by chemotherapy. Chemotherapy may, in eliciting cancer cell apoptosis, result in an increase in release of circulating procoagulant MP. We discuss a potential role of elevated tumour TF expression and increased circulating TF-positive MP in predicting VTE risk.
Collapse
Affiliation(s)
- Kathryn Date
- Department of Biological Sciences, University of Hull, Hull, HU6 7RX, UK.
| | | | | | | | | |
Collapse
|
|
50
|
|