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1
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Gayibov E, Karim AH. A Rapid Review of Adenocarcinoma and Pulmonary Tumor Thrombotic Microangiopathy: A Deadly Duo. Cureus 2025; 17:e76842. [PMID: 39897287 PMCID: PMC11787629 DOI: 10.7759/cureus.76842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2025] [Indexed: 02/04/2025] Open
Abstract
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare paraneoplastic syndrome associated with various adenocarcinomas, most commonly gastric adenocarcinoma. This condition can progressively worsen pulmonary arterial hypertension, leading to acute or subacute pulmonary heart failure and respiratory insufficiency. This paper examines the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of PTTM. Given PTTM's poor prognosis, we emphasize treatment strategies. PTTM in adenocarcinoma patients can mimic other pulmonary diseases, causing diagnostic delays. Current PTTM treatment strategies primarily focus on managing the underlying malignancy and addressing thrombotic complications. Anti-angiogenic therapy with bevacizumab and the platelet-derived growth factor receptor antagonist imatinib have shown promise in multiple cases. Further research is needed to develop more effective and targeted therapies for this challenging condition. The precise mechanisms underlying this association remain to be fully elucidated.
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Affiliation(s)
- Emin Gayibov
- Third Faculty of Medicine, Charles University, Prague, CZE
| | - Amin H Karim
- Department of Cardiovascular Disease, Baylor College of Medicine, Houston, USA
- Department of Cardiovascular Disease, Weill Medical College of Cornell University, New York City, USA
- Department of Cardiovascular Disease, Methodist Academy of Medicine, Houston, USA
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2
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Roy DC, Wang TF, Lun R, Zahrai A, Mallick R, Burger D, Zitikyte G, Hawken S, Wells P. Circulating Blood Biomarkers and Risk of Venous Thromboembolism in Cancer Patients: A Systematic Review and Meta-Analysis. Thromb Haemost 2024; 124:1117-1133. [PMID: 38768631 DOI: 10.1055/a-2330-1371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
BACKGROUND Cancer patients have an increased risk of venous thromboembolism (VTE). Currently, the availability of highly discriminatory prediction models for VTE in cancer patients is limited. The implementation of biomarkers in prediction models might lead to refined VTE risk prediction. In this systematic review and meta-analysis, we aimed to evaluate candidate biomarkers and their association with cancer-associated VTE. METHODS We searched Medline, EMBASE, and Cochrane Central for studies that evaluated biomarkers in adult cancer patients from inception to September 2022. We included studies reporting on VTE after a cancer diagnosis with biomarker measurements performed at a defined time point. Median/mean differences (for continuous measures) and odds ratios (for dichotomous measures) with 95% confidence intervals were estimated and pooled using random-effects models. RESULTS We included 113 studies in the systematic review. Of these, 50 studies were included in the meta-analysis. We identified two biomarkers at cancer diagnosis (factor VIII and time to peak thrombin), three biomarkers pre-chemotherapy (D-dimer, fibrinogen, and mean platelet volume), and one biomarker preoperatively (platelet count) that had significant median or mean differences. Additionally, we found that hemoglobin <100 g/L and white blood count >11 × 109/L were significantly associated with future VTE risk only when measured at cancer diagnosis. Pre-chemotherapy neutrophil-to-lymphocyte ratio ≥3 and preoperative platelet count ≥400 × 109/L were also found to be associated with future VTE risk. CONCLUSION In conclusion, this study identified nine candidate blood biomarkers that may help in optimizing VTE prediction in cancer patients that should be further explored in future studies.
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Affiliation(s)
- Danielle Carole Roy
- Faculty of Medicine, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Tzu-Fei Wang
- Faculty of Medicine, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Ronda Lun
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Vascular Neurology, Stanford Healthcare, Palo Alto, California, United States
| | - Amin Zahrai
- Faculty of Medicine, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | | | - Dylan Burger
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Gabriele Zitikyte
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - Steven Hawken
- Faculty of Medicine, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Philip Wells
- Faculty of Medicine, School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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3
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Favaloro EJ, Pasalic L, Lippi G. Laboratory Testing for ADAMTS13 for Thrombotic Thrombocytopenia Purpura and Beyond. Semin Thromb Hemost 2024. [PMID: 39467573 DOI: 10.1055/s-0044-1792003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/30/2024]
Abstract
ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also called von Willebrand factor (VWF) cleaving protease, acts as a moderator of VWF activity. ADAMTS13 cleaves VWF multimers, thereby reducing VWF activity in blood. When ADAMTS13 is absent (e.g., in patients with TTP [thrombotic thrombocytopenia purpura]), accumulation of VWF in plasma can occur, particularly as "ultra-large" VWF multimers, with this leading to adverse outcomes such as thrombosis. Relative ADAMTS13 deficiencies also occur in several other conditions, including secondary thrombotic microangiopathies (TMA), cancer, and with severe infections such as in COVID-19 (coronavirus disease 2019). These situations might therefore be accompanied with relative loss of ADAMTS13, thereby potentially also leading to pathological VWF accumulation, with this then generating a prothrombotic milieu, thus contributing to enhance the risk of thrombosis. Laboratory testing for ADAMTS13 can aid in the diagnosis of such disorders (i.e., TTP, TMA), and help guide their management, with testing now accomplished using various assays. As most presentations of TTP reflect an acquired condition due to anti-ADAMTS13 antibodies, there may also be a need to test for these, as this will also influence clinical management. We herein provide an overview of TTP, note other conditions in which low levels of ADAMTS13 may be present, and then detail laboratory testing for both ADAMTS13 and associated inhibitors.
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Affiliation(s)
- Emmanuel J Favaloro
- Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, NSW, Australia
- School of Dentistry and Medical Sciences, Faculty of Science and Health, Charles Sturt University, Wagga Wagga, NSW, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Westmead Hospital, Westmead, NSW, Australia
| | - Leonardo Pasalic
- Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead, Westmead Hospital, NSW, Australia
| | - Giuseppe Lippi
- Section of Clinical Biochemistry, University of Verona, Verona, Italy
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4
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Xu W, Tan X, Li ML, Xu H, Villegas J, Fu H. Von Willebrand factor and hematogenous cancer metastasis under flow. Front Cell Dev Biol 2024; 12:1435718. [PMID: 39282473 PMCID: PMC11401050 DOI: 10.3389/fcell.2024.1435718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 09/19/2024] Open
Abstract
Hematogenous metastasis involves cancer cell migration to different locations from the primary tumor through the blood circulation. Von Willebrand factor (VWF) has been shown to play an important role in tumor cell adhesion to and extravasation from the endothelial cell lining of blood vessel walls during cancer metastasis. VWF may contribute to this process by interacting with tumor cells, endothelial cells, and platelets through various cell membrane receptors, such as platelet glycoprotein (GP)Ibα, P-selectin, ανβ3 and αIIbβ3 integrins, and glycocalyx. Blood flow can mechanically extend and activate VWF to bind platelets and associate intermolecularly with other VWF molecules in plasma or on the surface of endothelial cells, cancer cells, or platelets. This suggests a mechanoregulatory role of VWF in mediating the interactions between VWF and these cells to promote cancer cell adhesion to blood vessels. In this review, we will summarize the current knowledge of VWF function and the role of hydrodynamic forces in hematogenous cancer metastasis.
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Affiliation(s)
- Wenxuan Xu
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Xi Tan
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Morgan L Li
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Hanzhi Xu
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Jasmine Villegas
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Hongxia Fu
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
- Bloodworks Research Institute, Seattle, WA, United States
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5
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Wang X, Zhang X, Zhang C, Qi L, Liu J. Plasma von Willebrand factor levels in patients with cancer: A meta‑analysis. Oncol Lett 2024; 28:399. [PMID: 38979552 PMCID: PMC11228924 DOI: 10.3892/ol.2024.14532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 06/17/2024] [Indexed: 07/10/2024] Open
Abstract
von Willebrand Factor (VWF) is well recognized for being dysregulated in various malignancies and has emerged as a potential biomarker for cancer detection. The present meta-analysis aimed to elucidate the association between plasma VWF and the incidence and metastasis of cancer. For this purpose, a comprehensive search was conducted across multiple databases from their inception until March 3, 2023. This culminated in the selection of 15 original studies on various types of cancer, including a collective sample of 1,403 individuals. The standardized mean difference (SMD) and 95% confidence intervals (CIs) were employed as statistical parameters to determine the association between plasma VWF and the incidence and metastasis of cancer. These were estimated using a random-effects model. The pooled data revealed that the plasma VWF levels of patients with cancer were significantly elevated compared with those of healthy controls (SMD, 0.98; 95% CI, 0.59-1.36), and a significant association was observed between plasma VWF levels and cancer metastasis (SMD, 0.69; 95% CI, 0.33-1.06). The symmetry of the Begg's funnel plots indicated that no significant bias was present in the analyses of VWF in cancer and its metastasis. In summary, the results of the present meta-analysis support the hypothesis that increased plasma VWF levels may serve as a biomarker for cancer and metastatic progression.
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Affiliation(s)
- Xitan Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Xiaoyu Zhang
- Department of Medical Physiology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Chaonan Zhang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Li Qi
- Department of Infectious Diseases, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Ju Liu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
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6
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Wang QF, Li ZW, Zhou HF, Zhu KZ, Wang YJ, Wang YQ, Zhang YW. Predicting the prognosis of hepatic arterial infusion chemotherapy in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:2380-2393. [PMID: 38994149 PMCID: PMC11236234 DOI: 10.4251/wjgo.v16.i6.2380] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/19/2024] [Accepted: 04/03/2024] [Indexed: 06/14/2024] Open
Abstract
Hepatic artery infusion chemotherapy (HAIC) has good clinical efficacy in the treatment of advanced hepatocellular carcinoma (HCC); however, its efficacy varies. This review summarized the ability of various markers to predict the efficacy of HAIC and provided a reference for clinical applications. As of October 25, 2023, 51 articles have been retrieved based on keyword predictions and HAIC. Sixteen eligible articles were selected for inclusion in this study. Comprehensive literature analysis found that methods used to predict the efficacy of HAIC include serological testing, gene testing, and imaging testing. The above indicators and their combined forms showed excellent predictive effects in retrospective studies. This review summarized the strategies currently used to predict the efficacy of HAIC in middle and advanced HCC, analyzed each marker's ability to predict HAIC efficacy, and provided a reference for the clinical application of the prediction system.
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Affiliation(s)
- Qi-Feng Wang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Zong-Wei Li
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Hai-Feng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Kun-Zhong Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Ya-Jing Wang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
| | - Ya-Qin Wang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
| | - Yue-Wei Zhang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
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7
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Wang QF, Li ZW, Zhou HF, Zhu KZ, Wang YJ, Wang YQ, Zhang YW. Predicting the prognosis of hepatic arterial infusion chemotherapy in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:2368-2381. [DOI: 10.4251/wjgo.v16.i6.2368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/19/2024] [Accepted: 04/03/2024] [Indexed: 06/13/2024] Open
Abstract
Hepatic artery infusion chemotherapy (HAIC) has good clinical efficacy in the treatment of advanced hepatocellular carcinoma (HCC); however, its efficacy varies. This review summarized the ability of various markers to predict the efficacy of HAIC and provided a reference for clinical applications. As of October 25, 2023, 51 articles have been retrieved based on keyword predictions and HAIC. Sixteen eligible articles were selected for inclusion in this study. Comprehensive literature analysis found that methods used to predict the efficacy of HAIC include serological testing, gene testing, and imaging testing. The above indicators and their combined forms showed excellent predictive effects in retrospective studies. This review summarized the strategies currently used to predict the efficacy of HAIC in middle and advanced HCC, analyzed each marker's ability to predict HAIC efficacy, and provided a reference for the clinical application of the prediction system.
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Affiliation(s)
- Qi-Feng Wang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Zong-Wei Li
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Hai-Feng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Kun-Zhong Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai University Affiliated Hospital, Xining 810000, Qinghai Province, China
| | - Ya-Jing Wang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
| | - Ya-Qin Wang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
| | - Yue-Wei Zhang
- Department of Hepatobiliary Pancreatic Center, Beijing Tsinghua Changgung Hospital Affiliated to Tsinghua University, Beijing 102218, China
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8
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Tatsumi K. The pathogenesis of cancer-associated thrombosis. Int J Hematol 2024; 119:495-504. [PMID: 38421488 DOI: 10.1007/s12185-024-03735-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/13/2024] [Accepted: 02/18/2024] [Indexed: 03/02/2024]
Abstract
Patients with cancer have a higher risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), compared to the general population. Cancer-associated thrombosis (CAT) is a thrombotic event that occurs as a complication of cancer or cancer therapy. Major factors determining VTE risk in cancer patients include not only treatment history and patient characteristics, but also cancer type and site. Cancer types can be broadly divided into three groups based on VTE risk: high risk (pancreatic, ovarian, brain, stomach, gynecologic, and hematologic), intermediate risk (colon and lung), and low risk (breast and prostate). This implies that the mechanism of VTE differs between cancer types and that specific VTE pathways may exist for different cancer types. This review summarizes the specific pathways that contribute to VTE in cancer patients, with a particular focus on leukocytosis, neutrophil extracellular traps (NETs), tissue factor (TF), thrombocytosis, podoplanin (PDPN), plasminogen activator inhibitor-1 (PAI-1), the intrinsic coagulation pathway, and von Willebrand factor (VWF).
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Affiliation(s)
- Kohei Tatsumi
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, 634-8521, Japan.
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9
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Willems RAL, Biesmans C, Campello E, Simioni P, de Laat B, de Vos-Geelen J, Roest M, Ten Cate H. Cellular Components Contributing to the Development of Venous Thrombosis in Patients with Pancreatic Cancer. Semin Thromb Hemost 2024; 50:429-442. [PMID: 38049115 DOI: 10.1055/s-0043-1777304] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer and has a poor prognosis. Patients with PDAC are at high risk of developing thromboembolic events, which is a leading cause of morbidity and mortality following cancer progression. Plasma-derived coagulation is the most studied process in cancer-associated thrombosis. Other blood components, such as platelets, red blood cells, and white blood cells, have been gaining less attention. This narrative review addresses the literature on the role of cellular components in the development of venous thromboembolism (VTE) in patients with PDAC. Blood cells seem to play an important role in the development of VTE. Altered blood cell counts, i.e., leukocytosis, thrombocytosis, and anemia, have been found to associate with VTE risk. Tumor-related activation of leukocytes leads to the release of tissue factor-expressing microvesicles and the formation of neutrophil extracellular traps, initiating coagulation and forming a scaffold for thrombi. Tissue factor-expressing microvesicles are also thought to be released by PDAC cells. PDAC cells have been shown to stimulate platelet activation and aggregation, proposedly via the secretion of podoplanin and mucins. Hypofibrinolysis, partially explained by increased plasminogen activator inhibitor-1 activity, is observed in PDAC. In short, PDAC-associated hypercoagulability is a complex and multifactorial process. A better understanding of cellular contributions to hypercoagulability might lead to the improvement of diagnostic tests to identify PDAC patients at highest risk of VTE.
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Affiliation(s)
- Ruth Anne Laura Willems
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
- Thrombosis Expert Center Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM, School for Cardiovascular Diseases, Maastricht, The Netherlands
| | - Charlotte Biesmans
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
- Thrombosis Expert Center Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Elena Campello
- General Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Paolo Simioni
- General Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Bas de Laat
- Department of Functional Coagulation, Synapse Research Institute, Maastricht, The Netherlands
- CARIM, School for Cardiovascular Diseases, Maastricht, The Netherlands
- Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
| | - Judith de Vos-Geelen
- Division of Medical Oncology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- GROW, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Mark Roest
- Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
| | - Hugo Ten Cate
- Thrombosis Expert Center Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM, School for Cardiovascular Diseases, Maastricht, The Netherlands
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Pamulapati S, Conroy M, Madireddy S, Kamaraju S, Cortina C, Moore H, Hartmann J. Applications of Viscoelastic Testing in Breast Cancer Patients: A Systematic Review Focusing on Hypercoagulability and Free Flap Thrombosis. Semin Thromb Hemost 2024; 50:413-422. [PMID: 37327882 DOI: 10.1055/s-0043-1769937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Viscoelastic testing is a clinically available method to assess hypercoagulability. This systematic review aims to provide a comprehensive overview of the existing literature and the potential use of such testing in patients with breast cancer. A systematic literature search for studies investigating the application of viscoelastic testing for patients with breast cancer was conducted. Studies were included as long as they were original, peer-reviewed, and in the English language. Studies were excluded if they were review articles, did not include breast cancer patients, or if the full text was unavailable. This review identified 10 articles that met the inclusion criteria. Two of the studies utilized rotational thromboelastometry, and an additional four studies used thromboelastography, to assess hypercoagulability in patients with breast cancer. Three of the identified articles discussed the use of thromboelastometry in free flap breast reconstruction for patients with breast cancer. One study was a retrospective chart review looking at thromboelastography and microsurgical breast reconstruction. Current literature regarding the application of viscoelastic testing in breast cancer and free flap breast reconstruction is limited, with no randomized trials thus far. However, some studies suggest that there may be potential utility in viscoelastic testing to assess risk for thromboembolism in breast cancer patients, and future research in this area is warranted.
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Affiliation(s)
| | | | | | - Sailaja Kamaraju
- Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Chandler Cortina
- Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Hunter Moore
- Division of Surgery-Transplant, University of Colorado School of Medicine, Aurora, Colorado
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11
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Gyldenholm T, Hvas AM, Christensen TD, Larsen JB. Thrombin Generation Markers as Predictors of Cancer-Associated Venous Thromboembolism: A Systematic Review. Semin Thromb Hemost 2024; 50:384-401. [PMID: 37813372 DOI: 10.1055/s-0043-1775856] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
Venous thromboembolism (VTE) is a main contributor to morbidity and mortality in cancer patients. Biomarkers with the potential to predict cancer-associated VTE are continually sought. Of these, markers of thrombin generation present a likely option. The present systematic review examines the ability of three widely used biomarkers of thrombin generation: prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT), and ex vivo thrombin generation, to predict VTE in both solid and hematologic adult cancer patients. Relevant studies were identified in the PubMed and Embase databases, and the review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Each study was evaluated using the quality assessment tool from the National Heart, Lung, and Blood Institute. The review protocol was published on PROSPERO with identifier CRD42022362339. In total, 24 papers were included in the review: 11 reporting data on F1.2, 9 on TAT, and 12 on ex vivo thrombin generation. The quality ratings of the included studies varied from good (n = 13), fair (n = 8), to poor (n = 3) with a high heterogenicity. However, F1.2, TAT complex, and ex vivo thrombin generation were all found to be associated with the development of VTE. This association was most pronounced for F1.2. Furthermore, the determination of F1.2 was able to improve the precision of several established risk assessment scores. In conclusion, markers of thrombin generation were found to be elevated in cancer patients with VTE, and particularly, F1.2 was found to be a promising predictor of cancer-associated VTE.
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Affiliation(s)
- Tua Gyldenholm
- Department of Clinical Biochemistry, Thrombosis and Haemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Thomas Decker Christensen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark
| | - Julie Brogaard Larsen
- Department of Clinical Biochemistry, Thrombosis and Haemostasis Research Unit, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Elsherif S, Zidan A, Saville O, Othman M. ABO Blood Group and the Risk of Thrombosis in Cancer Patients: A Mini-Review. Semin Thromb Hemost 2024; 50:423-428. [PMID: 37751774 DOI: 10.1055/s-0043-1775568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Abstract
Cancer-associated thrombosis (CT), especially venous thromboembolism (VTE), is a common occurrence with several factors contributing to a wide diversity in thrombosis risk. The association between ABO blood groups and the risk for CT has been examined in various studies, with non-O blood type associated with an increased thrombosis risk; however, these studies have reported varying results with recognized limitations. ABO blood groups are known to be implicated in hemostasis, in an association mediated through von Willebrand factor (VWF). In this narrative review, we aim to summarize the current knowledge surrounding the role of ABO blood groups in VTE, with a particular focus on the role of VWF and other contributing risk factors on VTE occurrence. We found evidence from literature for the impact of ABO blood groups in determining the risk of VTE in healthy populations, with a limited number of studies examining this effect in cancer patients. Additionally, research on the impact of ABO on different cancer types lacks rigor, particularly in regard to other risk factors. Overall, most studies showed strong association of increased risk of VTE amongst cancer patients with non-O blood groups and increased VWF levels. This association was weaker in a few studies. Further research is needed before a solid conclusion can be made about the ABO or ABO-VWF-mediated hypercoagulability and VTE risk in various cancers. These studies will help determine if ABO typing can be an added biomarker to improve VTE risk assessment models in cancer patients.
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Affiliation(s)
- Salah Elsherif
- Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Ali Zidan
- Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Olivia Saville
- Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Maha Othman
- Department of Biomedical and Molecular Sciences, School of Medicine, Queen's University, Kingston, Ontario, Canada
- Department of Nursing, School of Baccalaureate Nursing, St. Lawrence College, Kingston, Ontario, Canada
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansura, Egypt
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Najafi S, Asemani Y, Majidpoor J, Mahmoudi R, Aghaei-Zarch SM, Mortezaee K. Tumor-educated platelets. Clin Chim Acta 2024; 552:117690. [PMID: 38056548 DOI: 10.1016/j.cca.2023.117690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 11/29/2023] [Accepted: 12/02/2023] [Indexed: 12/08/2023]
Abstract
Beyond traditional roles in homeostasis and coagulation, growing evidence suggests that platelets also reflect malignant transformation in cancer. Platelets are present in the tumor microenvironment where they interact with cancer cells. This interaction results in direct and indirect "education" as evident by platelet alterations in adhesion molecules, glycoproteins, nucleic acids, proteins and various receptors. Subsequently, these tumor-educated platelets (TEPs) circulate throughout the body and play pivotal roles in promotion of tumor growth and dissemination. Accordingly, platelet status can be considered a unique blood-based biomarker that can potentially predict prognosis and therapeutic success. Recently, liquid biopsies including TEPs have received much attention as safe, minimally invasive and sensitive alternatives for patient management. Herein, we provide an overview of TEPs and explore their benefits and limitations in cancer.
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Affiliation(s)
- Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yahya Asemani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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Balbi GGM, Signorelli F, Gandara AP, Azam I, de Barros S, Marreiros D, Genta PR, Lotufo PA, Benseñor IM, Drager LF, Andrade D. Comorbid association of obstructive sleep apnea (OSA) and thrombotic primary antiphospholipid syndrome (tPAPS): A more severe phenotype? Clin Immunol 2023; 256:109781. [PMID: 37748561 DOI: 10.1016/j.clim.2023.109781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/23/2023] [Accepted: 09/19/2023] [Indexed: 09/27/2023]
Abstract
OBJECTIVE We aimed to evaluate the frequency of obstructive sleep apnea (OSA) in patients with thrombotic primary antiphospholipid syndrome (tPAPS), to investigate the performance of screening tools for OSA in this scenario and to compare clinical/laboratorial differences in tPAPS patients with and without OSA. METHODS We consecutively enrolled patients with tPAPS to undergo sleep studies using a portable monitor. OSA was defined as apnea-hypopnea index ≥15 events/h. Frequency of OSA in tPAPS was evaluated and compared with age-, gender-, and BMI-matched controls (1:3 ratio) from the Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Next, we tested the performance of three different screening tools for assessing OSA in patients with tPAPS. Finally, patients with tPAPS were stratified according to OSA status comparing their clinical and laboratory characteristics (including damage burden measured by Damage Index for Antiphospholipid Syndrome [DIAPS] and biomarkers associated with thrombosis) using standard statistical procedures. RESULTS Fifty-two patients were included for analysis (females: 82.7%; mean age: 48 ± 14 years; body-mass index: 31.1 ± 6.5 Kg/m2; 25% with moderate-severe OSA). When compared to matched controls from ELSA-Brasil (n = 115), there was no significant differences in the frequencies of OSA (tPAPS: 12/42 [28.6%] vs. controls: 35/115 [30.4%], p = 0.821). Among screening tools, NoSAS had the highest area under ROC curve (AUC 0.806, CI 95% 0.672-0.939, p = 0.001), followed by STOP-Bang (AUC 0.772, CI 95% 0.607-0.938, p = 0.004). Patients with comorbid tPAPS and OSA presented higher levels of von Willebrand factor (vWF) (median 38.9 vs. 32.6, p = 0.038) and DIAPS (median 5 vs. 2, p = 0.020), when compared to those without OSA. OSA remained statistically associated with higher DIAPS, even after controlling for age, disease duration and BMI. CONCLUSION OSA is common in patients with tPAPS, with rates comparable to a non-referred population. Both NoSAS and STOP-Bang scores seems to be useful for screening OSA in these patients. Patients with tPAPS+OSA had higher damage burden and higher levels of vWF, which might suggest a more severe phenotype of tPAPS in this scenario.
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Affiliation(s)
- Gustavo Guimarães Moreira Balbi
- Rheumatology Division, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil; Rheumatology Division, Internal Medicine Department, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil
| | - Flavio Signorelli
- Rheumatology Division, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil; Rheumatology Division, Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Ana Paula Gandara
- Rheumatology Division, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Indira Azam
- Unidade de Hipertensão, Disciplina de Nefrologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Silvana de Barros
- Unidade de Hipertensão, Disciplina de Nefrologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Dilson Marreiros
- Rheumatology Division, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Pedro Rodrigues Genta
- Laboratório do Sono, Divisão de Pneumologia, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Paulo Andrade Lotufo
- Center for Clinical and Epidemiological Research, University Hospital, University of Sao Paulo, Sao Paulo, Brazil
| | - Isabela M Benseñor
- Center for Clinical and Epidemiological Research, University Hospital, University of Sao Paulo, Sao Paulo, Brazil
| | - Luciano F Drager
- Unidade de Hipertensão, Disciplina de Nefrologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil; Center for Clinical and Epidemiological Research, University Hospital, University of Sao Paulo, Sao Paulo, Brazil; Unidade de Hipertensão, Instituto do Coração (InCor) do Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Danieli Andrade
- Rheumatology Division, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil.
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Spena S, Cairo A, Gianniello F, Pappalardo E, Mortarino M, Garagiola I, Martinelli I, Peyvandi F. Genetic Variants Identified by Whole Exome Sequencing in a Large Italian Family with High Plasma Levels of Factor VIII and Von Willebrand Factor. Int J Mol Sci 2023; 24:14167. [PMID: 37762470 PMCID: PMC10532311 DOI: 10.3390/ijms241814167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
High plasma levels of factor VIII (FVIII) and von Willebrand factor (VWF) have been indicated as independent risk factors for venous thromboembolism. However, the genetic factors responsible for their increase remain poorly known. In a large Italian family with high FVIII/VWF levels and thrombotic episodes, whole exome sequencing (WES) was performed on 12 family members to identify variants/genes involved in FVIII/VWF increase. Twenty variants spread over a 8300 Kb region on chromosome 5 were identified in 12 genes, including the low frequency rs13158382, located upstream of the MIR143/145 genes, which might affect miR-143/145 transcription or processing. The expression of miR-143/145 and VWF mRNA were evaluated in the peripheral blood mononuclear cells of six family members. Members with the variant (n = 3) showed lower levels of both miRNAs and higher levels of VWF mRNA compared to members without the variant (n = 3). An analysis of genetic and expression data from a larger cohort of individuals from the 1000 Genomes and GEUVADIS project confirmed a statistically significant reduction (p-value = 0.023) in miR-143 in heterozygous (n = 35) compared to homozygous wild-type individuals (n = 386). This family-based study identified a new genetic variant potentially involved in VWF increase by affecting miR-143/145 expression.
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Affiliation(s)
- Silvia Spena
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy; (S.S.); (A.C.); (F.G.); (M.M.); (I.G.); (I.M.)
| | - Andrea Cairo
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy; (S.S.); (A.C.); (F.G.); (M.M.); (I.G.); (I.M.)
| | - Francesca Gianniello
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy; (S.S.); (A.C.); (F.G.); (M.M.); (I.G.); (I.M.)
| | - Emanuela Pappalardo
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy;
| | - Mimosa Mortarino
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy; (S.S.); (A.C.); (F.G.); (M.M.); (I.G.); (I.M.)
| | - Isabella Garagiola
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy; (S.S.); (A.C.); (F.G.); (M.M.); (I.G.); (I.M.)
| | - Ida Martinelli
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy; (S.S.); (A.C.); (F.G.); (M.M.); (I.G.); (I.M.)
| | - Flora Peyvandi
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy; (S.S.); (A.C.); (F.G.); (M.M.); (I.G.); (I.M.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy;
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Kwiatkowska K, Rhone P, Koziorzemska P, Formanowicz D, Ruszkowska-Ciastek B. Complex Analysis of Endothelial Markers as Potential Prognostic Indicators in Luminal Invasive Breast Carcinoma Patients: Outcomes of a Six-Year Observational Study. Biomedicines 2023; 11:2246. [PMID: 37626742 PMCID: PMC10452676 DOI: 10.3390/biomedicines11082246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 07/22/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
(1) Background: Metastasis is a complex process in which the primary cancer cells spread to a distant organ or organs, creating a secondary tumor location, which in many patients leads to treatment failure and death. The aim of the present study was to assess the association of endothelial markers (i.e., sP-selectin, sE-selectin and von Willebrand factor) with the leptin-to-adiponectin ratio (LAR) and to perform an analysis of the predictive value on the survival of patients with luminal A and B invasive breast cancer (IBrC). (2) Methods: The trial included 70 treatment-naïve early-stage IBrC patients with a median age of 54.5 years and a median tumor diameter of 1.5 cm. The median duration of follow-up was 5.7 years, with a relapse rate of 15.71%. Specific immunoenzymatic kits were used to determine pre- and post-treatment concentrations of analyzed factors. (3) Results: Regardless of the treatment pattern, endothelial marker concentrations and the LAR increased after adjuvant treatment. The follow-up showed a significantly higher relapse rate in patients with IBrC who had higher pre-treatment sP-selectin and post-treatment LAR levels. According to receiver operating characteristic (ROC) analysis, a post-treatment LAR with a sensitivity of 88.9% and specificity of 57.9% discriminating cases with or without disease relapse. Additionally, a higher risk of breast cancer relapse was associated with a lower post-treatment sP-selectin concentration. (4) Conclusions: Our results showed mainly that pre-treatment sP-selectin levels and post-treatment LAR may have value as prognostic indicators and may contribute to predicting the future outcomes in patients with early-stage IBrC.
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Affiliation(s)
- Katarzyna Kwiatkowska
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum, 85-094 Bydgoszcz, Poland;
| | - Piotr Rhone
- Clinical Ward of Breast Cancer and Reconstructive Surgery, Oncology Centre Prof. F. Łukaszczyk Memorial Hospital, 85-796 Bydgoszcz, Poland;
| | - Paulina Koziorzemska
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum, 85-094 Bydgoszcz, Poland;
| | - Dorota Formanowicz
- Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants-National Research, 62-064 Plewiska, Poland
| | - Barbara Ruszkowska-Ciastek
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum, 85-094 Bydgoszcz, Poland;
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Edvardsen MS, Hansen ES, Ueland T, Aukrust P, Brækkan SK, Morelli VM, Hansen JB. Impact of the von Willebrand factor-ADAMTS-13 axis on the risk of future venous thromboembolism. J Thromb Haemost 2023; 21:1227-1237. [PMID: 36736832 DOI: 10.1016/j.jtha.2023.01.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 12/30/2022] [Accepted: 01/23/2023] [Indexed: 02/04/2023]
Abstract
BACKGROUND von Willebrand factor (VWF) and its cleaving protease, ADAMTS-13, form a pivotal axis that regulates hemostasis. However, the role of the VWF-ADAMTS-13 axis in the risk of future venous thromboembolism (VTE) is unknown. OBJECTIVES To investigate whether plasma ADAMTS-13 levels and an imbalance with VWF levels, assessed as the VWF/ADAMTS-13 ratio, are associated with the risk of future VTE. PATIENTS/METHODS A population-based nested case-control study, comprising 383 incident VTE cases and 780 age- and sex-matched controls, was derived from the Tromsø study cohort (1994-2007). Antigen levels of ADAMTS-13 and VWF were measured in plasma samples obtained at cohort baseline. Odds ratios (ORs) with 95% CIs were estimated according to quartile cutoffs of ADAMTS-13 and VWF/ADAMTS-13 ratio determined in controls. RESULTS In age- and sex-adjusted analysis, ADAMTS-13 levels were inversely associated with the VTE risk, with an OR of 1.40 (95% CI, 0.99-1.99) for the lowest vs highest quartiles. The VWF/ADAMTS-13 ratio was linearly associated with the VTE risk (P for trend = .001), with an OR of 1.70 (95% CI, 1.19-2.43) for the highest vs lowest quartiles, and the association was particularly pronounced for unprovoked VTE (OR, 2.81; 95% CI, 1.65-4.81). The ORs were only slightly attenuated after additional adjustments for body mass index and C-reactive protein. CONCLUSIONS Lowered ADAMTS-13 levels and an imbalance between ADAMTS-13 and VWF levels, reflected by an increased VWF/ADAMTS-13 ratio, were associated with an increased risk of future VTE. Our findings suggest that the VWF-ADAMTS-13 axis is involved in the pathogenesis of VTE.
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Affiliation(s)
- Magnus S Edvardsen
- Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Ellen-Sofie Hansen
- Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Thor Ueland
- Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Sigrid K Brækkan
- Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Vânia M Morelli
- Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.
| | - John-Bjarne Hansen
- Thrombosis Research Center (TREC), Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway; Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
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Woods AI, Paiva J, Dos Santos C, Alberto MF, Sánchez-Luceros A. From the Discovery of ADAMTS13 to Current Understanding of Its Role in Health and Disease. Semin Thromb Hemost 2023; 49:284-294. [PMID: 36368692 DOI: 10.1055/s-0042-1758059] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
ADAMTS13 (a disintegrin-like metalloprotease domain with thrombospondin type 1 motif, member 13) is a protease of crucial importance in the regulation of the size of von Willebrand factor multimers. Very low ADAMTS13 activity levels result in thrombotic thrombocytopenic purpura, a rare and life-threatening disease. The mechanisms involved can either be acquired (immune-mediated thrombotic thrombocytopenic purpura [iTTP]) or congenital (cTTP, Upshaw-Schulman syndrome) caused by the autosomal recessive inheritance of disease-causing variants (DCVs) located along the ADAMTS13 gene, which is located in chromosome 9q34. Apart from its role in TTP, and as a regulator of microthrombosis, ADAMTS13 has begun to be identified as a prognostic and/or diagnostic marker of other diseases, such as those related to inflammatory processes, liver damage, metastasis of malignancies, sepsis, and different disorders related to angiogenesis. Since its first description almost 100 years ago, the improvement of laboratory tests and the description of novel DCVs along the ADAMTS13 gene have contributed to a better and faster diagnosis of patients under critical conditions. The ability of ADAMTS13 to dissolve platelet aggregates in vitro and its antithrombotic properties makes recombinant human ADAMTS13 treatment a potential therapeutic approach targeting not only patients with cTTP but also other medical conditions.
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Affiliation(s)
- Adriana Inés Woods
- Laboratorio de Hemostasia y Trombosis, IMEX-CONICET-Academia Nacional de Medicina de Buenos Aires, CABA, Argentina
| | - Juvenal Paiva
- Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina
| | - Celia Dos Santos
- Laboratorio de Hemostasia y Trombosis, IMEX-CONICET-Academia Nacional de Medicina de Buenos Aires, CABA, Argentina
| | - María Fabiana Alberto
- Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina
| | - Analía Sánchez-Luceros
- Laboratorio de Hemostasia y Trombosis, IMEX-CONICET-Academia Nacional de Medicina de Buenos Aires, CABA, Argentina.,Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina
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Takaya H, Namisaki T, Enomoto M, Kubo T, Tsuji Y, Fujinaga Y, Nishimura N, Kaji K, Kawaratani H, Moriya K, Akahane T, Matsumoto M, Yoshiji H. The Ratio of von Willebrand Factor Antigen to ADAMTS13 Activity: Usefulness as a Prognostic Biomarker in Acute-on-Chronic Liver Failure. BIOLOGY 2023; 12:164. [PMID: 36829443 PMCID: PMC9952680 DOI: 10.3390/biology12020164] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/10/2023] [Accepted: 01/16/2023] [Indexed: 01/22/2023]
Abstract
Acute-on-chronic liver failure (ACLF) has a high risk of short-term mortality. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). Imbalance between ADAMTS13 and VWF is associated with portal hypertension, which induces ACLF development. A previous study reported that ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) are predictive biomarkers of ACLF development in patients with cirrhosis. This study investigated the changes in ADAMTS13:AC and VWF:Ag levels from before to after the development of ACLF to determine their usefulness as a prognostic biomarker in patients with ACLF. In total, 101 patients with cirrhosis were enrolled in this study. The level of ADAMTS13:AC and VWF:Ag was determined by an enzyme-linked immunosorbent assay. Cox proportional hazard regression analysis was conducted to determine independent prognostic factors for patients with liver cirrhosis in the post-ACLF group. ADAMTS13:AC levels gradually decreased in the order of non-ACLF group, pre-ACLF group, and finally post-ACLF group. VWF:Ag and the ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) levels gradually increased in the order of non-ACLF group, pre-ACLF group, followed by post-ACLF group. VWF:Ag/ADAMTS13:AC and CLIF-C ACLF scores were associated with prognosis in the post-ACLF group in multivariate analysis. The cumulative survival of the post-ACLF group was significantly lower for patients with high VWF:Ag/ADAMTS13:AC (>9) compared with those with low VWF:Ag/ADAMTS13:AC (≤9) (HR: 10.72, 95% confidence interval: 1.39-82.78, p < 0.05). The VWF:Ag/ADAMTS13:AC increased according to the progression of ACLF in patients with cirrhosis and predicted prognosis in patients with cirrhosis with ACLF.
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Affiliation(s)
- Hiroaki Takaya
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Masahide Enomoto
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Takahiro Kubo
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Yuki Tsuji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Yukihisa Fujinaga
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Kei Moriya
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
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Xiang Q, Tao JS, Li JJ, Tian RB, Li XH. What is the role of Von Willebrand factor in chronic hepatitis B virus infection to hepatocellular carcinoma: a review article. Ther Adv Chronic Dis 2022; 13:20406223221125683. [PMID: 36407018 PMCID: PMC9669690 DOI: 10.1177/20406223221125683] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/25/2022] [Indexed: 11/12/2023] Open
Abstract
Von Willebrand factor (VWF) is a glycoprotein synthesized and secreted by vascular endothelial cells and megakaryocytes, found on plasma surface, endothelial cells, and α-granule of platelets. VWF can be interacted with collagen and platelet membrane glycoproteins GPIb and GPIb-IIa and play an important role in platelet adhesion and aggregation. Growing research evidence suggests that VWF also mediates the prevention or protesting of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients from several clinical studies. While the mechanism of VWF in HCC protection or protest is still unclear, further study is required. This article aims to rationalize the role of VWF in the development of HCC, and the functional domain of VWF in cancer as well as cross-talking with platelets and miRNAs. This article also looks forward to the future development and challenges of VWF research.
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Affiliation(s)
- Qiong Xiang
- Medical Research Center, Institute of Medicine,
Jishou University, Jishou, China
| | - Jia-Sheng Tao
- Medical Research Center, Institute of Medicine,
Jishou University, Jishou, China
| | - Jing-Jing Li
- Medical Research Center, Institute of Medicine,
Jishou University, Jishou, China
| | - Rong-Bo Tian
- Medical Research Center, Institute of Medicine,
Jishou University, Jishou, China
| | - Xian-Hui Li
- Institute of Pharmaceutical Sciences, Jishou
University, 120 Ren min south road, Jishou 416000, China
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21
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Dhami SPS, Patmore S, Comerford C, Byrne C, Cavanagh B, Castle J, Kirwan CC, Kenny M, Schoen I, O'Donnell JS, O'Sullivan JM. Breast cancer cells mediate endothelial cell activation, promoting von Willebrand factor release, tumor adhesion, and transendothelial migration. J Thromb Haemost 2022; 20:2350-2365. [PMID: 35722954 PMCID: PMC9796425 DOI: 10.1111/jth.15794] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 05/23/2022] [Accepted: 06/11/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND Breast cancer results in a three- to four-fold increased risk of venous thromboembolism (VTE), which is associated with reduced patient survival. Despite this, the mechanisms underpinning breast cancer-associated thrombosis remain poorly defined. Tumor cells can trigger endothelial cell (EC) activation resulting in increased von Willebrand factor (VWF) secretion. Importantly, elevated plasma VWF levels constitute an independent biomarker for VTE risk. Moreover, in a model of melanoma, treatment with low molecular weight heparin (LMWH) negatively regulated VWF secretion and attenuated tumor metastasis. OBJECTIVE To investigate the role of VWF in breast cancer metastasis and examine the effect of LMWH in modulating EC activation and breast tumor transmigration. METHODS von Willebrand factor levels were measured by ELISA. Primary ECs were used to assess tumor-induced activation, angiogenesis, tumor adhesion, and transendothelial migration. RESULTS AND CONCLUSION Patients with metastatic breast cancer have markedly elevated plasma VWF:Ag levels that also correlate with poorer survival. MDA-MB-231 and MCF-7 breast cancer cells induce secretion of VWF, angiopoietin-2, and osteoprotegerin from ECs, which is further enhanced by the presence of platelets. Vascular endothelial growth factor-A (VEGF-A) plays an important role in modulating breast cancer-induced VWF release. Moreover, VEGF-A from breast tumor cells also contributes to a pro-angiogenic effect on ECs. VWF multimers secreted from ECs, in response to tumor-VEGF-A, mediate adhesion of breast tumor cells along the endothelium. LMWH inhibits VWF-breast tumor adhesion and transendothelial migration. Our findings highlight the significant crosstalk between tumor cells and the endothelium including increased VWF secretion which may contribute to tumor metastasis.
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Affiliation(s)
- Sukhraj Pal Singh Dhami
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
| | - Sean Patmore
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
| | - Claire Comerford
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
| | - Ciara M. Byrne
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
| | - Brenton Cavanagh
- Cellular and Molecular Imaging CoreRoyal College of Surgeons in IrelandDublinIreland
| | - John Castle
- Manchester Cancer Research CentreThe University of ManchesterManchesterUK
| | - Cliona C. Kirwan
- Manchester Cancer Research CentreThe University of ManchesterManchesterUK
- The Nightingale CentreManchester University Foundation TrustManchester, WythenshaweUK
| | - Martin Kenny
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
| | - Ingmar Schoen
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
| | - James S. O'Donnell
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
- National Coagulation CentreSt James HospitalDublinIreland
| | - Jamie M. O'Sullivan
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular BiologyRoyal College of Surgeons in IrelandDublinIreland
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22
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Comerford C, Glavey S, Quinn J, O’Sullivan JM. The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies. J Thromb Haemost 2022; 20:1766-1777. [PMID: 35644028 PMCID: PMC9546473 DOI: 10.1111/jth.15773] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/11/2022] [Accepted: 05/25/2022] [Indexed: 11/30/2022]
Abstract
Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis despite widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand factor (VWF) levels, activated protein C resistance, impaired fibrinolysis, and abnormal thrombin generation. In addition, the toxic effect of anti-myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/factor VIII (FVIII) plasma levels have been reported in heterogeneous cohorts of patients with MM and other hematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and A Disintegrin And Metalloprotease Thrombospondin type 1, motif 13 (ADAMTS-13) axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS-13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarize the role of VWF/FVIII in hematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression.
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Affiliation(s)
- Claire Comerford
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular SciencesRoyal College of Surgeons in IrelandDublinIreland
- Department of HaematologyBeaumont HospitalDublinIreland
| | - Siobhan Glavey
- Department of HaematologyBeaumont HospitalDublinIreland
- School of PathologyRoyal College of Surgeons in IrelandDublinIreland
| | - John Quinn
- Department of HaematologyBeaumont HospitalDublinIreland
- School of MedicineRoyal College of Surgeons in IrelandDublinIreland
| | - Jamie M. O’Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular SciencesRoyal College of Surgeons in IrelandDublinIreland
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23
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Sanfilippo KM, Wang TF, Carrier M, Falanga A, Gage BF, Khorana AA, Maraveyas A, Soff GA, Wells PS, Zwicker JI. Standardization of risk prediction model reporting in cancer-associated thrombosis: Communication from the ISTH SSC subcommittee on hemostasis and malignancy. J Thromb Haemost 2022; 20:1920-1927. [PMID: 35635332 DOI: 10.1111/jth.15759] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/27/2022]
Abstract
Since the development of the Khorana score to predict risk of cancer-associated venous thromboembolism (VTE), many modified and de novo risk prediction models (RPMs) have been proposed. Comparison of the prognostic performance across models requires comprehensive reporting and standardized methods for model development, validation and evaluation. To improve the standardization of RPM reporting, the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) tool was published in 2015. To better understand the quality of reporting and development of RPMs for cancer-associated VTE, we performed a literature search of published RPMs and assessed each model using the TRIPOD checklist. Our results yielded 29 RPMs for which 30 items were evaluated. There was a non-significant (p = 0.15) improvement in reporting of the 30 items in the post-TRIPOD era (81%) versus the pre-TRIPOD era (75%). Of seven items (title, sample size, missing data handling, baseline demographics, methods and results for model performance, and supplemental resources) with the lowest reporting in the pre-TRIPOD era (<70%), there was an average improvement of 22% in the post-TRIPOD era. Only two of the 22 studies published in the post-TRIPOD era acknowledged compliance with TRIPOD. Informed by the results of this assessment, the Scientific and Standardization Committee (SSC) Subcommittee on Hemostasis & Malignancy of the International Society on Thrombosis and Hemostasis (ISTH) advocates for standardization of four key elements of RPMs for cancer-associated VTE: (1) inclusion of the TRIPOD checklist, (2) clear definition of the derivation population, with justification of sample size, (3) clear definition of predictors, and (4) external validation prior to implementation.
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Affiliation(s)
- Kristen M Sanfilippo
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
- John Cochran Saint Louis Veterans Administration Medical Center, Saint Louis, Missouri, USA
| | - Tzu-Fei Wang
- Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Marc Carrier
- Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Anna Falanga
- Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - Brian F Gage
- Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Alok A Khorana
- Taussig Cancer Institute, Cleveland Clinic and Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Anthony Maraveyas
- Faculty of Health Sciences, Joint Centre for Cancer Studies, The Hull York Medical School, Castle Hill Hospital, Hull, UK
| | - Gerald A Soff
- Department of Medicine, University of Miami Health System/Sylvester Comprehensive Cancer Center, Miami, Florida, USA
| | - Phillip S Wells
- Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Jeffrey I Zwicker
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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24
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Strasenburg W, Jóźwicki J, Durślewicz J, Kuffel B, Kulczyk MP, Kowalewski A, Grzanka D, Drewa T, Adamowicz J. Tumor Cell-Induced Platelet Aggregation as an Emerging Therapeutic Target for Cancer Therapy. Front Oncol 2022; 12:909767. [PMID: 35814405 PMCID: PMC9259835 DOI: 10.3389/fonc.2022.909767] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor cells have the ability to induce platelet activation and aggregation. This has been documented to be involved in tumor progression in several types of cancers, such as lung, colon, breast, pancreatic, ovarian, and brain. During the process, platelets protect circulating tumor cells from the deleterious effects of shear forces, shield tumor cells from the immune system, and provide growth factors, facilitating metastatic spread and tumor growth at the original site as well as at the site of metastasis. Herein, we present a wider view on the induction of platelet aggregation by specific factors primarily developed by cancer, including coagulation factors, adhesion receptors, growth factors, cysteine proteases, matrix metalloproteinases, glycoproteins, soluble mediators, and selectins. These factors may be presented on the surface of tumor cells as well as in their microenvironment, and some may trigger more than just one simple receptor-ligand mechanism. For a better understanding, we briefly discuss the physiological role of the factors in the platelet activation process, and subsequently, we provide scientific evidence and discuss their potential role in the progression of specific cancers. Targeting tumor cell-induced platelet aggregation (TCIPA) by antiplatelet drugs may open ways to develop new treatment modalities. On the one hand, it may affect patients' prognosis by enhancing known therapies in advanced-stage tumors. On the other hand, the use of drugs that are mostly easily accessible and widely used in general practice may be an opportunity to propose an unparalleled antitumor prophylaxis. In this review, we present the recent discoveries of mechanisms by which cancer cells activate platelets, and discuss new platelet-targeted therapeutic strategies.
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Affiliation(s)
- Wiktoria Strasenburg
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Jakub Jóźwicki
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Błażej Kuffel
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Martyna Parol Kulczyk
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Adam Kowalewski
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Tomasz Drewa
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Jan Adamowicz
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
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25
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Li X, Lu Z. Role of von Willebrand factor in the angiogenesis of lung adenocarcinoma (Review). Oncol Lett 2022; 23:198. [PMID: 35572495 PMCID: PMC9100484 DOI: 10.3892/ol.2022.13319] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/19/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Xin Li
- Department of Oncology, Affiliated Hospital of Weifang Medical College, Weifang, Shandong 261053, P.R. China
| | - Zhong Lu
- Department of Oncology, Affiliated Hospital of Weifang Medical College, Weifang, Shandong 261053, P.R. China
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26
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Enomoto M, Takaya H, Namisaki T, Fujinaga Y, Nishimura N, Sawada Y, Kaji K, Kawaratani H, Moriya K, Akahane T, Inoue T, Matsumoto M, Yoshiji H. Ratio of von Willebrand factor antigen to ADAMTS13 activity is a useful biomarker for acute-on-chronic liver failure development and prognosis in patients with liver cirrhosis. Hepatol Res 2022; 52:390-400. [PMID: 34964539 DOI: 10.1111/hepr.13743] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 12/06/2021] [Accepted: 12/26/2021] [Indexed: 01/21/2023]
Abstract
AIM Acute-on-chronic liver failure (ACLF) is associated with a high risk of short-term mortality after progression to multiple organ failure. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). An imbalance between ADAMTS13 enzyme and VWF substrate is associated with liver cirrhosis progression that induces ACLF. This study examined the relationship between ADAMTS13 and VWF and ACLF development to determine whether ADAMTS13 and VWF are useful predictive biomarkers for ACLF development and prognosis of patients with liver cirrhosis. METHODS The study enrolled 67 patients with Child-Pugh class A and B liver cirrhosis. ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. The ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) was used to divide patients into two groups according to the classification and regression tree based on Gray model survival analysis. RESULTS Compared with patients with Child-Pugh class A liver cirrhosis, class B patients had a higher VWF:Ag/ADAMTS13:AC and a higher risk of ACLF development. Cumulative incidence of ACLF was significantly higher in patients with high (>7.9) versus low (≤7.9) VWF:Ag/ADAMTS13:AC (hazard ratio [HR], 6.50; 95% CI, 2.31-18.29; p < 0.001). Cumulative survival was significantly lower in cirrhotic patients with high versus low VWF:Ag/ADAMTS13:AC (HR 5.11; 95% CI, 1.85-14.14; p = 0.002). CONCLUSIONS For patients with liver cirrhosis, VWF:Ag/ADAMTS13:AC is associated with functional liver reserve and predicts the development of ACLF and the prognosis.
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Affiliation(s)
- Masahide Enomoto
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Hiroaki Takaya
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Yukihisa Fujinaga
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Yasuhiko Sawada
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Kei Moriya
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
| | - Takashi Inoue
- Institute for Clinical and Translational Science, Nara Medical University Hospital, Kashihara, Nara, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan
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27
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Takaya H, Namisaki T, Asada S, Iwai S, Kubo T, Suzuki J, Enomoto M, Tsuji Y, Fujinaga Y, Nishimura N, Sawada Y, Kaji K, Kawaratani H, Moriya K, Akahane T, Matsumoto M, Yoshiji H. ADAMTS13, VWF, and Endotoxin Are Interrelated and Associated with the Severity of Liver Cirrhosis via Hypercoagulability. J Clin Med 2022; 11:1835. [PMID: 35407443 PMCID: PMC8999602 DOI: 10.3390/jcm11071835] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/11/2022] [Accepted: 03/22/2022] [Indexed: 02/04/2023] Open
Abstract
ADAMTS13 specifically cleaves the multimeric von Willebrand factor (VWF), and an imbalance between ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) levels is associated with the severity of liver cirrhosis (LC). However, the reason for this imbalance in patients with LC is unknown. This study investigated the relationship among ADAMTS13:AC, VWF:Ag, and endotoxin (Et) levels in patients with LC. ADAMTS13:AC and VWF:Ag levels were determined using ELISA, whereas Et levels were estimated using a chromogenic substrate assay. The levels of ADAMTS13 inhibitor (ADAMTS13:INH) were evaluated by measuring the extent that heat-inactivated patient's plasma reduces the ADAMTS13:AC of the control. The status (degraded, normal, or unusually large [UL]) of the VWF multimer (VWFM) was determined through vertical agarose gel electrophoresis. ADAMTS13:AC, VWF:Ag, and Et levels decreased, increased, and increased, respectively, with the severity of LC. Patients with cirrhosis with high Et levels had lower and higher ADAMTS13:AC and VWF:Ag levels, respectively, than those with low Et levels. Patients with cirrhosis with detectable ADAMTS13:INH had higher Et levels than those with undetectable ADAMTS13:INH. Patients whose VWFM was either normal or UL had higher Et levels than those with degraded VWFM. In conclusion, ADAMTS13, VWF, and Et may be interrelated and associated with the severity of LC via hypercoagulability.
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Affiliation(s)
- Hiroaki Takaya
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Shohei Asada
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Satoshi Iwai
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Takahiro Kubo
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Junya Suzuki
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Masahide Enomoto
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Yuki Tsuji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Yukihisa Fujinaga
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Yasuhiko Sawada
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Kei Moriya
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara 634-8522, Japan;
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan; (T.N.); (S.A.); (S.I.); (T.K.); (J.S.); (M.E.); (Y.T.); (Y.F.); (N.N.); (Y.S.); (K.K.); (H.K.); (K.M.); (T.A.); (H.Y.)
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The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer. Healthcare (Basel) 2022; 10:healthcare10030557. [PMID: 35327035 PMCID: PMC8953111 DOI: 10.3390/healthcare10030557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/06/2022] [Accepted: 03/14/2022] [Indexed: 12/21/2022] Open
Abstract
von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities.
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Walker GE, Merlin S, Zanolini D, Vandoni A, Volpe A, Gaidano G, Valente G, Olivero M, Follenzi A. Factor VIII as a potential player in cancer pathophysiology. J Thromb Haemost 2022; 20:648-660. [PMID: 34847278 PMCID: PMC9306727 DOI: 10.1111/jth.15611] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 11/29/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Trousseau sign was the first demonstration of a close relationship between cancer and thrombosis. Currently, venous thromboembolism (VTE) is five to six times more likely to occur in cancer patients, whereas there is a greater risk of cancer diagnoses following thromboses. In considering novel players, factor VIII (FVIII), an essential coagulation cofactor with emerging extracoagulative functions, has been identified as an independent VTE risk factor in cancer; however, the basis of this increase is unknown. OBJECTIVE To investigate the possible direct expression and secretion of FVIII by cancer cells. METHODS Bladder cancer, with a high VTE risk, and normal bladder tissue and epithelium, were used to investigate FVIII. Factor VIII protein and secretion were examined in bladder cancer cell lines. Expanding to other cancers, the Cancer Cell line Encyclopedia database was used to analyze FVIII, tissue factor, FV, FVII, FIX, FX, and von Willebrand factor (VWF) mRNA in 811 cell lines subdivided according to origin. Factor VIII protein synthesis, secretion, and bioactivity were investigated in a profile of cancer cell lines of differing origins. RESULTS AND CONCLUSIONS Although expressed in the normal bladder epithelium, FVIII mRNA and protein were higher in matched bladder neoplasms, with synthesis and secretion of bioactive FVIII evident in bladder cancer cells. This can be extended to other cancer cell lines, with a pattern reflecting the tumor origin, and that is independent of VWF and other relevant players in the coagulation cascade. Here, evidence is provided of a possible independent role for FVIII in cancer-related pathophysiology.
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Affiliation(s)
- Gillian E. Walker
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
| | - Simone Merlin
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
| | - Diego Zanolini
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
| | - Andrea Vandoni
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Alessandro Volpe
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Gianluca Gaidano
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Guido Valente
- Department of Translational MedicineUniversità del Piemonte OrientaleNovaraItaly
| | - Martina Olivero
- Department of OncologyUniversity of TorinoTorinoItaly
- Candiolo Cancer Institute‐FPOIRCCSCandiolo, TorinoItaly
| | - Antonia Follenzi
- Department of Health SciencesUniversità del Piemonte OrientaleNovaraItaly
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30
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Michels A, Lillicrap D, Yacob M. Role of von Willebrand factor in venous thromboembolic disease. JVS Vasc Sci 2022; 3:17-29. [PMID: 35028601 PMCID: PMC8739873 DOI: 10.1016/j.jvssci.2021.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 08/23/2021] [Indexed: 02/07/2023] Open
Abstract
Objective Evolving evidence of the shared risk factors and pathogenic mechanisms in arterial and venous thrombosis questions of the strict vascular dichotomy of arterial vs venous. The connection between arterial and venous thrombosis has been highlighted by common underlying inflammatory processes, a concept known as thromboinflammatory disease. Using this relationship, we can apply knowledge from arterial disease to better understand and potentially mitigate venous disease. A protein that has been extensively studied in atherothrombotic disease and inflammation is von Willebrand factor (VWF). Because many predisposing and provoking factors of venous thromboembolism (VTE) have been shown to directly modulate VWF levels, it is, perhaps, not surprising that VWF has been highlighted by several recent association studies of patients with VTE. Methods In the present narrative review, we investigated more deeply the effects of VWF in venous disease by synthesizing the data from clinical studies of deep vein thrombosis of the limbs, pulmonary embolism, portal and cerebral vein thrombosis, and the complications of thrombosis, including post-thrombotic syndrome, venous insufficiency, and chronic thromboembolic pulmonary hypertension. We have also discussed the findings from preclinical studies to highlight novel VWF biochemistry in thrombosis and therapeutics. Results Across the spectrum of venous thromboembolic disease, we consistently observed that elevated VWF levels conferred an increased risk of VTE and long-term venous complications. We have highlighted important findings from VWF molecular research and have proposed mechanisms by which VWF participates in venous disease. Emerging evidence from preclinical studies might reveal novel targets for thromboinflammatory disease, including specific VWF pathophysiology. Furthermore, we have highlighted the utility of measuring VWF to prognosticate and risk stratify for VTE and its complications. Conclusions As the prevalence of inflammatory processes, such as aging, obesity, and diabetes increases in our population, it is critical to understand the evolving role of VWF in venous disease to guide clinical decisions and therapeutics.
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Affiliation(s)
- Alison Michels
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.,Division of Cardiovascular Surgery, Queen's University, Kingston Health Sciences Centre, Kingston, Ontario, Canada
| | - David Lillicrap
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Michael Yacob
- Division of Cardiovascular Surgery, Queen's University, Kingston Health Sciences Centre, Kingston, Ontario, Canada
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Guo H, Jiang W, Huang S, Huang X, Li C. Serum exosome-derived biomarkers for the early detection of oral squamous cell carcinoma. Mol Cell Biochem 2021; 476:4435-4447. [PMID: 34468926 DOI: 10.1007/s11010-021-04254-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/25/2021] [Indexed: 01/02/2023]
Abstract
Blood exosomes help regulate communication between tumour cells, moderating their behaviour. We sought to determine the protein content in serum exosomes (SEs), to characterise SEs, and to discover novel clinical biomarkers of oral squamous cell carcinoma (OSCC). Differentially expressed proteins (DEPs) of OSCC were identified using proteomics and then analysed using bioinformatics, before validation using ELISA, IHC, and RT-PCR. The influence of SEs on oral cancer cells was detected using CCK-8 and migration assays. Twelve DEPs were found in SEs from OSCC. Four proteins were targeted for further verification. New biomarkers exhibiting high sensitivity and specificity in diagnosing OSCC comprised C-reactive protein (CRP), von willebrand factor (VWF), and leucine-rich alpha-2-glycoprotein (LRG). Combined biomarkers outperformed any single protein. We also demonstrated that tumour-derived exosomes promoted tumour cell migration, but not proliferation and apoptosis. Our study indicates that CRP, VWF, and LRG are potential clinically relevant OSCC biomarkers. OSCC-related SEs may help promote migration of oral cells.
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Affiliation(s)
- Hejia Guo
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Guangxi Clinical Research Center for Craniofacial Deformity, College of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China
- Department of Oral and Maxillofacial Surgery, College & Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Weidong Jiang
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Guangxi Clinical Research Center for Craniofacial Deformity, College of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China
- Department of Oral and Maxillofacial Surgery, College & Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Suhua Huang
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Guangxi Clinical Research Center for Craniofacial Deformity, College of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Xuanping Huang
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Guangxi Clinical Research Center for Craniofacial Deformity, College of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.
- Department of Oral and Maxillofacial Surgery, College & Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.
| | - Cuiping Li
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Guangxi Clinical Research Center for Craniofacial Deformity, College of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.
- Medical Scientific Research Center, College of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.
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Rhone P, Zarychta E, Bielawski K, Ruszkowska-Ciastek B. Pre-surgical level of von Willebrand factor as an evident indicator of breast cancer recurrence. Cancer Biomark 2021; 29:359-372. [PMID: 32716345 DOI: 10.3233/cbm-191096] [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: 12/16/2022]
Abstract
BACKGROUND Endothelial and platelet activation as well as a disruption of haemostatic balance are crucial in cancer-dependent venous thromboembolism development. OBJECTIVE The aim of this study was to investigate the influence of von Willebrand factor (VWF), sE-selectin, sP-selectin as well as VWF/sE-selectin and sP-selectin/sE-selectin ratios on the probability of disease relapse in invasive breast carcinoma (IBrC) cases. METHODS Eighty-four patients with IA-IIB stage of IBrC who passed a comprehensive clinicopathologic evaluation were included in the study. Follow-up was completed in all patients with a 15.48 % recurrence rate. An immunoassay of VWF antigen, sE-selectin, sP-selectin, as well as an immunohistochemistry of oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was performed in all cases. RESULTS The VWF/sE-selectin ratio was significantly higher in patients with poorly differentiated tumours than in those with high-differentiated tumours. A positive correlation between VWF concentration and tumour grade was noted. Eleven of 13 events happened in patients with VWF value below 600 mU/mL with recurrence rate of 25%, but only two events occurred in subject with VWF values above the 600 mU/mL (5%; P= 0.0028). CONCLUSIONS Our study show that VWF could be considered as a suitable biomarker of breast cancer relapse.
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Affiliation(s)
- Piotr Rhone
- Clinical Ward of Breast Cancer and Reconstructive Surgery, Oncology Centre Prof. F. Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Elżbieta Zarychta
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Kornel Bielawski
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
| | - Barbara Ruszkowska-Ciastek
- Department of Pathophysiology, Faculty of Pharmacy, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland
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Yan AR, Samarawickrema I, Naunton M, Peterson GM, Yip D, De Rosa S, Mortazavi R. Risk Factors and Prediction Models for Venous Thromboembolism in Ambulatory Patients with Lung Cancer. Healthcare (Basel) 2021; 9:778. [PMID: 34205695 PMCID: PMC8233898 DOI: 10.3390/healthcare9060778] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/13/2021] [Accepted: 06/17/2021] [Indexed: 12/21/2022] Open
Abstract
Venous thromboembolism (VTE) is a significant cause of mortality in patients with lung cancer. Despite the availability of a wide range of anticoagulants to help prevent thrombosis, thromboprophylaxis in ambulatory patients is a challenge due to its associated risk of haemorrhage. As a result, anticoagulation is only recommended in patients with a relatively high risk of VTE. Efforts have been made to develop predictive models for VTE risk assessment in cancer patients, but the availability of a reliable predictive model for ambulate patients with lung cancer is unclear. We have analysed the latest information on this topic, with a focus on the lung cancer-related risk factors for VTE, and risk prediction models developed and validated in this group of patients. The existing risk models, such as the Khorana score, the PROTECHT score and the CONKO score, have shown poor performance in external validations, failing to identify many high-risk individuals. Some of the newly developed and updated models may be promising, but their further validation is needed.
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Affiliation(s)
- Ann-Rong Yan
- School of Health Sciences, Faculty of Health, University of Canberra, Canberra 2617, Australia; (A.-R.Y.); (M.N.); (G.M.P.); (D.Y.)
| | - Indira Samarawickrema
- School of Nursing, Midwifery and Public Health, Faculty of Health, University of Canberra, Canberra 2617, Australia;
| | - Mark Naunton
- School of Health Sciences, Faculty of Health, University of Canberra, Canberra 2617, Australia; (A.-R.Y.); (M.N.); (G.M.P.); (D.Y.)
| | - Gregory M. Peterson
- School of Health Sciences, Faculty of Health, University of Canberra, Canberra 2617, Australia; (A.-R.Y.); (M.N.); (G.M.P.); (D.Y.)
- College of Health and Medicine, University of Tasmania, Hobart 7005, Australia
| | - Desmond Yip
- School of Health Sciences, Faculty of Health, University of Canberra, Canberra 2617, Australia; (A.-R.Y.); (M.N.); (G.M.P.); (D.Y.)
- Department of Medical Oncology, The Canberra Hospital, Garran 2605, Australia
- ANU Medical School, Australian National University, Canberra 0200, Australia
| | - Salvatore De Rosa
- Department of Medical and Surgical Science, Magna Graecia University, 88100 Catanzaro, Italy;
| | - Reza Mortazavi
- School of Health Sciences, Faculty of Health, University of Canberra, Canberra 2617, Australia; (A.-R.Y.); (M.N.); (G.M.P.); (D.Y.)
- Prehab Activity Cancer Exercise Survivorship Research Group, Faculty of Health, University of Canberra, Canberra 2617, Australia
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Plasma levels of von Willebrand factor and future risk of incident venous thromboembolism. Blood Adv 2021; 5:224-232. [PMID: 33570640 DOI: 10.1182/bloodadvances.2020003135] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 11/25/2020] [Indexed: 01/01/2023] Open
Abstract
Several case-control studies have reported elevated plasma von Willebrand factor (VWF) levels in patients with venous thromboembolism (VTE) compared with controls. However, because few studies have investigated the association in a prospective design, it is unclear whether elevated plasma VWF is a risk factor or a consequence of the VTE event. Therefore, we aimed to investigate the prospective association between plasma VWF levels and risk of VTE, as well as to perform subgroup analyses of deep vein thrombosis (DVT) and pulmonary embolism. We established a population-based nested case-control study of 414 VTE cases and 843 age- and sex-matched controls based on the Tromsø study cohort (1994-2007). Blood samples were collected at cohort baseline (1994-1995). Odds ratios (ORs) with 95% confidence intervals (CIs) for VTE were estimated across quartiles of VWF levels. We found that the risk of VTE increased linearly across quartiles of VWF levels (P for trend = .023). Participants with VWF in the highest quartile had an OR of 1.45 (95% CI, 1.03-2.03) for VTE compared with those in the lowest quartile. The association was strongest for unprovoked VTE (OR, 2.74; 95% CI, 1.66-4.54) and unprovoked DVT in particular (OR, 6.73; 95% CI, 3.07-14.76). Further adjustment for body mass index, C-reactive protein, hypertension, estrogen use, and smoking had a modest effect on the risk estimates. To conclude, we found a dose-dependent relationship between plasma VWF levels and future risk of incident VTE, and unprovoked events in particular. Our findings suggest that VWF may represent a promising biomarker for future risk of incident VTE.
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He Y, Liu R, Yang M, Bi W, Zhou L, Zhang S, Jin J, Liang X, Zhang P. Identification of VWF as a Novel Biomarker in Lung Adenocarcinoma by Comprehensive Analysis. Front Oncol 2021; 11:639600. [PMID: 33968738 PMCID: PMC8100660 DOI: 10.3389/fonc.2021.639600] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 03/25/2021] [Indexed: 12/13/2022] Open
Abstract
Lung adenocarcinoma (LUAD) is one of the most malignant tumors with high morbidity and mortality worldwide due to the lack of reliable methods for early diagnosis and effective treatment. It’s imperative to study the mechanism of its development and explore new biomarkers for early detection of LUAD. In this study, the Gene Expression Omnibus (GEO) dataset GSE43458 and The Cancer Genome Atlas (TCGA) were used to explore the differential co-expressed genes between LUAD and normal samples. Three hundred sixity-six co-expressed genes were identified by differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) method. Those genes were mainly enriched in ameboidal-type cell migration (biological process), collagen-containing extracellular matrix (cell component), and extracellular matrix structure constituent (molecular function). The protein-protein network (PPI) was constructed and 10 hub genes were identified, including IL6, VWF, CDH5, PECAM1, EDN1, BDNF, CAV1, SPP1, TEK, and SELE. The expression level of hub genes was validated in the GEPIA database, compared with normal tissues, VWF is lowly expressed and SPP1 is upregulated in LUAD tissues. The survival analysis showed increased expression of SPP1 indicated unfavorable prognosis whereas high expression of VWF suggested favorable prognosis in LUAD (p < 0.05). Based on the immune infiltration analysis, the relationship between SPP1 and VWF expression and macrophage, neutrophil, and dendritic cell infiltration was weak in LUAD. Quantitative real-time PCR (qRT-PCR) and western blotting were used to validate the expression of VWF and SPP1 in normal human bronchial epithelial (HBE) cell and three LUAD cell lines, H1299, H1975, and A549. Immunohistochemistry (IHC) was further performed to detect the expression of VWF in 10 cases LUAD samples and matched normal tissues. In summary, the data suggest that VWF is a potential novel biomarker for prognosis of LUAD.
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Affiliation(s)
- Yi He
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ruijie Liu
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Mei Yang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wu Bi
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Liuyin Zhou
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Sai Zhang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jin Jin
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xujun Liang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Pengfei Zhang
- NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Xu X, Wang C, Wu Y, Houck K, Hilton T, Zhou A, Wu X, Han C, Yang M, Yang W, Shi FD, Stolla M, Cruz MA, Li M, Zhang J, Dong JF. Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice. Blood 2021; 137:544-555. [PMID: 33507292 PMCID: PMC7845006 DOI: 10.1182/blood.2020007364] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 07/27/2020] [Indexed: 12/22/2022] Open
Abstract
Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through intraperitoneal injection or IV infusion reduced TBI-induced death by >50% and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury. A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state. A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI. These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBI.
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Affiliation(s)
- Xin Xu
- Bloodworks Research Institute, Seattle, WA
- Departments of Neurosurgery, Neurology, and Obstetrics & Gynecology, Tianjin Medical University General Hospital, Tianjin, China
- Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Chenyu Wang
- Institute of Pathology, School of Medical Sciences, and the Gansu Provincial Key Laboratory of Preclinical Study for New Drug Development, Lanzhou University, Lanzhou, China
| | - Yingang Wu
- Department of Neurosurgery, the First Affiliated Hospital, University of Science and Technology, Hefei, China
| | | | | | | | | | - Cha Han
- Departments of Neurosurgery, Neurology, and Obstetrics & Gynecology, Tianjin Medical University General Hospital, Tianjin, China
| | - Mengchen Yang
- Departments of Neurosurgery, Neurology, and Obstetrics & Gynecology, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei Yang
- Bloodworks Research Institute, Seattle, WA
- NanoString Technologies, Seattle, WA
| | - Fu-Dong Shi
- Departments of Neurosurgery, Neurology, and Obstetrics & Gynecology, Tianjin Medical University General Hospital, Tianjin, China
| | | | - Miguel A Cruz
- Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX
- Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs (VA) Medical Center, Houston, TX; and
| | - Min Li
- Institute of Pathology, School of Medical Sciences, and the Gansu Provincial Key Laboratory of Preclinical Study for New Drug Development, Lanzhou University, Lanzhou, China
| | - Jianning Zhang
- Departments of Neurosurgery, Neurology, and Obstetrics & Gynecology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing-Fei Dong
- Bloodworks Research Institute, Seattle, WA
- Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA
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Takaya H, Namisaki T, Moriya K, Shimozato N, Kaji K, Ogawa H, Ishida K, Tsuji Y, Kaya D, Takagi H, Fujinaga Y, Nishimura N, Sawada Y, Kawaratani H, Akahane T, Matsumoto M, Yoshiji H. Association between ADAMTS13 activity-VWF antigen imbalance and the therapeutic effect of HAIC in patients with hepatocellular carcinoma. World J Gastroenterol 2020; 26:7232-7241. [PMID: 33362379 PMCID: PMC7723670 DOI: 10.3748/wjg.v26.i45.7232] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 10/09/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Prediction of HAIC treatment response is important for improving the prognosis in patients with hepatocellular carcinoma (HCC). The progression of HCC is related to hypercoagulability and angiogenesis. It is known that ADAMTS13 and von Willebrand factor (VWF) are related to hypercoagulability. In addition, previous study reported that the association between ADAMTS13 and VWF, and angiogenesis via vascular endothelial growth factor (VEGF). Recently, ADAMTS13 and VWF have been associated with the prognosis in patients with various kinds of cancer undergoing chemotherapy. AIM To investigate whether ADAMTS13 and VWF become useful biomarkers of treatment response in HCC patients before the initiation of HAIC treatment. METHODS Seventy-two patients were enrolled in this study. ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag) and VEGF levels were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were performed to determine the predictive factors of treatment response in patients with HCC undergoing HAIC treatment. RESULTS ADAMTS13:AC levels in HCC patients with stable disease (SD) + partial response (PR) of HAIC treatment were significantly higher than those with progressive disease (PD) (P < 0.05). In contrast, VWF:Ag/ADAMTS13:AC ratio and VEGF levels in HCC patients with SD + PR were significantly lower than those with PD (both P < 0.05). Patients with high VWF:Ag/ADAMTS13:AC ratio (> 2.7) had higher VEGF levels than those with low ratio (≤ 2.7). Multivariable analysis revealed that VWF:Ag/ADAMTS13:AC ratio was a predictive factor of HAIC treatment response. CONCLUSION VWF:Ag/ADAMTS13:AC ratio may become a useful biomarker of treatment response in HCC patients before the initiation of HAIC treatment.
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Affiliation(s)
- Hiroaki Takaya
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Naotaka Shimozato
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kosuke Kaji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hiroyuki Ogawa
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Koji Ishida
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yuki Tsuji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Daisuke Kaya
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | | | - Yukihisa Fujinaga
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Norihisa Nishimura
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Yasuhiko Sawada
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hideto Kawaratani
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634-8522, Japan
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Setiawan B, Permatadewi CO, de Samakto B, Bugis A, Naibaho RM, Pangarsa EA, Santosa D, Suharti C. Von Willebrand factor:antigen and ADAMTS-13 level, but not soluble P-selectin, are risk factors for the first asymptomatic deep vein thrombosis in cancer patients undergoing chemotherapy. Thromb J 2020; 18:33. [PMID: 33292287 PMCID: PMC7659107 DOI: 10.1186/s12959-020-00247-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/05/2020] [Indexed: 12/12/2022] Open
Abstract
Background There is a high incidence of deep vein thrombosis (DVT) among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is characterized by increased plasma levels of von Willebrand factor (vWF) and soluble P-selectin (sP-selectin), leading to the activation of endothelial cells and signaling cascades. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) is to control the activity of vWF and consequently the risk of thrombosis. The objective of this study was to investigate the roles of sP-selectin, vWF, and ADAMTS-13 as risk factors for the first episode of DVT in cancer patients undergoing chemotherapy. Methods This prospective cohort study was conducted at Dr. Kariadi Hospital, Indonesia, on 40 cancer patients. Prechemotherapy (baseline) and postchemotherapy sP-selectin, vWF antigen (vWF:Ag), and ADAMTS-13 plasma levels were determined with ELISAs before and 3 months after chemotherapy. The clinical characteristics of the patients, cancer type, cancer stage, chemotherapy regimen, ABO blood type, D-dimer level and Khorana risk score were also analyzed using logistic regression. Patients were observed for the possibility of developing DVT during chemotherapy. Results DVT was confirmed in 5 patients (12.5%) after a period of 3 months. In patients with DVT, sP-selectin and vWF were significantly higher while ADAMTS-13 was lower than in their counterparts. The levels of baseline vWF:Ag and ADAMTS-13, with cut-off points ≥ 2.35 IU/mL and ≤ 1.03 IU/mL, respectively, were found to independently predict the incidence of DVT. In the multivariate logistic regression analysis, the relative risk (RR) for DVT in patients with high vWF:Ag was 3.80 (95% CI 1.15–12.48, p = 0.028), and that for patients with low ADAMTS-13 was 2.67 (95% CI 1.22–23.82, p = 0.005). The vWF:Ag/ADAMTS-13 ratio and both vWF:Ag and ADAMTS-13 dynamics during treatment were also able to differentiate those with prospective DVT. However, sP-selectin and other covariates showed no statistical significance. Conclusion We found that prechemotherapy plasma levels of vWF:Ag ≥ 2.35 IU/mL and ADAMTS-13 ≤ 1.03 IU/mL are independent risk factors for DVT incidence among cancer patients.
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Affiliation(s)
- Budi Setiawan
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia.
| | - Cecilia Oktaria Permatadewi
- Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia
| | - Baringin de Samakto
- Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia
| | - Ashar Bugis
- Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia
| | - Ridho M Naibaho
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia.,Fellow in Hematology and Medical Oncology, Department of Internal Medicine, Medical Faculty of Mulawarman University, Parikesit General Hospital, Kutai Kartanegara, Indonesia
| | - Eko Adhi Pangarsa
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia
| | - Damai Santosa
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia
| | - Catharina Suharti
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Medical Faculty of Diponegoro University and Dr. Kariadi Hospital, Semarang, Indonesia
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Pagliari MT, Boscarino M, Cairo A, Mancini I, Martinelli I, Bucciarelli P, Rossi F, Rosendaal FR, Peyvandi F. ADAMTS13 activity, high VWF and FVIII levels in the pathogenesis of deep vein thrombosis. Thromb Res 2020; 197:132-137. [PMID: 33212380 DOI: 10.1016/j.thromres.2020.10.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/02/2020] [Accepted: 10/31/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Deep vein thrombosis (DVT) is a common multi-factorial disease with a partially understood aetiology. Although the roles of high factor (F)VIII and von Willebrand factor (VWF) levels are recognized, that of ADAMTS13 is still unclear. AIM To assess the association between ADAMTS13 activity levels, VWF antigen (VWF:Ag) and FVIII coagulant activity (FVIII:C) levels and DVT. MATERIALS AND METHODS 365 Italian DVT patients and 292 age- and sex-matched controls were considered. Plasma ADAMTS13 activity was measured using FRETS-VWF73 assay. VWF:Ag and FVIII:C were measured using immunoassay and one-stage clotting assay (ACL TOP analyzer), respectively. Quartile analyses were performed to evaluate the individual association between ADAMTS13 activity, VWF:Ag, FVIII:C and DVT. The combined effect of high VWF levels (> 4th quartile) and low ADAMTS13 levels (< 1st quartile) was evaluated using binary variables. All models were age- and sex-adjusted. Estimated risks were reported as Odds ratio (OR) with 95% confidence intervals (CI). RESULTS ADAMTS13 activity was lower in DVT patients (94% vs. 98% of controls). Patients with an ADAMTS13 activity <1st quartile (86%) showed a 1.6-fold increased risk of DVT (95%CI, 1.05-2.55). The combination of low ADAMTS13 activity and high VWF:Ag levels was associated with a 15-fold increased risk (95%CI, 7.80-33.80). VWF:Ag and FVIII:C were associated to DVT with a dose-response relationship. CONCLUSIONS ADAMTS13 activity < 86% was associated with a moderate risk of DVT. The co-presence of low ADAMTS13 activity and high VWF levels resulted in a strong synergistic effect on DVT risk. The association of VWF:Ag and FVIII:C with DVT was confirmed.
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Affiliation(s)
- Maria Teresa Pagliari
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy
| | - Marco Boscarino
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy
| | - Andrea Cairo
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy
| | - Ilaria Mancini
- Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy
| | - Ida Martinelli
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Paolo Bucciarelli
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Federica Rossi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
| | - Frits R Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Flora Peyvandi
- Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy.
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Patmore S, Dhami SPS, O'Sullivan JM. Von Willebrand factor and cancer; metastasis and coagulopathies. J Thromb Haemost 2020; 18:2444-2456. [PMID: 32573945 DOI: 10.1111/jth.14976] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/05/2020] [Accepted: 06/12/2020] [Indexed: 12/16/2022]
Abstract
Von Willebrand factor (VWF) is a multimeric procoagulant plasma glycoprotein that mediates platelet adhesion along the endothelium. In addition to its role maintaining normal hemostasis, more recently novel biological functions for VWF have been described, including inflammation, angiogenesis, and metastasis. Significantly increased plasma VWF levels have been reported across a variety of cancer patient cohorts. Given that VWF is established as a risk factor for venous thrombosis, this is of direct clinical importance. Moreover, elevated VWF has also been observed localized within the tumor microenvironment, correlating with advanced disease stage and poorer clinical outcome. Critically, evidence suggests that elevated VWF levels in cancer patients may not only contribute to cancer associated coagulopathies but may also mediate cancer progression and metastasis. Studies have shown that VWF can promote pro-inflammatory signaling, regulate angiogenesis and vascular permeability, which may facilitate tumor cell growth and extravasation across the vessel wall. Endothelial secreted VWF multimers contribute to the adhesion and transendothelial migration of tumor cells key for tumor dissemination. In support of this, VWF inhibition attenuated metastasis in vivo. Perhaps most intriguingly, specific tumor cells have been reported to acquire de novo VWF expression which increases tumor-platelet heteroaggregates and confers enhanced metastatic activity. Current knowledge on the roles of VWF in cancer and in particular its contribution to metastasis and cancer associated coagulopathies is summarized in this review.
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Affiliation(s)
- Sean Patmore
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Sukhraj Pal S Dhami
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jamie M O'Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
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Yang SY, Zeng LY, Li C, Yan H. Correlation between an ABO Blood Group and Primary Femoral Head Necrosis: A Case-Control Study. Orthop Surg 2020; 12:450-456. [PMID: 32167665 PMCID: PMC7189034 DOI: 10.1111/os.12628] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/06/2020] [Accepted: 01/14/2020] [Indexed: 11/28/2022] Open
Abstract
Objective To investigate the relationship between primary femoral head necrosis (ONFH) and an ABO blood group. Methods This study was a retrospective case–control trial. An analysis of the clinical data of an ABO blood group with 516 patients (case group) with ONFH and 489 limb‐fracture patients (control group) without previous hip pain was obtained from the Second Hospital of Shanxi Medical University from November 2015 to November 2018. The clinical data included gender, age, height, weight, a history of smoking, alcohol abuse, prior medical history, hormone use, and ABO blood type. A logistic regression model was used for univariate and multivariate analysis. Results From November 2015 to November 2018, there were 267 males and 249 females in the 516 cases of ONFH in the case group. The control group included 289 males and 200 females. In terms of age, the average age of the case group was significantly lower than that of the control group. In terms of body mass index (BMI), the BMI of the case group was significantly higher than that of the control group (P < 0.05). From the previous medical history of patients in the two groups (coronary heart disease, hypertension, cerebrovascular disease, diabetes, and peripheral vascular disease), there was no significant difference between the two groups from a statistical perspective (P < 0.05). However, according to the risk factors of ONFH (smoking, alcohol abuse, hyperlipidemia, and hormone‐use history), there were significant differences between the case group and the control group. There was no statistical difference in the quantitative distribution ratio of the four blood types – A, B, O, and AB – between the case group and the control group. The outcomes of logistic multiple regression analysis presented that there was no significant correlation between the occurrence of ONFH and blood type A, B, AB, and O (P > 0.05). However, there are significant differences in the disease progression between the different blood types. There was a significant difference in the progression of disease between type A and type O. Among them, patients with ONFH and type A blood had the fastest progression with an average of 2.318 years, and the slowest progression was found in type O blood with an average of 5.15 years. Conclusions The ABO blood group has no correlation with the occurrence of ONFH, but the ABO blood type is closely related to the disease progression of ONFH.
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Affiliation(s)
- Shu-Yan Yang
- Department of Blood Transfusion, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Ling-Yuan Zeng
- Department of Orthopaedic Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chao Li
- Department of Blood Transfusion, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Hong Yan
- Department of Blood Transfusion, The Second Hospital of Shanxi Medical University, Taiyuan, China
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The Incidence of Venous Thromboembolism and Impact on Survival in Hodgkin Lymphoma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:542-547. [PMID: 32245743 DOI: 10.1016/j.clml.2020.02.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/22/2020] [Accepted: 02/29/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Thrombosis increase the acute and long-term morbidity and mortality in malignancy patients. We analyzed venous thromboembolism (VTE) in patients with Hodgkin lymphoma, the impact of VTE on survival, predisposing factors for VTE, and predicting value of Khorana and ThroLy score models. PATIENTS AND METHODS We included 150 adult patients with Hodgkin lymphoma between January 2010 and 2018 at our university hospital. RESULTS VTE was observed in 31 patients (20.7%). The types of VTE were 18 upper and 3 lower extremity deep vein thrombosis and 10 pulmonary embolism (1 with lower extremity deep vein thrombosis). Twenty-nine patients developed VTE during the treatment with a median time of episode as 5 months. In logistic regression analysis, a body mass index of >32 kg/m2, high fibrinogen levels, initial thrombocytosis and leukocytosis, splenic and extranodal involvement, presence of a central venous line, advanced stage, line of treatment status of thromboprophylaxis, VTE timing, and better Eastern Cooperative Oncology Group performance scores were observed to be related with VTE. Kaplan Meier survival analysis showed a negative impact of VTE on survival. Khorana and ThroLy risk assessment models were found predictive for VTE (P = .000 and P = .003, respectively), although only ThroLy score was associated with the survival. CONCLUSION Thromboprophylaxis and precautions for VTE in patients with Hodgkin lymphoma according to validated risk assessment models can improve prognosis and quality of life owing to the impact of VTE on survival in the study.
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Thrombin generation, thrombin-antithrombin complex, and prothrombin fragment F1+2 as biomarkers for hypercoagulability in cancer patients. Thromb Res 2020; 186:80-85. [DOI: 10.1016/j.thromres.2019.12.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 11/23/2019] [Accepted: 12/23/2019] [Indexed: 11/18/2022]
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Obermeier HL, Riedl J, Ay C, Koder S, Quehenberger P, Bartsch R, Kaider A, Zielinski CC, Pabinger I. The role of ADAMTS-13 and von Willebrand factor in cancer patients: Results from the Vienna Cancer and Thrombosis Study. Res Pract Thromb Haemost 2019; 3:503-514. [PMID: 31294335 PMCID: PMC6611368 DOI: 10.1002/rth2.12197] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 01/08/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Cancer-associated venous thromboembolism (VTE) is an important complication in the course of a malignant disease. Low ADAMTS-13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13) and increased von Willebrand Factor (VWF) levels in cancer patients have been described numerously. OBJECTIVES Investigation of the influence of ADAMTS-13 and VWF on the probability of VTE and survival in malignancy. PATIENTS/METHODS In the framework of the ongoing prospective Cancer and Thrombosis Study (CATS) ADAMTS-13 activity and VWF antigen levels were investigated in cancer patients. RESULTS In total, 795 patients with various tumor types (364 female/431 male, median age 62 years) were included; of those, 56 developed VTE and 359 patients died during a median follow-up time of 730 days. The hazard ratio (HR) of VTE per doubling of VWF level was 1.56 (95% confidence interval [CI] 1.13-2.16) in multivariable competing risk analysis. ADAMTS-13 levels showed no correlation with the incidence of VTE in univariate competing risk analysis. The HR of mortality per doubling of VWF level was 1.46 (95% CI 1.28-1.66) and per SD increment of ADAMTS-13was 0.90 (95% CI 0.81-1.00) in multivariable Cox regression analysis. Patients with VWF >75th percentile and concomitant low (<25th percentile) or medium (25-75th percentile) ADAMTS-13 values had the highest probability of mortality (HR 4.31 and 4.75, respectively). CONCLUSIONS High VWF levels were significantly associated with the risk of developing VTE in cancer patients, whereas ADAMTS-13 was not. Low ADAMTS-13 and increased VWF levels were independently associated with worse overall survival.
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Affiliation(s)
- Hanna L. Obermeier
- Clinical Division of Hematology and HemostaseologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Julia Riedl
- Clinical Division of Hematology and HemostaseologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Cihan Ay
- Clinical Division of Hematology and HemostaseologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Silvia Koder
- Clinical Division of Hematology and HemostaseologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Peter Quehenberger
- Department of Medical and Chemical Laboratory DiagnosticsMedical University of ViennaViennaAustria
| | - Rupert Bartsch
- Clinical Division of OncologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Alexandra Kaider
- Section for Clinical BiometricsCenter for Medical Statistics, Informatics and Intelligent SystemsMedical University of ViennaViennaAustria
| | - Christoph C. Zielinski
- Clinical Division of OncologyDepartment of Medicine IMedical University of ViennaViennaAustria
| | - Ingrid Pabinger
- Clinical Division of Hematology and HemostaseologyDepartment of Medicine IMedical University of ViennaViennaAustria
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Haen P, Mege D, Crescence L, Dignat-George F, Dubois C, Panicot-Dubois L. Thrombosis Risk Associated with Head and Neck Cancer: A Review. Int J Mol Sci 2019; 20:E2838. [PMID: 31212608 PMCID: PMC6600456 DOI: 10.3390/ijms20112838] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/30/2019] [Accepted: 06/07/2019] [Indexed: 12/12/2022] Open
Abstract
Venous thromboembolism (VTE) is a common complication for cancer patients. VTE-associated risk varies according to the type of tumor disease. Head and neck cancer is a common cancer worldwide, and most tumors are squamous cell carcinomas due to tobacco and alcohol abuse. The risk of VTE associated with head and neck (H&N) cancer is considered empirically low, but despite the high incidence of H&N cancer, few data are available on this cancer; thus, it is difficult to state the risk of VTE. Our review aims to clarify this situation and tries to assess the real VTE risk associated with H&N cancer. We report that most clinical studies have concluded that there is a very low thrombosis risk associated with H&N cancer. Even with the biases that often exist, this clinical review seems to confirm that the risk of VTE was empirically hypothesized. Furthermore, we highlight that H&N cancer has all the biological features of a cancer associated with a high thrombosis risk, including a strong expression of procoagulant proteins, modified thrombosis/fibrinolysis mechanisms, and secretions of procoagulant microparticles and procoagulant cytokines. Thus, this is a paradoxical situation, and some undiscovered mechanisms that could explain this clinical biological ambivalence might exist.
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Affiliation(s)
- Pierre Haen
- Aix Marseille Univ, INSERM 1263, INRA, Center for CardioVascular and Nutrition Research (C2VN), 27 Boulevard Jean Moulin, 13385 Marseille, France.
- Department of Maxillo-Facial Surgery, Army Training Hospital, Laveran, 13013 Marseille, France.
| | - Diane Mege
- Aix Marseille Univ, INSERM 1263, INRA, Center for CardioVascular and Nutrition Research (C2VN), 27 Boulevard Jean Moulin, 13385 Marseille, France.
- Department of Digestive Surgery, Timone University Hospital, AP-HM, 13005 Marseille, France.
| | - Lydie Crescence
- Aix Marseille Univ, INSERM 1263, INRA, Center for CardioVascular and Nutrition Research (C2VN), 27 Boulevard Jean Moulin, 13385 Marseille, France.
| | - Françoise Dignat-George
- Aix Marseille Univ, INSERM 1263, INRA, Center for CardioVascular and Nutrition Research (C2VN), 27 Boulevard Jean Moulin, 13385 Marseille, France.
- Laboratoire d'Hématologie, Centre Hospitalo-Universitaire Conception, 385 Boulevard Baille, 13385 Marseille, France.
| | - Christophe Dubois
- Aix Marseille Univ, INSERM 1263, INRA, Center for CardioVascular and Nutrition Research (C2VN), 27 Boulevard Jean Moulin, 13385 Marseille, France.
| | - Laurence Panicot-Dubois
- Aix Marseille Univ, INSERM 1263, INRA, Center for CardioVascular and Nutrition Research (C2VN), 27 Boulevard Jean Moulin, 13385 Marseille, France.
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Takaya H, Namisaki T, Shimozato N, Kaji K, Kitade M, Moriya K, Sato S, Kawaratani H, Akahane T, Matsumoto M, Yoshiji H. ADAMTS13 and von Willebrand factor are useful biomarkers for sorafenib treatment efficiency in patients with hepatocellular carcinoma. World J Gastrointest Oncol 2019; 11:424-435. [PMID: 31139312 PMCID: PMC6522768 DOI: 10.4251/wjgo.v11.i5.424] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 03/26/2019] [Accepted: 04/08/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Many advanced hepatocellular carcinoma (HCC) patients are receiving sorafenib treatment. Sorafenib reportedly improves overall survival (OS) significantly in patients with HCC. Prediction of sorafenib response and prognosis in patients with HCC receiving sorafenib treatment are important due to the potentially serious side effects of sorafenib. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) and von Willebrand factor (VWF) are associated with the pathophysiology of liver cirrhosis and HCC through their roles in hypercoagulability; they are also associated with angiogenesis via vascular endothelial growth factor (VEGF). The imbalance between ADAMTS13 and VWF was associated with prognosis of various cancers in patients undergoing chemotherapy. AIM To investigate ADAMTS13 and VWF as potential biomarkers for sorafenib response and prognosis in patients with HCC receiving sorafenib treatment. METHODS Forty-one patients with HCC receiving sorafenib treatment were included in this study. The initial daily sorafenib dose was 400 mg in all patients. ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag), VEGF levels were determined by enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine predictive factors for sorafenib response and prognosis in patients with HCC receiving sorafenib treatment. RESULTS ADAMTS13:AC was significantly higher in patients with stable disease (SD), partial response (PR), and complete response (CR) than in those with progressive disease (PD) (P < 0.05). In contrast, VWF:Ag and the VWF:Ag/ADAMTS13:AC ratio were significantly lower in patients with SD, PR, and CR than in those with PD (P < 0.05 for both). Multivariate analysis showed that the VWF:Ag/ADAMTS13:AC ratio was the only predictive factor for sorafenib response and ADAMTS13:AC was the only prognostic factor in patients with HCC receiving sorafenib treatment. The patients with a low ADAMTS13:AC (< 78.0) had significantly higher VEGF levels than those with a high ADAMTS13:AC (≥ 78.0) (P < 0.05). CONCLUSION The VWF:Ag/ADAMTS13:AC ratio and ADAMTS13:AC are potentially useful biomarkers for sorafenib response and prognosis, respectively, in patients with HCC receiving sorafenib treatment.
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Affiliation(s)
- Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan
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Riedl J, Ay C. Venous Thromboembolism in Brain Tumors: Risk Factors, Molecular Mechanisms, and Clinical Challenges. Semin Thromb Hemost 2019; 45:334-341. [PMID: 31041803 DOI: 10.1055/s-0039-1688493] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Venous thromboembolism (VTE) is a common complication in patients with primary brain tumors, with up to 20% of patients per year having a VTE event. Clinical risk factors for VTE include glioblastoma subtype, paresis, or surgery. Furthermore, specific factors playing a role in tumor biology were recently identified to predispose to prothrombotic risk. For instance, mutations in the isocitrate dehydrogenase 1 (IDH1) gene, which occurs in a subgroup of glioma, correlate with risk of VTE, with low incidence in patients with presence of an IDH1 mutation compared with those with IDH1 wild-type status. In addition, expression of the glycoprotein podoplanin on brain tumors was associated with both intratumoral thrombi and high risk of VTE. As podoplanin has the ability to activate platelets, a mechanistic role of podoplanin-mediated platelet activation in VTE development has been suggested. From a clinical point of view, the management of patients with primary brain tumors and VTE is challenging. Anticoagulation is required to treat patients; however, it is associated with increased risk of intracranial hemorrhage. This review focuses on describing the epidemiology, risk factors, and mechanisms of brain tumor-associated thrombosis and discusses clinical challenges in the prevention and treatment of VTE in patients with brain tumors.
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Affiliation(s)
- Julia Riedl
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Cihan Ay
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.,I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
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Serum ADAMTS-13 Levels as an Indicator of Portal Vein Thrombosis. Gastroenterol Res Pract 2018; 2018:3287491. [PMID: 29849584 PMCID: PMC5937451 DOI: 10.1155/2018/3287491] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 01/21/2018] [Accepted: 02/20/2018] [Indexed: 12/15/2022] Open
Abstract
Background Coagulation disorders in patients with liver cirrhosis are a common clinical problem. Cirrhosis should be considered a state of impaired blood clotting or an imbalance of the whole coagulation system. Cirrhosis-induced coagulopathy encompasses disturbances in both the procoagulant and anticoagulant systems. This mechanism may promote the development of thrombosis with portal vein thrombosis (PVT), which is considered an obstacle to orthotopic liver transplantation (OLT). We assessed serum ADAMTS-13 levels in patients with decompensated liver cirrhosis, with and without PVT. Material and Methods Serum ADAMTS-13 levels, age, platelet count (PLT), and INR (international normalized ratio) were evaluated in (n = 64) patients with liver cirrhosis either with PVT (group 1, n = 31) or without PVT (group 2, n = 33). The results were compared with those from healthy volunteers (group 3, n = 37). Liver cirrhosis was based on Desmet's classification of chronic hepatitis in liver biopsy stage ≥ 3 or liver elastography F-score ≥ 3. Serum ADAMTS-13 levels were measured with Quantikine® ELISA Human ADAMTS13 Immunoassay, R&D Systems Inc. We used Welch's F-test, Games-Howell, one-way ANOVA, Bonferroni test, and logistic regression to determine whether ADAMTS-13 levels were a predictor that was independent of MELD and Child-Pugh scores. All results (P < 0.05) were considered statistically significant. Results The mean serum ADAMTS-13 level in patients with PVT was significantly lower than that in patients without PVT (P = 0.001) and controls (P = 0.001). The mean serum ADAMTS-13 level in patients without PVT was significantly lower than that in controls (P = 0.001). ADAMTS-13 levels were significantly associated with PVT accounting for the Child-Pugh or MELD score in the logistic regression model. Conclusions Low serum ADAMTS-13 levels can be a useful indicator of portal thrombosis in patients with decompensated liver cirrhosis irrespective of Child-Pugh or MELD scores. Further research is needed to determine whether ADAMTS-13 levels will find use in everyday clinical practice.
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Panova-Noeva M, Schulz A, Arnold N, Hermanns MI, Prochaska JH, Laubert-Reh D, Spronk HM, Blettner M, Beutel M, Pfeiffer N, Münzel T, Lackner KJ, Ten Cate H, Wild PS. Coagulation and inflammation in long-term cancer survivors: results from the adult population. J Thromb Haemost 2018; 16:699-708. [PMID: 29431889 DOI: 10.1111/jth.13975] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Indexed: 01/07/2023]
Abstract
Essentials The increase of cancer survival remains curtailed by cardiovascular mortality. We studied a large range of inflammatory and coagulation biomarkers in long-term cancer survivors. Cancer history has an important impact on mortality independent of cardiovascular risk factors. Fibrinogen and von Willebrand factor are potential biomarkers in survivors of increased mortality. SUMMARY Background The advances in cancer treatment and detection of early cancer have resulted in a steady increase in the number of of cancer survivors over the years. However, because of the long-term toxic effects of chemotherapy and radiotherapy, the incidence of cardiovascular disease (CVD) is increasing in survivors. Objectives To investigate traditional cardiovascular risk factors (CVRFs), inflammation and the coagulation profile in long-term cancer survivors (cancer diagnosis ≥ 5 years) from a large adult population-based study sample. Methods The presence of cardiovascular risk factors (CVRFs) and laboratory markers were compared in individuals with (n = 723) and without (n = 13626) a long-term history of cancer from the Gutenberg Health Study. Data on coagulation factors, D-dimer and von Willebrand factor (VWF) activity were available for 4974 individuals (n = 244 cancer survivors). Results In multivariable regression models, a history of cancer was, independently of CVRFs and CVD, associated with higher fibrinogen levels (β 6.99, 95% confidence interval [CI] 1.16-12.8), VWF activity (β 5.08, 95% CI 0.02-10.1), and antithrombin activity (β 1.85, 95% CI 0.44-3.27). Cancer survivors with CVD showed notably higher VWF activity than individuals with CVD without a history of cancer, with a difference in the means of 23.0 (7.9-38.1). Multivariate Cox regression analysis, adjusted for CVRFs, confirmed that a long-term history of cancer is associated with a 72% higher mortality. Increased mortality in cancer survivors was dependent on fibrinogen level and VWF activity level. Conclusion Cancer survivors showed a worse inflammation and coagulation profile than individuals without a history of cancer. Overall mortality in long-term cancer survivors was increased independently of traditional CVRFs. These results underline the need to further investigate plasma biomarkers as complementary cardiovascular risk predictors in cancer survivors.
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Affiliation(s)
- M Panova-Noeva
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - A Schulz
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - N Arnold
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - M I Hermanns
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - J H Prochaska
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site RhineMain, Mainz, Germany
| | - D Laubert-Reh
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - H M Spronk
- Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
| | - M Blettner
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - M Beutel
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - N Pfeiffer
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - T Münzel
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site RhineMain, Mainz, Germany
- Center for Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - K J Lackner
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - H Ten Cate
- Laboratory for Clinical Thrombosis and Hemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
| | - P S Wild
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site RhineMain, Mainz, Germany
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Polyantsev AA, Mozgovoy PV, Frolov DV, Linchenko AM, Shchelokova YV, Litvinova TA, Dyakova YA, Frolenko IA. [Pathogenesis and prevention of venous and arterial thromboembolic events in patients after deep vein thrombosis of lower extremities]. Khirurgiia (Mosk) 2018:33-40. [PMID: 29376955 DOI: 10.17116/hirurgia2018133-40] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AIM To define the role of thrombophilic and other procoagulant conditions in pathogenesis of deep vein thrombosis and the effectiveness of pathogenetic secondary prevention of venous and arterial thromboembolic events. MATERIAL AND METHODS The study included 107 patients for the period 2007-2016 who were divided into 3 groups. The main group (n=40) - lifelong individual antithrombotic therapy with warfarin predominantly; the second (control) group (n=39) - warfarin administration for 3-6 months; the third (additional) group (n=28) - specific life-long therapy depending on procoagulant status which was assessed according to original scale. The main anticoagulants were rivoroxaban or dabigatran etexilate. Recurrent venous thromboembolic complications (RVTE) were observed in one (2.5%) patient of the first group and in 8 (20.5%) cases of the second group. In the third group RVTE were absent (significant differences, p<0.03 and 0.001, respectively). Arterial thromboembolic diseases were noted in 1 (2.5%) patient of the first group, in 4 (10.25%) cases of the second group and in none of the third group (significantly only for group II vs. group III, p<0.01). RESULTS Individual antithrombotic therapy reduces the incidence of recurrent venous and arterial thromboembolic events in patients with idiopathic deep vein thrombosis.
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Affiliation(s)
- A A Polyantsev
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
| | - P V Mozgovoy
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
| | - D V Frolov
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
| | - A M Linchenko
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
| | - Yu V Shchelokova
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
| | - T A Litvinova
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
| | - Yu A Dyakova
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
| | - I A Frolenko
- Department of General Surgery with Urology of Volgograd State Medical University of Healthcare Ministry of Russia, Volgograd, Russia
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