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Cao W, Liu Y, Zhang XF, Zheng XL. A mutant complement factor H (W1183R) enhances proteolytic cleavage of von Willebrand factor by ADAMTS-13 under shear. J Thromb Haemost 2025; 23:1229-1240. [PMID: 39798927 DOI: 10.1016/j.jtha.2024.11.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 10/31/2024] [Accepted: 11/22/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND A loss-of-functional mutation (W1183R) in human complement factor H (CFH) is associated with complement-associated hemolytic uremic syndrome; mice carrying a similar mutation (W1206R) in CFH also develop thrombotic microangiopathy but its plasma von Willebrand factor (VWF) multimer sizes were dramatically reduced. The mechanism underlying such a dramatic change in plasma VWF multimer distribution in these mice is not fully understood. OBJECTIVES To determine the VWF and CFH interaction and how CFH proteins affect VWF multimer distribution. METHODS We employed recombinant protein expression, purification, and various biochemical and biophysical tools. RESULTS Purified recombinant W1183R-CFH but not wild-type (WT) CFH protein enhanced the proteolytic cleavage of both peptidyl and multimeric VWF substrates by recombinant ADAMTS-13 in a concentration-dependent manner. Microscale thermophoresis assay demonstrated that both W1183R-CFH and WT-CFH proteins bound various VWF fragments (eg, AIM-A1, A1-A2-A3, D'D3, D'D3-A1, and D'D3-A1-A2) with high affinities. Optical tweezer experiments further showed a concentration-dependent alteration in the contour length (Lc) and the persistent length (Lp) following pulling VWF-A2 domain in the presence of W1183R-CFH or WT-CFH protein. AlphaFold experiments revealed conformational changes in the VWF-A2, particularly the central region where the cleavage bond resides following addition of W1183R-CFH or WT-CFH protein. CONCLUSION These results demonstrate for the first time that W1183R-CFH but not WT-CFH protein enhances the proteolytic cleavage of VWF by ADAMTS-13 under shear. This may be achieved by mechanic-induced conformational changes of the central A2 domain, leading to an enhanced cleavage of Tyr1605-Met1606 bond by ADAMTS-13 under pathophysiological conditions.
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Affiliation(s)
- Wenjing Cao
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Yi Liu
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - X Frank Zhang
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA 01003, USA.
| | - X Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
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Liu S, Ma M, Qu J, Muia J, Wu Z, Bonnez Q, Vanhoorelbeke K, Zheng L, Zhao X, Zheng XL. Arginine Methylation by PRMT1 Affects ADAMTS13 Secretion and Enzymatic Activity. Arterioscler Thromb Vasc Biol 2025; 45:506-522. [PMID: 39945068 PMCID: PMC11945488 DOI: 10.1161/atvbaha.124.322249] [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: 11/29/2024] [Accepted: 01/29/2025] [Indexed: 03/14/2025]
Abstract
BACKGROUND ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13), primarily synthesized in hepatic stellate and endothelial cells, plays a pivotal role in regulation of hemostasis by proteolytic cleavage of von Willebrand factor. Severe deficiency of plasma ADAMTS13 activity may result in thrombotic thrombocytopenic purpura, a potentially fatal blood disorder. ADAMTS13 undergoes posttranslational modifications including glycosylation, citrullination, oxidation. The present study determines the impact of arginine methylation by PRMT1 (protein arginine methyltransferase 1) on ADAMTS13 secretion and function. METHODS Cell culture, recombinant protein, biochemical analysis, site-directed mutagenesis, and animal models were utilized. RESULTS An inhibition of arginine methylation by a type I methyl transferase PRMT inhibitor (MS023) in HEK (human embryonic kidney) 293 cells expressing recombinant ADAMTS13 and in mice results in a significant reduction of ADAMTS13 secretion, but the secreted ADAMTS13 shows an increased specific activity; conversely, an overexpression of PRMT1 in HEK-293 cells and in transgenic mice results in an increase of ADAMTS13 secretion, but the secreted ADAMTS13 exhibits a significantly reduced specific activity. The altered ADAMTS13 activity appeared to be related to its conformational changes. LC-MS/MS (liquid chromatography with tandem mass spectrometry) identified greater than100 arginine methylation events on purified recombinant ADAMTS13. Site-directed mutagenesis performed on 5 highly conserved methylation sites (R193, R498, R692, R1123, and R1206) identifies the critical role of R1206 in ADAMTS13 function. The ADAMTS13 R1206K variant exhibits a 4- to 5-fold increase of specific activity, likely resulting from an alleviation of allosteric inhibition. CONCLUSIONS These results demonstrate the crucial role of arginine methylation in ADAMTS13 secretion and function. Our findings may shed new light on the mechanism of allosteric regulation of ADAMTS13, which may have a therapeutic implication.
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Affiliation(s)
- Szumam Liu
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
- Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160
| | - Min Ma
- Department of Pharmaceutical Sciences at the University at Buffalo, State University of New York, Amherst, New York 14261
| | - Jun Qu
- Department of Pharmaceutical Sciences at the University at Buffalo, State University of New York, Amherst, New York 14261
| | - Joshua Muia
- Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Miwakee, MI
| | - Zhijian Wu
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
| | | | | | - Liang Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
- Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160
| | - Xinyang Zhao
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
- Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160
| | - X. Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160
- Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160
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Abu El-Asrar AM, Nawaz MI, Ahmad A, Siddiquei M, Allegaert E, Adyns L, Vanbrabant L, Gikandi PW, De Hertogh G, Struyf S, Opdenakker G. ADAMTS13 Improves Endothelial Function and Reduces Inflammation in Diabetic Retinopathy. Cells 2025; 14:85. [PMID: 39851513 PMCID: PMC11764296 DOI: 10.3390/cells14020085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 01/05/2025] [Accepted: 01/08/2025] [Indexed: 01/26/2025] Open
Abstract
The protease, a disintegrin and metalloproteinase with thrombospondin type 1 motif member 13 (ADAMTS13), known to cleave only the von Willebrand factor (VWF), has powerful regulatory effects on microvascular platelet adhesion, thrombosis, inflammation, and endothelial dysfunction. We study the protection against diabetes-induced retinal injury in experimental rats by supplementation with recombinant ADAMTS13. We compare human epiretinal membranes and vitreous samples from nondiabetic subjects and patients with proliferative diabetic retinopathy (PDR) and extend in vitro analyses with the use of various immunodetection and spectrofluorimetric methods on rat retina and human retinal glial and endothelial cell cultures. Functional studies include the assessment of the blood-retinal barrier (BRB), cell adhesion, and in vitro angiogenesis. In epiretinal membranes, endothelial cells and monocytes/macrophages express ADAMTS13. The levels of VWF, the platelet marker CD41, ADAMTS13, and the biomarkers of endothelial cell injury soluble VE-cadherin and soluble syndecan-1 are increased in PDR vitreous. ADAMTS13 is downregulated in diabetic rat retinas. The intravitreal administration of ADAMTS13 attenuates diabetes-induced BRB breakdown, the downregulation of VE-cadherin and β-catenin, and the upregulation of VWF, CD41, phospho-ERK1/2, HMGB1, VCAM-1, and ICAM-1. In Müller cells, ADAMTS13 attenuates MCP-1, MMP-9, and ROS upregulation induced by diabetic mimetic conditions. In HRMECs, ADAMTS13 attenuates the shedding of the soluble VE-cadherin and soluble syndecan-1 and the levels of phospho-ERK1/2, MCP-1, fractalkine, and ROS induced by diabetic mimetic conditions, the upregulation of ICAM-1 and VCAM-1 elicited by TNF-α, the adherence of monocytes induced by TNF-α, and VEGF-induced migration of human retinal microvascular endothelial cells. Our findings suggest that enhancing ADAMTS13 levels in situ ameliorates diabetes-induced retinal inflammation and vascular dysfunction.
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Affiliation(s)
- Ahmed M. Abu El-Asrar
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
- Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia
| | - Mohd I. Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Ajmal Ahmad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Mairaj Siddiquei
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Eef Allegaert
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, 3000 Leuven, Belgium; (E.A.); (G.D.H.)
- University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium
| | - Lowie Adyns
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium; (L.A.); (L.V.); (S.S.)
| | - Lotte Vanbrabant
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium; (L.A.); (L.V.); (S.S.)
| | - Priscilla W. Gikandi
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
| | - Gert De Hertogh
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, 3000 Leuven, Belgium; (E.A.); (G.D.H.)
- University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium; (L.A.); (L.V.); (S.S.)
| | - Ghislain Opdenakker
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia; (M.I.N.); (A.A.); (M.S.); (P.W.G.); (G.O.)
- University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium
- Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium
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Kokoris S, Polyviou A, Evangelidis P, Grouzi E, Valsami S, Tragiannidis K, Gialeraki A, Tsakiris DA, Gavriilaki E. Thrombosis in Paroxysmal Nocturnal Hemoglobinuria (PNH): From Pathogenesis to Treatment. Int J Mol Sci 2024; 25:12104. [PMID: 39596172 PMCID: PMC11594924 DOI: 10.3390/ijms252212104] [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: 10/16/2024] [Revised: 11/04/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024] Open
Abstract
Paroxysmal Nocturnal Hemoglobinuria (PNH) constitutes a rare bone marrow failure syndrome characterized by hemolytic anemia, thrombotic events (TEs), and bone marrow aplasia of variable degrees. Thrombosis is one of the major clinical manifestations of the disease, affecting up to 40% of individuals with PNH. Venous thrombosis is more prevalent, affecting mainly unusual sites, such as intrabdominal and hepatic veins. TEs might be the first clinical manifestation of PNH. Complement activation, endothelial dysfunction, hemolysis, impaired bioavailability of nitric oxide, and activation of platelets and neutrophils are implicated in the pathogenesis of TEs in PNH patients. Moreover, a vicious cycle involving the coagulation cascade, complement system, and inflammation cytokines, such as interleukin-6, is established. Complement inhibitors, such as eculizumab and ravulizumab (C5 inhibitors), have revolutionized the care of patients with PNH. C5 inhibitors should be initiated in patients with PNH and thrombosis, while they constitute a great prophylactic measure for TEs in those individuals. Anticoagulants, such as warfarin and low-molecular-weight heparin, and, in selected cases, direct oral anticoagulants (DOACs) should be used in combination with C5 inhibitors in patients who develop TEs. Novel complement inhibitors are considered an alternative treatment option, especially for those who develop extravascular or breakthrough hemolysis when terminal inhibitors are administered.
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Affiliation(s)
- Styliani Kokoris
- Laboratory of Hematology and Blood Bank Unit, “Attikon” University General Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.K.); (A.G.)
| | - Antri Polyviou
- Department of Hematology and Lymphoma, BMT Unit, Evangelismos General Hospital, 10676 Athens, Greece;
| | - Paschalis Evangelidis
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (P.E.); (K.T.)
| | - Elisavet Grouzi
- Department of Transfusion Service and Clinical Hemostasis, “Saint Savvas” Oncology Hospital, 11522 Athens, Greece;
| | - Serena Valsami
- Hematology Laboratory-Blood Bank, Aretaieion Hospital, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Konstantinos Tragiannidis
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (P.E.); (K.T.)
| | - Argyri Gialeraki
- Laboratory of Hematology and Blood Bank Unit, “Attikon” University General Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece; (S.K.); (A.G.)
| | - Dimitrios A. Tsakiris
- Department of Hemostasis and Thrombosis, University of Basel, 4001 Basel, Switzerland;
| | - Eleni Gavriilaki
- Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (P.E.); (K.T.)
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Sarani N, Dasgupta A, Enders M, Rowan L, Elsarraj H, Gralnek S, Shay M, Lemar LR, Simpson SQ, Cunningham MT, Zheng XL. Clinical Utility of Recently Food and Drug Administration-Approved IntelliSep Test (Sepsis Biomarker) for Early Diagnosis of Sepsis: Comparison with Other Biomarkers. J Clin Med 2024; 13:4852. [PMID: 39200994 PMCID: PMC11355800 DOI: 10.3390/jcm13164852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/02/2024] Open
Abstract
Context: IntelliSep by Cytovale has received United States (U.S.) Food and Drug Administration (FDA) approval as a sepsis biomarker test. However, the clinical utility of this new test is not assessed in emergency departments. Objective: We investigated the clinical utility of this test using 44 patients visiting the emergency department at The University of Kansas Medical Center by comparing it with the monocyte distribution width (MDW) and other biomarkers including the von Willebrand factor (vWF) and ADAMTS13. Design and Methods: IntelliSep assesses the cellular host response via deformability cytometry of biophysical leukocyte properties and produces a score (IntelliSep Index; ISI: from 0.1 (lowest risk) to 10 (highest risk). We measured the ISI in 44 patients (19 high probability and 25 low probability of sepsis groups) using EDTA-anticoagulated blood. Left over plasma was used for measuring the plasma von Willebrand factor (vWF) and ADAMTS13 antigen by ELISA assays. The MDW was obtained during routine CBC analysis using a Beckman hematology analyzer. The lactate and high-sensitivity troponin I levels were measured using a Beckman analyzer. Procalcitonin was measured using a Cobas e801 analyzer. Results: The median ISI was twofold higher in the high-probability group than in the low-probability group (p < 0.01) while the median MDW was 34.5% higher in the high-probability group than in the low-probability group (p < 0.01). However, the correlation between the ISI and MDW was only modest (r = 0.66). In addition, significantly higher levels of plasma vWF antigen but lower levels of plasma ADAMTS13 antigen in the high-probability group were found, resulting in significantly higher vWF/ADAMTS13 ratios in the high-probability group than in the low-probability group. Conclusions: The new IntelliSep test along with vWF/ADAMTS13 ratios may be useful for the early diagnosis of sepsis in patients visiting the emergency department, which appears to be superior to the traditional marker, MDW.
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Affiliation(s)
- Nima Sarani
- Department of Emergency Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (N.S.); (M.E.); (L.R.); (L.R.L.)
| | - Amitava Dasgupta
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (A.D.); (H.E.); (S.G.); (M.S.); (M.T.C.)
| | - Maria Enders
- Department of Emergency Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (N.S.); (M.E.); (L.R.); (L.R.L.)
| | - Lauren Rowan
- Department of Emergency Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (N.S.); (M.E.); (L.R.); (L.R.L.)
| | - Hanan Elsarraj
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (A.D.); (H.E.); (S.G.); (M.S.); (M.T.C.)
| | - Sarah Gralnek
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (A.D.); (H.E.); (S.G.); (M.S.); (M.T.C.)
| | - Madison Shay
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (A.D.); (H.E.); (S.G.); (M.S.); (M.T.C.)
| | - Lucas R. Lemar
- Department of Emergency Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (N.S.); (M.E.); (L.R.); (L.R.L.)
| | - Steven Q. Simpson
- Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Mark T. Cunningham
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (A.D.); (H.E.); (S.G.); (M.S.); (M.T.C.)
| | - X. Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; (A.D.); (H.E.); (S.G.); (M.S.); (M.T.C.)
- Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160, USA
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Braune M, Metelmann M, de Fallois J, Pfrepper C, Barrantes-Freer A, Hiller GGR, Unger S, Seelow E, Halbritter J, Pelz JO. Imbalance of the von Willebrand Factor - ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S). Neurol Res Pract 2024; 6:32. [PMID: 38898536 PMCID: PMC11188181 DOI: 10.1186/s42466-024-00327-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 05/08/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an ultra-rare, autosomal-dominant small vessel disease caused by loss-of-function variants in the gene TREX1. Recently, elevated serum levels of von Willebrand Factor Antigen (vWF-Ag) pointed to an underlying endotheliopathy, and microvascular ischemia was suggested to contribute to the neurodegeneration in RVCL-S. Aim of this study was to further elucidate the endotheliopathy in RVCL-S. METHODS vWF-Ag and ADAMTS-13 activity were repeatedly measured in two patients with genetically confirmed RVCL-S. Renal biopsy of both RVCL-S patients and autoptic brain, renal, hepatic, and pulmonary specimen of one patient with RVCL-S were examined immunohistochemically in comparison to matched controls. In addition, cerebral methylome analysis was performed in the autoptic brain specimen calculating differentially methylated positions compared to controls. RESULTS While vWF-Ag and activity was strongly elevated, ADAMTS-13 activity was low in RVCL-S and further decreased over the course of the disease. Autoptic brain specimen showed signs of thromboinflammation in cerebral small vessels, and vWF-Ag staining was strongly positive in cerebral and renal small vessels in RVCL-S, while only a light to moderate vWF-Ag staining was found in controls. Cerebral methylome analysis yielded 115 differentially methylated CpGs (p < 0.05) in the deceased RVCL-S patient compared to the eight controls without brain pathology. One of the hypomethylated genes coded for ADAMTS-13 (p = 0.00056). CONCLUSIONS These findings point to an imbalance of the vWF - ADAMTS-13 axis in patients with RVCL-S, that may finally lead to an accumulation of vWF-Ag in renal and cerebral small vessels. Elevated vWF-Ag levels may serve as an early serum marker reflecting disease activity. If confirmed, therapeutic approaches might aim at an inhibition of vWF-Ag or increase of ADAMTS-13 activity in the future.
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Affiliation(s)
- Max Braune
- Paul-Flechsig-Institute for Neuropathology, University Hospital Leipzig, Leipzig, Germany
| | - Moritz Metelmann
- Department of Neurology, University Hospital Leipzig, Liebigstraße 20, Leipzig, 04103, Germany
| | | | - Christian Pfrepper
- Division of Haemostaseology, Medical Department I, University Hospital Leipzig, Leipzig, Germany
| | - Alonso Barrantes-Freer
- Paul-Flechsig-Institute for Neuropathology, University Hospital Leipzig, Leipzig, Germany
| | | | - Susette Unger
- Division of Rheumatology, Hospital St. Georg, Leipzig, Germany
| | - Evelyn Seelow
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Jan Halbritter
- Division of Nephrology, University Hospital Leipzig, Leipzig, Germany.
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.
| | - Johann Otto Pelz
- Department of Neurology, University Hospital Leipzig, Liebigstraße 20, Leipzig, 04103, Germany.
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Huang LH, Huang CY, Liu YW, Chien PC, Hsieh TM, Liu HT, Lin HP, Wu CJ, Chuang PC, Hsieh CH. Circadian Rhythm Disruption in Hepatocellular Carcinoma Investigated by Integrated Analysis of Bulk and Single-Cell RNA Sequencing Data. Int J Mol Sci 2024; 25:5748. [PMID: 38891936 PMCID: PMC11171588 DOI: 10.3390/ijms25115748] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
Circadian rhythms are essential regulators of a multitude of physiological and behavioral processes, such as the metabolism and function of the liver. Circadian rhythms are crucial to liver homeostasis, as the liver is a key metabolic organ accountable for the systemic equilibrium of the body. Circadian rhythm disruption alone is sufficient to cause liver cancer through the maintenance of hepatic metabolic disorder. Although there is evidence linking CRD to hepatocarcinogenesis, the precise cellular and molecular mechanisms that underlie the circadian crosstalk that leads to hepatocellular carcinoma remain unknown. The expression of CRD-related genes in HCC was investigated in this study via bulk RNA transcriptomic analysis and single-cell sequencing. Dysregulated CRD-related genes are predominantly found in hepatocytes and fibroblasts, according to the findings. By using a combination of single-cell RNA sequencing and bulk RNA sequencing analyses, the dysregulated CRD-related genes ADAMTS13, BIRC5, IGFBP3, MARCO, MT2A, NNMT, and PGLYRP2 were identified. The survival analysis using the Kaplan-Meier method revealed a significant correlation between the expression levels of BIRC5 and IGFBP3 and the survival of patients diagnosed with HCC.
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Affiliation(s)
- Lien-Hung Huang
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (L.-H.H.); (C.-Y.H.); (T.-M.H.); (H.-T.L.)
| | - Chun-Ying Huang
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (L.-H.H.); (C.-Y.H.); (T.-M.H.); (H.-T.L.)
| | - Yueh-Wei Liu
- Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Peng-Chen Chien
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (P.-C.C.); (H.-P.L.); (C.-J.W.)
| | - Ting-Min Hsieh
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (L.-H.H.); (C.-Y.H.); (T.-M.H.); (H.-T.L.)
| | - Hang-Tsung Liu
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (L.-H.H.); (C.-Y.H.); (T.-M.H.); (H.-T.L.)
| | - Hui-Ping Lin
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (P.-C.C.); (H.-P.L.); (C.-J.W.)
| | - Chia-Jung Wu
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (P.-C.C.); (H.-P.L.); (C.-J.W.)
| | - Pei-Chin Chuang
- Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Ching-Hua Hsieh
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (P.-C.C.); (H.-P.L.); (C.-J.W.)
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Minciuna I, Taru MG, Procopet B, Stefanescu H. The Interplay between Liver Sinusoidal Endothelial Cells, Platelets, and Neutrophil Extracellular Traps in the Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease. J Clin Med 2024; 13:1406. [PMID: 38592258 PMCID: PMC10932189 DOI: 10.3390/jcm13051406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 04/10/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a societal burden due to the lack of effective treatment and incomplete pathophysiology understanding. This review explores the intricate connections among liver sinusoidal endothelial cells (LSECs), platelets, neutrophil extracellular traps (NETs), and coagulation disruptions in MASLD pathogenesis. In MASLD's early stages, LSECs undergo capillarization and dysfunction due to excessive dietary macronutrients and gut-derived products. Capillarization leads to ischemic changes in hepatocytes, triggering pro-inflammatory responses in Kupffer cells (KCs) and activating hepatic stellate cells (HSCs). Capillarized LSECs show a pro-inflammatory phenotype through adhesion molecule overexpression, autophagy loss, and increased cytokines production. Platelet interaction favors leucocyte recruitment, NETs formation, and liver inflammatory foci. Liver fibrosis is facilitated by reduced nitric oxide, HSC activation, profibrogenic mediators, and increased angiogenesis. Moreover, platelet attachment, activation, α-granule cargo release, and NETs formation contribute to MASLD progression. Platelets foster fibrosis and microthrombosis, leading to parenchymal extinction and fibrotic healing. Additionally, platelets promote tumor growth, epithelial-mesenchymal transition, and tumor cell metastasis. MASLD's prothrombotic features are exacerbated by insulin resistance, diabetes, and obesity, manifesting as increased von Willebrand factor, platelet hyperaggregability, hypo-fibrinolysis, and a prothrombotic fibrin clot structure. Improving LSEC health and using antiplatelet treatment appear promising for preventing MASLD development and progression.
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Affiliation(s)
- Iulia Minciuna
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
- Deaprtment IV, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Madalina Gabriela Taru
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
- Deaprtment IV, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Bogdan Procopet
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
- Deaprtment IV, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400394 Cluj-Napoca, Romania (H.S.)
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9
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Madarati H, Singh K, Sparring T, Andrisani P, Liaw PC, Fox-Robichaud AE, Kretz CA. REVIEWING THE DYSREGULATION OF ADAMTS13 AND VWF IN SEPSIS. Shock 2024; 61:189-196. [PMID: 38150358 DOI: 10.1097/shk.0000000000002291] [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: 12/29/2023]
Abstract
ABSTRACT Sepsis is defined as a life-threatening organ dysfunction caused by excessive host response to infection, and represents the most common cause of in-hospital deaths. Sepsis accounts for 30% of all critically ill patients in the intensive care unit (ICU), and has a global mortality rate of 20%. Activation of blood coagulation during sepsis and septic shock can lead to disseminated intravascular coagulation, which is characterized by microvascular thrombosis. Von Willebrand factor (VWF) and ADAMTS13 are two important regulators of blood coagulation that may be important links between sepsis and mortality in the ICU. Herein we review our current understanding of VWF and ADAMTS13 in sepsis and other critical illnesses and discuss their contribution to disease pathophysiology, their use as markers of severe illness, and potential targets for new therapeutic development.
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Affiliation(s)
- Hasam Madarati
- Department of Medicine and the Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
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10
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Neave L, Thomas M, de Groot R, Doyle AJ, Singh D, Adams G, David AL, Maksym K, Scully M. Alterations in the von Willebrand factor/ADAMTS-13 axis in preeclampsia. J Thromb Haemost 2024; 22:455-465. [PMID: 37926193 DOI: 10.1016/j.jtha.2023.10.022] [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: 06/13/2023] [Revised: 10/07/2023] [Accepted: 10/25/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Preeclampsia is a gestational hypertensive disorder characterized by maternal endothelial activation and increased ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) inhibitor to placental growth factor (PlGF). The von Willebrand factor (VWF)/ADAMTS-13 axis is of interest because of the underlying endothelial activation and clinical overlap with pregnancy-associated thrombotic thrombocytopenic purpura. OBJECTIVES To assess VWF, ADAMTS-13, and VWF/ADAMTS-13 ratio in preeclampsia and look for associations with sFlt-1/PlGF ratio and clinical features. METHODS Thirty-four preeclampsia cases and 48 normal pregnancies were assessed in a case-control study. Twelve normal pregnancies in women with a history of preeclampsia formed an additional comparator group. VWF antigen (VWF:Ag) and VWF activity (VWF:Ac [VWF:glycoprotein IbM]) were measured via automated immunoturbidimetric assay, ADAMTS-13 activity was measured via fluorescence resonance energy transfer-VWF73 assay, and sFlt-1 and PlGF were measured via enzyme-linked immunosorbent assay. RESULTS VWF:Ag was higher in preeclampsia than in normal pregnancy (median, 3.07 vs 1.87 IU/mL; P < .0001). ADAMTS-13 activity was slightly lower (median, 89.6 vs 94.4 IU/dL; P = .02), with no severe deficiencies. Significant elevations in VWF:Ac were not observed in preeclampsia, resulting in reduced VWF:Ac/VWF:Ag ratios (median, 0.77 vs 0.97; P < .0001). VWF:Ag/ADAMTS-13 ratios were significantly higher in preeclampsia (median, 3.42 vs 2.06; P < .0001), with an adjusted odds ratio of 19.2 for a ratio of >2.7 (>75th centile of normal pregnancy). Those with a history of preeclampsia had similar ratios to normal pregnant controls. VWF:Ag/ADAMTS-13 and sFlt-1/PlGF were not correlated. However, percentage reduction in platelets correlated positively with VWF:Ac (P = .01), VWF:Ac/VWF:Ag ratio (P = .004), and sFlt-1/PlGF ratio (P = .01). CONCLUSION The VWF/ADAMTS-13 axis is significantly altered in preeclampsia. Further investigation of potential clinical utility is warranted.
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Affiliation(s)
- Lucy Neave
- Department of Clinical Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; Haemostasis Research Unit, University College London, London, United Kingdom.
| | - Mari Thomas
- Department of Clinical Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; National Institute for Health and Care Research University College London Hospital/University College London Biomedical Research Centre, London, United Kingdom
| | - Rens de Groot
- Institute of Cardiovascular Science, University College London, London, United Kingdom
| | - Andrew J Doyle
- Department of Clinical Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Deepak Singh
- Special Coagulation, Health Services Laboratories, London, United Kingdom
| | - George Adams
- Department of Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Anna L David
- Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom
| | - Katarzyna Maksym
- Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom
| | - Marie Scully
- Department of Clinical Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom; National Institute for Health and Care Research University College London Hospital/University College London Biomedical Research Centre, London, United Kingdom
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11
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Xu J, He J, Zhou YL, Weng Z, Li M, Wang ZX, He Y. Von Willebrand factor promotes radiation-induced intestinal injury (RIII) development and its cleavage enzyme rhADAMTS13 protects against RIII by reducing inflammation and oxidative stress. Free Radic Biol Med 2024; 210:1-12. [PMID: 37956910 DOI: 10.1016/j.freeradbiomed.2023.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/20/2023]
Abstract
Patients with abdominopelvic cancer undergoing radiotherapy commonly develop radiation-induced intestinal injury (RIII); however, its underlying pathogenesis remains elusive. The von Willebrand factor (vWF)/a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) axis has been implicated in thrombosis, inflammation, and oxidative stress. However, its role in RIII remains unclear. In this study, the effect of radiation on vWF and ADAMTS13 expression was firstly evaluated in patients with cervical cancer undergoing radiotherapy and C57BL/6J mice exposed to different doses of total abdominal irradiation. Then, mice with the specific deletion of vWF in the platelets and endothelium were established to demonstrate the contribution of vWF to RIII. Additionally, the radioprotective effect of recombinant human (rh) ADAMTS13 against RIII was assessed. Results showed that both the patients with cervical cancer undergoing radiotherapy and RIII mouse model exhibited increased vWF levels and decreased ADAMTS13 levels. The knockout of platelet- and endothelium-derived vWF rectified the vWF/ADAMTS13 axis imbalance; improved intestinal structural damage; increased crypt epithelial cell proliferation; and reduced radiation-induced apoptosis, inflammation, and oxidative stress, thereby alleviating RIII. Administration of rhADAMTS13 could equally alleviate RIII. Our results demonstrated that abdominal irradiation affected the balance of the vWF/ADAMTS13 axis. vWF exerted a deleterious role and ADAMTS13 exhibited a protective role in RIII progression. rhADAMTS13 has the potential to be developed into a radioprotective agent.
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Affiliation(s)
- Jie Xu
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Jun He
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Ya-Li Zhou
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Zhen Weng
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Ming Li
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, 215123, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
| | - Zhen-Xin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
| | - Yang He
- MOE Engineering Center of Hematological Disease, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China.
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12
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Liu W, Patel K, Wang Y, Nodzenski M, Nguyen A, Teramura G, Higgins HA, Hoogeveen RC, Couper D, Fu X, Konkle BA, Loop MS, Dong JF. Dynamic and functional linkage between von Willebrand factor and ADAMTS-13 with aging: an Atherosclerosis Risk in Community study. J Thromb Haemost 2023; 21:3371-3382. [PMID: 37574196 DOI: 10.1016/j.jtha.2023.07.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/10/2023] [Accepted: 07/16/2023] [Indexed: 08/15/2023]
Abstract
BACKGROUND von Willebrand factor (VWF) is a multimeric glycoprotein critically involved in hemostasis, thrombosis, and inflammation. VWF function is regulated by its antigen levels, multimeric structures, and the state of enzymatic cleavage. Population studies in the past have focused almost exclusively on VWF antigen levels in cross-sectional study designs. OBJECTIVE To identify subjects in the Atherosclerosis Risk in Community study who had persistently low and high VWF antigen over 10 years and to quantify longitudinal changes in the biological activities and cleavage of VWF in these subjects. METHODS We measured VWF antigen, propeptide, adhesive activities, and cleavage by ADAMTS-13 quantified using a mass spectrometry method that detected the cleaved VWF peptide EQAPNLVY, as well as coagulation factor VIII activity. RESULTS We determined the mean subject-specific increase in VWF to be 22.0 International Units (IU)/dL over 10 years, with 95% between -0.3 and 59.7 IU/dL. This aging-related increase was also detected in VWF propeptide levels, ristocetin cofactor activity, and VWF binding to collagen. We identified 4.1% and 25.0% of subjects as having persistently low (<50 IU/dL) and high (>200 IU/dL) VWF antigen, respectively. Subjects with persistently low VWF had enhanced ristocetin cofactor activity, whereas those with persistently high VWF had elevated levels of ADAMTS-13, resulting in a comparable rate of VWF cleavage between the 2 groups. CONCLUSIONS These results provide new information about the effects of aging on VWF antigens and adhesive activity and identify a functional coordination between VWF and the rate of its cleavage by ADAMTS-13.
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Affiliation(s)
- Wei Liu
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China; Bloodworks Research Institute, Seattle, WA, USA
| | | | - Yi Wang
- Bloodworks Research Institute, Seattle, WA, USA
| | - Michael Nodzenski
- Department of Biostatistics, Collaborative Studies Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | | | | | - Ron C Hoogeveen
- Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - David Couper
- Department of Biostatistics, Collaborative Studies Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Xiaoyun Fu
- Bloodworks Research Institute, Seattle, WA, USA
| | - Barbara A Konkle
- Washington Center for Bleeding Disorders, Seattle, WA, USA; Division of Hematology, University of Washington School of Medicine, Seattle, WA, USA.
| | - Matthew Shane Loop
- Department of Health Outcomes Organization and Policy, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA
| | - Jing-Fei Dong
- Bloodworks Research Institute, Seattle, WA, USA; Division of Hematology, University of Washington School of Medicine, Seattle, WA, USA.
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13
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Zhang Q, Bignotti A, Yada N, Ye Z, Liu S, Han Z, Zheng XL. Dynamic Assessment of Plasma von Willebrand Factor and ADAMTS13 Predicts Mortality in Hospitalized Patients with SARS-CoV-2 Infection. J Clin Med 2023; 12:7174. [PMID: 38002786 PMCID: PMC10672082 DOI: 10.3390/jcm12227174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Plasma levels of von Willebrand factor (VWF) are significantly elevated in patients with coronavirus disease 2019 (COVID-19). However, dynamic changes and prognostic value of this biomarker in hospitalized patients with COVID-19 have not been determined. METHODS A total of 124 patients infected with SARS-CoV-2 were prospectively recruited for the study. Serial blood samples were obtained at the time of admission (D1), 3-4 days following standard-care treatments (D2), and 1-2 days prior to discharge or any time collected prior to death (D3). Plasma VWF antigen, ADAMTS13 antigen, and ADAMTS13 proteolytic activity, as well as the ratio of VWF/ADAMTS13 were determined, followed by various statistical analyses. RESULTS On admission, plasma levels of VWF in COVID-19 patients were significantly elevated compared with those in the healthy controls, but no statistical significance was detected among patients with different disease severity. Plasma ADAMTS13 activity but not its antigen levels were significantly lower in patients with severe or critical COVID-19 compared with that in other patient groups. Interestingly, the ratios of plasma VWF antigen to ADAMTS13 antigen were significantly higher in patients with severe or critical COVID-19 than in those with mild to moderate disease. More importantly, plasma levels of VWF and the ratios of VWF/ADAMTS13 were persistently elevated in patients with COVID-19 throughout hospitalization. Kaplan-Meier and Cox proportional hazard regression analyses demonstrated that an increased plasma level of VWF or ratio of VWF/ADAMTS13 at D2 and D3 was associated with an increased mortality rate. CONCLUSIONS Persistent endotheliopathy, marked by the elevated levels of plasma VWF or VWF/ADAMTS13 ratio, is present in all hospitalized patients following SARS-CoV-2 infection, which is strongly associated with mortality.
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Affiliation(s)
- Quan Zhang
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Antonia Bignotti
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Noritaka Yada
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Zhan Ye
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Szumam Liu
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Zhe Han
- Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, Baltimore, MD 21201, USA
| | - X. Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA
- Institute of Reproductive and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160, USA
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14
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Saeki M, Munesue S, Higashi Y, Harashima A, Takei R, Takada S, Nakanuma S, Ohta T, Yagi S, Tajima H, Yamamoto Y. Assaying ADAMTS13 Activity as a Potential Prognostic Biomarker for Sinusoidal Obstruction Syndrome in Mice. Int J Mol Sci 2023; 24:16328. [PMID: 38003518 PMCID: PMC10671412 DOI: 10.3390/ijms242216328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/08/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Sinusoidal obstruction syndrome (SOS) is a serious liver disorder that occurs after liver transplantation, hematopoietic stem cell transplantation, and the administration of anticancer drugs. Since SOS is a life-threatening condition that can progress to liver failure, early detection and prompt treatment are required for the survival of patients with this condition. In this study, female CD1 mice were divided into treatment and control groups after the induction of an SOS model using monocrotaline (MCT, 270 mg/kg body weight intraperitoneally). The mice were analyzed at 0, 12, 24, and 48 h after MCT administration, and blood and liver samples were collected for assays and histopathology tests. SOS was observed in the livers 12 h after MCT injection. In addition, immunohistochemical findings demonstrated CD42b-positive platelet aggregations, positive signals for von Willebrand factor (VWF), and a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) in the MCT-exposed liver sinusoid. Although ADAMTS13's plasma concentrations peaked at 12 h, its enzyme activity continuously decreased by 75% at 48 h and, inversely and proportionally, concentrations in the VWF-A2 domain, in which the cleavage site of ADAMTS13 is located, increased after MCT injection. These findings suggest that the plasma concentration and activity of ADAMTS13 could be useful biomarkers for early detection and therapeutic intervention in patients with SOS.
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Affiliation(s)
- Masakazu Saeki
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640, Japan; (S.M.); (A.H.)
| | - Seiichi Munesue
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640, Japan; (S.M.); (A.H.)
| | - Yuri Higashi
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640, Japan; (S.M.); (A.H.)
| | - Ai Harashima
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640, Japan; (S.M.); (A.H.)
| | - Ryohei Takei
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
| | - Satoshi Takada
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
| | - Shinichi Nakanuma
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
| | - Shintaro Yagi
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8641, Japan; (M.S.); (Y.H.); (R.T.); (S.N.); (T.O.); (S.Y.); (H.T.)
- Department of Gastroenterological Surgery, Dokkyo Medical University Saitama Medical Center, 2-1-50 Minami-Koshigaya, Koshigaya City 343-8555, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa 920-8640, Japan; (S.M.); (A.H.)
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15
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Yang C, Nguyen J, Yen Y. Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies. J Biomed Sci 2023; 30:89. [PMID: 37864230 PMCID: PMC10590030 DOI: 10.1186/s12929-023-00982-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/12/2023] [Indexed: 10/22/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapies have been approved by FDA to treat relapsed or refractory hematological malignancies. However, the adverse effects of CAR-T cell therapies are complex and can be challenging to diagnose and treat. In this review, we summarize the major adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR T-cell associated HLH (carHLH), and discuss their pathophysiology, symptoms, grading, and diagnosis systems, as well as management. In a future outlook, we also provide an overview of measures and modifications to CAR-T cells that are currently being explored to limit toxicity.
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Affiliation(s)
- Chieh Yang
- Department of Internal Medicine, School of Medicine, University of California Riverside, Riverside, CA USA
| | - John Nguyen
- Covina Discovery Center, Theragent Inc., Covina, CA USA
| | - Yun Yen
- College of Medical Technology, Taipei Medical University, Taipei City, Taiwan
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16
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Zheng L, Zheng XL. Animal models for thrombotic thrombocytopenic purpura: a narrative review. ANNALS OF BLOOD 2023; 8:23. [PMID: 39148951 PMCID: PMC11326488 DOI: 10.21037/aob-22-18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Background and Objective Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal blood disorder, resulting from severe deficiency of plasma ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, 13) activity. ADAMTS13 is crucial for normal hemostasis through proteolytic cleavage of ultra large von Willebrand factor (VWF). Since the discovery of ADAMTS13 in 2001, several animal models for TTP have been established. In this narrative review, we summarize the creation and characterization of the established animal models for TTP to date. Methods We performed a literature search through PubMed from 1969 to 2022 using free text: TTP and animal model. We found 67 peer-reviewed articles but only 33 articles were included for review and 34 articles that did not discuss TTP were excluded. Key Content and Findings There were genetically modified or antibody-mediated TTP models being established and fully characterized in mouse, rat, baboon, and zebrafish. However, we are still in urgent need of a true autoimmune TTP animal model. Conclusions These animal models allowed researchers to further evaluate the contribution of various potential environmental factors and/or genetic modifiers to the pathogenesis, progression, and outcome of TTP; and to help assess the efficacy and safety of novel approaches for prevention and treatment of both hereditary and acquired TTP.
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Affiliation(s)
- Liang Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, USA
| | - X Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, USA
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17
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Zhao J, Xu X, Gao Y, Yu Y, Li C. Crosstalk between Platelets and SARS-CoV-2: Implications in Thrombo-Inflammatory Complications in COVID-19. Int J Mol Sci 2023; 24:14133. [PMID: 37762435 PMCID: PMC10531760 DOI: 10.3390/ijms241814133] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/14/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
The SARS-CoV-2 virus, causing the devastating COVID-19 pandemic, has been reported to affect platelets and cause increased thrombotic events, hinting at the possible bidirectional interactions between platelets and the virus. In this review, we discuss the potential mechanisms underlying the increased thrombotic events as well as altered platelet count and activity in COVID-19. Inspired by existing knowledge on platelet-pathogen interactions, we propose several potential antiviral strategies that platelets might undertake to combat SARS-CoV-2, including their abilities to internalize the virus, release bioactive molecules to interfere with viral infection, and modulate the functions of immune cells. Moreover, we discuss current and potential platelet-targeted therapeutic strategies in controlling COVID-19, including antiplatelet drugs, anticoagulants, and inflammation-targeting treatments. These strategies have shown promise in clinical settings to alleviate the severity of thrombo-inflammatory complications and reduce the mortality rate among COVID-19 patients. In conclusion, an in-depth understanding of platelet-SARS-CoV-2 interactions may uncover novel mechanisms underlying severe COVID-19 complications and could provide new therapeutic avenues for managing this disease.
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Affiliation(s)
| | | | | | - Yijing Yu
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (J.Z.); (X.X.); (Y.G.)
| | - Conglei Li
- School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China; (J.Z.); (X.X.); (Y.G.)
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18
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Gong H, Zhong H, Xu HM, Liu XC, Li LP, Zhang DK. Insight into increased risk of portal vein thrombosis in nonalcoholic fatty liver disease. Eur J Intern Med 2023; 114:23-34. [PMID: 37330315 DOI: 10.1016/j.ejim.2023.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the leading chronic liver diseases with increased morbidity and mortality rates for extrahepatic diseases (including cardiovascular disease, portal vein thrombosis, etc.). There is an increased risk of thrombosis in both the portal and systemic circulation in patients with NAFLD, independent of traditional liver cirrhosis. However, increased portal pressure, the most critical factor, is frequently observed in NAFLD patients, predisposing them to portal vein thrombosis (PVT). It has been reported that there is an 8.5% incidence of PVT among patients with non-cirrhotic NAFLD in a prospective cohort study. Based on the prothrombotic status of NAFLD itself, patients combined with cirrhosis may accelerate the development of PVT and lead to a poor prognosis. Moreover, PVT has been shown to complicate the procedure and adversely affect the outcome during liver transplantation surgery. NAFLD is in a prothrombotic state, and its underlying mechanisms have not been fully understood so far. Particularly noteworthy is that gastroenterologists currently overlook the higher risk of PVT in NAFLD. We investigate the pathogenesis of NAFLD complicated with PVT from the perspective of primary, secondary, and tertiary hemostasis, and also summarize relevant studies in humans. Some treatment options that may affect NAFLD and its PVT are also explored to improve patient-oriented outcomes.
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Affiliation(s)
- Hang Gong
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
| | - Huang Zhong
- Department of Gastroenterology, Zigong First People's Hospital, Zigong, Sichuan Province, China
| | - Hui-Mei Xu
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China
| | - Xiong-Chang Liu
- Department of Gastroenterology, Lanzhou Second People's Hospital, Lanzhou, Gansu Province, China
| | - Liang-Ping Li
- Department of Gastroenterology, Sichuan Academy of Medical Sciences and Sichuan People's Hospital, Chengdu, Sichuan Province, China.
| | - De-Kui Zhang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu Province, China.
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19
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Gao D, Zhou Z, Ma R, Wu H, Nguyen T, Liu L, Dong J. Recombinant ADAMTS-13 Improves Survival of Mice Subjected to Endotoxemia. Int J Mol Sci 2023; 24:11782. [PMID: 37511541 PMCID: PMC10380474 DOI: 10.3390/ijms241411782] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/11/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
When stimulated by proinflammatory mediators, endothelial cells release ultra-large von Willebrand factor (ULVWF) multimers that are hyperactive in activating and aggregating platelets. These ULVWF multimers can accumulate in the circulation and on the inflamed endothelium because they are insufficiently cleaved by the metalloprotease ADAMTS-13, which becomes moderately deficient under conditions of systemic inflammation. This moderate ADAMTS-13 deficiency may lead to thrombotic complications that contribute to ischemic tissue injury and organ failure that are associated with severe infections. To test this hypothesis, we investigated whether recombinant ADAMTS-13 improves the pathological course of endotoxemia in lipopolysaccharide (LPS)-treated mice. C57BL/J6 mice received a bolus infusion of either 5 µg/mouse of ADAMTS-13 or vehicle control 30 min after LPS challenge and were monitored for seven-day survival. During the monitoring period, platelet counts, VWF antigen, and ADAMTS-13 activity were measured. Thrombosis was also examined by the immunohistochemistry in the liver. We found that ADAMTS-13 reduced mortality from 66% to 34.9%. The improved survival was associated with a greater recovery from thrombocytopenia, higher plasma ADAMTS-13 activity, and less thrombotic vascular occlusion. These results suggest that systemic inflammation could result in deficient ULVWF proteolysis by ADAMTS-13 and that ADAMTS-13 improves the outcomes of endotoxemia-induced inflammation.
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Affiliation(s)
- Daniel Gao
- Bloodworks Research Institute, Seattle, WA 98102, USA
- Department of Chemistry, Pomona College, Claremont, CA 91711, USA
| | - Zhou Zhou
- Bloodworks Research Institute, Seattle, WA 98102, USA
| | - Ruidong Ma
- Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Huaizhu Wu
- Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Trung Nguyen
- Division of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Translational Research on Inflammatory Diseases at the Michael E. DeBakey Veteran Administration Medical Center, Houston, TX 77030, USA
| | - Li Liu
- Tianjin Neurology Research Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jingfei Dong
- Bloodworks Research Institute, Seattle, WA 98102, USA
- Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
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20
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Cauchois R, Muller R, Lagarde M, Dignat-George F, Tellier E, Kaplanski G. Is Endothelial Activation a Critical Event in Thrombotic Thrombocytopenic Purpura? J Clin Med 2023; 12:jcm12030758. [PMID: 36769407 PMCID: PMC9918301 DOI: 10.3390/jcm12030758] [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: 11/04/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy. The current pathophysiologic paradigm suggests that the ADAMTS13 deficiency leads to Ultra Large-Von Willebrand Factor multimers accumulation with generation of disseminated microthrombi. Nevertheless, the role of endothelial cells in this pathology remains an issue. In this review, we discuss the various clinical, in vitro and in vivo experimental data that support the important role of the endothelium in this pathology, suggesting that ADAMTS13 deficiency may be a necessary but not sufficient condition to induce TTP. The "second hit" model suggests that in TTP, in addition to ADAMTS13 deficiency, endogenous or exogenous factors induce endothelial activation affecting mainly microvascular cells. This leads to Weibel-Palade bodies degranulation, resulting in UL-VWF accumulation in microcirculation. This endothelial activation seems to be worsened by various amplification loops, such as the complement system, nucleosomes and free heme.
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Affiliation(s)
- Raphael Cauchois
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, INSERM, INRAE, C2VN, CHU Conception, Internal Medicine and Clinical Immunology, 13005 Marseille, France
- French Reference Center for Thrombotic Microangiopathies, 75571 Paris, France
- Correspondence:
| | - Romain Muller
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, INSERM, INRAE, C2VN, CHU Conception, Internal Medicine and Clinical Immunology, 13005 Marseille, France
| | - Marie Lagarde
- French Reference Center for Thrombotic Microangiopathies, 75571 Paris, France
- Aix Marseille University, INSERM, INRAE, C2VN, 13005 Marseille, France
| | - Françoise Dignat-George
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, INSERM, INRAE, C2VN, CHU Conception, Hematology Laboratory, 13005 Marseille, France
| | - Edwige Tellier
- French Reference Center for Thrombotic Microangiopathies, 75571 Paris, France
- Aix Marseille University, INSERM, INRAE, C2VN, 13005 Marseille, France
| | - Gilles Kaplanski
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, INSERM, INRAE, C2VN, CHU Conception, Internal Medicine and Clinical Immunology, 13005 Marseille, France
- French Reference Center for Thrombotic Microangiopathies, 75571 Paris, France
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21
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Zhang Q, Ye Z, McGowan P, Jurief C, Ly A, Bignotti A, Yada N, Zheng XL. Effects of convalescent plasma infusion on the ADAMTS13-von Willebrand factor axis and endothelial integrity in patients with severe and critical COVID-19. Res Pract Thromb Haemost 2023; 7:100010. [PMID: 36531671 PMCID: PMC9744678 DOI: 10.1016/j.rpth.2022.100010] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 10/28/2022] [Accepted: 10/30/2022] [Indexed: 01/13/2023] Open
Abstract
Background Convalescent plasma infusion (CPI) was given to patients with COVID-19 during the early pandemic with mixed therapeutic efficacy. However, the impacts of CPI on the ADAMTS13-von Willebrand factor (VWF) axis and vascular endothelial functions are not known. Objectives To determine the impacts of CPI on the ADAMTS13-VWF axis and vascular endothelial functions. Methods Sixty hospitalized patients with COVID-19 were enrolled in the study; 46 received CPI and 14 received no CPI. Plasma ADAMTS13 activity, VWF antigen, endothelial syndecan-1, and soluble thrombomodulin (sTM) were assessed before and 24 hours after treatment. Results Patients with severe and critical COVID-19 exhibited significantly lower plasma ADAMTS13 activity than the healthy controls. Conversely, these patients showed a significantly increased VWF antigen. This resulted in markedly reduced ratios of ADAMTS13 to VWF in these patients. The levels of plasma ADAMTS13 activity in each patient remained relatively constant throughout hospitalization. Twenty-four hours following CPI, plasma ADAMTS13 activity increased by ∼12% from the baseline in all patients and ∼21% in those who survived. In contrast, plasma levels of VWF antigen varied significantly over time. Patients who died exhibited a significant reduction of plasma VWF antigen from the baseline 24 hours following CPI, whereas those who survived did not. Furthermore, patients with severe and critical COVID-19 showed significantly elevated plasma levels of syndecan-1 and sTM, similar to those found in patients with immune thrombotic thrombocytopenic purpura. Both syndecan-1 and sTM levels were significantly reduced 24 hours following CPI. Conclusion Our results demonstrate the relative deficiency of plasma ADAMTS13 activity and endothelial damage in patients with severe and critical COVID-19, which could be modestly improved following CPI therapy.
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Affiliation(s)
- Quan Zhang
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Zhan Ye
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Paul McGowan
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Christopher Jurief
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Andrew Ly
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Antonia Bignotti
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Noritaka Yada
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
| | - X. Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas, USA
- Institute of Reproductive and Developmental Sciences, The University of Kansas Medical Center, Kansas City, Kansas, USA
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22
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Pillai VG, Zheng XL. A novel mechanism underlying allosteric regulation of ADAMTS-13 revealed by hydrogen-deuterium exchange plus mass spectrometry. Res Pract Thromb Haemost 2022; 7:100012. [PMID: 36852110 PMCID: PMC9958085 DOI: 10.1016/j.rpth.2022.100012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 02/15/2023] Open
Abstract
Background ADAMTS-13, a plasma metalloprotease, cleaves von Willebrand factor. ADAMTS-13 activity appears to be regulated through allosteric inhibition by its distal C-terminus. Objectives The objective of this study was to better understand how domain-domain interactions may affect ADAMTS-13 conformations and functions. Methods We performed deuterium-hydrogen exchange plus mass spectrometry to assess the number and rate of deuterium incorporation into various peptides of full-length ADAMTS-13 and its truncated variants. Results Under physiological conditions, a bimodal distribution of deuterium incorporation was detected in the peptides from metalloprotease (217-230 and 282-304), cysteine-rich (446-482), and CUB (for complement C1r/C1s, Uegf, Bmp1) domains (1185-1214, 1313-1330, 1341-1347, 1358-1378, and 1393-1407) of full-length recombinant ADAMTS-13, but not of truncated variants. These results suggest that the full-length ADAMTS-13 undergoes conformational changes. On removal of the middle and distal C-terminal domains, the number and rate of deuterium incorporation were increased in the peptides from cysteine-rich (445-467, 467-482, and 495-503) and spacer domains (621-642 and 655-654) but decreased in the peptides from metalloprotease (115-124, 217-230, and 274-281). Moreover, most peptides, except for 217-230 and 1357-1376, exhibited a pD-dependent deuterium incorporation in the full-length ADAMTS-13, but not in the truncated variant (eg, MDTCS or T5C). These results further suggest that the bimodal deuterium incorporation observed in the peptides from the full-length ADAMTS-13 is the result of potential impact from the middle to distal C-terminal domains. Surface plasmon resonance revealed the direct binding interactions between the distal and proximal domains of ADAMTS-13. Conclusion Our results provide novel insight on how intramolecular interactions may affect conformations of ADAMTS-13, thus regulating its proteolytic functions.
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Affiliation(s)
- Vikram G. Pillai
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, USA,Department of Biophysics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - X. Long Zheng
- Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, USA,Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, USA,Correspondence X. Long Zheng, MD, PhD, Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, 3901 Rainbow Boulevard, 5016 Delp, Kansas City, Kansas 66160, USA.
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23
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DeYoung V, Singh K, Kretz CA. Mechanisms of ADAMTS13 regulation. J Thromb Haemost 2022; 20:2722-2732. [PMID: 36074019 PMCID: PMC9826392 DOI: 10.1111/jth.15873] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/29/2022] [Accepted: 09/06/2022] [Indexed: 01/13/2023]
Abstract
Recombinant ADAMTS13 is currently undergoing clinical trials as a treatment for hereditary thrombotic thrombocytopenic purpura, a lethal microvascular condition resulting from ADAMTS13 deficiency. Preclinical studies have also demonstrated its efficacy in treating arterial thrombosis and inflammation without causing bleeding, suggesting that recombinant ADAMTS13 may have broad applicability as an antithrombotic agent. Despite this progress, we currently do not understand the mechanisms that regulate ADAMTS13 activity in vivo. ADAMTS13 evades canonical means of protease regulation because it is secreted as an active enzyme and has a long half-life in circulation, suggesting that it is not inhibited by natural protease inhibitors. Although shear can spatially and temporally activate von Willebrand factor to capture circulating platelets, it is also required for cleavage by ADAMTS13. Therefore, spatial and temporal regulation of ADAMTS13 activity may be required to stabilize von Willebrand factor-platelet strings at sites of vascular injury. This review outlines potential mechanisms that regulate ADAMTS13 in vivo including shear-dependency, local inactivation, and biochemical and structural regulation of substrate binding. Recently published structural data of ADAMTS13 is discussed, which may help to generate novel hypotheses for future research.
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Affiliation(s)
- Veronica DeYoung
- Department of Medicine, McMaster UniversityThrombosis and Atherosclerosis Research InstituteHamiltonOntarioCanada
| | - Kanwal Singh
- Department of Medicine, McMaster UniversityThrombosis and Atherosclerosis Research InstituteHamiltonOntarioCanada
| | - Colin A. Kretz
- Department of Medicine, McMaster UniversityThrombosis and Atherosclerosis Research InstituteHamiltonOntarioCanada
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24
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Sacco M, Tardugno M, Lancellotti S, Ferretti A, Ponziani FR, Riccardi L, Zocco MA, De Magistris A, Santopaolo F, Pompili M, De Cristofaro R. ADAMTS-13/von Willebrand factor ratio: A prognostic biomarker for portal vein thrombosis in compensated cirrhosis. A prospective observational study. Dig Liver Dis 2022; 54:1672-1680. [PMID: 35778228 DOI: 10.1016/j.dld.2022.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/13/2022] [Accepted: 06/07/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS In cirrhosis, decreased portal flow velocity, thrombophilia factors, and portal hypertension are considered risk factors for portal vein thrombosis (PVT). In cirrhosis, the transformation of the stellate cells causes a progressive decrease of ADAMTS-13, while VWF multimers secretion by endothelial cells is strongly enhanced. This imbalance leads to an accumulation of ultra-large VWF multimers that in sinusoidal circulation could favor PVT both in intra- and extra-hepatic branches, mostly in decompensated cirrhosis. This prospective study was aimed at identifying possible clinical, biochemical, and hemostatic factors predictive for non-tumoral PVT in a cohort of patients with compensated cirrhosis. METHODS Seventynine compensated cirrhosis patients were prospectively followed for 48 months, receiving a periodic Doppler-ultrasound liver examination associated with an extensive evaluation of clinical, biochemical, and hemostatic profile. RESULTS Five patients developed PVT (cumulative prevalence = 6.3%), occurring 4-36 months after enrollment. In logistic regression analysis, the ADAMTS-13/VWF:GpIbR ratio < 0.4 was the only independent variable significantly associated with PVT (OR 14.6, 95% C.I.:1.36-157.2, p = 0.027). A Cox-regression-analysis confirmed this finding (HR = 7.7, p = 0.027). CONCLUSIONS The ADAMTS-13/VWF ratio < 0.4 measured in compensated cirrhosis could be a reliable predictive biomarker for PVT development, paving the way to novel therapeutic strategies to prevent and treat PVT in this clinical setting.
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Affiliation(s)
- Monica Sacco
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica S. Cuore, Facoltà di Medicina e Chirurgia "Agostino Gemelli", Roma, Italy
| | - Maira Tardugno
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica S. Cuore, Facoltà di Medicina e Chirurgia "Agostino Gemelli", Roma, Italy
| | - Stefano Lancellotti
- Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - Antonietta Ferretti
- Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
| | - Francesca Romana Ponziani
- Dipartimento di Scienze Mediche e Chirurgiche, Hepatology Service, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica S. Cuore, Roma, Italy
| | - Laura Riccardi
- Dipartimento di Scienze Mediche e Chirurgiche, Hepatology Service, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica S. Cuore, Roma, Italy
| | - Maria Assunta Zocco
- Dipartimento di Scienze Mediche e Chirurgiche, Hepatology Service, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica S. Cuore, Roma, Italy
| | - Antonio De Magistris
- Dipartimento di Scienze Mediche e Chirurgiche, Hepatology Service, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica S. Cuore, Roma, Italy
| | - Francesco Santopaolo
- Dipartimento di Scienze Mediche e Chirurgiche, Hepatology Service, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica S. Cuore, Roma, Italy
| | - Maurizio Pompili
- Dipartimento di Scienze Mediche e Chirurgiche, Hepatology Service, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica S. Cuore, Roma, Italy
| | - Raimondo De Cristofaro
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica S. Cuore, Facoltà di Medicina e Chirurgia "Agostino Gemelli", Roma, Italy; Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy.
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25
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Zhang X, Zhu L, Zhang H, Chen S, Xiao Y. CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges. Front Immunol 2022; 13:927153. [PMID: 35757715 PMCID: PMC9226391 DOI: 10.3389/fimmu.2022.927153] [Citation(s) in RCA: 155] [Impact Index Per Article: 51.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 05/16/2022] [Indexed: 12/13/2022] Open
Abstract
Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.
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Affiliation(s)
- Xiaomin Zhang
- Department of Hematology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Institute of Clinical Medicine College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lingling Zhu
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Hui Zhang
- School of Medicine, Jishou University, Jishou, China
| | - Shanshan Chen
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Yang Xiao
- Institute of Clinical Medicine College, Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Hematology, Shenzhen Qianhai Shekou Pilot Free Trade Zone Hospital, Shenzhen, China
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26
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Graça NAG, Joly BS, Voorberg J, Vanhoorelbeke K, Béranger N, Veyradier A, Coppo P. TTP: From empiricism for an enigmatic disease to targeted molecular therapies. Br J Haematol 2022; 197:156-170. [PMID: 35146746 PMCID: PMC9304236 DOI: 10.1111/bjh.18040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/29/2021] [Accepted: 12/31/2021] [Indexed: 12/19/2022]
Abstract
The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized.
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Affiliation(s)
- Nuno A. G. Graça
- Department of Molecular Hematology, Sanquin‐Academic Medical CenterLandsteiner LaboratoryAmsterdamThe Netherlands
| | - Bérangère S. Joly
- Service d'hématologie biologique and EA3518‐ Institut universitaire d'hématologieGroupe Hospitalier Saint Louis‐Lariboisière, AP‐HP, Université Paris DiderotParisFrance
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
| | - Jan Voorberg
- Department of Molecular Hematology, Sanquin‐Academic Medical CenterLandsteiner LaboratoryAmsterdamThe Netherlands
- Department of Experimental Vascular MedicineAmsterdam UMCAmsterdamThe Netherlands
| | - Karen Vanhoorelbeke
- Laboratory for Thrombosis Research, IRF Life SciencesKU Leuven Campus Kulak KortrijkKortrijkBelgium
| | - Nicolas Béranger
- Service d'hématologie biologique and EA3518‐ Institut universitaire d'hématologieGroupe Hospitalier Saint Louis‐Lariboisière, AP‐HP, Université Paris DiderotParisFrance
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
| | - Agnès Veyradier
- Service d'hématologie biologique and EA3518‐ Institut universitaire d'hématologieGroupe Hospitalier Saint Louis‐Lariboisière, AP‐HP, Université Paris DiderotParisFrance
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
| | - Paul Coppo
- Centre de Référence des Microangiopathies ThrombotiquesHôpital Saint‐Antoine, AP‐HPParisFrance
- Service d'HématologieHôpital Saint‐Antoine, AP‐HPParisFrance
- Sorbonne UniversitéUPMC Univ ParisParisFrance
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27
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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: 21] [Impact Index Per Article: 7.0] [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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28
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Swan D, Thachil J. Management of haemostatic complications of chimaeric antigen receptor T-cell therapy. Br J Haematol 2022; 197:250-259. [PMID: 35146749 DOI: 10.1111/bjh.18045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Dawn Swan
- Department of Haematology, St James' Hospital, Dublin, Republic of Ireland
| | - Jecko Thachil
- Department of Haematology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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29
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Shi J, Ren Y, Liu S, Zhao Q, Kong F, Guo Y, Xu J, Liu S, Qiao Y, Li Y, Liu Y, Liu Y, Cheng Y. Circulating miR-3656 induces human umbilical vein endothelial cell injury by targeting eNOS and ADAMTS13: a novel biomarker for hypertension. J Hypertens 2022; 40:310-317. [PMID: 34475349 DOI: 10.1097/hjh.0000000000003010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hypertension, as one of the most common chronic diseases, is a major public health issue. Previous studies have shown that there are miRNAs differentially expressed in hypertensive patients. In addition, hypertension is closely related to endothelial dysfunction, and miRNAs have been identified as important molecular mediators for endothelial function. Therefore, it is necessary to identify specific miRNAs related to hypertension and explore their molecular mechanism in the progression of hypertension. METHODS We investigated the association of circulating levels of miR-3656 with hypertension. Furthermore, in-vitro studies were performed to investigate its possible mechanisms for hypertension in that the direct target genes of miR-3656 were confirmed using dual-luciferase reporter assay; moreover, the effects of miR-3656 on proliferation, migration, apoptosis, and microvascular rarefaction of HUVECs were investigated using MTS kit, wound-healing assay, FITC Annexin V apoptosis detection kit, and tube formation assay, correspondingly. RESULTS Circulating miR-3656 was upregulated in patients with hypertension. MiR-3656 suppressed the proliferation, migration, and angiogenesis of HUVECs, but promoted the apoptosis of HUVECs. In addition, eNOS and ADAMTS13 were direct target genes of miR-3656, and overexpression of eNOS and ADAMTS13 abolished the effect of miR-3656 on HUVECs. CONCLUSION MiR-3656 is a potential biomarker for hypertension. MiR-3656 is involved in endothelial cellular injury implicated in hypertension by targeting eNOS and ADAMTS13.
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Affiliation(s)
- Jikang Shi
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yaxuan Ren
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Sainan Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Qian Zhao
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Fei Kong
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yanbo Guo
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Jiayi Xu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Siyu Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yichun Qiao
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yong Li
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yunkai Liu
- The Cardiovascular Center, the First Hospital of Jilin University, Changchun, China
| | - Yawen Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yi Cheng
- The Cardiovascular Center, the First Hospital of Jilin University, Changchun, China
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30
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Plautz WE, Haldeman SH, Dyer MR, Sperry JL, Guyette FX, Loughran PA, Alvikas J, Hassoune A, Hoteit L, Alsaadi N, Zuckerbraun BS, Rollins-Raval MA, Raval JS, Mota RI, Neal MD. Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma. Blood Coagul Fibrinolysis 2022; 33:14-24. [PMID: 34889809 PMCID: PMC8728687 DOI: 10.1097/mbc.0000000000001089] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/30/2021] [Accepted: 09/06/2021] [Indexed: 11/25/2022]
Abstract
Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253-349) vs. 100% (87-117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1-44.7) vs. 100.0% (83.1-121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4-35.3) vs. 27.8% (24.6-30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.
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Affiliation(s)
| | | | | | - Jason L. Sperry
- Pittsburgh Trauma Research Center and the Department of Surgery
| | - Francis X. Guyette
- Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Jurgis Alvikas
- Pittsburgh Trauma Research Center and the Department of Surgery
| | - Adnan Hassoune
- Pittsburgh Trauma Research Center and the Department of Surgery
| | - Lara Hoteit
- Pittsburgh Trauma Research Center and the Department of Surgery
| | - Nijmeh Alsaadi
- Pittsburgh Trauma Research Center and the Department of Surgery
| | | | - Marian A. Rollins-Raval
- Department of Pathology, University of North Carolina –Chapel Hill, Chapel Hill, North Carolina
- Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Jay S. Raval
- Department of Pathology, University of North Carolina –Chapel Hill, Chapel Hill, North Carolina
- Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Roberto I. Mota
- Pittsburgh Trauma Research Center and the Department of Surgery
| | - Matthew D. Neal
- Pittsburgh Trauma Research Center and the Department of Surgery
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31
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Xiao X, Huang S, Chen S, Wang Y, Sun Q, Xu X, Li Y. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:367. [PMID: 34794490 PMCID: PMC8600921 DOI: 10.1186/s13046-021-02148-6] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/20/2021] [Indexed: 02/08/2023]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.
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Affiliation(s)
- Xinyi Xiao
- The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Shengkang Huang
- The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Sifei Chen
- The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People's Republic of China
| | - Yazhuo Wang
- The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People's Republic of China.,Medical College of Rehabilitation, Southern Medical University, Guangzhou, Guangdong, 510515, People's Republic of China
| | - Qihang Sun
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510623, People's Republic of China
| | - Xinjie Xu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People's Republic of China.
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, People's Republic of China. .,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong, 510005, People's Republic of China.
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32
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Laghmouchi A, Graça NAG, Voorberg J. Emerging Concepts in Immune Thrombotic Thrombocytopenic Purpura. Front Immunol 2021; 12:757192. [PMID: 34858410 PMCID: PMC8631936 DOI: 10.3389/fimmu.2021.757192] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/27/2021] [Indexed: 12/23/2022] Open
Abstract
Immune thrombotic thrombocytopenic purpura (iTTP) is an autoimmune disorder of which the etiology is not fully understood. Autoantibodies targeting ADAMTS13 in iTTP patients have extensively been studied, the immunological mechanisms leading to the breach of tolerance remain to be uncovered. This review addresses the current knowledge on genetic factors associated with the development of iTTP and the interplay between the patient's immune system and environmental factors in the induction of autoimmunity against ADAMTS13. HLA-DRB1*11 has been identified as a risk factor for iTTP in the Caucasian population. Interestingly, HLA-DRB1*08:03 was recently identified as a risk factor in the Japanese population. Combined in vitro and in silico MHC class II peptide presentation approaches suggest that an ADAMTS13-derived peptide may bind to both HLA-DRB1*11 and HLA-DRB1*08:03 through different anchor-residues. It is apparent that iTTP is associated with the presence of infectious microorganisms, viruses being the most widely associated with development of iTTP. Infections may potentially lead to loss of tolerance resulting in the shift from immune homeostasis to autoimmunity. In the model we propose in this review, infections disrupt the epithelial barriers in the gut or lung, promoting exposure of antigen presenting cells in the mucosa-associated lymphoid tissue to the microorganisms. This may result in breach of tolerance through the presentation of microorganism-derived peptides that are homologous to ADAMTS13 on risk alleles for iTTP.
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Affiliation(s)
| | | | - Jan Voorberg
- Department of Molecular Hematology, Sanquin-Academic Medical Center Landsteiner Laboratory, Amsterdam, Netherlands
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33
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Cappadona C, Paraboschi EM, Ziliotto N, Bottaro S, Rimoldi V, Gerussi A, Azimonti A, Brenna D, Brunati A, Cameroni C, Campanaro G, Carloni F, Cavadini G, Ciravegna M, Composto A, Converso G, Corbella P, D’Eugenio D, Dal Rì G, Di Giorgio SM, Grondelli MC, Guerrera L, Laffoucriere G, Lando B, Lopedote L, Maizza B, Marconi E, Mariola C, Matronola GM, Menga LM, Montorsi G, Papatolo A, Patti R, Profeta L, Rebasti V, Smidili A, Tarchi SM, Tartaglia FC, Tettamanzi G, Tinelli E, Stuani R, Bolchini C, Pattini L, Invernizzi P, Degenhardt F, Franke A, Duga S, Asselta R. MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity. J Pers Med 2021; 11:1166. [PMID: 34834519 PMCID: PMC8622845 DOI: 10.3390/jpm11111166] [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: 10/14/2021] [Revised: 11/04/2021] [Accepted: 11/06/2021] [Indexed: 12/23/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides virus intrinsic characteristics, the host genetic makeup is predicted to account for the extreme clinical heterogeneity of the disease, which is characterized, among other manifestations, by a derangement of hemostasis associated with thromboembolic events. To date, large-scale studies confirmed that genetic predisposition plays a role in COVID-19 severity, pinpointing several susceptibility genes, often characterized by immunologic functions. With these premises, we performed an association study of common variants in 32 hemostatic genes with COVID-19 severity. We investigated 49,845 single-nucleotide polymorphism in a cohort of 332 Italian severe COVID-19 patients and 1668 controls from the general population. The study was conducted engaging a class of students attending the second year of the MEDTEC school (a six-year program, held in collaboration between Humanitas University and the Politecnico of Milan, allowing students to gain an MD in Medicine and a Bachelor's Degree in Biomedical Engineering). Thanks to their willingness to participate in the fight against the pandemic, we evidenced several suggestive hits (p < 0.001), involving the PROC, MTHFR, MTR, ADAMTS13, and THBS2 genes (top signal in PROC: chr2:127192625:G:A, OR = 2.23, 95%CI = 1.50-3.34, p = 8.77 × 10-5). The top signals in PROC, MTHFR, MTR, ADAMTS13 were instrumental for the construction of a polygenic risk score, whose distribution was significantly different between cases and controls (p = 1.62 × 10-8 for difference in median levels). Finally, a meta-analysis performed using data from the Regeneron database confirmed the contribution of the MTHFR variant chr1:11753033:G:A to the predisposition to severe COVID-19 (pooled OR = 1.21, 95%CI = 1.09-1.33, p = 4.34 × 10-14 in the weighted analysis).
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Affiliation(s)
- Claudio Cappadona
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Elvezia Maria Paraboschi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Nicole Ziliotto
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Sandro Bottaro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Valeria Rimoldi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Andrea Azimonti
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Daniele Brenna
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Andrea Brunati
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Charlotte Cameroni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Giovanni Campanaro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Francesca Carloni
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Giacomo Cavadini
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Martina Ciravegna
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Antonio Composto
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Giuseppe Converso
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Pierluigi Corbella
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Davide D’Eugenio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Giovanna Dal Rì
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Sofia Maria Di Giorgio
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Maria Chiara Grondelli
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Lorenza Guerrera
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Georges Laffoucriere
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Beatrice Lando
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Leandro Lopedote
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Benedetta Maizza
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Elettra Marconi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Carlotta Mariola
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Guia Margherita Matronola
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Luca Maria Menga
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Giulia Montorsi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Antonio Papatolo
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Riccardo Patti
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Lorenzo Profeta
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Vera Rebasti
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Alice Smidili
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Sofia Maria Tarchi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Francesco Carlo Tartaglia
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Gaia Tettamanzi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Elena Tinelli
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Riccardo Stuani
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
| | - Cristiana Bolchini
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy; (C.B.); (L.P.)
| | - Linda Pattini
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, 20133 Milan, Italy; (C.B.); (L.P.)
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (P.I.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, 24105 Kiel, Germany; (F.D.); (A.F.)
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, 24105 Kiel, Germany; (F.D.); (A.F.)
- University Hospital Schleswig-Holstein (UKSH), 24105 Kiel, Germany
| | - Stefano Duga
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (C.C.); (E.M.P.); (N.Z.); (S.B.); (V.R.); (A.A.); (D.B.); (A.B.); (C.C.); (G.C.); (F.C.); (G.C.); (M.C.); (A.C.); (G.C.); (P.C.); (D.D.); (G.D.R.); (S.M.D.G.); (M.C.G.); (L.G.); (G.L.); (B.L.); (L.L.); (B.M.); (E.M.); (C.M.); (G.M.M.); (L.M.M.); (G.M.); (A.P.); (R.P.); (L.P.); (V.R.); (A.S.); (S.M.T.); (F.C.T.); (G.T.); (E.T.); (R.S.); (S.D.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
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Theofilis P, Sagris M, Antonopoulos AS, Oikonomou E, Tsioufis C, Tousoulis D. Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19. Int J Mol Sci 2021; 22:11170. [PMID: 34681830 PMCID: PMC8539848 DOI: 10.3390/ijms222011170] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/09/2021] [Accepted: 10/15/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Atherosclerotic cardiovascular diseases are characterized by a dysregulated inflammatory and thrombotic state, leading to devastating complications with increased morbidity and mortality rates. SUMMARY In this review article, we present the available evidence regarding the impact of inflammation on platelet activation in atherosclerosis. Key messages: In the context of a dysfunctional vascular endothelium, structural alterations by means of endothelial glycocalyx thinning or functional modifications through impaired NO bioavailability and increased levels of von Willebrand factor result in platelet activation. Moreover, neutrophil-derived mediators, as well as neutrophil extracellular traps formation, have been implicated in the process of platelet activation and platelet-leukocyte aggregation. The role of pro-inflammatory cytokines is also critical since their receptors are also situated in platelets while TNF-α has also been found to induce inflammatory, metabolic, and bone marrow changes. Additionally, important progress has been made towards novel concepts of the interaction between inflammation and platelet activation, such as the toll-like receptors, myeloperoxidase, and platelet factor-4. The accumulating evidence is especially important in the era of the coronavirus disease-19 pandemic, characterized by an excessive inflammatory burden leading to thrombotic complications, partially mediated by platelet activation. Lastly, recent advances in anti-inflammatory therapies point towards an anti-thrombotic effect secondary to diminished platelet activation.
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Affiliation(s)
- Panagiotis Theofilis
- Department of Cardiology, “Hippokration” General Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (A.S.A.); (E.O.); (C.T.)
| | - Marios Sagris
- Department of Cardiology, “Hippokration” General Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (A.S.A.); (E.O.); (C.T.)
| | - Alexios S. Antonopoulos
- Department of Cardiology, “Hippokration” General Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (A.S.A.); (E.O.); (C.T.)
| | - Evangelos Oikonomou
- Department of Cardiology, “Hippokration” General Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (A.S.A.); (E.O.); (C.T.)
- Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece
| | - Costas Tsioufis
- Department of Cardiology, “Hippokration” General Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (A.S.A.); (E.O.); (C.T.)
| | - Dimitris Tousoulis
- Department of Cardiology, “Hippokration” General Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece; (P.T.); (M.S.); (A.S.A.); (E.O.); (C.T.)
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Islek A, Ilhan D, Ozturk N, Guven B, Sag E. Altered von Willebrand Factor and ADAMTS13 Levels in Children With Cirrhosis and Extrahepatic Portal Hypertension. J Pediatr Hematol Oncol 2021; 43:e951-e956. [PMID: 33369998 DOI: 10.1097/mph.0000000000002038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/18/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND/AIM This study was concerned with whether vWF (von Willebrand factor) and a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) has altered in patients with cirrhosis and extrahepatic portal hypertension (EPH). We aimed to investigate changes to vWF and ADAMTS13 in children with cirrhosis and EPH. PATIENTS AND METHODS This study was conducted between January and October 2019 with both cirrhosis and EPH patients and with healthy volunteers. The von Willebrand factor antigen (vWF:Ag), von Willebrand Ristocetin cofactor (vWF:RCo), and ADAMTS13 antigen and activity were studied. RESULTS Twenty-eight children with cirrhosis, 16 children with EPH, and 20 healthy controls were included in the study. vWF:Ag and vWF:RCo levels were higher in patients with cirrhosis than in healthy controls (171.65±101.67 vs. 85.86±30.58, P<0.01 and 121.62±55.83 vs. 61.52±27.03, P<0.01, respectively). vWF:Ag and vWF:RCo levels were higher in patients with EPH than in healthy controls (133.93±80.13 vs. 85.86±30.58, P<0.01 and 103.18±58.55 vs. 61.52±27.03, P=0.02, respectively). The ADAMTS13 antigen and activity levels were lower in patients with cirrhosis than in healthy controls (0.58±0.23 vs. 0.97±0.15, P<0.01 and 49.91±22.43 vs. 86.51±22.07, P=0.02, respectively). The ADAMTS13 antigen and activity levels were lower in patients with EPH than in healthy controls (0.69±0.11 vs. 0.97±0.15, P=0.03; and 68.50±13.29 vs. 86.51±22.07, P=0.02, respectively). The increase in vWF and the decrease in ADAMTS13 were more pronounced in cirrhotic patients with autoimmune hepatitis (AIH) than in non-AIH patients. CONCLUSIONS While levels of vWF:Ag and vWF:RCo increased in children with cirrhosis and EPH, levels of the ADAMTS13 antigen and ADAMTS13 activity decreased. These alterations were more pronounced in patients with AIH-derived cirrhosis.
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Affiliation(s)
- Ali Islek
- Departments of Pediatric Gastroenterology
| | | | - Nurinnisa Ozturk
- Medical Biochemistry, Atatürk University School of Medicine, Erzurum
| | - Burcu Guven
- Department of Pediatric Gastroenterology, Karadeniz Technical University School of Medicine, Trabzon, Turkey
| | - Elif Sag
- Department of Pediatric Gastroenterology, Karadeniz Technical University School of Medicine, Trabzon, Turkey
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Dushianthan A, Abdul N, Dmochowski J, James I, Heesom L, Westwood J, Effney J, Bruty S, Saeed K, Rangarajan S, Kazmi R. Predictive Role of Haematological Determinants on Outcomes of Critically Ill COVID-19 Patients Admitted to Intensive Care Unit. Cureus 2021; 13:e16764. [PMID: 34476137 PMCID: PMC8403496 DOI: 10.7759/cureus.16764] [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] [Accepted: 07/30/2021] [Indexed: 12/11/2022] Open
Abstract
Background: The mortality of patients admitted to the intensive care unit (ICU) with COVID-19 remains significantly high. Severe COVID-19 pneumonia is characterised by refractory hypoxemia with significant shunting due to a combination of alveolar damage, vascular vasoconstriction, and occlusion due to microthrombi. Similar pathological features are seen in extra-pulmonary organs. However, the influence of thrombotic markers on the risk of mechanical ventilation (MV) and the development of acute kidney injury (AKI) is not fully defined. Methods: This was a cross-sectional evaluation of haemostatic and thrombotic markers of COVID-19 patients admitted to the ICU to determine their predictability for the development of thromboembolism and the need for non-invasive or invasive MV, development of AKI, and mortality. Results: An extended coagulation profile was obtained in 71 SARS-CoV-2 positive patients admitted to the ICU. All patients had acute severe hypoxic respiratory failure and required non-invasive or invasive MV. There were increases in peak D-dimer (3.0 mg/L), factor VIII levels (255 IU/dL) vWF antigen (471 IU/dL) with low ADAMTS13 activity (54.7 IU/dL) compared to the reference ranges. Peak D-dimer was consistently raised in patients who developed AKI and required invasive MV. ADAMTS13/vWF/platelet axis was associated with disease severity, multi-organ dysfunction, and mortality. Conclusions: Haematological abnormalities are a common feature of severe COVID-19 pneumonia. We found peak D-dimer and vWF-ADAMTS13-platelet axis are associated with increased ICU severity and outcome in severe COVID-19 patients admitted to ICU. Larger studies are needed to evaluate this more comprehensively.
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Affiliation(s)
- Ahilanandan Dushianthan
- Faculty of Medicine, University of Southampton, Southampton, GBR.,National Institute for Health Research Southampton Clinical Research Facility and National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, GBR.,General Intensive Care Unit, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Nabil Abdul
- General Intensive Care Unit, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Josh Dmochowski
- Haematology, University Hospital Southmapton, Southampton, GBR
| | - Izabela James
- Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Lesley Heesom
- General Intensive Care Unit, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Jennifer Westwood
- General Intensive Care Unit, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Judith Effney
- Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Sarah Bruty
- Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Kordo Saeed
- Microbiology Innovation and Research Unit, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Savita Rangarajan
- Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
| | - Rashid Kazmi
- Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, GBR
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Complete ADAMTS13 remission in a patient with refractory autoimmune-mediated thrombotic thrombocytopenic purpura after infliximab. Transfus Apher Sci 2021; 60:103213. [PMID: 34400095 DOI: 10.1016/j.transci.2021.103213] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/26/2021] [Accepted: 07/02/2021] [Indexed: 11/20/2022]
Abstract
Autoimmune thrombotic thrombocytopenic purpura (aTTP) is caused by autoantibodies to the von Willebrand Factor cleaving enzyme, ADAMTS13. Despite recent advances in the treatment of acute aTTP, relapse rates remain high. Guidance for the treatment of patients in clinical remission but with persistent severe ADAMTS13 deficiency who fail to respond to rituximab remains unclear. We report a case of a 29-year-old man diagnosed with aTTP at the age of 11. Over a period of 18 years, he had five clinical relapses with persistent severe ADAMTS13 deficiency (<10%) and presence of autoantibodies during clinical remissions despite immunosuppressive therapy with rituximab, bortezomib and azathioprine. While in a clinical remission, he was diagnosed with Crohn's disease and initially treated with adalimumab. When he subsequently developed antibodies to adalimumab, he was transitioned to infliximab. ADAMTS13 activity increased to 24% by 2 months of infliximab induction, and four months later the ADAMTS13 activity improved to 42%. This case demonstrates the importance of managing concurrent inflammatory disorders and suggests that TNF may play a role in autoantibody development and ADAMTS13 depletion.
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Popa M, Hecker M, Wagner AH. Inverse Regulation of Confluence-Dependent ADAMTS13 and von Willebrand Factor Expression in Human Endothelial Cells. Thromb Haemost 2021; 122:611-622. [PMID: 34352896 DOI: 10.1055/s-0041-1733800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a zinc-containing metalloprotease also known as von Willebrand factor (vWF)-cleaving protease. Low ADAMTS13 plasma levels are associated with an increased risk of arterial thrombosis, including myocardial infarction and cerebrovascular disease. The expression and regulation of this metalloprotease in human endothelial cells have not been systematically investigated. In this study, we demonstrate that ADAMTS13 expression is inhibited by proinflammatory cytokines tumor necrosis factor-α and interferon-γ as well as by CD40 ligand, which was hitherto unknown. Factors protecting against atherosclerosis such as exposure to continuous unidirectional shear stress, interleukin-10, or different HMG-CoA reductase inhibitors like, e.g., simvastatin, atorvastatin, or rosuvastatin, did not influence ADAMTS13 expression. Unidirectional periodic orbital shear stress, mimicking oscillatory flow conditions found at atherosclerosis-prone arterial bifurcations, had also no effect. In contrast, a reciprocal correlation between ADAMTS13 and vWF expression in endothelial cells depending on the differentiation state was noted. ADAMTS13 abundance significantly rose on both the mRNA and intracellular protein level and also tethered to the endothelial glycocalyx with the degree of confluency while vWF protein levels were highest in proliferating cells but significantly decreased upon reaching confluence. This finding could explain the anti-inflammatory and antithrombotic phenotype of dormant endothelial cells mediated by contact inhibition.
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Affiliation(s)
- Miruna Popa
- Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Markus Hecker
- Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Andreas H Wagner
- Division of Cardiovascular Physiology, Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
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Mobayen G, Dhutia A, Clarke C, Prendecki M, McAdoo S, Keniyopoullos R, Malik T, Laffan M, Willicombe M, McKinnon T. Severe COVID-19 is associated with endothelial activation and abnormal glycosylation of von Willebrand factor in patients undergoing hemodialysis. Res Pract Thromb Haemost 2021; 5:e12582. [PMID: 34532629 PMCID: PMC8435526 DOI: 10.1002/rth2.12582] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/19/2021] [Accepted: 07/27/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND A major clinical feature of severe coronavirus diease 2019 (COVID-19) is microvascular thrombosis linked to endothelial cell activation. Consistent with this, a number of studies have shown that patients with severe COVID-19 have highly elevated plasma levels of von Willebrand Factor (VWF) that may contribute to the prothrombotic phenotype. In the current study, we investigated the extent of endothelial activation in patients receiving hemodialysis who had either mild or severe COVID-19. METHODS Plasma VWF, ADAMTS-13, angiopoietin-2 (Ang2), and syndecan-1 levels were determined by ELISA. The sialic acid content of VWF was investigated using a modified ELISA to measure elderberry bark lectin, specific for sialic acid residues, binding to VWF. RESULTS Patients receiving hemodialysis with severe COVID-19 had significantly higher plasma levels of VWF and lower ADAMTS-13. VWF levels peaked and were sustained during the first 10 days after positive confirmation of infection. While Ang2 trended toward being higher in severely ill patients, this did not reach significance; however, severely ill patients had significantly higher soluble syndecan-1 levels, with high levels related to risk of death. Finally, higher VWF levels in severely ill patients were correlated with lower VWF sialic acid content. CONCLUSIONS Severe COVID-19 in patients undergoing hemodialysis is associated with both acute and sustained activation of the endothelium, leading to alteration of the VWF/ADAMTS-13 axis. Lower VWF sialic acid content represents altered VWF processing and further confirms the disturbance caused to the endothelium in COVID-19.
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Affiliation(s)
- Golzar Mobayen
- Department of Immunology and InflammationCentre for HaematologyCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Amrita Dhutia
- Department of Immunology and InflammationCentre for Inflammatory DiseaseCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Candice Clarke
- Department of Immunology and InflammationCentre for Inflammatory DiseaseCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Maria Prendecki
- Department of Immunology and InflammationCentre for Inflammatory DiseaseCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Stephen McAdoo
- Department of Immunology and InflammationCentre for Inflammatory DiseaseCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Renos Keniyopoullos
- Department of Immunology and InflammationCentre for HaematologyCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Talat Malik
- Department of Immunology and InflammationCentre for Inflammatory DiseaseCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Michael Laffan
- Department of Immunology and InflammationCentre for HaematologyCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Michelle Willicombe
- Department of Immunology and InflammationCentre for Inflammatory DiseaseCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
| | - Thomas McKinnon
- Department of Immunology and InflammationCentre for HaematologyCommonwealth BuildingHammersmith CampusImperial College of Science Technology and MedicineLondonUK
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Zeineddin A, Dong JF, Wu F, Terse P, Kozar RA. Role of Von Willebrand Factor after Injury: It May Do More Than We Think. Shock 2021; 55:717-722. [PMID: 33156241 PMCID: PMC10363401 DOI: 10.1097/shk.0000000000001690] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
ABSTRACT Acute traumatic coagulopathy is a complex phenomenon following injury and a main contributor to hemorrhage. It remains a leading cause of preventable death in trauma patients. This phenomenon is initiated by systemic injury to the vascular endothelium that is exacerbated by hypoperfusion, acidosis, and hypothermia and leads to systemic activation of the coagulation cascades and resultant coagulopathy. Many previous studies have focused on endotheliopathy with targeted markers such as syndecan-1, soluble thrombomodulin, and plasma adrenaline as potential culprits for initiation and propagation of this state. However, in more recent studies, hyperadhesive von Willebrand factor (VWF), which is released following endothelial injury, and its cleaving metalloprotease ADAMTS13 have emerged as significant targets of the downstream effect of endothelial breakdown and coagulation dysregulation. Elucidation of the mechanism by which the dysregulated VWF-ADAMTS13 axis leads to endothelial dysfunction and coagulopathy after trauma can help identify new targets for therapy and sites for intervention. Much of what is known mechanistically regarding VWF stems from work done in traumatic brain injury. Following localized brain injury, brain-derived extracellular vesicles are released into circulation where they induce a hypercoagulable state that rapidly turns into consumptive coagulopathy. VWF released from injured endothelial cells binds to these extracellular vesicles to enhance their activity in promoting coagulopathy and increasing endothelial permeability. However, there are numerous gaps in our knowledge of VWF following injury, providing a platform for further investigation.
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Affiliation(s)
- Ahmad Zeineddin
- Shock Trauma Center and the University of Maryland School of Medicine, Baltimore, Maryland; and
| | - Jing-Fei Dong
- Bloodworks Research Institute and Hematology Division, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Feng Wu
- Shock Trauma Center and the University of Maryland School of Medicine, Baltimore, Maryland; and
| | - Pranaya Terse
- Shock Trauma Center and the University of Maryland School of Medicine, Baltimore, Maryland; and
| | - Rosemary A. Kozar
- Shock Trauma Center and the University of Maryland School of Medicine, Baltimore, Maryland; and
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Turecek PL, Peck RC, Rangarajan S, Reilly-Stitt C, Laffan MA, Kazmi R, James I, Dushianthan A, Schrenk G, Gritsch H, Ewenstein BM, Mellgard B, Erdlenbruch W, Jain N, Binder NB, Mumford AD. Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19. Thromb Res 2021; 201:100-112. [PMID: 33662796 PMCID: PMC7890348 DOI: 10.1016/j.thromres.2021.02.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/14/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.
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Affiliation(s)
| | - Rachel C Peck
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | - Savita Rangarajan
- University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; K J Somaiya Superspecialty Hospital and Research Centre, Mumbai, India
| | | | - Michael A Laffan
- Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Rashid Kazmi
- University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Izabela James
- University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | | | - Gerald Schrenk
- Baxalta Innovations GmbH, a Takeda company, Vienna, Austria
| | | | | | | | | | - Nisha Jain
- Baxalta US Inc., a Takeda company, Cambridge, MA, USA
| | - Nikolaus B Binder
- Technoclone Herstellung von Diagnostika und Arzneimitteln GmbH, Vienna, Austria
| | - Andrew D Mumford
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.
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Gust J, Ponce R, Liles WC, Garden GA, Turtle CJ. Cytokines in CAR T Cell-Associated Neurotoxicity. Front Immunol 2020; 11:577027. [PMID: 33391257 PMCID: PMC7772425 DOI: 10.3389/fimmu.2020.577027] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.
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Affiliation(s)
- Juliane Gust
- Department of Neurology, University of Washington, Seattle, WA, United States
- Seattle Children’s Research Institute, Center for Integrative Brain Research, Seattle, WA, United States
| | | | - W. Conrad Liles
- Department of Medicine, University of Washington, Seattle, WA, United States
| | - Gwenn A. Garden
- Department of Neurology, University of North Carolina, Chapel Hill, NC, United States
| | - Cameron J. Turtle
- Department of Medicine, University of Washington, Seattle, WA, United States
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
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Translational insight into prothrombotic state and hypercoagulation in nonalcoholic fatty liver disease. Thromb Res 2020; 198:139-150. [PMID: 33340925 DOI: 10.1016/j.thromres.2020.12.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/17/2020] [Accepted: 12/07/2020] [Indexed: 02/08/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging and threatening pathological condition, ranging from fatty liver (FL) to chronic steatohepatitis (NASH), liver cirrhosis, and eventually to hepatocellular carcinoma (HCC). Recent findings suggest that patients with NAFLD have a higher risk of cardiovascular events and thromboembolism and that this risk is independent of metabolic diseases that are frequently associated with NAFLD, such as diabetes, hyperlipidaemia, and obesity. The vascular involvement of NAFLD might be considered its systemic burden, conditioning higher mortality in patients affected by the disease. These clinical findings suggested the existence of a prothrombotic state in NAFLD, which is partially unexplored and whose underlying mechanisms are to date not completely understood. Here, we review the mechanisms involved in the pathogenesis of the prothrombotic state in NAFLD across the progression from the healthy liver through the different stages of the disease. We focused on the possible role of several metabolic features of NAFLD possibly leading to hypercoagulation other than endothelial and platelet activation, such as insulin-resistance, nitric oxide production regulation, and gut microbiota homeostasis. Also, we analysed the involvement of plasminogen activator inhibitor-1 (PAI-1) and thromboinflammation taking place in NAFLD. Finally, we described factors striking a prothrombotic imbalance in NASH cirrhosis, with a particular focus on the pathogenesis of portal vein thrombosis.
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Ziliotto N, Zivadinov R, Jakimovski D, Baroni M, Bergsland N, Ramasamy DP, Weinstock-Guttman B, Ramanathan M, Marchetti G, Bernardi F. Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis. Front Neurol 2020; 11:553616. [PMID: 33178104 PMCID: PMC7593335 DOI: 10.3389/fneur.2020.553616] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 08/31/2020] [Indexed: 12/14/2022] Open
Abstract
Background: Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS). Objectives: This study aimed to evaluate the combined contribution of the hemostasis inhibitor protein C (PC) and chemokine C-C motif ligand 18 (CCL18) levels to brain atrophy in MS and to identify disease-relevant correlations among circulating levels of hemostasis inhibitors, chemokines, and adhesion molecules, particularly in CMB occurrence in MS. Methods: Plasma levels of hemostasis inhibitors (ADAMTS13, PC, and PAI1), CCL18, and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138 MS patients [85 relapsing-remitting (RR-MS) and 53 progressive (P-MS)] and 42 healthy individuals (HI) who underwent 3-T MRI exams. Association of protein levels with MRI outcomes was performed by regression analysis. Correlations among protein levels were assessed by partial correlation and Pearson's correlation. Results: In all patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including the brain parenchyma (p = 0.002), gray matter (p < 0.001), cortex (p = 0.001), deep gray matter (p = 0.001), and thalamus (p = 0.001). These associations were detectable in RR-MS but not in P-MS patients. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p = 0.03) and in the P-MS (p = 0.003). In the P-MS, higher CCL18 levels were also associated with lower volumes of the gray matter (p = 0.024), cortex (p = 0.043), deep gray matter (p = 0.029), and thalamus (p = 0.022). PC-CCL18 and CCL18-PAI1 levels were positively correlated in both MS and HI, PC–sVAP1 and PAI1–sVCAM1 only in MS, and PC–sICAM1 and PC–sNCAM only in HI. In MS patients with CMBs (n = 12), CCL18–PAI1 and PAI1–sVCAM1 levels were better correlated than those in MS patients without CMBs, and a novel ADAMTS13–sVAP1 level correlation (r = 0.78, p = 0.003) was observed. Conclusions: Differences between clinical phenotype groups in association of PC and CCL18 circulating levels with MRI outcomes might be related to different aspects of neurodegeneration. Disease-related pathway dysregulation is supported by several protein level correlation differences between MS patients and HI. The integrated analysis of plasma proteins and MRI measures provide evidence for new relationships among hemostasis, inflammation, and immunity pathways, relevant for MS and for the occurrence of CMBs.
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Affiliation(s)
- Nicole Ziliotto
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Robert Zivadinov
- Department of Neurology, Buffalo Neuroimaging Analysis Center, State University of New York, Buffalo, NY, United States.,Center for Biomedical Imaging at the Clinical Translational Science Institute, State University of New York, Buffalo, NY, United States
| | - Dejan Jakimovski
- Department of Neurology, Buffalo Neuroimaging Analysis Center, State University of New York, Buffalo, NY, United States
| | - Marcello Baroni
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Niels Bergsland
- Department of Neurology, Buffalo Neuroimaging Analysis Center, State University of New York, Buffalo, NY, United States.,Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione Don Carlo Gnocchi, Milan, Italy
| | - Deepa P Ramasamy
- Department of Neurology, Buffalo Neuroimaging Analysis Center, State University of New York, Buffalo, NY, United States
| | - Bianca Weinstock-Guttman
- Center for Biomedical Imaging at the Clinical Translational Science Institute, State University of New York, Buffalo, NY, United States
| | - Murali Ramanathan
- Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY, United States
| | - Giovanna Marchetti
- Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy
| | - Francesco Bernardi
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
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Ozawa K, Muller MA, Varlamov O, Tavori H, Packwood W, Mueller PA, Xie A, Ruggeri Z, Chung D, López JA, Lindner JR. Proteolysis of Von Willebrand Factor Influences Inflammatory Endothelial Activation and Vascular Compliance in Atherosclerosis. ACTA ACUST UNITED AC 2020; 5:1017-1028. [PMID: 33145464 PMCID: PMC7591934 DOI: 10.1016/j.jacbts.2020.08.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/26/2020] [Accepted: 08/26/2020] [Indexed: 12/15/2022]
Abstract
In murine models of atherosclerosis, excess endothelial-associated vWF results not only in platelet adhesion, but also endothelial expression of leukocyte adhesion molecules, indicating a role of platelets in endothelial activation. The events triggered by excess endothelial-associated vWF lead to accelerated plaque growth and abnormal arterial mechanical properties. The cellular and molecular events described herein can be assessed noninvasively through molecular imaging. This study used in vivo molecular imaging to characterize endotheliall activation attributable to von Willebrand factor (vWF)-mediated platelet adhesion in atherosclerosis. In atherosclerotic mice lacking the low-density lipoprotein receptor on Western diet, the additional genetic deletion of the ADAMTS13, which cleaves endothelial-associated vWF, produced greater aortic molecular imaging signal for not only vWF and platelets, but also for endothelial adhesion molecules VCAM1 and P-selectin, larger plaque size, and lower aortic distensibility. Sustained ADAMTS13 therapy reduced signal for all 4 molecular targets and plaque size. We conclude that excess endothelial-associated vWF contributes to not only platelet adhesion, but also to up-regulation of endothelial cell adhesion molecules.
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Key Words
- AD13−/−, deficient for ADAMTS13
- Apo-E−/−, deficient for apolipoprotein-E
- BP, blood pressure
- GPIbα, glycoprotein-Ibα
- LDL, low-density lipoprotein
- LDL-R, low-density lipoprotein receptor
- LDL-R−/−, deficient for low-density lipoprotein receptor
- MB, microbubble
- NFκB, nuclear factor κ-light-chain-enhancer of activated B cells
- WSD, Western-style diet
- atherosclerosis
- molecular imaging
- platelets
- vWF, von Willebrand factor
- von Willebrand factor
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Affiliation(s)
- Koya Ozawa
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
| | - Matthew A. Muller
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
| | - Oleg Varlamov
- Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon
| | - Hagai Tavori
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
| | - William Packwood
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
| | - Paul A. Mueller
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
| | - Aris Xie
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
| | - Zaverio Ruggeri
- Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California
| | | | | | - Jonathan R. Lindner
- Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
- Oregon National Primate Research Center, Oregon Health and Science University, Portland, Oregon
- Address for correspondence: Dr. Jonathan R. Lindner, Cardiovascular Division, UHN-62, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239.
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46
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South K, McCulloch L, McColl BW, Elkind MSV, Allan SM, Smith CJ. Preceding infection and risk of stroke: An old concept revived by the COVID-19 pandemic. Int J Stroke 2020; 15:722-732. [PMID: 32618498 PMCID: PMC7534199 DOI: 10.1177/1747493020943815] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 06/26/2020] [Indexed: 01/08/2023]
Abstract
Anecdotal reports and clinical observations have recently emerged suggesting a relationship between COVID-19 disease and stroke, highlighting the possibility that infected individuals may be more susceptible to cerebrovascular events. In this review we draw on emerging studies of the current pandemic and data from earlier, viral epidemics, to describe possible mechanisms by which SARS-CoV-2 may influence the prevalence of stroke, with a focus on the thromboinflammatory pathways, which may be perturbed. Some of these potential mechanisms are not novel but are, in fact, long-standing hypotheses linking stroke with preceding infection that are yet to be confirmed. The current pandemic may present a renewed opportunity to better understand the relationship between infection and stroke and possible underlying mechanisms.
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Affiliation(s)
- Kieron South
- Division of Neuroscience and Experimental Psychology, Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Laura McCulloch
- Centre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Barry W McColl
- Centre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
| | - Mitchell SV Elkind
- Vagelos College of Physicians and Surgeons and Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Stuart M Allan
- Division of Neuroscience and Experimental Psychology, Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Craig J Smith
- Division of Cardiovascular Sciences, Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- Manchester Centre for Clinical Neurosciences, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK
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Dyer MR, Plautz WE, Ragni MV, Alexander W, Haldeman S, Sperry JL, Guyette FX, Zuckerbraun BS, Rollins-Raval MA, Raval JS, Neal MD. Traumatic injury results in prolonged circulation of ultralarge von Willebrand factor and a reduction in ADAMTS13 activity. Transfusion 2020; 60:1308-1318. [PMID: 32441353 DOI: 10.1111/trf.15856] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 02/19/2020] [Accepted: 04/05/2020] [Indexed: 01/02/2023]
Abstract
BACKGROUND Increases in plasma von Willebrand Factor (VWF) levels, accompanied by decreases in the metalloprotease ADAMTS13, have been demonstrated soon after traumatic injury while downstream effects remain unclear. STUDY DESIGN AND METHODS A cohort of 37 injured trauma patients from a randomized control trial investigating the use of prehospital plasma transfusion were analyzed for activity and antigen levels of ADAMTS13 and VWF at 0 and 24 hours after admission. Relevant clinical data were abstracted from the medical records. Trauma patient plasma was analyzed via agarose gel electrophoresis to evaluate the effects of injury on VWF multimer composition compared to healthy controls. RESULTS von Willebrand factor levels were elevated at presentation (189% [110%-263%] vs. 95% [74%-120%]), persisting through 24 hours (213% [146%-257%] vs. 132% [57%-160%]), compared to healthy controls. Ultralarge VWF (UL-VWF) forms were elevated in trauma patients at both 0 and 24 hours, when compared to pooled normal plasma (10.0% [8.9%-14.3%] and 11.3% [9.1%-21.2%], respectively, vs. 0.6%). Circulating plasma ADAMTS13 activity was decreased at 0 hours (66% [47%-86%] vs. 100% [98%-100%]) and at 24 hours (72.5% [56%-87.3%] vs. 103% [103%-103%]) in trauma patients. ADAMTS13 activity independently predicted the development of coagulopathy and correlated with international normalized ratio, thromboelastography values, injury severity, and blood product transfusion. CONCLUSION Traumatic injury is associated with acute coagulopathy that is characterized by increased UL-VWF multimers and reduction in ADAMTS13, which correlates with blood loss, transfusion requirement, and injury severity. These findings suggest the potential for future trials targeting ADAMTS13 repletion to enhance clearance of VWF multimers.
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Affiliation(s)
- Mitchell R Dyer
- Pittsburgh Trauma Research Center and the Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - William E Plautz
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Margaret V Ragni
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Wyeth Alexander
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Shannon Haldeman
- Pittsburgh Trauma Research Center and the Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jason L Sperry
- Pittsburgh Trauma Research Center and the Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Francis X Guyette
- Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Brian S Zuckerbraun
- Pittsburgh Trauma Research Center and the Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Marian A Rollins-Raval
- Department of Pathology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Jay S Raval
- Department of Pathology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Matthew D Neal
- Pittsburgh Trauma Research Center and the Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Peetermans M, Meyers S, Liesenborghs L, Vanhoorelbeke K, De Meyer SF, Vandenbriele C, Lox M, Hoylaerts MF, Martinod K, Jacquemin M, Vanassche T, Verhamme P. Von Willebrand factor and ADAMTS13 impact on the outcome of Staphylococcus aureus sepsis. J Thromb Haemost 2020; 18:722-731. [PMID: 31758651 DOI: 10.1111/jth.14686] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 11/18/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND Previous clinical evidence correlates levels of von Willebrand factor (VWF) and its cleaving protease ADAMTS13 with outcome in septic patients. No previous studies addressed if VWF and ADAMTS13 affected the outcome of Staphylococcus aureus sepsis. OBJECTIVES We studied the role of VWF and ADAMTS13 in S. aureus sepsis both in patients and in mice. METHODS VWF levels and ADAMTS13 activity levels were measured in plasma samples from 89 S. aureus bacteremia patients by chemiluminescent assays and were correlated with clinical sepsis outcome parameters. In wild-type mice and mice deficient in VWF and ADAMTS13, we investigated the outcome of S. aureus sepsis and quantified bacterial clearance and organ microthrombi. RESULTS In patients with S. aureus bloodstream infections, high VWF levels and low ADAMTS13 activity levels correlated with disease severity and with parameters of inflammation and disseminated intravascular coagulation. In septic mice, VWF deficiency attenuated mortality, whereas ADAMTS13 deficiency increased mortality. Bacterial clearance was enhanced in VWF-deficient mice. The differences in mortality for the studied genotypes were associated with differential loads of organ microthrombi in both liver and kidneys. CONCLUSIONS In conclusion, this study reports the consistent relation of VWF, ADAMTS13 and their ratio to disease severity in patients and mice with S. aureus sepsis. Targeting VWF multimers and/or the relative ADAMTS13 deficiency that occurs in sepsis should be explored as a potential new therapeutic target in S. aureus endovascular infections.
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Affiliation(s)
- Marijke Peetermans
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Severien Meyers
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Laurens Liesenborghs
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Karen Vanhoorelbeke
- Laboratory for Thrombosis Research, University of Leuven campus Kulak Kortrijk, Kortrijk, Belgium
| | - Simon F De Meyer
- Laboratory for Thrombosis Research, University of Leuven campus Kulak Kortrijk, Kortrijk, Belgium
| | - Christophe Vandenbriele
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Marleen Lox
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Marc F Hoylaerts
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Kimberly Martinod
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Marc Jacquemin
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Thomas Vanassche
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
| | - Peter Verhamme
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
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Lu K, Liu L, Xu X, Zhao F, Deng J, Tang X, Wang X, Zhao BQ, Zhang X, Zhao Y. ADAMTS13 ameliorates inflammatory responses in experimental autoimmune encephalomyelitis. J Neuroinflammation 2020; 17:67. [PMID: 32075652 PMCID: PMC7029584 DOI: 10.1186/s12974-020-1713-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/13/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) plays a vital role in preventing microvascular thrombosis and inflammation. Reduced ADAMTS13 levels in plasma have been detected in multiple sclerosis (MS) patients. In the present study, we have determined the role of ADAMTS13 in the disease progression of MS using a mouse model of experimental autoimmune encephalomyelitis (EAE). METHODS Female C57BL/6 mice were immunized with MOG35-55 peptide and then treated with ADAMTS13 or vehicle in preventive and therapeutic settings. Mice were analyzed for clinical deficit, white matter demyelination and inflammatory cell infiltration. To explore the underlying mechanism, VWF expression and blood-spinal cord barriers (BSCB) were determined. RESULTS Plasma ADAMTS13 activity was suppressed in EAE mice. ADAMTS13-treated EAE mice exhibited an ameliorated disease course, reduced demyelination, and decreased T lymphocyte, neutrophil and monocyte infiltration into the spinal cord. Consistently, ADAMTS13 treatment reduced VWF levels and inhibited BSCB breakdown in the spinal cords of EAE mice. However, leukocytes in the blood and spleen of EAE mice remained unaffected by ADAMTS13 administration. CONCLUSION Our results demonstrate that ADAMTS13 treatment ameliorates inflammatory responses, demyelination and disease course in EAE mice. Therefore, our study suggests that ADAMTS13 may represent a potential therapeutic strategy for MS patients.
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Affiliation(s)
- Kaili Lu
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China
| | - Lan Liu
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China
| | - Xiaofeng Xu
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China
| | - Fei Zhao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China
| | - Jiangshan Deng
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China
| | - Xin Tang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China
| | - Xiuzhe Wang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China
| | - Bing-Qiao Zhao
- Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China
| | - Xiaojie Zhang
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China.
| | - Yuwu Zhao
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Xuhui District, Shanghai, China.
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50
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Platelet function defects in patients with Gaucher disease on long term ERT- implications for evaluation at bleeding challenges. Blood Cells Mol Dis 2020; 80:102371. [DOI: 10.1016/j.bcmd.2019.102371] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 09/22/2019] [Indexed: 11/24/2022]
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