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Smith AG, McNamee AP, Chan CHH, Headrick J, Simmonds MJ. An enhanced and rapid method for von Willebrand factor multimer analysis for mechanical circulatory device testing. Artif Organs 2024; 48:1438-1448. [PMID: 39101288 DOI: 10.1111/aor.14838] [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: 12/30/2023] [Revised: 07/02/2024] [Accepted: 07/22/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND Von Willebrand factor (VWF) is a critical glycoprotein in hemostasis and is an important factor in diagnosing bleeding disorders. Albeit the analysis of VWF is often compromised by inconsistent methodologies and challenges quantifying multimeric size. Current VWF multimer analysis methods are costly, time-consuming, and often inconsistent; thus, demanding skilled professionals. This study aimed to streamline and optimize the VWF multimer analysis technique, making it more efficient and reproducible, particularly for identifying or predicting mechanical circulatory support (MCS) induced bleeding disorders. METHODS Blood samples from healthy volunteers were exposed to high shear forces via a Medtronic HeartWare ventricular assist device. VWF multimers were analyzed using vertical-gel agarose electrophoresis and Western blotting. Differences in VWF distribution were determined using densitometry, and two methods of densitometric analysis were compared: proprietary software against open-source software. RESULTS Using the developed method: (i) protocol duration was accelerated from three days (in classical methods) to ~ eight hours; (ii) the resolution of the high molecular weight (HMW) VWF multimers were substantially improved; and (iii) densitometric analysis tools were validated. Additionally, the densitometry analysis using two software types showed a strong correlation between results, with the proprietary software reporting slightly higher HMW VWF percentages. CONCLUSION This methodology is recommended for affordable, accurate, and reproducible VWF multimer evaluations during MCS use and testing. Further research comparing this method with semi-automated methods would provide additional insight and improve inter-laboratory comparisons.
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Affiliation(s)
- Amanda G Smith
- Biorheology Research Laboratory, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Antony P McNamee
- Biorheology Research Laboratory, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
| | - Chris H H Chan
- Innovative Device & Engineering Applications (IDEA) Lab, Texas Heart Institute, Houston, Texas, USA
| | - John Headrick
- School of Pharmacy and Medical Science, Griffith University, Gold Coast, Queensland, Australia
| | - Michael J Simmonds
- Biorheology Research Laboratory, Menzies Health Institute Queensland, Griffith University, Gold Coast, Queensland, Australia
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2
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Tainio JM, Vanhatupa S, Miettinen S, Massera J. Borosilicate bioactive glasses with added Mg/Sr enhances human adipose-derived stem cells osteogenic commitment and angiogenic properties. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2024; 35:71. [PMID: 39614975 PMCID: PMC11608307 DOI: 10.1007/s10856-024-06830-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 09/06/2024] [Indexed: 12/22/2024]
Abstract
Bioactive glasses are one of the most promising materials for applications in bone tissue engineering. In this study, the focus was on borosilicate bioactive glasses with composition 47.12 SiO2 - 6.73 B2O3 - 21.77-x-y CaO - 22.65 Na2O - 1.72 P2O5 - x MgO - y SrO (mol%). These compositions are based on silicate S53P4 bioactive glass, from where 12.5% of SiO2 is replaced with B2O3, and additionally, part of CaO is substituted for MgO and/or SrO. The impact of ion release, both as extract and in direct contact, on human adipose-derived stem cells' (hADSCs) viability, proliferation, ECM maturation, osteogenic commitment and endothelial marker expression was assessed. Osteogenic media supplements were utilized with the extracts, and in part of the direct cell/material culturing conditions. While it has been reported in other studies that boron release can induce cytotoxicity, the glasses in this study supported cells viability and proliferation. Moreover, borosilicate's, especially with further Mg/Sr substitutions, upregulated several osteogenic markers (such as RUNX2a, OSTERIX, DLX5, OSTEOPONTIN), as well as angiogenic factors (e.g., vWF and PECAM-1). Furthermore, the studied glasses supported collagen-I production even in the absence of osteogenic supplements, when hADSCs were cultured in contact with the glasses, suggesting that while the bioactive glass degradation products are beneficial for osteogenesis, the glasses surface physico-chemical properties play a significant role on hADSCs differentiation. This study brings critical information on the impact of bioactive glass compositional modification to control glass dissolution and the subsequent influence on stem cells proliferation and differentiation. Furthermore, the role of the material surface chemistry on promoting cell differentiation is reported.
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Affiliation(s)
- Jenna M Tainio
- Bioceramics, Bioglasses and Biocomposites Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33720, Finland.
| | - Sari Vanhatupa
- Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland
| | - Susanna Miettinen
- Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33520, Finland
- Tays Research Services, Wellbeing Services County of Pirkanmaa, Tampere University Hospital, Elämänaukio, Kuntokatu 2, 33520, Tampere, Finland
| | - Jonathan Massera
- Bioceramics, Bioglasses and Biocomposites Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, 33720, Finland
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van Kwawegen CB, Leebeek FW. Prophylaxis in von Willebrand disease with von Willebrand factor concentrate and nonfactor therapies. Res Pract Thromb Haemost 2024; 8:102599. [PMID: 39628990 PMCID: PMC11609638 DOI: 10.1016/j.rpth.2024.102599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/03/2024] [Accepted: 10/03/2024] [Indexed: 12/06/2024] Open
Abstract
This manuscript summarizes the current status of prophylaxis and novel potential therapies to prevent bleeding in patients with von Willebrand disease (VWD). VWD is the most common inherited bleeding disorder, which is associated mainly with mucocutaneous bleeding and bleeding during surgical and dental interventions. More severely affected VWD patients, mostly those with type 2 and type 3, can also suffer from joint, muscle, and gastrointestinal bleeds. Most patients with mild and moderate VWD are treated with desmopressin. The majority of patients with type 2 and 3 are treated with von Willebrand factor concentrates, with or without factor VIII. These patients suffer from severe and frequent bleeds and may require regular infusions of von Willebrand factor concentrate to prevent bleeding, so-called prophylaxis, 1 to 3 times per week. In this article, we review the current status of prophylaxis in VWD. We will also discuss emerging treatments that may be used as long-term prophylaxis in patients with severe VWD. We include relevant new data on this topic that were presented during the 2024 International Society on Thrombosis and Haemostasis (ISTH) Congress.
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Affiliation(s)
| | - Frank W.G. Leebeek
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Sloan G, Donatien P, Privitera R, Shillo P, Caunt S, Selvarajah D, Anand P, Tesfaye S. Vascular and nerve biomarkers in thigh skin biopsies differentiate painful from painless diabetic peripheral neuropathy. FRONTIERS IN PAIN RESEARCH 2024; 5:1485420. [PMID: 39512388 PMCID: PMC11543357 DOI: 10.3389/fpain.2024.1485420] [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: 08/23/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024] Open
Abstract
Background Identifying distinct mechanisms and biomarkers for painful diabetic peripheral neuropathy (DPN) is required for advancing the treatment of this major global unmet clinical need. We previously provided evidence in calf skin biopsies that disproportion between reduced sensory small nerve fibers and increased blood vessels may distinguish painful from non-painful DPN. We proposed that overexposure of the reduced nerve fibers in DPN to increased hypoxemia-induced vasculature and related algogenic factors, e.g., nerve growth factor (NGF), leads to neuropathic pain. To further investigate this proposed mechanism, we have now studied more proximal thigh skin biopsies, to see if the same disproportion between increased vasculature and decreased nerve fibers generally differentiates painful DPN from painless DPN. Methods A total of 28 subjects with type 2 diabetes (T2DM) and 13 healthy volunteers (HV) underwent detailed clinical and neurophysiological assessments, based on the neuropathy composite score of the lower limbs [NIS(LL)] plus 7 tests. T2DM subjects were subsequently divided into three groups: painful DPN (n = 15), painless DPN (n = 7), and no DPN (n = 6). All subjects underwent skin punch biopsy from the upper lateral thigh 20 cm below the anterior iliac spine. Results Skin biopsies showed decreased PGP 9.5-positive intraepidermal nerve fiber (IENF) density in both painful DPN (p < 0.0001) and painless DPN (p = 0.001). Vascular marker von Willebrand Factor (vWF) density was markedly increased in painful DPN vs. other groups, including painless DPN (p = 0.01). There was a resulting significant decrease in the ratio of intraepidermal nerve fiber density to vasculature and PGP9.5 to vWF, in painful DPN vs. painless DPN (p = 0.05). These results were similar in pattern to those observed in these HV and T2DM groups previously in distal calf biopsies; however, the increase in vWF was much higher and nerve fiber density much lower in the calf than thigh for painful DPN. Thigh skin vWF density was significantly correlated with several metabolic (waist/hip ratio, HbA1c), clinical (e.g., pain score), and neurophysiological measures. Conclusion This study supports our proposal that increased dermal vasculature, and its disproportionate ratio to reduced nociceptors, may help differentiate painful DPN from painless DPN. This disproportion is greater in the distal calf than the proximal thigh skin; hence, neuropathic pain in DPN is length-dependent and first localized to the distal lower limbs, mainly feet.
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Affiliation(s)
- Gordon Sloan
- Division of Clinical Medicine, University of Sheffield, Sheffield, United Kingdom
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Philippe Donatien
- Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Rosario Privitera
- Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Pallai Shillo
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Sharon Caunt
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Dinesh Selvarajah
- Division of Clinical Medicine, University of Sheffield, Sheffield, United Kingdom
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Praveen Anand
- Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
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Maksić M, Corović I, Stanisavljević I, Radojević D, Veljković T, Todorović Ž, Jovanović M, Zdravković N, Stojanović B, Marković BS, Jovanović I. Heyde Syndrome Unveiled: A Case Report with Current Literature Review and Molecular Insights. Int J Mol Sci 2024; 25:11041. [PMID: 39456826 PMCID: PMC11507012 DOI: 10.3390/ijms252011041] [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: 08/08/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 10/28/2024] Open
Abstract
Heyde syndrome, marked by aortic stenosis, gastrointestinal bleeding from angiodysplasia, and acquired von Willebrand syndrome, is often underreported. Shear stress from a narrowed aortic valve degrades von Willebrand factor multimers, leading to angiodysplasia formation and von Willebrand factor deficiency. This case report aims to raise clinician awareness of Heyde syndrome, its complexity, and the need for a multidisciplinary approach. We present a 75-year-old man with aortic stenosis, gastrointestinal bleeding from angiodysplasia, and acquired von Willebrand syndrome type 2A. The patient was successfully treated with argon plasma coagulation and blood transfusions. He declined further treatment for aortic stenosis but was in good overall health with improved laboratory results during follow-up. Additionally, we provide a comprehensive review of the molecular mechanisms involved in the development of this syndrome, discuss current diagnostic and treatment approaches, and offer future perspectives for further research on this topic.
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Affiliation(s)
- Mladen Maksić
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (M.M.); (D.R.); (Ž.T.); (M.J.); (N.Z.)
| | - Irfan Corović
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (I.C.); (I.S.); (I.J.)
| | - Isidora Stanisavljević
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (I.C.); (I.S.); (I.J.)
| | - Dušan Radojević
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (M.M.); (D.R.); (Ž.T.); (M.J.); (N.Z.)
| | - Tijana Veljković
- Department of Pediatrics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia;
| | - Željko Todorović
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (M.M.); (D.R.); (Ž.T.); (M.J.); (N.Z.)
| | - Marina Jovanović
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (M.M.); (D.R.); (Ž.T.); (M.J.); (N.Z.)
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (I.C.); (I.S.); (I.J.)
| | - Nataša Zdravković
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (M.M.); (D.R.); (Ž.T.); (M.J.); (N.Z.)
| | - Bojan Stojanović
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia;
| | - Bojana Simović Marković
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (I.C.); (I.S.); (I.J.)
| | - Ivan Jovanović
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia; (I.C.); (I.S.); (I.J.)
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6
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Dal-Fabbro R, Anselmi C, Swanson WB, Medeiros Cardoso L, Toledo PTA, Daghrery A, Kaigler D, Abel A, Becker ML, Soliman S, Bottino MC. Amino Acid-Based Poly(ester urea) Biodegradable Membrane for Guided Bone Regeneration. ACS APPLIED MATERIALS & INTERFACES 2024; 16:53419-53434. [PMID: 39329195 DOI: 10.1021/acsami.4c09742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
Abstract
Barrier membranes (BM) for guided bone regeneration (GBR) aim to support the osteogenic healing process of a defined bony defect by excluding epithelial (gingival) ingrowth and enabling osteoprogenitor and stem cells to proliferate and differentiate into bone tissue. Currently, the most widely used membranes for these approaches are collagen-derived, and there is a discrepancy in defining the optimal collagen membrane in terms of biocompatibility, strength, and degradation rates. Motivated by these clinical observations, we designed a collagen-free membrane based on l-valine-co-l-phenylalanine-poly(ester urea) (PEU) copolymer via electrospinning. Degradation and mechanical properties of these membranes were performed on as-spun and water-aged samples. Alveolar-bone-derived stem cells (AvBMSCs) were seeded on the PEU BM to assess their cell compatibility and osteogenic characteristics, including cell viability, attachment/spreading, proliferation, and mineralized tissue-associated gene expression. In vivo, PEU BMs were subcutaneously implanted in rats to evaluate their potential to cause inflammatory responses and facilitate angiogenesis. Finally, critical-size calvarial defects and a periodontal model were used to assess the regenerative capacity of the electrospun PEU BM compared to clinically available Cytoflex synthetic membranes. PEU BM demonstrated equal biocompatibility to Cytoflex with superior mechanical performance in strength and elasticity. Additionally, after 14 days, PEU BM exhibited a higher expression of BGLAP/osteocalcin and superior in vivo performance-less inflammation and increased CD31 and VWF expression over time. When placed in critical-sized defects in the calvaria of rats, the PEU BM led to robust bone formation with high expression of osteogenesis and angiogenesis markers. Moreover, our membrane enhanced alveolar bone and cementum regeneration in an established periodontal model after 8 weeks. We demonstrate that the PEU BM exhibits favorable clinical properties, including mechanical stability, cytocompatibility, and facilitated bone formation in vitro and in vivo. This highlights its suitability for GBR in periodontal and craniofacial bone defects.
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Affiliation(s)
- Renan Dal-Fabbro
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48104, United States
| | - Caroline Anselmi
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48104, United States
- Department of Morphology and Pediatric Dentistry, School of Dentistry, São Paulo State University (UNESP), Araraquara, São Paulo 01049-010, Brazil
| | - W Benton Swanson
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48104, United States
| | - Lais Medeiros Cardoso
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48104, United States
- Department of Dental Materials and Prosthodontics, School of Dentistry, São Paulo State University (UNESP), Araraquara, São Paulo 01049-010, Brazil
| | - Priscila T A Toledo
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48104, United States
- Department of Preventive and Restorative Dentistry, School of Dentistry, São Paulo State University (UNESP), Araçatuba, São Paulo 01049-010, Brazil
| | - Arwa Daghrery
- Department of Restorative Dental Sciences, School of Dentistry, Jazan University, Jazan 82943, Kingdom of Saudi Arabia
| | - Darnell Kaigler
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48104, United States
- Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan 48104, United States
| | - Alexandra Abel
- Departments of Chemistry, Mechanical Engineering and Material Science, Orthopaedic Surgery, Duke University, Durham, North Carolina 27710, United States
| | - Matthew L Becker
- Departments of Chemistry, Mechanical Engineering and Material Science, Orthopaedic Surgery, Duke University, Durham, North Carolina 27710, United States
| | - Sherif Soliman
- Matregenix, Inc., Mission Viejo, California 92691, United States
| | - Marco C Bottino
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48104, United States
- Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan 48104, United States
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Atiq F, O’Donnell JS. Novel functions for von Willebrand factor. Blood 2024; 144:1247-1256. [PMID: 38728426 PMCID: PMC11561537 DOI: 10.1182/blood.2023021915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 03/20/2024] [Accepted: 04/24/2024] [Indexed: 05/12/2024] Open
Abstract
ABSTRACT For many years, it has been known that von Willebrand factor (VWF) interacts with factor VIII, collagen, and platelets. In addition, the key roles played by VWF in regulating normal hemostasis have been well defined. However, accumulating recent evidence has shown that VWF can interact with a diverse array of other novel ligands. To date, over 60 different binding partners have been described, with interactions mapped to specific VWF domains in some cases. Although the biological significance of these VWF-binding interactions has not been fully elucidated, recent studies have identified some of these novel ligands as regulators of various aspects of VWF biology, including biosynthesis, proteolysis, and clearance. Conversely, VWF binding has been shown to directly affect the functional properties for some of its ligands. In keeping with those observations, exciting new roles for VWF in regulating a series of nonhemostatic biological functions have also emerged. These include inflammation, wound healing, angiogenesis, and bone metabolism. Finally, recent evidence supports the hypothesis that the nonhemostatic functions of VWF directly contribute to pathogenic mechanisms in a variety of diverse diseases including sepsis, malaria, sickle cell disease, and liver disease. In this manuscript, we review the accumulating data regarding novel ligand interactions for VWF and critically assess how these interactions may affect cellular biology. In addition, we consider the evidence that nonhemostatic VWF functions may contribute to the pathogenesis of human diseases beyond thrombosis and bleeding.
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Affiliation(s)
- Ferdows Atiq
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - James S. O’Donnell
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- National Coagulation Centre, St James’s Hospital, Dublin, Ireland
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Szczodra A, Houaoui A, Agniel R, Sicard L, Miettinen S, Massera J, Gorin C. Boron substitution in silicate bioactive glass scaffolds to enhance bone differentiation and regeneration. Acta Biomater 2024; 186:489-506. [PMID: 39098444 DOI: 10.1016/j.actbio.2024.07.053] [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: 05/29/2024] [Revised: 07/12/2024] [Accepted: 07/29/2024] [Indexed: 08/06/2024]
Abstract
Commercially available bioactive glasses (BAGs) are exclusively used in powder form, due to their tendency to crystallize. Silicate BAG 1393 was developed to allow fiber drawing and scaffold sintering, but its slow degradation limits its potential. To enable scaffold manufacturing while maintaining glass dissolution rate close to that of commercially available BAGs, the borosilicate glass 1393B20 was developed. This study investigates the potential of 1393B20 scaffolds to support bone regeneration and mineralization in vitro and in vivo, in comparison to silicate 1393. Both scaffolds supported human adipose stem cells proliferation, either in direct contact for the 1393, or mainly around for the 1393B20. Similarly, both BAGs induced osteogenesis and angiogenesis in vitro, with a better pro-angiogenic influence of the 1393B20. In addition, these scaffolds supported bone regeneration and osteoclast/osteoblast activity in vivo in critical-sized rat calvarial defect. Nevertheless, mineralization and collagen formation were significantly enhanced for the 1393B20, at 3-months post-implantation, assigned to faster and more complete dissolution of the scaffolds. Thus, 1393B20 demonstrates greater promise for bone tissue engineering certainly due to its time-controlled release of boron and silicon. STATEMENT OF SIGNIFICANCE: Bioactive glasses (BAGs) show great promise in bone tissue engineering as they effectively bond with bone tissue, fostering integration and regeneration. Silicate BAG 1393 was developed to allow fiber drawing and scaffold sintering, but its slow degradation limits its potential. To enable scaffold manufacturing while maintaining glass dissolution rate close to that of commercially available BAGs, the borosilicate glass 1393B20 was developed. Both BAGs induced osteogenesis and angiogenesis in vitro, with a better pro-angiogenic influence of the 1393B20. The presence of boron in the 1393B20 enhanced mineralization and collagen formation in vivo compared to 1393, probably due to its faster dissolution rate. Here, 1393B20 demonstrated greater promise for bone tissue engineering compared to the well-known 1393 BAG.
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Affiliation(s)
- Agata Szczodra
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland
| | - Amel Houaoui
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland; CY Cergy Paris Université, Biomaterials for Health group, ERRMECe, Neuville sur Oise, France
| | - Rémy Agniel
- CY Cergy Paris Université, Biomaterials for Health group, ERRMECe, Neuville sur Oise, France
| | - Ludovic Sicard
- Laboratory URP2496 Orofacial Pathologies, Imaging and Biotherapies, Faculty of Odontology, Université Paris Cité, Montrouge, France; Oral Medicine Service, Prosthetics Department, AP-HP/GH Nord, Paris, France
| | - Susanna Miettinen
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland; Research Services, Wellbeing Services County of Pirkanmaa, Tampere University Hospital, Tampere, Finland
| | - Jonathan Massera
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland
| | - Caroline Gorin
- Laboratory URP2496 Orofacial Pathologies, Imaging and Biotherapies, Faculty of Odontology, Université Paris Cité, Montrouge, France; Oral Medicine Service, Prosthetics Department, AP-HP/GH Nord, Paris, France.
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9
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Ceasovschih A, Alexa RE, Șorodoc V, Balta A, Constantin M, Coman AE, Petriș OR, Stătescu C, Sascău RA, Onofrei V, Diaconu AD, Morărașu BC, Rusu-Zota G, Șorodoc L. Persistent Gastrointestinal Bleeding after Aortic Valve Replacement in Heyde's Syndrome. J Clin Med 2024; 13:4515. [PMID: 39124781 PMCID: PMC11313494 DOI: 10.3390/jcm13154515] [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: 05/14/2024] [Revised: 07/10/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Heyde's syndrome (HS) represents an association between aortic stenosis and intestinal angiodysplasias, and it has been demonstrated that acquired von Willebrand disease plays a pivotal role in the pathophysiology of this syndrome. In patients with HS, von Willebrand factor deficiency represents an additional risk factor, further contributing to the risk of bleeding and anemia. We present the case of an 86-year-old patient diagnosed with HS and von Willebrand deficiency in 2018. Four years prior, the patient underwent surgical aortic valve replacement. Since then, she has been receiving chronic oral anticoagulation therapy with a vitamin K antagonist. The patient was admitted to the Internal Medicine Clinic due to semi-solid dark stools, diffuse abdominal pain, and asthenia. Upon examination, the patient presented with an altered general status and clinical signs suggestive of anemia. Laboratory findings revealed anemia with elevated INR and aPTT values. Colonic angiodysplasias were identified during a colonoscopy, although no sources of active bleeding were detected. On the 9th day of hospitalization, the patient experienced an episode of lower gastrointestinal bleeding. The pharmacological management was adjusted, and argon plasma coagulation was recommended. Following treatment of the angiodysplastic lesions, the patient's clinical evolution was favorable, with the correction of the anemia.
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Affiliation(s)
- Alexandr Ceasovschih
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Raluca-Elena Alexa
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Victorița Șorodoc
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Anastasia Balta
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Mihai Constantin
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Adorata Elena Coman
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Ovidiu Rusalim Petriș
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Cristian Stătescu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Department of Cardiology, “Prof. Dr. George I.M. Georgescu” Cardiovascular Diseases Institute, 700503 Iasi, Romania
| | - Radu A. Sascău
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Department of Cardiology, “Prof. Dr. George I.M. Georgescu” Cardiovascular Diseases Institute, 700503 Iasi, Romania
| | - Viviana Onofrei
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Department of Cardiology, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Alexandra-Diana Diaconu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Bianca Codrina Morărașu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
| | - Gabriela Rusu-Zota
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Department of Pharmacology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Laurențiu Șorodoc
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.); (M.C.); (A.E.C.); (O.R.P.); (C.S.); (R.A.S.); (V.O.); (A.-D.D.); (B.C.M.); (G.R.-Z.); (L.Ș.)
- Second Internal Medicine Clinic, Sf. Spiridon Clinical Emergency Hospital, 700111 Iasi, Romania; (R.-E.A.); (A.B.)
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Li P, Shang Y, Yuan L, Tong J, Chen Q. Targeting BMP2 for therapeutic strategies against hepatocellular carcinoma. Transl Oncol 2024; 46:101970. [PMID: 38797016 PMCID: PMC11152749 DOI: 10.1016/j.tranon.2024.101970] [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: 12/08/2023] [Revised: 04/15/2024] [Accepted: 04/19/2024] [Indexed: 05/29/2024] Open
Abstract
OBJECTIVES This study aimed to investigate the role of BMP2 in hepatocellular carcinoma (HCC) growth and metastasis using a dual approach combining single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. METHODS scRNA-seq data from the GEO database and bulk RNA-seq data from the TCGA database were analyzed. Differentially expressed marker genes of endothelial cells were identified and analyzed using enrichment analysis, PPI analysis, correlation analysis, and GSEA. In vitro, experiments were conducted using the Huh-7 HCC cell line, and in vivo, models of HCC growth and metastasis were established by knocking down BMP2. RESULTS The scRNA-seq analysis identified BMP2 as a key marker gene in endothelial cells of HCC samples. Elevated BMP2 expression correlated with poor prognosis in HCC. In vitro experiments showed that silencing BMP2 inhibited the proliferation, migration, and invasion of liver cancer cells. In vivo studies confirmed increased BMP2 expression in HCC tissues, promoting angiogenesis and HCC growth. CONCLUSION This study highlights the role of BMP2 in tumor angiogenesis and HCC progression. Targeting BMP2 could be a promising therapeutic strategy against HCC.
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Affiliation(s)
- Ping Li
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, PR China
| | - You Shang
- Department of Anesthesiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, PR China
| | - Liying Yuan
- Department of Anesthesiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, PR China
| | - Jialing Tong
- Department of Anesthesiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, PR China
| | - Quan Chen
- Department of Anesthesiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, PR China.
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11
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Laan SNJ, de Boer S, Dirven RJ, van Moort I, Kuipers TB, Mei H, Bierings R, Eikenboom J. Transcriptional and functional profiling identifies inflammation and endothelial-to-mesenchymal transition as potential drivers for phenotypic heterogeneity within a cohort of endothelial colony forming cells. J Thromb Haemost 2024; 22:2027-2038. [PMID: 38574861 DOI: 10.1016/j.jtha.2024.03.018] [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: 10/19/2023] [Revised: 03/14/2024] [Accepted: 03/24/2024] [Indexed: 04/06/2024]
Abstract
BACKGROUND Endothelial colony-forming cells (ECFCs) derived from patients can be used to investigate pathogenic mechanisms of vascular diseases like von Willebrand disease. Considerable phenotypic heterogeneity has been observed between ECFC clones derived from healthy donors. This heterogeneity needs to be well understood in order to use ECFCs as endothelial models for disease. OBJECTIVES Therefore, we aimed to determine phenotypic and gene expression differences between control ECFCs. METHODS A total of 34 ECFC clones derived from 16 healthy controls were analyzed. The transcriptome of a selection of ECFC clones (n = 15) was analyzed by bulk RNA sequencing and gene set enrichment analysis. Gene expression was measured in all ECFC clones by quantitative polymerase chain reaction. Phenotypic profiling was performed and migration speed of the ECFCs was measured using confocal microscopy, followed by automated quantification of cell morphometrics and migration speed. RESULTS Through hierarchical clustering of RNA expression profiles, we could distinguish 2 major clusters within the ECFC cohort. Major differences were associated with proliferation and migration in cluster 1 and inflammation and endothelial-to-mesenchymal transition in cluster 2. Phenotypic profiling showed significantly more and smaller ECFCs in cluster 1, which contained more and longer Weibel-Palade bodies. Migration speed in cluster 1 was also significantly higher. CONCLUSION We observed a range of different RNA expression patterns between ECFC clones, mostly associated with inflammation and clear differences in Weibel-Palade body count and structure. We developed a quantitative polymerase chain reaction panel that can be used for the characterization of ECFC clones, which is essential for the correct analysis of pathogenic mechanisms in vascular disorders.
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Affiliation(s)
- Sebastiaan N J Laan
- Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, the Netherlands; Department of Hematology, Erasmus University Medical Centre, Rotterdam, the Netherlands. https://twitter.com/laan_bas
| | - Suzan de Boer
- Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, the Netherlands
| | - Richard J Dirven
- Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, the Netherlands
| | - Iris van Moort
- Department of Hematology, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Thomas B Kuipers
- Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands
| | - Ruben Bierings
- Department of Hematology, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - Jeroen Eikenboom
- Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Centre, Leiden, the Netherlands.
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12
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James P, Leebeek F, Casari C, Lillicrap D. Diagnosis and treatment of von Willebrand disease in 2024 and beyond. Haemophilia 2024; 30 Suppl 3:103-111. [PMID: 38481079 DOI: 10.1111/hae.14970] [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: 01/13/2024] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 04/22/2024]
Abstract
MANUSCRIPT BACKGROUND AND AIM The diagnosis and clinical care of patients with von Willebrand disease (VWD) has continued to evolve since the characterization of the von Willebrand factor (VWF) gene in 1985. This condition is almost certainly the most common inherited bleeding disorder, and the major symptomatic burden of the disease is experienced by females during their reproductive years. Diagnosis relies on the identification of a personal and family history of excessive mucocutaneous bleeding, and laboratory features consistent with quantitative and/or qualitative abnormalities of VWF. This review focuses on three aspects of VWD management, with current updates and a look into the future. MANUSCRIPT THEMES First, we will address the role of genetics in the diagnosis and possible therapies for VWD. With current technologies, VWD genetic diagnosis is usually confined to the confirmation of type 2 subtypes of the disease and type 3 VWD analysis for family planning. While type 3 VWD is a potential candidate for the application of gene therapy, no treatments are currently close to entering the clinic. Second, the peri-procedural management of patients with VWD remains an important element of care. The choice of product, its dose and schedule all require careful consideration depending upon the type and disruptive nature of the planned procedure. Lastly, in addition to gene therapy, several other novel therapeutic interventions are also being developed for bleeding and prophylaxis in VWD. These include a VWF aptamer interfering with VWF clearance and bioengineered forms of VWF.
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Affiliation(s)
- Paula James
- Departments of Medicine and Pathology and Molecular Medicine, Queen's University, Kingston, Canada
| | - Frank Leebeek
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Caterina Casari
- University Paris-Saclay, INSERM, Hemostasis Inflammation Thrombosis HITH U1176, Le Kremlin-Bicêtre, France
| | - David Lillicrap
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada
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13
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Sunohara M, Morikawa S, Shimada K, Suzuki K. Spatiotemporal expression profiles of c-Mpl mRNA in the tooth germ: Comparative expression dynamics of vascularization-related genes. Ann Anat 2024; 253:152227. [PMID: 38336176 DOI: 10.1016/j.aanat.2024.152227] [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: 07/21/2023] [Revised: 12/06/2023] [Accepted: 02/05/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND Vascularization is an essential event for both embryonic organ development and tissue repair in adults. During mouse tooth development, endothelial cells migrate into dental papilla during the cap stage, and form blood vessels through angiogenesis. Megakaryocytes and/or platelets, as other hematopoietic cells, express angiogenic molecules and can promote angiogenesis in adult tissues. However, it remains unknown which cells are responsible for attracting and leading blood vessels through the dental papilla during tooth development. METHODS Here we analyzed the spatiotemporal expression of c-Mpl mRNA in developing molar teeth of fetal mice. Expression patterns were then compared with those of several markers of hematopoietic cells as well as of angiogenic elements including CD41, erythropoietin receptor, CD34, angiopoietin-1 (Ang-1), Tie-2, and vascular endothelial growth factor receptor2 (VEGFR2) through in situ hybridization or immunohistochemistry. RESULTS Cells expressing c-Mpl mRNA was found in several parts of the developing tooth germ, including the peridental mesenchyme, dental papilla, enamel organ, and dental lamina. This expression occurred in a spatiotemporally controlled fashion. CD41-expressing cells were not detected during tooth development. The spatiotemporal expression pattern of c-Mpl mRNA in the dental papilla was similar to that of Ang-1, which preceded invasion of endothelial cells. Eventually, at the early bell stage, the c-Mpl mRNA signal was detected in morphologically differentiating odontoblasts that accumulated in the periphery of the dental papilla along the inner enamel epithelium layer of the future cusp region. CONCLUSION During tooth development, several kinds of cells express c-Mpl mRNA in a spatiotemporally controlled fashion, including differentiating odontoblasts. We hypothesize that c-Mpl-expressing cells appearing in the forming dental papilla at the cap stage are odontoblast progenitor cells that migrate to the site of odontoblast differentiation. There they attract vascular endothelial cells into the forming dental papilla and lead cells toward the inner enamel epithelium layer through production of angiogenic molecules (e.g., Ang-1) during migration to the site of differentiation. C-Mpl may regulate apoptosis and/or proliferation of expressing cells in order to execute normal development of the tooth.
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Affiliation(s)
- Masataka Sunohara
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan.
| | - Shigeru Morikawa
- Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan
| | - Kazuto Shimada
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
| | - Kingo Suzuki
- Department of Anatomy, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan
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Orozco-García E, Getova V, Calderón JC, Harmsen MC, Narvaez-Sanchez R. Angiogenesis is promoted by hypoxic cervical carcinoma-derived extracellular vesicles depending on the endothelial cell environment. Vascul Pharmacol 2024; 154:107276. [PMID: 38242295 DOI: 10.1016/j.vph.2024.107276] [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: 10/12/2023] [Revised: 01/04/2024] [Accepted: 01/15/2024] [Indexed: 01/21/2024]
Abstract
INTRODUCTION Cancer needs perfusion for its growth and metastasis. Cancer cell-derived extracellular vesicles (CA-EVs) alter the tumor microenvironment (TME), potentially promoting angiogenesis. We hypothesize that conditions in the tumor, e.g., hypoxia, and in the target cells of the TME, e.g., nutrient deprivation or extracellular matrix, can affect the angiogenic potential of CA-EVs, which would contribute to explaining the regulation of tumor vascularization and its influence on cancer growth and metastasis. METHODS CA-EVs were isolated and characterized from cervical carcinoma cell lines HeLa and SiHa cultured under normoxia and hypoxia, and their angiogenic potential was evaluated in vitro in three endothelial cells (ECs) lines and aortic rings, cultured in basal (growth factor-reduced) or complete medium. RESULTS Hypoxia increased EV production 10-100 times and protein content 2-4 times compared to normoxic CA-EVs. HeLa-EVs contained six times more RNA than SiHa-EVs, and this concentration was not affected by hypoxia. Treatment with CA-EVs increased tube formation and sprouting in ECs and aortic rings cultured in basal medium and long-term stabilized the stablished vascular networks formed by ECs cultured in complete medium. CONCLUSION Hypoxia differentially affects CA-EVs in a cell line-dependent manner. The cellular environment (nutrient availability and extracellular matrix scaffold) influences the effect of CA-EV on the angiogenic potential of ECs.
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Affiliation(s)
- E Orozco-García
- Physiology and Biochemistry Research Group - PHYSIS, Faculty of Medicine, University of Antioquia, Medellin, Colombia; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Hanzeplein 1 (EA11), Groningen 9713 GZ, the Netherlands; University of Groningen, University Medical Center Groningen, W.J. Kolff Research Institute, Groningen, the Netherlands
| | - V Getova
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Hanzeplein 1 (EA11), Groningen 9713 GZ, the Netherlands; University of Groningen, University Medical Center Groningen, W.J. Kolff Research Institute, Groningen, the Netherlands
| | - J C Calderón
- Physiology and Biochemistry Research Group - PHYSIS, Faculty of Medicine, University of Antioquia, Medellin, Colombia
| | - M C Harmsen
- University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Hanzeplein 1 (EA11), Groningen 9713 GZ, the Netherlands; University of Groningen, University Medical Center Groningen, W.J. Kolff Research Institute, Groningen, the Netherlands.
| | - R Narvaez-Sanchez
- Physiology and Biochemistry Research Group - PHYSIS, Faculty of Medicine, University of Antioquia, Medellin, Colombia
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Galeone A, Buccoliero C, Barile B, Nicchia GP, Onorati F, Luciani GB, Brunetti G. Cellular and Molecular Mechanisms Activated by a Left Ventricular Assist Device. Int J Mol Sci 2023; 25:288. [PMID: 38203459 PMCID: PMC10779015 DOI: 10.3390/ijms25010288] [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: 11/20/2023] [Revised: 12/13/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Left ventricular assist devices (LVADs) represent the final treatment for patients with end-stage heart failure (HF) not eligible for transplantation. Although LVAD design has been further improved in the last decade, their use is associated with different complications. Specifically, inflammation, fibrosis, bleeding events, right ventricular failure, and aortic valve regurgitation may occur. In addition, reverse remodeling is associated with substantial cellular and molecular changes of the failing myocardium during LVAD support with positive effects on patients' health. All these processes also lead to the identification of biomarkers identifying LVAD patients as having an augmented risk of developing associated adverse events, thus highlighting the possibility of identifying new therapeutic targets. Additionally, it has been reported that LVAD complications could cause or exacerbate a state of malnutrition, suggesting that, with an adjustment in nutrition, the general health of these patients could be improved.
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Affiliation(s)
- Antonella Galeone
- Department of Surgery, Dentistry, Pediatrics and Gynecology, Division of Cardiac Surgery, University of Verona, 37129 Verona, Italy; (A.G.); (F.O.); (G.B.L.)
| | - Cinzia Buccoliero
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (C.B.); (B.B.); (G.P.N.)
| | - Barbara Barile
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (C.B.); (B.B.); (G.P.N.)
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (C.B.); (B.B.); (G.P.N.)
| | - Francesco Onorati
- Department of Surgery, Dentistry, Pediatrics and Gynecology, Division of Cardiac Surgery, University of Verona, 37129 Verona, Italy; (A.G.); (F.O.); (G.B.L.)
| | - Giovanni Battista Luciani
- Department of Surgery, Dentistry, Pediatrics and Gynecology, Division of Cardiac Surgery, University of Verona, 37129 Verona, Italy; (A.G.); (F.O.); (G.B.L.)
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy; (C.B.); (B.B.); (G.P.N.)
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16
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Ferroni L, D'Amora U, Gardin C, Leo S, Dalla Paola L, Tremoli E, Giuliani A, Calzà L, Ronca A, Ambrosio L, Zavan B. Stem cell-derived small extracellular vesicles embedded into methacrylated hyaluronic acid wound dressings accelerate wound repair in a pressure model of diabetic ulcer. J Nanobiotechnology 2023; 21:469. [PMID: 38062461 PMCID: PMC10702007 DOI: 10.1186/s12951-023-02202-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 11/07/2023] [Indexed: 12/18/2023] Open
Abstract
Over the past years, the development of innovative smart wound dressings is revolutionizing wound care management and research. Specifically, in the treatment of diabetic foot wounds, three-dimensional (3D) bioprinted patches may enable personalized medicine therapies. In the present work, a methacrylated hyaluronic acid (MeHA) bioink is employed to manufacture 3D printed patches to deliver small extracellular vesicles (sEVs) obtained from human mesenchymal stem cells (MSC-sEVs). The production of sEVs is maximized culturing MSCs in bioreactor. A series of in vitro analyses are carried out to demonstrate the influence of MSC-sEVs on functions of dermal fibroblasts and endothelial cells, which are the primary functional cells in skin repair process. Results demonstrate that both cell populations are able to internalize MSC-sEVs and that the exposure to sEVs stimulates proliferation and migration. In vivo experiments in a well-established diabetic mouse model of pressure ulcer confirm the regenerative properties of MSC-sEVs. The MeHA patch enhances the effectiveness of sEVs by enabling controlled release of MSC-sEVs over 7 days, which improve wound epithelialization, angiogenesis and innervation. The overall findings highlight that MSC-sEVs loading in 3D printed biomaterials represents a powerful technique, which can improve the translational potential of parental stem cell in terms of regulatory and economic impact.
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Affiliation(s)
- Letizia Ferroni
- Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy.
| | - Ugo D'Amora
- Institute of Polymers, Composites and Biomaterials, National Research Council, Naples, 80125, Italy
| | - Chiara Gardin
- Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy
| | - Sara Leo
- Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy
| | - Luca Dalla Paola
- Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy
| | - Elena Tremoli
- Maria Cecilia Hospital, GVM Care and Research, Cotignola, 48033, Italy
| | - Alessandro Giuliani
- Department of Veterinary Medical Science (DIMEVET), University of Bologna, Ozzano Emilia, 40064, Italy
| | - Laura Calzà
- Department of Pharmacy and Biotechnology and CIRI-SDV, University of Bologna, Bologna, 40126, Italy
| | - Alfredo Ronca
- Institute of Polymers, Composites and Biomaterials, National Research Council, Naples, 80125, Italy
| | - Luigi Ambrosio
- Institute of Polymers, Composites and Biomaterials, National Research Council, Naples, 80125, Italy
| | - Barbara Zavan
- Translational Medicine Department, University of Ferrara, Ferrara, 44121, Italy.
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Saladino A, Gonzalez ML, Chuliber FA, Serra MM. Glanzmann's thrombasthenia associated with gastrointestinal angiodysplasias successfully treated with bevacizumab. Blood Coagul Fibrinolysis 2023; 34:545-548. [PMID: 37942747 DOI: 10.1097/mbc.0000000000001249] [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: 11/10/2023]
Abstract
Glanzmann's Thrombasthenia (GT) is a rare hemorrhagic condition caused by a platelet surface receptor disorder of the glycoprotein (GP) IIb/IIIa. Symptoms of GT are various forms of hemorrhages, such as purpura, epistaxis and menorrhagia. Gastrointestinal bleeding (GIB) is a rare expression of the condition and may occur due to traumas in the GI tract or as a consequence of gastrointestinal angiodysplasia (GIADs). In this case report, we present a middle-aged woman with recurrent GIB consequent to GIADs with persistent melena and iron deficiency anemia. After several unsuccessful therapeutic interventions, the patient was studied by the hereditary hemorrhagic telangiectasia's (HHT - Osler-Weber-Rendu disease) unit, where she received bevacizumab, showing a complete improvement in symptoms as well as a reduction in her GIADs. This case shows that bevacizumab could be a possible line of treatment for patients with coagulation disorders with GIADs.
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Affiliation(s)
- Agustina Saladino
- Hospital Italiano de Buenos Aires
- Argentine Rendu Study Group
- Instituto Universitario Hospital Italiano de Buenos Aires, Argentina
| | - María L Gonzalez
- Hospital Italiano de Buenos Aires
- Argentine Rendu Study Group
- Hereditary Hemorrhagic Telangiectasia Unit
- Gastroenterology Department
- Instituto Universitario Hospital Italiano de Buenos Aires, Argentina
| | | | - Marcelo M Serra
- Hospital Italiano de Buenos Aires
- Argentine Rendu Study Group
- Hereditary Hemorrhagic Telangiectasia Unit
- Internal Medicine Department
- Instituto Universitario Hospital Italiano de Buenos Aires, Argentina
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Jiang T, Cai Z, Mu M, Zhao Z, Shen C, Zhang B. The Global Burden of Vascular Intestinal Disorders in 204 Countries and Territories From 1990 to 2019: Global Burden of Diseases Study. Int J Public Health 2023; 68:1606297. [PMID: 37822566 PMCID: PMC10562586 DOI: 10.3389/ijph.2023.1606297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 08/21/2023] [Indexed: 10/13/2023] Open
Abstract
Objectives: Assess the prevalence, mortality, and disability-adjusted life years (DALYs) of vascular intestinal disorders (VID) from 1990 to 2019. Methods: This study conducted a secondary data analysis utilizing the Global Burden of Diseases Study 2019. The prevalence, mortality and DALYs of VID were analyzed by sex, age and socio-demographic index (SDI), respectively. Analyses were performed by using R software. Results: Globally, the number of prevalent VID cases increased from 100,158 (95% uncertainty interval: 89,428-114,013) in 1,990-175,740 (157,941-198,969) in 2019. However, the age-standardized rates (ASR) of VID prevalence declined from 2.47 (95% uncertainty interval: 2.24-2.76) per 100,000 population to 2.21 (1.98-2.48) per 100,000 population between 1990 and 2019. Furthermore, the ASR of mortality also decreased from 1990 to 2019. Between 1990 and 2019, the regions with high and high-middle level exhibited the highest diseases burden. Conclusion: Globally, the diseases burden associated with VID demonstrated a decline from 1990 to 2019. However, concerted efforts are still required to enhance measures to combat VID within countries categorized as high and high-middle SDI.
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Affiliation(s)
- Tianxiang Jiang
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhaolun Cai
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mingchun Mu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhou Zhao
- Department of Gastrointestinal Cancer Center, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyong Shen
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Zhang
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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19
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Wong SWK, Tey SK, Mao X, Fung HL, Xiao Z, Wong DKH, Mak L, Yuen M, Ng IO, Yun JP, Gao Y, Yam JWP. Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2302677. [PMID: 37387563 PMCID: PMC10502836 DOI: 10.1002/advs.202302677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/07/2023] [Indexed: 07/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor-derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV-vWF levels are found in a larger cohort of HCC-sEV samples and metastatic HCC cell lines compared to their respective normal counterparts. Circulating sEVs of late-stage HCC patients markedly augment angiogenesis, tumor-endothelial adhesion, pulmonary vascular leakiness, and metastasis, which are significantly compromised by anti-vWF antibody. The role of vWF is further corroborated by the enhanced promoting effect of sEVs collected from vWF-overexpressing cells. sEV-vWF modulates endothelial cells through an elevated level of vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor 2 (FGF2). Mechanistically, secreted FGF2 elicits a positive feedback response in HCC via the FGFR4/ERK1 signaling pathway. The co-administration of anti-vWF antibody or FGFR inhibitor significantly improves the treatment outcome of sorafenib in a patient-derived xenograft mouse model. This study reveals mutual stimulation between HCC and endothelial cells by tumor-derived sEVs and endothelial angiogenic factors, facilitating angiogenesis and metastasis. It also provides insights into a new therapeutic strategy involving blocking tumor-endothelial intercellular communication.
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Affiliation(s)
- Samuel Wan Ki Wong
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Sze Keong Tey
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- Department of SurgerySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Xiaowen Mao
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver Research, The University of Hong KongHong Kong
| | - Hiu Ling Fung
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Zhi‐Jie Xiao
- Research CentreThe Seventh Affiliated HospitalSun Yat‐sen University518107ShenzhenP. R. China
| | - Danny Ka Ho Wong
- Department of MedicineSchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Lung‐Yi Mak
- Department of MedicineSchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Man‐Fung Yuen
- Department of MedicineSchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
| | - Irene Oi‐Lin Ng
- State Key Laboratory of Liver Research, The University of Hong KongHong Kong
| | - Jing Ping Yun
- Department of PathologySun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Yi Gao
- Department of Hepatobiliary Surgery IIZhuJiang HospitalSouthern Medical UniversityGuangzhouGuangdong510280P. R. China
| | - Judy Wai Ping Yam
- Department of PathologySchool of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong Kong
- State Key Laboratory of Liver Research, The University of Hong KongHong Kong
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Al-Ghadban S, Walczak SG, Isern SU, Martin EC, Herbst KL, Bunnell BA. Enhanced Angiogenesis in HUVECs Preconditioned with Media from Adipocytes Differentiated from Lipedema Adipose Stem Cells In Vitro. Int J Mol Sci 2023; 24:13572. [PMID: 37686378 PMCID: PMC10487727 DOI: 10.3390/ijms241713572] [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: 08/01/2023] [Revised: 08/25/2023] [Accepted: 08/31/2023] [Indexed: 09/10/2023] Open
Abstract
Lipedema is a connective tissue disorder characterized by increased dilated blood vessels (angiogenesis), inflammation, and fibrosis of the subcutaneous adipose tissue. This project aims to gain insights into the angiogenic processes in lipedema using human umbilical vein endothelial cells (HUVECs) as an in vitro model. HUVECs were cultured in conditioned media (CM) collected from healthy (non-lipedema, AQH) and lipedema adipocytes (AQL). The impacts on the expression levels of multiple endothelial and angiogenic markers [CD31, von Willebrand Factor (vWF), angiopoietin 2 (ANG2), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMPs), NOTCH and its ligands] in HUVECs were investigated. The data demonstrate an increased expression of CD31 and ANG2 at both the gene and protein levels in HUVECs treated with AQL CM in 2D monolayer and 3D cultures compared to untreated cells. Furthermore, the expression of the vWF, NOTCH 4, and DELTA-4 genes decreased. In contrast, increased VEGF, MMP9, and HGF gene expression was detected in HUVECs treated with AQL CM cultured in a 2D monolayer. In addition, the results of a tube formation assay indicate that the number of formed tubes increased in lipedema-treated HUVECs cultured in a 2D monolayer. Together, the data indicate that lipedema adipocyte-CM promotes angiogenesis through paracrine-driven mechanisms.
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Affiliation(s)
- Sara Al-Ghadban
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
| | - Samantha G. Walczak
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
| | - Spencer U. Isern
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
| | - Elizabeth C. Martin
- Department of Medicine, Section of Hematology and Oncology, Tulane University, New Orleans, LA 70118, USA;
| | | | - Bruce A. Bunnell
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (S.G.W.); (S.U.I.)
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21
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Sugino S, Inoue K, Zen K, Yashige M, Kobayashi R, Takamatsu K, Ito N, Iwai N, Hirose R, Doi T, Dohi O, Yoshida N, Uchiyama K, Takagi T, Ishikawa T, Konishi H, Matoba S, Itoh Y. Gastrointestinal Angiodysplasia in Patients with Severe Aortic Stenosis: The Endoscopic Features of Heyde's Syndrome. Digestion 2023; 104:468-479. [PMID: 37619533 DOI: 10.1159/000533237] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 07/22/2023] [Indexed: 08/26/2023]
Abstract
INTRODUCTION Aortic stenosis (AS) is sometimes associated with gastrointestinal bleeding, and this phenomenon is known as Heyde's syndrome. Such bleeding is most often considered to originate from gastrointestinal angiodysplasias, but the frequency and endoscopic features of such bleeding remain unclear. This study aimed to determine the frequency and endoscopic features of gastrointestinal angiodysplasia in patients with severe AS. PATIENTS AND METHODS In this multicenter, retrospective study, we evaluated consecutive patients who underwent transcatheter aortic valve implantation (TAVI) with severe AS from May 2016 to December 2019. We extracted the data on the clinicopathological features according to the status of anemia, the proportion of patients who underwent gastrointestinal endoscopic examinations and demonstrated gastrointestinal angiodysplasia, and identified the endoscopic features associated with such patients. RESULTS In 325 patients, the rates of moderate/severe anemia (hemoglobin < 11 g/dL) were 52%. Regarding medicine, there were no significant differences between the patients with and without moderate/severe anemia. Patients were examined by esophagogastroduodenoscopy (21%), colonoscopy (12%), and balloon-assisted enteroscopy or small bowel capsule endoscopy (1.5%). Patients with moderate/severe anemia had significantly more angiodysplasia (38.3% vs. 7.7%; p < 0.0001) and active bleeding (23.4% vs. 0%; p < 0.01). Angiodysplasia was detected in 21 patients (stomach, n = 9; small intestine, n = 5, and colon, n = 10). CONCLUSIONS The results suggest, for the first time, that patients with severe AS who underwent TAVI and moderate/severe anemia frequently had gastrointestinal angiodysplasia and active bleeding throughout the entire gastrointestinal tract.
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Affiliation(s)
- Satoshi Sugino
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan,
- Department of Gastroenterology and Hepatology, Asahi University Hospital, Gifu, Japan,
| | - Ken Inoue
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kan Zen
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Masaki Yashige
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Reo Kobayashi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuaki Takamatsu
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Nobuyasu Ito
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Naoto Iwai
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryohei Hirose
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshifumi Doi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Osamu Dohi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naohisa Yoshida
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuhiko Uchiyama
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomohisa Takagi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Ishikawa
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hideyuki Konishi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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22
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Kang DH, Kim MJ, Mohamed EA, Kim DS, Jeong JS, Kim SY, Kang HG, Lee GS, Hong EJ, Ahn C, Jung EM, An BS, Kim SC. Regulation of uterus and placenta remodeling under high estradiol levels in gestational diabetes mellitus models†. Biol Reprod 2023; 109:215-226. [PMID: 37255320 DOI: 10.1093/biolre/ioad059] [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: 01/30/2023] [Revised: 04/25/2023] [Accepted: 05/18/2023] [Indexed: 06/01/2023] Open
Abstract
The present study aimed to investigate the regulation of placentas and uterus remodeling and involvement of estradiol in gestational diabetes mellitus. To achieve this, we established in vitro and in vivo models for gestational diabetes mellitus placentas by culturing human placental choriocarcinoma cells (BeWo) under hyperglycemic concentration and treating pregnant rats with streptozotocin. We evaluated the expression of angiogenesis-related proteins. The expression of the anti-angiogenic factor, excess placental soluble fms-like tyrosine kinase 1 was increased in our in vitro gestational diabetes mellitus model compared with the control. Moreover, the expressions of placental soluble fms-like tyrosine kinase 1 and the von Willebrand factor were also significantly elevated in the placenta of streptozotocin-treated rats. These data indicate the disruption of angiogenesis in the gestational diabetes mellitus placentas. The expression levels of connexin 43, a component of the gap junction and collagen type I alpha 2 chain, a component of the extracellular matrix, were decreased in the gestational diabetes mellitus uterus. These results suggest that uterus decidualization and placental angiogenesis are inhibited in gestational diabetes mellitus rats. Our results also showed upregulation of the expression of genes regulating estradiol synthesis as well as estrogen receptors in vivo models. Accordingly, the concentration of estradiol measured in the culture medium under hyperglycemic conditions, as well as in the serum and placenta of the streptozotocin-treated rats, was significantly elevated compared with the control groups. These results suggest that the dysregulated remodeling of the placenta and uterus may result in the elevation of estradiol and its signaling pathway in the gestational diabetes mellitus animal model to maintain pregnancy.
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Affiliation(s)
- Da Hee Kang
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
| | - Min Jae Kim
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
- Developmental and Reproductive Toxicology Research Group, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Elsayed A Mohamed
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
- Department of Genetics, Assiut University, Assiut, Egypt
| | - Da Som Kim
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
| | - Jea Sic Jeong
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
| | - So Young Kim
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
| | - Hyeon-Gu Kang
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
| | - Geun-Shik Lee
- Department of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon, Republic of Korea
| | - Eui-Ju Hong
- Department of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Changhwan Ahn
- Department of Veterinary Medicine, Jeju National University, Jeju, Republic of Korea
| | - Eui-Man Jung
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan, Republic of Korea
| | - Beum-Soo An
- Department of Biomaterials Science (BK21 Four Program), College of Natural Resources & Life Science, Pusan National University, Miryang, Republic of Korea
| | - Seung-Chul Kim
- Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Busan, Republic of Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
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23
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Mahmoud AH, Han Y, Dal-Fabbro R, Daghrery A, Xu J, Kaigler D, Bhaduri SB, Malda J, Bottino MC. Nanoscale β-TCP-Laden GelMA/PCL Composite Membrane for Guided Bone Regeneration. ACS APPLIED MATERIALS & INTERFACES 2023; 15:32121-32135. [PMID: 37364054 PMCID: PMC10982892 DOI: 10.1021/acsami.3c03059] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
Major advances in the field of periodontal tissue engineering have favored the fabrication of biodegradable membranes with tunable physical and biological properties for guided bone regeneration (GBR). Herein, we engineered innovative nanoscale beta-tricalcium phosphate (β-TCP)-laden gelatin methacryloyl/polycaprolactone (GelMA/PCL-TCP) photocrosslinkable composite fibrous membranes via electrospinning. Chemo-morphological findings showed that the composite microfibers had a uniform porous network and β-TCP particles successfully integrated within the fibers. Compared with pure PCL and GelMA/PCL, GelMA/PCL-TCP membranes led to increased cell attachment, proliferation, mineralization, and osteogenic gene expression in alveolar bone-derived mesenchymal stem cells (aBMSCs). Moreover, our GelMA/PCL-TCP membrane was able to promote robust bone regeneration in rat calvarial critical-size defects, showing remarkable osteogenesis compared to PCL and GelMA/PCL groups. Altogether, the GelMA/PCL-TCP composite fibrous membrane promoted osteogenic differentiation of aBMSCs in vitro and pronounced bone formation in vivo. Our data confirmed that the electrospun GelMA/PCL-TCP composite has a strong potential as a promising membrane for guided bone regeneration.
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Affiliation(s)
- Abdel H Mahmoud
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Yuanyuan Han
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, United States
- Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, 999077 Hong Kong, China
| | - Renan Dal-Fabbro
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Arwa Daghrery
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Restorative Dental Sciences, School of Dentistry, Jazan University, Jazan 45142, Kingdom of Saudi Arabia
| | - Jinping Xu
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Darnell Kaigler
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Sarit B Bhaduri
- Department of Mechanical, Industrial and Manufacturing Engineering, University of Toledo, Toledo, Ohio 43606-3390, United States
- EEC Division, Directorate of Engineering, The National Science Foundation, Alexandria, Virginia 22314, United States
| | - Jos Malda
- Regenerative Medicine Center Utrecht, 3584 CT Utrecht, The Netherlands
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3508 TC Utrecht, the Netherlands
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Ut Utrecht, The Netherlands
| | - Marco C Bottino
- Department of Cariology, Restorative Sciences, and Endodontics, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
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24
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Ocran E, Chornenki NLJ, Bowman M, Sholzberg M, James P. Gastrointestinal bleeding in von Willebrand patients: special diagnostic and management considerations. Expert Rev Hematol 2023; 16:575-584. [PMID: 37278227 DOI: 10.1080/17474086.2023.2221846] [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: 03/20/2023] [Accepted: 06/01/2023] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Severe and recurrent gastrointestinal (GI) bleeding caused by angiodysplasia is a significant problem in patients with von Willebrand disease (VWD) and in those with acquired von Willebrand syndrome (AVWS). At present, angiodysplasia-related GI bleeding is often refractory to standard treatment including replacement therapy with von Willebrand factor (VWF) concentrates and continues to remain a major challenge and cause of significant morbidity in patients despite advances in diagnostics and therapeutics. AREAS COVERED This paper reviews the available literature on GI bleeding in VWD patients, examines the molecular mechanisms implicated in angiodysplasia-related GI bleeding, and summarizes existing strategies in the management of bleeding GI angiodysplasia in patients with VWF abnormalities. Suggestions are made for further research directions. EXPERT OPINION Bleeding from angiodysplasia poses a significant challenge for individuals with abnormal VWF. Diagnosis remains a challenge and may require multiple radiologic and endoscopic investigations. Additionally, there is a need for enhanced understanding at a molecular level to identify effective therapies. Future studies of VWF replacement therapies using newer formulations as well as other adjunctive treatments to prevent and treat bleeding will hopefully improve care.
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Affiliation(s)
- Edwin Ocran
- Department of Medicine, Queen's University, Kingston, Canada
| | | | | | - Michelle Sholzberg
- Division of Hematology-Oncology, St. Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada
| | - Paula James
- Department of Medicine, Queen's University, Kingston, Canada
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25
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van den Berg J, Haslbauer JD, Stalder AK, Romanens A, Mertz KD, Studt JD, Siegemund M, Buser A, Holbro A, Tzankov A. Von Willebrand factor and the thrombophilia of severe COVID-19: in situ evidence from autopsies. Res Pract Thromb Haemost 2023; 7:100182. [PMID: 37333991 PMCID: PMC10192064 DOI: 10.1016/j.rpth.2023.100182] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 04/29/2023] [Accepted: 05/08/2023] [Indexed: 06/20/2023] Open
Abstract
Background COVID-19 is accompanied by a hypercoagulable state and characterized by microvascular and macrovascular thrombotic complications. In plasma samples from patients with COVID-19, von Willebrand factor (VWF) levels are highly elevated and predictive of adverse outcomes, especially mortality. Yet, VWF is usually not included in routine coagulation analyses, and histologic evidence of its involvement in thrombus formation is lacking. Objectives To determine whether VWF, an acute-phase protein, is a bystander, ie, a biomarker of endothelial dysfunction, or a causal factor in the pathogenesis of COVID-19. Methods We compared autopsy samples from 28 patients with lethal COVID-19 to those from matched controls and systematically assessed for VWF and platelets by immunohistochemistry. The control group comprised 24 lungs, 23 lymph nodes, and 9 hearts and did not differ significantly from the COVID-19 group in age, sex, body mass index (BMI), blood group, or anticoagulant use. Results In lungs, assessed for platelets by immunohistochemistry for CD42b, microthrombi were more frequent in patients with COVID-19 (10/28 [36%] vs 2/24 [8%]; P = .02). A completely normal pattern of VWF was rare in both groups. Accentuated endothelial staining was found in controls, while VWF-rich thrombi were only found in patients with COVID-19 (11/28 [39%] vs 0/24 [0%], respectively; P < .01), as were NETosis thrombi enriched with VWF (7/28 [25%] vs 0/24 [0%], respectively; P < .01). Forty-six percent of the patients with COVID-19 had VWF-rich thrombi, NETosis thrombi, or both. Trends were also seen in pulmonary draining lymph nodes (7/20 [35%] vs 4/24 [17%]; P = .147), where the overall presence of VWF was very high. Conclusion We provide in situ evidence of VWF-rich thrombi, likely attributable to COVID-19, and suggest that VWF may be a therapeutic target in severe COVID-19.
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Affiliation(s)
- Jana van den Berg
- Department of Hematology, University Hospital Basel, Basel, Switzerland
| | - Jasmin D Haslbauer
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
- Department of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Anna K Stalder
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Anna Romanens
- Department of Oncology, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Kirsten D Mertz
- Department of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland
| | - Jan-Dirk Studt
- Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland
| | - Martin Siegemund
- Intensive Care Unit, Department of Acute Medicine, University Hospital, Basel, Switzerland
| | - Andreas Buser
- Department of Hematology, University Hospital Basel, Basel, Switzerland
- Regional Blood Transfusion Service, Swiss Red Cross, Basel, Switzerland
| | - Andreas Holbro
- Department of Hematology, University Hospital Basel, Basel, Switzerland
- Regional Blood Transfusion Service, Swiss Red Cross, Basel, Switzerland
| | - Alexandar Tzankov
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
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26
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Lin B, Ma J, Fang Y, Lei P, Wang L, Qu L, Wu W, Jin L, Sun D. Advances in Zebrafish for Diabetes Mellitus with Wound Model. Bioengineering (Basel) 2023; 10:bioengineering10030330. [PMID: 36978721 PMCID: PMC10044998 DOI: 10.3390/bioengineering10030330] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/01/2023] [Accepted: 03/04/2023] [Indexed: 03/08/2023] Open
Abstract
Diabetic foot ulcers cause great suffering and are costly for the healthcare system. Normal wound healing involves hemostasis, inflammation, proliferation, and remodeling. However, the negative factors associated with diabetes, such as bacterial biofilms, persistent inflammation, impaired angiogenesis, inhibited cell proliferation, and pathological scarring, greatly interfere with the smooth progress of the entire healing process. It is this impaired wound healing that leads to diabetic foot ulcers and even amputations. Therefore, drug screening is challenging due to the complexity of damaged healing mechanisms. The establishment of a scientific and reasonable animal experimental model contributes significantly to the in-depth research of diabetic wound pathology, prevention, diagnosis, and treatment. In addition to the low cost and transparency of the embryo (for imaging transgene applications), zebrafish have a discrete wound healing process for the separate study of each stage, resulting in their potential as the ideal model animal for diabetic wound healing in the future. In this review, we examine the reasons behind the delayed healing of diabetic wounds, systematically review various studies using zebrafish as a diabetic wound model by different induction methods, as well as summarize the challenges and improvement strategies which provide references for establishing a more reasonable diabetic wound zebrafish model.
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Affiliation(s)
- Bangchang Lin
- Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310000, China
| | - Jiahui Ma
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Yimeng Fang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Pengyu Lei
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Lei Wang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Linkai Qu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Wei Wu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing 400044, China
- Correspondence: (W.W.); (L.J.); (D.S.)
| | - Libo Jin
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
- Wenzhou City and WenZhouOuTai Medical Laboratory Co., Ltd. Joint Doctoral Innovation Station, Wenzhou Association for Science and Technology, Wenzhou 325000, China
- Correspondence: (W.W.); (L.J.); (D.S.)
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
- Correspondence: (W.W.); (L.J.); (D.S.)
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Effect of Supplemental Oxygen on von Willebrand Factor Activity and Ristocetin Cofactor Activity in Patients at Risk for Cardiovascular Complications Undergoing Moderate-to High-Risk Major Noncardiac Surgery-A Secondary Analysis of a Randomized Trial. J Clin Med 2023; 12:jcm12031222. [PMID: 36769870 PMCID: PMC9918071 DOI: 10.3390/jcm12031222] [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: 01/03/2023] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Increased von Willebrand Factor (vWF) activity mediates platelet adhesion and might be a contributor to the development of thrombotic complications after surgery. Although in vitro studies have shown that hyperoxia induces endovascular damage, the effect of perioperative supplemental oxygen as a possible trigger for increased vWF activity has not been investigated yet. We tested our primary hypothesis that the perioperative administration of 80% oxygen concentration increases postoperative vWF activity as compared to 30% oxygen concentration in patients at risk of cardiovascular complications undergoing major noncardiac surgery. A total of 260 patients were randomly assigned to receive 80% versus 30% oxygen throughout surgery and for two hours postoperatively. We assessed vWF activity and Ristocetin cofactor activity in all patients shortly before the induction of anesthesia, within two hours after surgery and on the first and third postoperative day. Patient characteristics were similar in both groups. We found no significant difference in vWF activity in the overall perioperative time course between both randomization groups. We observed significantly increased vWF activity in the overall study population throughout the postoperative time course. Perioperative supplemental oxygen showed no significant effect on postoperative vWF and Ristocetin cofactor activity in cardiac risk patients undergoing major noncardiac surgery. In conclusion, we found no significant influence of supplemental oxygen in patients undergoing major non-cardiac surgery on postoperative vWF activity and Ristocetin cofactor activity.
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Abou-Ismail MY, James PD, Flood VH, Connell NT. Beyond the guidelines: how we approach challenging scenarios in the diagnosis and management of von Willebrand disease. JOURNAL OF THROMBOSIS AND HAEMOSTASIS : JTH 2023; 21:204-214. [PMID: 36700502 DOI: 10.1016/j.jtha.2022.11.042] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/28/2022] [Accepted: 11/30/2022] [Indexed: 01/26/2023]
Abstract
Although von Willebrand disease (VWD) is the most common inherited bleeding disorder, its diagnosis and management are often challenging. Clinical practice guidelines, developed through systematic review of the medical literature and considering the best available evidence, provide guidance for common clinical scenarios. However, in the clinical setting, patients often present with characteristics and nuances that may fall outside the realm of available evidence and guidelines, and hence, shared decision-making will be essential in the evaluation and management of these patients. The challenges in the diagnosis of VWD are mainly attributable to the heterogeneity of the disorder, limitations of laboratory assays, and the significant impact of various physiologic processes on von Willebrand factor. The impact of physiologic normalization of von Willebrand factor, which may occur in various settings such as pregnancy, inflammation, or aging, remains uncertain, as is the optimal management in these scenarios. Multidisciplinary and individualized care, based on evolving evidence supported by clinicians, patients, caregivers, and stakeholders, will be needed to ensure the highest quality care for those who live with VWD.
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Affiliation(s)
- Mouhamed Yazan Abou-Ismail
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Paula D James
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Veronica H Flood
- Versiti Blood Research Institute and Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Nathan T Connell
- Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
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Chornenki NLJ, Ocran E, James PD. Special considerations in GI bleeding in VWD patients. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:624-630. [PMID: 36485078 PMCID: PMC9820382 DOI: 10.1182/hematology.2022000390] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Gastrointestinal (GI) bleeding is an important cause of morbidity and mortality in von Willebrand disease (VWD). It has been noted that GI bleeding caused by angiodysplasia is overrepresented in VWD patients compared to other causes. The bleeding from angiodysplasia is notoriously difficult to treat; recurrences and rebleeds are common. A growing body of basic science evidence demonstrates that von Willebrand factor negatively regulates angiogenesis through multiple pathways. VWD is clinically highly associated with angiodysplasia. The predisposition to angiodysplasia likely accounts for many of the clinical difficulties related to managing GI bleeding in VWD patients. Diagnosis and treatment are challenging with the current tools available, and much further research is needed to further optimize care for these patients with regard to acute treatment, prophylaxis, and adjunctive therapies. In this review we provide an overview of the available literature on GI bleeding in VWD and explore the molecular underpinnings of angiodysplasia-related GI bleeding. Considerations for diagnostic effectiveness are discussed, as well as the natural history and recurrence of these lesions and which therapeutic options are available for acute and prophylactic management.
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Affiliation(s)
| | - Edwin Ocran
- Department of Medicine, Queen's University, Kingston, Canada
| | - Paula D James
- Department of Medicine, Queen's University, Kingston, Canada
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Influence of Von Willebrand Disease (VWD) and pregnancy on the expression of angiogenic factors in the porcine female reproductive tract. Reprod Biol 2022; 22:100700. [DOI: 10.1016/j.repbio.2022.100700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/26/2022] [Accepted: 10/01/2022] [Indexed: 11/05/2022]
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Pomej K, Scheiner B, Balcar L, Nussbaumer RJ, Weinzierl J, Paternostro R, Simbrunner B, Bauer D, Pereyra D, Starlinger P, Stättermayer AF, Pinter M, Trauner M, Quehenberger P, Reiberger T, Mandorfer M. Clinical significance of substantially elevated von Willebrand factor antigen levels in patients with advanced chronic liver disease. Dig Liver Dis 2022; 54:1376-1384. [PMID: 35871985 DOI: 10.1016/j.dld.2022.06.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/01/2022] [Accepted: 06/15/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Von Willebrand factor antigen (VWF) is a non-invasive marker for clinically significant portal hypertension (HVPG≥10 mmHg) and confers HVPG-independent prognostic information. While quantification of increased VWF-levels is not relevant in the context of von Willebrand disease, highly elevated VWF may be of clinical significance in ACLD. Thus, we have modified our analytical approach to quantify very high VWF-levels (i.e.,>420%) and investigated their prognostic value. METHODS Patients undergoing HVPG-measurement at the Vienna Hepatic Hemodynamic Lab with evidence of ACLD and information on VWF were considered. Clinical stages (CS) were defined as follows: Probable compensated ACLD (cACLD): LSM≥10kPa&HVPG<6 mmHg; 0: cACLD&6-9 mmHg; 1: cACLD&HVPG≥10 mmHg; 2: bleeding; 3: non-bleeding decompensation; 4: ≥2 decompensations. RESULTS 124 (16%) of 793 patients had VWF>420%. The proportion of VWF>420% increased with disease severity (probable cACLD-0: 5(4%) vs. 1: 22(10%) vs. 2-4: 97(23%),p ≤ 0.001) as well as across HVPG (<6mmHg: 1(2%) vs. 6-9: 6(6%) vs. 10-15: 17(9%) vs. ≥16: 100(22%),p ≤ 0.001) and MELD (<10: 17(6%) vs. 10-14: 27(10%) vs. ≥15: 79(32%),p ≤ 0.001) strata. In patients with VWF>420%, median VWF was 533 (IQR:466-611)% and VWF was unrelated to HVPG (Spearman's ρ=0.139,p = 0.123), but showed direct correlations of weak/moderate strength with MELD (ρ=0.336,p < 0.001) and CRP (ρ=0.286,p = 0.001). In the subgroup with VWF>420%, VWF was predictive of decompensation/liver-related mortality (VWF per 10%; hazard ratio (HR): 1.02(95% confidence interval (95%CI): 1.01-1.04),p = 0.008, even after adjusting for other factors (VWF per 10%; adjusted HR: 1.02(95%CI: 1.00-1.05),p = 0.031). CONCLUSION The proportion of patients with substantially elevated VWF values steadily increases with disease progression. While VWF is not reflective of HVPG in these patients, it is correlated with hepatic dysfunction and systemic inflammation. Importantly, quantification of high values provides prognostic information.
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Affiliation(s)
- Katharina Pomej
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Rosa Johanna Nussbaumer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Johanna Weinzierl
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Rafael Paternostro
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - David Bauer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - David Pereyra
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Albert Friedrich Stättermayer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Peter Quehenberger
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
| | - Mattias Mandorfer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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Francisco JS, Terra MABL, Klein GCT, Dias de Oliveira BCEP, Pelajo-Machado M. The hepatic extramedullary hematopoiesis during experimental murine Schistosomiasis mansoni. Front Immunol 2022; 13:955034. [PMID: 36091027 PMCID: PMC9453041 DOI: 10.3389/fimmu.2022.955034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 08/08/2022] [Indexed: 01/18/2023] Open
Abstract
Many years ago, our research group has demonstrated extramedullary hematopoiesis in the peripheral zone of murine hepatic schistosomal granulomas. In the present study, we revisit this phenomenon using new technical and conceptual approaches. Therefore, newborn mice were percutaneously infected by Schistosoma mansoni cercariae and euthanized between 35- and 60-days post infection. Liver samples were submitted to histopathology and immunohistochemical analyses. Cells under mitosis and/or expressing Ki67 demonstrated the proliferation of hematopoietic cells both around the parasite's eggs trapped in the liver and around hepatic vessels. After 50 days post infection, proliferating cells at different levels on differentiation were located preferentially in the peripheral zone of the granulomas, around the vessels and inside the sinusoids. The presence of acidic and sulfated glycoconjugates, reticular fibers and the absence of fibronectin characterized the microenvironment for attraction and maintenance of hematopoiesis. Some neutrophils secreted MMP9 from the earliest points of infection, indicating degradation of the extracellular matrix in regions of histolysis and a possible chemoattraction of hematopoietic stem cells to the liver. Fall-3+ cells and Sca-1+ cells indicated that early hematopoietic progenitors could be mobilized to the liver. Groups of vWF+ megakaryocytes suggest chemoattraction of these cells and/or migration, proliferation, and differentiation of very immature progenitors to this organ. The increase of blood vessels and extramedullary hematopoiesis in this environment, where markers of immature hematopoietic and endothelial cells have been identified, points to the possibility of the presence of progenitors for endothelial and hematopoietic cells in the liver during the infection. There is also the possibility of concomitant migration of more differentiated hematopoietic progenitors, that proliferate and differentiate in the liver, and the occurrence of angiogenesis caused by inflammation or release of ovular antigens that stimulate the activation and proliferation of endothelial cells. Altogether, these data increase knowledge about a murine model that is of interest for investigating the pathology of the schistosomiasis and also the dynamics of hematopoiesis.
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Affiliation(s)
| | | | | | | | - Marcelo Pelajo-Machado
- Laboratory of Pathology, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil
- Brazilian National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
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Ye B, Shen Y, Chen H, Lin S, Mao W, Dong Y, Li X. Differential proteomic analysis of plasma-derived exosomes as diagnostic biomarkers for chronic HBV-related liver disease. Sci Rep 2022; 12:14428. [PMID: 36002595 PMCID: PMC9402575 DOI: 10.1038/s41598-022-13272-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 05/23/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatitis B virus (HBV) infection is still a major public health problem worldwide. We aimed to identify new, non-invasive biomarkers for the early diagnosis of chronic HBV-related diseases, reveal alterations in the progression of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Here, exosomes were isolated and characterized through size exclusion chromatography and nanoparticle tracking analysis. Profiles of differentially expressed proteins (DEPs) were analyzed through liquid chromatography-tandem mass spectrometry (LC–MS/MS), Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. Results showed that the DEPs, including CO9, LBP, SVEP1, and VWF levels in extracellular vesicles (EVs) were significantly higher in CHB than in healthy controls (HCs). VWF expression levels in EVs were significantly lower in CHB than in those with LC. KV311 expression levels in EVs were significantly higher, whereas LBP levels were significantly lower in patients with CHB than in those with HCC. All biomarkers seemed to exhibit a high diagnostic capacity for HBV-related liver disease. Patients with HBV-induced chronic liver disease exhibit characteristic protein profiles in their EVs. Thus, serum exosomes may be used as novel, liquid biopsy biomarkers to provide useful clinical information for the diagnosis of HBV-related liver diseases at different stages.
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Affiliation(s)
- Bo Ye
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
| | - Yifei Shen
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
| | - Hui Chen
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
| | - Sha Lin
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
| | - Weilin Mao
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
| | - Yuejiao Dong
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China
| | - Xuefen Li
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People's Republic of China.
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Van Belle E, Debry N, Vincent F, Kuchcinski G, Cordonnier C, Rauch A, Robin E, Lassalle F, Pontana F, Delhaye C, Schurtz G, JeanPierre E, Rousse N, Casari C, Spillemaeker H, Porouchani S, Pamart T, Denimal T, Neiger X, Verdier B, Puy L, Cosenza A, Juthier F, Richardson M, Bretzner M, Dallongeville J, Labreuche J, Mazighi M, Dupont-Prado A, Staels B, Lenting PJ, Susen S. Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort. Circulation 2022; 146:383-397. [PMID: 35722876 PMCID: PMC9345525 DOI: 10.1161/circulationaha.121.057145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Cerebral microbleeds (CMBs) have been observed in healthy elderly people undergoing systematic brain magnetic resonance imaging. The potential role of acute triggers on the appearance of CMBs remains unknown. We aimed to describe the incidence of new CMBs after transcatheter aortic valve replacement (TAVR) and to identify clinical and procedural factors associated with new CMBs including hemostatic measures and anticoagulation management. METHODS We evaluated a prospective cohort of patients with symptomatic aortic stenosis referred for TAVR for CMBs (METHYSTROKE [Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly]). Standardized neurologic assessment, brain magnetic resonance imaging, and analysis of hemostatic measures including von Willebrand factor were performed before and after TAVR. Numbers and location of microbleeds on preprocedural magnetic resonance imaging and of new microbleeds on postprocedural magnetic resonance imaging were reported by 2 independent neuroradiologists blinded to clinical data. Measures associated with new microbleeds and postprocedural outcome including neurologic functional outcome at 6 months were also examined. RESULTS A total of 84 patients (47% men, 80.9±5.7 years of age) were included. On preprocedural magnetic resonance imaging, 22 patients (26% [95% CI, 17%-37%]) had at least 1 microbleed. After TAVR, new microbleeds were observed in 19 (23% [95% CI, 14%-33%]) patients. The occurrence of new microbleeds was independent of the presence of microbleeds at baseline and of diffusion-weighted imaging hypersignals. In univariable analysis, a previous history of bleeding (P=0.01), a higher total dose of heparin (P=0.02), a prolonged procedure (P=0.03), absence of protamine reversion (P=0.04), higher final activated partial thromboplastin time (P=0.05), lower final von Willebrand factor high-molecular-weight:multimer ratio (P=0.007), and lower final closure time with adenosine-diphosphate (P=0.02) were associated with the occurrence of new postprocedural microbleeds. In multivariable analysis, a prolonged procedure (odds ratio, 1.22 [95% CI, 1.03-1.73] for every 5 minutes of fluoroscopy time; P=0.02) and postprocedural acquired von Willebrand factor defect (odds ratio, 1.42 [95% CI, 1.08-1.89] for every lower 0.1 unit of high-molecular-weight:multimer ratio; P=0.004) were independently associated with the occurrence of new postprocedural microbleeds. New CMBs were not associated with changes in neurologic functional outcome or quality of life at 6 months. CONCLUSIONS One out of 4 patients undergoing TAVR has CMBs before the procedure and 1 out of 4 patients develops new CMBs. Procedural or antithrombotic management and persistence of acquired von Willebrand factor defect were associated with the occurrence of new CMBs. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT02972008.
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Affiliation(s)
- Eric Van Belle
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France.,INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
| | - Nicolas Debry
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France.,INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
| | - Flavien Vincent
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France.,INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
| | | | - Charlotte Cordonnier
- Degenerative and Vascular Cognitive Disorders, Department of Neurology (C. Cordonnier, L.P.), France.,(C. Cordonnier, L.P.), Université Lille, France
| | - Antoine Rauch
- Hematology and Transfusion Department (A.R., F.L., E.J., A.D.-P., S.S.), France.,INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
| | | | - Fanny Lassalle
- Hematology and Transfusion Department (A.R., F.L., E.J., A.D.-P., S.S.), France
| | | | - Cédric Delhaye
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Guillaume Schurtz
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Emmanuelle JeanPierre
- Hematology and Transfusion Department (A.R., F.L., E.J., A.D.-P., S.S.), France.,INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
| | | | - Caterina Casari
- INSERM UMR_S 1176 (C. Casari, P.J.L.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Hugues Spillemaeker
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Sina Porouchani
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Thibault Pamart
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Tom Denimal
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Xavier Neiger
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Basile Verdier
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | - Laurent Puy
- Degenerative and Vascular Cognitive Disorders, Department of Neurology (C. Cordonnier, L.P.), France.,(C. Cordonnier, L.P.), Université Lille, France
| | - Alessandro Cosenza
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | | | - Marjorie Richardson
- Cardiology Department (E.V.B., N.D., F.V., C.D., G.S., H.S., S.P., T.P., T.D., X.N., B.V., M.R.), France
| | | | | | - Julien Labreuche
- CHU Lille (J.L.), France.,EA 2694–Santé Publique: Épidémiologie et Qualité des Soins (J.L.), Université Lille, France
| | - Mikael Mazighi
- Department of Neurology, Hôpital Laribosière, APHP-NORD (M.M.), Université de Paris, France.,Department of Interventional Neuroradiology, Fondation Adolphe de Rothschild, FHU NeuroVasc, INSERM U 1148 (M.M.), Université de Paris, France
| | - Annabelle Dupont-Prado
- Hematology and Transfusion Department (A.R., F.L., E.J., A.D.-P., S.S.), France.,INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
| | - Bart Staels
- INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
| | - Peter J. Lenting
- INSERM UMR_S 1176 (C. Casari, P.J.L.), Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Sophie Susen
- Hematology and Transfusion Department (A.R., F.L., E.J., A.D.-P., S.S.), France.,INSERM Unité 1011 (E.V.B., N.D., F.V., A.R., E.J., A.D.-P., B.S., S.S.), Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France
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Ferroni L, Gardin C, D'Amora U, Calzà L, Ronca A, Tremoli E, Ambrosio L, Zavan B. Exosomes of mesenchymal stem cells delivered from methacrylated hyaluronic acid patch improve the regenerative properties of endothelial and dermal cells. BIOMATERIALS ADVANCES 2022; 139:213000. [PMID: 35891601 DOI: 10.1016/j.bioadv.2022.213000] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 06/10/2022] [Accepted: 06/21/2022] [Indexed: 12/19/2022]
Abstract
Wound care management urgently needs the development of innovative smart wound dressings. The complexity of the wound often requires the use of personalized medication and the advent of three-dimensional (3D) bioprinting fits strongly with this need. In this view, in the present work a methacrylated hyaluronic acid (MeHA) bioink was tested for the fabrication of advanced smart patches as a delivery system of exosomes derived from human mesenchymal stem cells (hMSC-EXOs) suitable for wound healing purposes. MeHA patches were realized by 3D bioprinting technique and they were loaded with hMSC-EXOs. The 3D printed MeHA patches revealed improved mechanical performance, appropriate swelling ratio, extended degradation time, and suitable biocompatibility. Furthermore, MeHA patches loaded with hMSC-EXOs improved the proliferation, migration, angiogenic ability, and expression of specific markers related to wound healing process in human fibroblasts and human endothelial cells.
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Affiliation(s)
- Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy
| | - Chiara Gardin
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy
| | - Ugo D'Amora
- Institute of Polymers, Composites and Biomaterials, National Research Council, 80125 Naples, Italy
| | - Laura Calzà
- IRET Foundation, Ozzano Emilia, 40064 Bologna, Italy
| | - Alfredo Ronca
- Institute of Polymers, Composites and Biomaterials, National Research Council, 80125 Naples, Italy.
| | - Elena Tremoli
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy
| | - Luigi Ambrosio
- Institute of Polymers, Composites and Biomaterials, National Research Council, 80125 Naples, Italy
| | - Barbara Zavan
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
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Pablo-Moreno JAD, Serrano LJ, Revuelta L, Sánchez MJ, Liras A. The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V. Int J Mol Sci 2022; 23:ijms23158283. [PMID: 35955419 PMCID: PMC9425441 DOI: 10.3390/ijms23158283] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 11/27/2022] Open
Abstract
The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.
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Affiliation(s)
- Juan A. De Pablo-Moreno
- Department of Genetics, Physiology and Microbiology, School of Biology, Complutense University, 28040 Madrid, Spain; (J.A.D.P.-M.); (L.J.S.)
| | - Luis Javier Serrano
- Department of Genetics, Physiology and Microbiology, School of Biology, Complutense University, 28040 Madrid, Spain; (J.A.D.P.-M.); (L.J.S.)
| | - Luis Revuelta
- Department of Physiology, School of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
| | - María José Sánchez
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía, Pablo de Olavide University, 41013 Sevilla, Spain;
| | - Antonio Liras
- Department of Genetics, Physiology and Microbiology, School of Biology, Complutense University, 28040 Madrid, Spain; (J.A.D.P.-M.); (L.J.S.)
- Correspondence:
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Graça AL, Gómez-Florit M, Osório H, Rodrigues MT, Domingues RMA, Reis RL, Gomes ME. Controlling the fate of regenerative cells with engineered platelet-derived extracellular vesicles. NANOSCALE 2022; 14:6543-6556. [PMID: 35420605 DOI: 10.1039/d1nr08108j] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Extracellular vesicles (EVs) have emerged as cell-free nanotherapeutic agents for the potential treatment of multiple diseases and for tissue engineering and regenerative medicine strategies. Nevertheless, the field has typically relied on EVs derived from stem cells, the production of which in high quantities and high reproducibility is still under debate. Platelet-derived EVs were produced by a freeze-thaw method of platelet concentrates, a highly available clinical waste material. The aim of this study was to produce and thoroughly characterize platelet-derived EVs and understand their effects in adipose-tissue derived stem cells (hASCs), endothelial cells (HUVECs) and macrophages. Two different EV populations were obtained after differential centrifugation, namely small EVs (sEVs) and medium EVs (mEVs), which showed different size distributions and unique proteomic signatures. EV interaction with hASCs resulted in the modulation of the gene expression of markers related to their commitment toward different lineages. Moreover, mEVs showed higher angiogenic potential than sEVs, in a tube formation assay with HUVECs. Also, the EVs were able to modulate macrophage polarization. Altogether, these results suggest that platelet-derived EVs are promising candidates to be used as biochemical signals or therapeutic tools in tissue engineering and regenerative medicine approaches.
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Affiliation(s)
- Ana L Graça
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Manuel Gómez-Florit
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Hugo Osório
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
| | - Márcia T Rodrigues
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Rui M A Domingues
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Rui L Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Manuela E Gomes
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal.
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
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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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Insight in Hypoxia-Mimetic Agents as Potential Tools for Mesenchymal Stem Cell Priming in Regenerative Medicine. Stem Cells Int 2022; 2022:8775591. [PMID: 35378955 PMCID: PMC8976669 DOI: 10.1155/2022/8775591] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/28/2022] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
Hypoxia-mimetic agents are new potential tools in MSC priming instead of hypoxia incubators or chambers. Several pharmaceutical/chemical hypoxia-mimetic agents can be used to induce hypoxia in the tissues: deferoxamine (DFO), dimethyloxaloylglycine (DMOG), 2,4-dinitrophenol (DNP), cobalt chloride (CoCl2), and isoflurane (ISO). Hypoxia-mimetic agents can increase cell proliferation, preserve or enhance differentiation potential, increase migration potential, and induce neovascularization in a concentration- and stem cell source-dependent manner. Moreover, hypoxia-mimetic agents may increase HIF-1α, changing the metabolism and enhancing glycolysis like hypoxia. So, there is clear evidence that treatment with hypoxia-mimetic agents is beneficial in regenerative medicine, preserving stem cell capacities. These agents are not studied so wildly as hypoxia but, considering the low cost and ease of use, are believed to find application as pretreatment of many diseases such as ischemic heart disease and myocardial fibrosis and promote cardiac and cartilage regeneration. The knowledge of MSC priming is critical in evaluating safety procedures and use in clinics. In this review, similarities and differences between hypoxia and hypoxia-mimetic agents in terms of their therapeutic efficiency are considered in detail. The advantages, challenges, and future perspectives in MSC priming with hypoxia mimetic agents are also discussed.
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40
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The Role of von Willebrand Factor Antigen in Predicting Survival of Patients with HBV-Related Cirrhosis. Can J Gastroenterol Hepatol 2022; 2022:9035971. [PMID: 35360443 PMCID: PMC8964228 DOI: 10.1155/2022/9035971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 02/20/2022] [Accepted: 03/01/2022] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE The model for end-stage liver disease (MELD) scoring system cannot be used to assess the deterioration of patients with liver cirrhosis caused by infection and portal hypertension. Elevated von Willebrand factor antigen (vWF-Ag) in plasma is associated with portal pressure and complications in patients with liver cirrhosis. We aimed to evaluate whether the addition of vWF-Ag can improve the risk prediction ability of the MELD scoring system. METHODS A total of 228 patients with hepatitis B virus (HBV)-related liver cirrhosis were eligible for inclusion in this retrospective study. The vWF-Ag level was assessed by enzyme-linked immunosorbent assay (ELISA). The endpoint of this study was defined as the time to liver transplantation or death. Univariate and multivariate analyses were performed to assess the risk factors associated with transplant-free mortality. Receiver operating characteristic (ROC) curve analysis was used to assess potential discriminatory variables for transplant-free mortality. RESULTS During a median follow-up interval of 30.23 months, 124 patients (54.4%) reached the endpoint of this study. Patients who died or underwent liver transplantation had elevated levels of MELD and vWF-Ag. Moreover, vWF-Ag and MELD showed comparable predictive potential for transplant-free survival (area under the curve [AUC], vWF-Ag = 0.71; AUC, MELD = 0.73). Ultimately, vWF-Ag can significantly improve the predictive potential of MELD in determining transplant-free mortality (AUC, MELD-vWF-Ag = 0.79, P = 0.006). CONCLUSION An elevated vWF-Ag level was independently associated with transplant-free mortality in patients with liver cirrhosis. The inclusion of vWF-Ag in the MELD scoring system can improve mortality predictions in patients with liver cirrhosis.
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Fujimura Y, Holland LZ. COVID-19 microthrombosis: unusually large VWF multimers are a platform for activation of the alternative complement pathway under cytokine storm. Int J Hematol 2022; 115:457-469. [PMID: 35316498 PMCID: PMC8938647 DOI: 10.1007/s12185-022-03324-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 02/08/2023]
Abstract
ADAMTS13, a metalloproteinase, specifically cleaves unusually large multimers of von Willebrand factor (VWF), newly released from vascular endothelial cells. The ratio of ADAMTS13 activity to VWF antigen (ADAMTS13/VWF) and indicators of the alternative complement pathway (C3a and sC5b-9) are both related to the severity of COVID-19. The ADAMTS13/VWF ratio is generally moderately decreased (0.18–0.35) in patients with severe COVID-19. When these patients experience cytokine storms, both interleukin-8 and TNFα stimulate VWF release from vascular endothelial cells, while interleukin-6 inhibits both production of ADAMTS13 and its interaction with VWF, resulting in localized severe deficiency of ADAMTS13 activity. Platelet factor 4 and thrombospondin-1, both released upon platelet activation, bind to the VWF-A2 domain and enhance the blockade of ADAMTS13 function. Thus, the released unusually-large VWF multimers remain associated with the vascular endothelial cell surface, via anchoring with syndecan-1 in the glycocalyx. Unfolding of the VWF-A2 domain, which has high sequence homology with complement factor B, allows the domain to bind to activated complement C3b, providing a platform for complement activation of the alternative pathway. The resultant C3a and C5a generate tissue factor-rich neutrophil extracellular traps (NETs), which induce the mixed immunothrombosis, fibrin clots and platelet aggregates typically seen in patients with severe COVID-19.
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Affiliation(s)
- Yoshihiro Fujimura
- Department of Blood Transfusion Medicine, Nara Medical University, Shijyocho-840, Kashihara City, Nara, Japan.
| | - Linda Z Holland
- Marine Biology Research Division, Scripps Institution Oceanography, University California San Diego, 4400 Hubbs Hall, La Jolla, CA, 92093-0202, USA
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Nouri-Vaskeh M, Khalili N, Sadighi A, Yazdani Y, Zand R. Biomarkers for Transient Ischemic Attack: A Brief Perspective of Current Reports and Future Horizons. J Clin Med 2022; 11:jcm11041046. [PMID: 35207321 PMCID: PMC8877275 DOI: 10.3390/jcm11041046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/09/2022] [Accepted: 02/16/2022] [Indexed: 02/05/2023] Open
Abstract
Cerebrovascular disease is the leading cause of long-term disability in the world and the third-leading cause of death in the United States. The early diagnosis of transient ischemic attack (TIA) is of great importance for reducing the mortality and morbidity of cerebrovascular diseases. Patients with TIA have a high risk of early subsequent ischemic stroke and the development of permanent nervous system lesions. The diagnosis of TIA remains a clinical diagnosis that highly relies on the patient's medical history assessment. There is a growing list of biomarkers associated with different components of the ischemic cascade in the brain. In this review, we take a closer look at the biomarkers of TIA and their validity with a focus on the more clinically important ones using recent evidence of their reliability for practical usage.
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Affiliation(s)
- Masoud Nouri-Vaskeh
- Tropical and Communicable Diseases Research Centre, Iranshahr University of Medical Sciences, Iranshahr 7618815676, Iran;
- Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran 1419733151, Iran
| | - Neda Khalili
- School of Medicine, Tehran University of Medical Sciences, Tehran 1449614535, Iran;
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
| | - Alireza Sadighi
- Neuroscience Institute, Geisinger Health System, Danville, PA 17822, USA;
| | - Yalda Yazdani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran;
| | - Ramin Zand
- Neuroscience Institute, Geisinger Health System, Danville, PA 17822, USA;
- Neuroscience Institute, Pennsylvania State University, State College, PA 16801, USA
- Correspondence: or ; Tel.: +1-570-808-7330; Fax: +1-570-808-3209
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Zhao C, Pu W, Niu M, Wazir J, Song S, Wei L, Li L, Su Z, Wang H. Respiratory exposure to PM2.5 soluble extract induced chronic lung injury by disturbing the phagocytosis function of macrophage. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:13983-13997. [PMID: 34601671 DOI: 10.1007/s11356-021-16797-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/24/2021] [Indexed: 06/13/2023]
Abstract
Exposure to airborne urban particles is a contributing factor for the development of multiple types of respiratory diseases; its pathological role as a cause of lung injury is still unclear. In this study, PM2.5 soluble extract was collected, and its toxicological effect on lung pathological changes was examined. To assess its pathological mechanism, Human Monocyte-Like Cell Line, THP-1, and mouse macrophage, RAW264.7, were used to determine the effects of PM2.5 soluble extract on cell toxicity, phagocytosis, and transcriptome. We found that PM2.5 soluble extract exposure activated NF-κB and MAPK signaling pathways, then induces the production of pro-inflammatory cytokines. RNA-seq results showed that the transcription profiles, including 1213 genes, have been changed in responses to PM2.5 exposure. Additionally, PM2.5 led to phagocytic dysfunction, which may exacerbate the cause of lung injury. Exposure to PM2.5 soluble extract triggers the death of respiratory macrophages, impairs its phagocytosis capacity, thus delaying the inflammatory cell clearance in the lung, which results in chronic lung injury.
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Affiliation(s)
- Chen Zhao
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China
| | - Wenyuan Pu
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China
| | - Mengyuan Niu
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China
| | - Junaid Wazir
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China
| | - Shiyu Song
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China
| | - Lulu Wei
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China
| | - Li Li
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China
| | - Zhonglan Su
- Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China.
| | - Hongwei Wang
- State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China.
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Hong JY, Kim SH, Seo Y, Jeon J, Davaa G, Hyun JK, Kim SH. Self-assembling peptide gels promote angiogenesis and functional recovery after spinal cord injury in rats. J Tissue Eng 2022; 13:20417314221086491. [PMID: 35340425 PMCID: PMC8943448 DOI: 10.1177/20417314221086491] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/23/2022] [Indexed: 12/30/2022] Open
Abstract
Spinal cord injury (SCI) leads to disruption of the blood–spinal cord barrier,
hemorrhage, and tissue edema, which impair blood circulation and induce
ischemia. Angiogenesis after SCI is an important step in the repair of damaged
tissues, and the extent of angiogenesis strongly correlates with the neural
regeneration. Various biomaterials have been developed to promote angiogenesis
signaling pathways, and angiogenic self-assembling peptides are useful for
producing diverse supramolecular structures with tunable functionality. RADA16
(Ac-RARADADARARADADA-NH2), which forms nanofiber networks under physiological
conditions, is a self-assembling peptide that can provide mechanical support for
tissue regeneration and reportedly has diverse roles in wound healing. In this
study, we applied an injectable form of RADA16 with or without the neuropeptide
substance P to the contused spinal cords of rats and examined angiogenesis
within the damaged spinal cord and subsequent functional improvement.
Histological and immunohistochemical analyses revealed that the inflammatory
cell population in the lesion cavity was decreased, the vessel number and
density around the damaged spinal cord were increased, and the levels of
neurofilaments within the lesion cavity were increased in SCI rats that received
RADA16 and RADA16 with substance P (rats in the RADA16/SP group). Moreover,
real-time PCR analysis of damaged spinal cord tissues showed that IL-10
expression was increased and that locomotor function (as assessed by the Basso,
Beattie, and Bresnahan (BBB) scale and the horizontal ladder test) was
significantly improved in the RADA16/SP group compared to the control group. Our
findings indicate that RADA16 modified with substance P effectively stimulates
angiogenesis within the damaged spinal cord and is a candidate agent for
promoting functional recovery post-SCI.
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Affiliation(s)
- Jin Young Hong
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
| | - Su Hee Kim
- Center for Biomaterials, Biomedical
Research Institute, Korea Institute of Science and Technology, Seoul, Republic of
Korea
- Medifab Ltd., Seoul, Republic of
Korea
| | - Yoojin Seo
- Center for Biomaterials, Biomedical
Research Institute, Korea Institute of Science and Technology, Seoul, Republic of
Korea
| | - Jooik Jeon
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
| | - Ganchimeg Davaa
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
| | - Jung Keun Hyun
- Department of Nanobiomedical Science
and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University,
Cheonan, Republic of Korea
- Institute of Tissue Regeneration
Engineering, Dankook University, Cheonan, Republic of Korea
- Department of Rehabilitation Medicine,
College of Medicine, Dankook University, Cheonan, Republic of Korea
- Jung Keun Hyun, Department of
Rehabilitation Medicine, College of Medicine, Dankook University, 119 Dandae-ro,
Anseo-dong, Dongnam-gu, Cheonan 31116, Republic of Korea.
| | - Soo Hyun Kim
- Center for Biomaterials, Biomedical
Research Institute, Korea Institute of Science and Technology, Seoul, Republic of
Korea
- Korea Institute of Science and
Technology Europe, Saarbrücken, Germany
- NBIT, KU-KIST Graduate School of
Converging Science and Technology, Korea University, Seoul, Republic of Korea
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45
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El Shazli LB, Ragab DA, Abdelhady KA, Abdelaziz AW. Role of plasma von Willebrand factor antigen in prediction of esophageal varices in pediatric and adolescent patients with portal hypertension. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00159-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Ruptured esophageal varices (EVs) are a leading cause of death in Portal hypertension (PHT), it has been a big concern of research to screen EVs through non-invasive approaches. This study aimed to evaluate the role of plasma von Willebrand factor antigen (VWF-Ag) assay for early detection of EVs in patients with portal hypertension. This was a cross-sectional study, done on 47 portal hypertensive children and adolescents who were collected from the Pediatrics Hepatology Clinic, Children Hospital, Ain Shams University. All patients were subjected to comprehensive history taking, thorough clinical examination, routine investigations, abdominal ultrasound, upper GI endoscopy, and measurement of plasma VWF-Ag level. The patients were divided based on their endoscopic findings into two groups; a varices group which included 37 patients, and a non-varices group which included 10 patients.
Results
VWF-Ag rise significantly in patients with EVs, revealing a direct positive association with the degree of EVs.
Conclusion
The plasma VWF-Ag can be applied as a non-invasive evidence of the presence and grading of EVs.
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Schwickert A, Henrich W, Vogel M, Melchior K, Ehrlich L, Ochs M, Braun T. Placenta Percreta Presents with Neoangiogenesis of Arteries with Von Willebrand Factor-Negative Endothelium. Reprod Sci 2021; 29:1136-1144. [PMID: 34766259 PMCID: PMC8907099 DOI: 10.1007/s43032-021-00763-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 10/02/2021] [Indexed: 11/28/2022]
Abstract
In placenta percreta cases, large vessels are present on the precrete surface area. As these vessels are not found in normal placentation, we examined their histological structure for features that might explain the pathogenesis of neoangiogenesis induced by placenta accreta spectrum disorders (PAS). In two patients with placenta percreta (FIGO grade 3a) of the anterior uterine wall, one strikingly large vessel of 2 cm length was excised. The samples were formalin fixed and paraffin-embedded. Gomori trichrome staining was used to evaluate the muscular layers and Weigert-Van Gieson staining for elastic fibers. Immunohistochemical staining of the vessel endothelium was performed for Von Willebrand factor (VWF), platelet endothelial cell adhesion molecule (CD31), Ephrin B2, and EPH receptor B4. The structure of the vessel walls appeared artery-like. The vessel of patient one further exhibited an unorderly muscular layer and a lack of elastic laminae, whereas these features appeared normal in the vessel of the other patient. The endothelium of both vessels stained VWF-negative and CD31-positive. In conclusion, this study showed VWF-negative vessel endothelia of epiplacental arteries in placenta accreta spectrum. VWF is known to regulate artery formation, as the absence of VWF has been shown to cause enhanced vascularization. Therefore, we suppose that PAS provokes increased vascularization through suppression of VWF. This process might be associated with the immature vessel architecture as found in one of the vessels and Ephrin B2 and EPH receptor B4 negativity of both artery-like vessels. The underlying pathomechanism needs to be evaluated in a greater set of patients.
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Affiliation(s)
- Alexander Schwickert
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Obstetrics, Berlin, Germany. .,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Experimental Obstetrics, Berlin, Germany.
| | - Wolfgang Henrich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Obstetrics, Berlin, Germany
| | - Martin Vogel
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pathology, Pediatric Pathology and Placentology, Berlin, Germany
| | - Kerstin Melchior
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Experimental Obstetrics, Berlin, Germany
| | - Loreen Ehrlich
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Experimental Obstetrics, Berlin, Germany
| | - Matthias Ochs
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Functional Anatomy, Berlin, Germany
| | - Thorsten Braun
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Obstetrics, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Experimental Obstetrics, Berlin, Germany
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47
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Amaihunwa K, Etim EA, Osime E, Jeremiah ZA. Effect of Obesity on Soluble Vascular Cell–Adhesion Molecules, Fibrinogen, and von Willebrand Factor Antigen among Obese People in Sapele, Southern Nigeria. PATHOLOGY AND LABORATORY MEDICINE INTERNATIONAL 2021. [DOI: 10.2147/plmi.s328891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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48
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Choudhary S, Sharma K, Singh PK. Von Willebrand factor: A key glycoprotein involved in thrombo-inflammatory complications of COVID-19. Chem Biol Interact 2021; 348:109657. [PMID: 34516971 PMCID: PMC8432980 DOI: 10.1016/j.cbi.2021.109657] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/25/2021] [Accepted: 09/09/2021] [Indexed: 02/08/2023]
Abstract
COVID-19 is an ongoing public health emergency that has affected millions of people worldwide and is still a threat to many more. One of the pathophysiological features of COVID-19 is associated with the activation of vascular endothelial cells (ECs) leading to the disruption of vascular integrity, coagulation and inflammation. An interlink mechanism between coagulation and inflammatory pathways has been reported in COVID-19. Multiple components are involved in these pathological pathways. Out of all, Von Willebrand Factor (VWF) is one of the primary components of coagulation pathway and also a mediator of vascular inflammation that plays an important role in thrombo-inflammation that further leads to acute respiratory distress syndrome (ARDS). The thrombo-inflammatory co-morbidities such as hyper-coagulation, thrombosis, ARDS etc. have become the major cause of mortality in the patients of COVID-19 admitted to the ICU. Thus, VWF can be explored as a potential target to manage COVID-19 associated co-morbidities. Supporting this hypothesis, there are literature reports which disclose previous attempts to target VWF for the management of thrombo-inflammation in other pathological conditions. The current report summarizes emerging insights into the pathophysiology, mechanism(s), diagnosis, management and foundations for research on this less explored clinically relevant glycoprotein as coagulation biomarker in COVID-19.
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Affiliation(s)
- Shalki Choudhary
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Kajal Sharma
- Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Pankaj Kumar Singh
- Integrative Physiology and Pharmacology, Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland.
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49
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Alavi P, Rathod AM, Jahroudi N. Age-Associated Increase in Thrombogenicity and Its Correlation with von Willebrand Factor. J Clin Med 2021; 10:4190. [PMID: 34575297 PMCID: PMC8472522 DOI: 10.3390/jcm10184190] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
Endothelial cells that cover the lumen of all blood vessels have the inherent capacity to express both pro and anticoagulant molecules. However, under normal physiological condition, they generally function to maintain a non-thrombogenic surface for unobstructed blood flow. In response to injury, certain stimuli, or as a result of dysfunction, endothelial cells release a highly adhesive procoagulant protein, von Willebrand factor (VWF), which plays a central role in formation of platelet aggregates and thrombus generation. Since VWF expression is highly restricted to endothelial cells, regulation of its levels is among the most important functions of endothelial cells for maintaining hemostasis. However, with aging, there is a significant increase in VWF levels, which is concomitant with a significant rise in thrombotic events. It is not yet clear why and how aging results in increased VWF levels. In this review, we have aimed to discuss the age-related increase in VWF, its potential mechanisms, and associated coagulopathies as probable consequences.
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Affiliation(s)
| | | | - Nadia Jahroudi
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2S2, Canada; (P.A.); (A.M.R.)
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50
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Milicic D, Ben Avraham B, Chioncel O, Barac YD, Goncalvesova E, Grupper A, Altenberger J, Frigeiro M, Ristic A, De Jonge N, Tsui S, Lavee J, Rosano G, Crespo-Leiro MG, Coats AJS, Seferovic P, Ruschitzka F, Metra M, Anker S, Filippatos G, Adamopoulos S, Abuhazira M, Elliston J, Gotsman I, Hamdan R, Hammer Y, Hasin T, Hill L, Itzhaki Ben Zadok O, Mullens W, Nalbantgil S, Piepoli MF, Ponikowski P, Potena L, Ruhparwar A, Shaul A, Tops LF, Winnik S, Jaarsma T, Gustafsson F, Ben Gal T. Heart Failure Association of the European Society of Cardiology position paper on the management of left ventricular assist device-supported patients for the non-left ventricular assist device specialist healthcare provider: Part 2: at the emergency department. ESC Heart Fail 2021; 8:4409-4424. [PMID: 34523254 PMCID: PMC8712806 DOI: 10.1002/ehf2.13587] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/21/2021] [Accepted: 08/19/2021] [Indexed: 01/12/2023] Open
Abstract
The improvement in left ventricular assist device (LVAD) technology and scarcity of donor hearts have increased dramatically the population of the LVAD‐supported patients and the probability of those patients to present to the emergency department with expected and non‐expected device‐related and patient–device interaction complications. The ageing of the LVAD‐supported patients, mainly those supported with the ‘destination therapy’ indication, increases the risk for those patients to suffer from other co‐morbidities common in the older population. In this second part of the trilogy on the management of LVAD‐supported patients for the non‐LVAD specialist healthcare provider, definitions and structured approach to the LVAD‐supported patient presenting to the emergency department with bleeding, neurological event, pump thrombosis, chest pain, syncope, and other events are presented. The very challenging issue of declaring death in an LVAD‐supported patient, as the circulation is artificially preserved by the device despite no other signs of life, is also discussed in detail.
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Affiliation(s)
- Davor Milicic
- Department for Cardiovascular Diseases, Hospital Center Zagreb, University of Zagreb, Zagreb, Croatia
| | - Binyamin Ben Avraham
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', Bucharest, Romania.,University of Medicine Carol Davila, Bucharest, Romania
| | - Yaron D Barac
- Department of Cardiothoracic Surgery, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Avishai Grupper
- Heart Failure Institute, Lev Leviev Heart Center, Chaim Sheba Medical Center, Tel HaShomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Maria Frigeiro
- Transplant Center and De Gasperis Cardio Center, Niguarda Hospital, Milan, Italy
| | - Arsen Ristic
- Department of Cardiology of the Clinical Center of Serbia, Belgrade University School of Medicine, Belgrade, Serbia
| | - Nicolaas De Jonge
- Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Steven Tsui
- Transplant Unit, Royal Papworth Hospital, Cambridge, UK
| | - Jacob Lavee
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Heart Transplantation Unit, Leviev Cardiothoracic and Vascular Center, Sheba Medical Center, Ramat Gan, Israel
| | - Giuseppe Rosano
- Cardiovascular Clinical Academic Group, St George's Hospitals NHS Trust University of London, London, UK.,IRCCS San Raffaele Pisana, Rome, Italy
| | - Marisa Generosa Crespo-Leiro
- Complexo Hospitalario Universitario A Coruña (CHUAC), CIBERCV, Instituto de Investigacion Biomedica A Coruña (INIBIC), Universidade da Coruña (UDC), A Coruña, Spain
| | | | - Petar Seferovic
- Serbian Academy of Sciences and Arts, Heart Failure Center, Faculty of Medicine, Belgrade University Medical Center, Belgrade, Serbia
| | - Frank Ruschitzka
- Department of Cardiology, University Hospital, University Heart Center, Zürich, Switzerland
| | - Marco Metra
- Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy
| | - Stefan Anker
- Department of Cardiology (CVK), Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Berlin, Germany.,Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Gerasimos Filippatos
- Heart Failure Unit, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.,School of Medicine, University of Cyprus, Nicosia, Cyprus
| | - Stamatis Adamopoulos
- Heart Failure and Heart Transplantation Unit, Onassis Cardiac Surgery Center, Athens, Greece
| | - Miriam Abuhazira
- Department of Cardiothoracic Surgery, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jeremy Elliston
- Anesthesiology Department, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Israel Gotsman
- Heart Institute, Hadassah University Hospital, Jerusalem, Israel
| | - Righab Hamdan
- Department of Cardiology, Beirut Cardiac Institute, Beirut, Lebanon
| | - Yoav Hammer
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tal Hasin
- Jesselson Integrated Heart Center, Shaare Zedek Medical Center, Jerusalem, Israel
| | - Lorrena Hill
- School of Nursing and Midwifery, Queen's University, Belfast, UK
| | - Osnat Itzhaki Ben Zadok
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Wilfried Mullens
- Ziekenhuis Oost-Limburg, Genk, Belgium.,Hasselt University, Hasselt, Belgium
| | | | | | - Piotr Ponikowski
- Centre for Heart Diseases, University Hospital, Wrocław, Poland.,Department of Heart Diseases, Wrocław Medical University, Wrocław, Poland
| | - Luciano Potena
- Heart and Lung Transplant Program, Bologna University Hospital, Bologna, Italy
| | - Arjang Ruhparwar
- Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
| | - Aviv Shaul
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Laurens F Tops
- Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Stephan Winnik
- Department of Cardiology, University Heart Center, University Hospital Zürich, Zürich, Switzerland.,Switzerland Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland
| | - Tiny Jaarsma
- Department of Nursing, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Finn Gustafsson
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Tuvia Ben Gal
- Heart Failure Unit, Cardiology Department, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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