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Bünger V, Hunsicker O, Krannich A, Balzer F, Spies CD, Kuebler WM, Weber-Carstens S, Menk M, Graw JA. HAPTOGLOBIN DEPLETION DURING THE FIRST 7 DAYS OF VENO-VENOUS EXTRACORPOREAL MEMBRANE OXYGENATION THERAPY IS ASSOCIATED WITH INCREASED MORTALITY AND ADVERSE OUTCOMES IN PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME. Shock 2024; 61:828-835. [PMID: 38661177 DOI: 10.1097/shk.0000000000002352] [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: 04/26/2024]
Abstract
ABSTRACT Background: Hemolysis is a frequent complication in patients with sepsis, ARDS, or extracorporeal membrane oxygenation (ECMO). Haptoglobin (Hp) can scavenge released cell-free hemoglobin (CFH). Hemolysis and low plasma concentrations of Hp may be independently associated with mortality in critically ill patients. Methods: This study used a retrospective analysis of 435 patients with ARDS and veno-venous ECMO therapy, admitted to a tertiary ARDS referral center (01/2007-12/2018). Hp depletion was defined as decrease in plasma Hp concentration <0.39 g/L within the first week after ECMO initiation. Patients with Hp depletion were compared to patients without Hp depletion. The primary endpoint was 28-day mortality. Secondary endpoints included organ dysfunction-free, renal replacement therapy-free, vasopressor-free, and ECMO-free composites. Results: Patients with Hp depletion (n = 269) had a significantly higher mortality 28 days after ECMO initiation compared to patients without Hp depletion (43.5% [95% CI 37.52-49.66] vs. 25.3% [19.03-32.74], P < 0.001). Furthermore, patients with Hp depletion had fewer organ dysfunction-free days (subdistribution hazard ratio [SHR] 0.35 [95% CI 0.25-0.50], P < 0.001), lower chances for successful weaning from renal replacement therapy (SHR 0.50 [0.32-0.79], P < 0.001), vasopressor therapy (SHR 0.39 [0.28-0.54], P < 0.001), and ECMO therapy (SHR 0.41 [0.30-0.57], P < 0.001) within 28 days after ECMO initiation. Patients with initial Hp <0.66 g/L had higher risks for Hp depletion than patients with initial Hp ≥0.66 g/L. Conclusion: Patients with Hp depletion within the first week of ECMO therapy might benefit from close monitoring of hemolysis with early detection and elimination of the underlying cause. They might be potential candidates for future Hp supplementation therapy to prevent overload of the CFH-scavenger system.
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Affiliation(s)
| | | | | | - Felix Balzer
- Institute of Medical Informatics, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | | | - Wolfgang M Kuebler
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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2
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Hugelshofer M, Buzzi RM, Schaer CA, Richter H, Akeret K, Anagnostakou V, Mahmoudi L, Vaccani R, Vallelian F, Deuel JW, Kronen PW, Kulcsar Z, Regli L, Baek JH, Pires IS, Palmer AF, Dennler M, Humar R, Buehler PW, Kircher PR, Keller E, Schaer DJ. Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm. J Clin Invest 2020; 129:5219-5235. [PMID: 31454333 DOI: 10.1172/jci130630] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/20/2019] [Indexed: 12/13/2022] Open
Abstract
Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.
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Affiliation(s)
- Michael Hugelshofer
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Raphael M Buzzi
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland
| | - Christian A Schaer
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland
| | - Henning Richter
- Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Kevin Akeret
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Vania Anagnostakou
- Department of Neuroradiology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Leila Mahmoudi
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.,Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Raphael Vaccani
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland
| | - Florence Vallelian
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland
| | - Jeremy W Deuel
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland
| | - Peter W Kronen
- Veterinary Anaesthesia Services - International, Winterthur, Switzerland.,Center for Applied Biotechnology and Molecular Medicine (CABMM), University of Zurich, Zurich, Switzerland
| | - Zsolt Kulcsar
- Department of Neuroradiology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Luca Regli
- Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
| | - Jin Hyen Baek
- Center of Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Ivan S Pires
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, USA
| | - Andre F Palmer
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, USA
| | - Matthias Dennler
- Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Rok Humar
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland
| | - Paul W Buehler
- Center of Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Patrick R Kircher
- Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Emanuela Keller
- Neurointensive Care Unit, University Hospital of Zurich, Zurich, Switzerland
| | - Dominik J Schaer
- Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland
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3
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Early Intervention in Ischemic Tissue with Oxygen Nanocarriers Enables Successful Implementation of Restorative Cell Therapies. Cell Mol Bioeng 2020; 13:435-446. [PMID: 33184576 DOI: 10.1007/s12195-020-00621-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 05/20/2020] [Indexed: 01/01/2023] Open
Abstract
Background Tissue ischemia contributes to necrosis and infection. While angiogenic cell therapies have emerged as a promising strategy against ischemia, current approaches to cell therapies face multiple hurdles. Recent advances in nuclear reprogramming could potentially overcome some of these limitations. However, under severely ischemic conditions necrosis could outpace reprogramming-based repair. As such, adjunctive measures are required to maintain a minimum level of tissue viability/activity for optimal response to restorative interventions. Methods Here we explored the combined use of polymerized hemoglobin (PolyHb)-based oxygen nanocarriers with Tissue Nano-Transfection (TNT)-driven restoration to develop tissue preservation/repair strategies that could potentially be used as a first line of care. Random-pattern cutaneous flaps were created in a mouse model of ischemic injury. PolyHbs with high and low oxygen affinity were synthesized and injected into the tissue flap at various timepoints of ischemic injury. The degree of tissue preservation was evaluated in terms of perfusion, oxygenation, and resulting necrosis. TNT was then used to deploy reprogramming-based vasculogenic cell therapies to the flaps via nanochannels. Reprogramming/repair outcomes were evaluated in terms of vascularity and necrosis. Results Flaps treated with PolyHbs exhibited a gradual decrease in necrosis as a function of time-to-intervention, with low oxygen affinity PolyHb showing the best outcomes. TNT-based intervention of the flap in combination with PolyHb successfully curtailed advanced necrosis compared to flaps treated with only PolyHb or TNT alone. Conclusions These results indicate that PolyHb and TNT technologies could potentially be synergistically deployed and used as early intervention measures to combat severe tissue ischemia.
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4
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Munoz CJ, Pires IS, Baek JH, Buehler PW, Palmer AF, Cabrales P. Apohemoglobin-haptoglobin complex attenuates the pathobiology of circulating acellular hemoglobin and heme. Am J Physiol Heart Circ Physiol 2020; 318:H1296-H1307. [PMID: 32302494 DOI: 10.1152/ajpheart.00136.2020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Haptoglobin (Hp) is the plasma protein that binds and clears cell-free hemoglobin (Hb), whereas apohemoglobin (apoHb, i.e., Hb devoid of heme) can bind heme. Therefore, the apoHb-Hp protein complex should facilitate holoHb-apoHb αβ-dimer exchange and apoHb-heme intercalation. Thus, we hypothesized that apoHb-Hp could facilitate both Hb and heme clearance, which, if not alleviated, could have severe microcirculatory consequences. In this study, we characterized apoHb-Hp and Hb/heme ligand interactions and assessed their in vivo consequences. Hb exchange and heme binding with the apoHb-Hp complex was studied with transfer assays using size-exclusion high-performance liquid chromatography coupled with UV-visible spectrophotometry. Exchange/transfer experiments were conducted in guinea pigs dosed with Hb or heme-albumin followed by a challenge with equimolar amounts of apoHb-Hp. Finally, systemic and microcirculatory parameters were studied in hamsters instrumented with a dorsal window chamber via intravital microscopy. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. Dosing with the apoHb-Hp complex reversed Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, reduced microvascular blood flow, and diminished functional capillary density. Therefore, this study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure.NEW & NOTEWORTHY This study highlights the apoHb-Hp complex as a novel therapeutic strategy to attenuate the adverse systemic and microvascular responses to intravascular Hb and heme exposure. In vitro and in vivo Hb exchange and heme transfer experiments demonstrated proof-of-concept Hb/heme ligand transfer to apoHb-Hp. The apoHb-Hp complex reverses Hb- and heme-induced systemic hypertension and microvascular vasoconstriction, preserves microvascular blood flow, and functional capillary density. In summary, the unique properties of the apoHb-Hp complex prevent adverse systemic and microvascular responses to Hb and heme-albumin exposure and introduce a novel therapeutic approach to facilitate simultaneous removal of extracellular Hb and heme.
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Affiliation(s)
- Carlos J Munoz
- Department of Bioengineering, University of California San Diego, La Jolla, California
| | - Ivan S Pires
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio
| | - Jin Hyen Baek
- Division of Blood Components and Devices, Office of Blood Research and Review, Laboratory of Biochemistry and Vascular Biology, Food and Drug Administration, Silver Spring, Maryland
| | - Paul W Buehler
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.,The Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Andre F Palmer
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio
| | - Pedro Cabrales
- Department of Bioengineering, University of California San Diego, La Jolla, California
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5
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Buehler PW, Humar R, Schaer DJ. Haptoglobin Therapeutics and Compartmentalization of Cell-Free Hemoglobin Toxicity. Trends Mol Med 2020; 26:683-697. [PMID: 32589936 DOI: 10.1016/j.molmed.2020.02.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/17/2020] [Accepted: 02/18/2020] [Indexed: 02/06/2023]
Abstract
Hemolysis and accumulation of cell-free hemoglobin (Hb) in the circulation or in confined tissue compartments such as the subarachnoid space is an important driver of disease. Haptoglobin is the Hb binding and clearance protein in human plasma and an efficient antagonist of Hb toxicity resulting from physiological red blood cell turnover. However, endogenous concentrations of haptoglobin are insufficient to provide protection against Hb-driven disease processes in conditions such as sickle cell anemia, sepsis, transfusion reactions, medical-device associated hemolysis, or after a subarachnoid hemorrhage. As a result, there is increasing interest in developing haptoglobin therapeutics to target 'toxic' cell-free Hb exposures. Here, we discuss key concepts of Hb toxicity and provide a perspective on the use of haptoglobin as a therapeutic protein.
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Affiliation(s)
- Paul W Buehler
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA; Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Rok Humar
- Division of Internal Medicine, University Hospital, Zurich, Switzerland
| | - Dominik J Schaer
- Division of Internal Medicine, University Hospital, Zurich, Switzerland.
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6
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Malaria in Pregnancy and Adverse Birth Outcomes: New Mechanisms and Therapeutic Opportunities. Trends Parasitol 2019; 36:127-137. [PMID: 31864896 DOI: 10.1016/j.pt.2019.12.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 12/28/2022]
Abstract
Malaria infection during pregnancy is associated with adverse birth outcomes but underlying mechanisms are poorly understood. Here, we discuss the impact of malaria in pregnancy on three pathways that are important regulators of healthy pregnancy outcomes: L-arginine-nitric oxide biogenesis, complement activation, and the heme axis. These pathways are not mutually exclusive, and they collectively create a proinflammatory, antiangiogenic milieu at the maternal-fetal interface that interferes with placental function and development. We hypothesize that targeting these host-response pathways would mitigate the burden of adverse birth outcomes attributable to malaria in pregnancy.
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7
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Kerchberger VE, Bastarache JA, Shaver CM, Nagata H, McNeil JB, Landstreet SR, Putz ND, Yu WK, Jesse J, Wickersham NE, Sidorova TN, Janz DR, Parikh CR, Siew ED, Ware LB. Haptoglobin-2 variant increases susceptibility to acute respiratory distress syndrome during sepsis. JCI Insight 2019; 4:131206. [PMID: 31573976 DOI: 10.1172/jci.insight.131206] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 09/20/2019] [Indexed: 01/15/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is an inflammatory lung disorder that frequently complicates critical illness and commonly occurs in sepsis. Although numerous clinical and environmental risk factors exist, not all patients with risk factors develop ARDS, raising the possibility of genetic underpinnings for ARDS susceptibility. We have previously reported that circulating cell-free hemoglobin (CFH) is elevated during sepsis, and higher levels predict worse outcomes. Excess CFH is rapidly scavenged by haptoglobin (Hp). A common HP genetic variant, HP2, is unique to humans and is common in many populations worldwide. HP2 haptoglobin has reduced ability to inhibit CFH-mediated inflammation and oxidative stress compared with the alternative HP1. We hypothesized that HP2 increases ARDS susceptibility during sepsis when plasma CFH levels are elevated. In a murine model of sepsis with elevated CFH, transgenic mice homozygous for Hp2 had increased lung inflammation, pulmonary vascular permeability, lung apoptosis, and mortality compared with wild-type mice. We then tested the clinical relevance of our findings in 496 septic critically ill adults, finding that HP2 increased ARDS susceptibility after controlling for clinical risk factors and plasma CFH. These observations identify HP2 as a potentially novel genetic ARDS risk factor during sepsis and may have important implications in the study and treatment of ARDS.
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Affiliation(s)
- V Eric Kerchberger
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.,Department of Biomedical Informatics
| | - Julie A Bastarache
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.,Department of Cell and Developmental Biology, and.,Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ciara M Shaver
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine
| | - Hiromasa Nagata
- Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan
| | - J Brennan McNeil
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine
| | - Stuart R Landstreet
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine
| | - Nathan D Putz
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine
| | - Wen-Kuang Yu
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.,Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Jordan Jesse
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine
| | - Nancy E Wickersham
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine
| | - Tatiana N Sidorova
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine
| | - David R Janz
- Section of Pulmonary and Critical Care Medicine, Louisiana State University School of Medicine, New Orleans, Louisiana, USA
| | - Chirag R Parikh
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Edward D Siew
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lorraine B Ware
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.,Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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8
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Lu DY, Lin CP, Wu CH, Cheng TM, Pan JP. Plasma haptoglobin level can augment NT-proBNP to predict poor outcome in patients with severe acute decompensated heart failure. J Investig Med 2018; 67:20-27. [PMID: 30287475 DOI: 10.1136/jim-2018-000710] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2018] [Indexed: 12/31/2022]
Abstract
To evaluate the use of plasma haptoglobin (Hp) levels and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in predicting survival in patients with severe acute decompensated heart failure (AHF). Management of AHF is challenging. Identifying markers associated with patient prognosis in this disease is clinically important. In this prospective observational study, plasma Hp and NT-proBNP levels were measured. Receiver operating characteristic (ROC) curves were used to identify cut-offs of Hp and NT-proBNP with the greatest specificity and sensitivity for predicting overall survival and cardiovascular-related survival. The cut-off values were tested in patients with AHF (n=41). The cut-off value with the greatest specificity and sensitivity with respect to overall survival and for cardiovascular-related survival for Hp was 177. 1 ng/mL for both outcomes and for NT-proBNP was 34 246.0 pg/mL and 11 848.5 ng/mL, respectively. Using these cut-off values, this study found that patients with lower baseline Hp levels (<177. 1 ng/mL) or higher baseline NT-proBNP (≥34 246 pg/mL) were more likely to have shorter overall survival. Similarly, patients with <177. 1 ng/mL of Hp and ≥11 848.5 pg/mL of NT-proBNP had the highest risk of death related to cardiovascular disease. Our findings indicate that Hp and NT-proBNP using specific cut-off values for AHF can be used to determine risk of survival in these patients.
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Affiliation(s)
- Dai-Yin Lu
- Divisionof Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.,Schoolof Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Chih-Pei Lin
- Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.,Section of Central Laboratory, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Cheng-Hsueh Wu
- Schoolof Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.,Department of Critical Care, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Tsai-Mu Cheng
- Graduate Institute of Translational Medicine, College of Medicine and Technology Taipei Medical University, Taipei, Taiwan, ROC
| | - Ju-Pin Pan
- Divisionof Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.,Schoolof Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
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9
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Remy KE, Cortés-Puch I, Solomon SB, Sun J, Pockros BM, Feng J, Lertora JJ, Hantgan RR, Liu X, Perlegas A, Warren HS, Gladwin MT, Kim-Shapiro DB, Klein HG, Natanson C. Haptoglobin improves shock, lung injury, and survival in canine pneumonia. JCI Insight 2018; 3:123013. [PMID: 30232287 PMCID: PMC6237235 DOI: 10.1172/jci.insight.123013] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 08/09/2018] [Indexed: 11/17/2022] Open
Abstract
During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our antibiotic-treated canine model of S. aureus pneumonia that simulates the cardiovascular abnormalities of human septic shock. In this 96-hour model, resuscitative treatments, mechanical ventilation, sedation, and continuous care are translatable to management in human intensive care units. We found, in this S. aureus pneumonia model inducing septic shock, that commercial human haptoglobin concentrate infusions over 48-hours bind canine CFH, increase CFH clearance, and lower circulating iron. Over the 96-hour study, this treatment was associated with an improved metabolic profile (pH, lactate), less lung injury, reversal of shock, and increased survival. Haptoglobin binding compartmentalized CFH to the intravascular space. This observation, in combination with increasing CFHs clearance, reduced available iron as a potential source of bacterial nutrition while decreasing the ability for CFH and iron to cause extravascular oxidative tissue injury. In contrast, haptoglobin therapy had no measurable antiinflammatory effect on elevations in proinflammatory C-reactive protein and cytokine levels. Haptoglobin therapy enhances normal host defense mechanisms in contrast to previously studied antiinflammatory sepsis therapies, making it a biologically plausible novel approach to treat septic shock.
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Affiliation(s)
- Kenneth E. Remy
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA.,Department of Pediatrics, Division of Critical Care, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Irene Cortés-Puch
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Steven B. Solomon
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Junfeng Sun
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Benjamin M. Pockros
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Jing Feng
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Juan J. Lertora
- Clinical Pharmacology Program, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Roy R. Hantgan
- Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
| | - Xiaohua Liu
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Andreas Perlegas
- Department of Physics, Wake Forest University, Winston-Salem, North Carolina, USA
| | - H. Shaw Warren
- Infectious Disease Unit, Massachusetts General Hospital, and Shriners Hospital for Crippled Children, Boston, Massachusetts, USA
| | - Mark T. Gladwin
- Department of Medicine, The University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Harvey G. Klein
- Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Charles Natanson
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, Maryland, USA
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10
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Phenotype-specific recombinant haptoglobin polymers co-expressed with C1r-like protein as optimized hemoglobin-binding therapeutics. BMC Biotechnol 2018; 18:15. [PMID: 29544494 PMCID: PMC5856381 DOI: 10.1186/s12896-018-0424-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 03/07/2018] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Preclinical studies have evaluated haptoglobin (Hp) polymers from pooled human plasma as a therapeutic protein to attenuate toxic effects of cell-free hemoglobin (Hb). Proof of concept studies have demonstrated efficacy of Hp in hemolysis associated with transfusion and sickle cell anemia. However, phenotype-specific Hp products might be desirable to exploit phenotype specific activities of Hp 1-1 versus Hp 2-2, offering opportunities for recombinant therapeutics. Prohaptoglobin (proHp) is the primary translation product of the Hp mRNA. ProHp is proteolytically cleaved by complement C1r subcomponent-like protein (C1r-LP) in the endoplasmic reticulum. Two main allelic Hp variants, HP1 and HP2 exist. The larger HP2 is considered to be the ancestor variant of all human Hp alleles and is characterized by an α2-chain, which contains an extra cysteine residue that pairs with additional α-chains generating multimers with molecular weights of 200-900 kDa. The two human HP1 alleles (HP1F and HP1S) differ by a two-amino-acid substitution polymorphism within the α-chain and are derived from HP2 by recurring exon deletions. RESULTS In the present study, we describe a process for the production of recombinant phenotype specific Hp polymers in mammalian FS293F cells. This approach demonstrates that efficient expression of mature and fully functional protein products requires co-expression of active C1r-LP. The functional characterization of our proteins, which included monomer/polymer distribution, binding affinities as well as NO-sparing and antioxidant functions, demonstrated that C1r-LP-processed recombinant Hp demonstrates equal protective functions as plasma derived Hp in vitro as well as in animal studies. CONCLUSIONS We present a recombinant production process for fully functional phenotype-specific Hp therapeutics. The proposed process could accelerate the development of Hb scavengers to treat patients with cell-free Hb associated disease states, such as sickle cell disease and other hemolytic conditions.
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11
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Hunt R, Yalamanoglu A, Tumlin J, Schiller T, Baek JH, Wu A, Fogo AB, Yang H, Wong E, Miller P, Buehler PW, Kimchi-Sarfaty C. A mechanistic investigation of thrombotic microangiopathy associated with IV abuse of Opana ER. Blood 2017; 129:896-905. [PMID: 27864296 PMCID: PMC5314814 DOI: 10.1182/blood-2016-08-736579] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/07/2016] [Indexed: 12/17/2022] Open
Abstract
Since 2012, a number of case reports have described the occurrence of thrombotic microangiopathy (TMA) following IV abuse of extended-release oxymorphone hydrochloride (Opana ER), an oral opioid for long-term treatment of chronic pain. Here, we present unique clinical features of 3 patients and investigate IV exposure to the tablet's inert ingredients as a possible causal mechanism. Guinea pigs were used as an animal model to understand the hematopathologic and nephrotoxic potential of the inert ingredient mixture (termed here as PEO+) which primarily contains high-molecular-weight polyethylene oxide (HMW PEO). Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury were found in a group of 3 patients following recent injection of adulterated extended-release oxymorphone tablets. Varying degrees of cardiac involvement and retinal ischemia occurred, with TMA evident on kidney biopsy. A TMA-like state also developed in guinea pigs IV administered PEO+. Acute tubular and glomerular renal injury was accompanied by nonheme iron deposition and hypoxia-inducible factor-1α upregulation in the renal cortex. Similar outcomes were observed following dosing with HMW PEO alone. IV exposure to the inert ingredients in reformulated extended-release oxymorphone can elicit TMA. Although prescription opioid abuse shows geographic variation, all physicians should be highly inquisitive of IV drug abuse when presented with cases of TMA.
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Affiliation(s)
- Ryan Hunt
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and
| | - Ayla Yalamanoglu
- Division of Blood Components and Devices, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
| | - James Tumlin
- Department of Internal Medicine, University of Tennessee College of Medicine at Chattanooga, Chattanooga, TN
| | - Tal Schiller
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and
| | - Jin Hyen Baek
- Division of Blood Components and Devices, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
| | - Andrew Wu
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Haichun Yang
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Edward Wong
- Department of Pediatrics and
- Department of Pathology, George Washington School of Medicine and Health Sciences, Washington, DC
- Department of Coagulation, Quest Diagnostics/Nichols Institute, Chantilly, VA; and
| | - Peter Miller
- Section on Hematology and Oncology, Department of Internal Medicine
- Section on Pulmonary, Critical Care, Allergy and Immunology, and
- Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC
| | - Paul W Buehler
- Division of Blood Components and Devices, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
| | - Chava Kimchi-Sarfaty
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and
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Bozhkov AI, Klimova OM, Nikitchenko YV, Kurguzova NI, Linkevych OS, M. Lebid K, Protsenko OS, Remneva NA, Al-Bahadly AMM, Al-Begai MAY. Ontogenetic Approach to the Study of Mechanisms of Copper-Induced Liver Fibrosis. ACTA ACUST UNITED AC 2017. [DOI: 10.4236/aar.2017.63005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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13
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Mitsunaga F, Umezawa M, Takeda K, Nakamura S. Maternal administration of nanomaterials elicits hemoglobin upregulation in the neonatal brain of non-human primates. J Toxicol Sci 2016; 41:265-71. [DOI: 10.2131/jts.41.265] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Fusako Mitsunaga
- Biomedical Institute, NPO Primate Agora
- The Center for Environmental Health Science for the Next Generation, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science
- Primate Research Institute, Kyoto University
| | - Masakazu Umezawa
- The Center for Environmental Health Science for the Next Generation, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science
| | - Ken Takeda
- The Center for Environmental Health Science for the Next Generation, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science
- Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science
| | - Shin Nakamura
- Biomedical Institute, NPO Primate Agora
- The Center for Environmental Health Science for the Next Generation, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science
- Primate Research Institute, Kyoto University
- Intelligence and Technology Lab Inc
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14
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Wegiel B, Hauser CJ, Otterbein LE. Heme as a danger molecule in pathogen recognition. Free Radic Biol Med 2015; 89:651-61. [PMID: 26456060 DOI: 10.1016/j.freeradbiomed.2015.08.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 08/08/2015] [Indexed: 01/13/2023]
Abstract
Appropriate control of redox mechanisms are critical for and effective innate immune response, which employs multiple cell types, receptors and molecules that recognize danger signals when they reach the host. Recognition of pathogen-associated pattern molecules (PAMPs) is a fundamental host survival mechanism for efficient elimination of invading pathogens and resolution of the infection and inflammation. In addition to PAMPs, eukaryotic cells contain a plethora of intracellular molecules that are normally secured within the confines of the plasma membrane, but if liberated and encountered in the extracellular milieu can provoke rapid cell activation. These are known as Alarmins or Danger-Associated Molecular Patterns (DAMPs) and can be released actively by cells or passively as a result of sterile cellular injury after trauma, ischemia, or toxin-induced cell rupture. Both PAMPs and DAMPs are recognized by a series of cognate receptors that increase the generation of free radicals and activate specific signaling pathways that result in regulation of a variety of stress response, redox sensitive genes. Multiple mediators released, as cells die include, but are not limited to ATP, hydrogen peroxide, heme, formyl peptides, DNA or mitochondria provide the second signal to amplify immune responses. In this review, we will focus on how sterile and infective stimuli activate the stress response gene heme oxygenase-1 (Hmox1, HO-1), a master gene critical to an appropriate host response that is now recognized as one with enormous therapeutic potential. HO-1 gene expression is regulated in large part by redox-sensitive proteins including but not limited to nrf2. Both PAMPs and DAMPs increase the activation of nrf2 and HO-1. Heme is a powerful pro-oxidant and as such should be qualified as a DAMP. With its degradation by HO-1a molecule of carbon monoxide (CO) is generated that in turn serves as a bioactive signaling molecule. PAMPs such as bacterial endotoxin activate HO-1, and the CO that is generated diffuses into the extracellular milieu where it interacts with bacteria, altering their behavior to increase production of ATP, which then functions as a second signal danger molecule. This two-hit cycle scenario results in efficient and effective activation of host leukocytes to attack and clear bacteria in part via enhanced reactive oxygen species generation. We discuss this intimate communication that occurs between host and bacteria and how these molecules serve as critical regulators of the acute inflammatory response, the overall redox status of the cell, and survival of the host.
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Affiliation(s)
- Barbara Wegiel
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Carl J Hauser
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Leo E Otterbein
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
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Abstract
PURPOSE OF REVIEW This article will analyze and evaluate the current evidence regarding the use of older, longer-stored red blood cells (RBCs) for transfusion in pediatric patients and will examine some of the postulated mechanisms of injury related to prolonged refrigerated storage of RBCs and studies reporting clinical outcomes. RECENT FINDINGS Three randomized controlled trials and seven observational studies have been conducted entirely in pediatric patients. The outcomes, mortality and morbidity in critically ill patients and children undergoing cardiac surgery, and necrotizing enterocolitis in premature infants, have been inconsistent. However, many of these studies have been confounded by study design, mixed patient populations, red cell preparation, and other factors. SUMMARY Further exploration into the possible deleterious effects of older, longer-stored RBC transfusions on mortality and morbidity in different pediatric populations is merited. Understanding the potential mechanisms of injury should help explain the clinical findings.
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Chmiela M, Gajewski A, Rudnicka K. Helicobacter pylori vs coronary heart disease - searching for connections. World J Cardiol 2015; 7:187-203. [PMID: 25914788 PMCID: PMC4404374 DOI: 10.4330/wjc.v7.i4.187] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 01/16/2015] [Accepted: 02/09/2015] [Indexed: 02/07/2023] Open
Abstract
In this review, we discussed the findings and concepts underlying the potential role of Helicobacter pylori (H. pylori) infections in the initiation, development or persistence of atherosclerosis and coronary heart disease (CHD). This Gram-negative bacterium was described by Marshall and Warren in 1984. The majority of infected subjects carries and transmits H. pylori with no symptoms; however, in some individuals these bacteria may cause peptic ulcers, and even gastric cancers. The widespread prevalence of H. pylori infections and the fact that frequently they remain asymptomatic may suggest that, similarly to intestinal microflora, H. pylori may deliver antigens that stimulate not only local, but also systemic inflammatory response. Recently, possible association between H. pylori infection and extragastric disorders has been suggested. Knowledge on the etiology of atherosclerosis together with current findings in the area of H. pylori infections constitute the background for the newly proposed hypothesis that those two processes may be related. Many research studies confirm the indirect association between the prevalence of H. pylori and the occurrence of CHD. According to majority of findings the involvement of H. pylori in this process is based on the chronic inflammation which might facilitate the CHD-related pathologies. It needs to be elucidated, if the infection initiates or just accelerates the formation of atheromatous plaque.
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Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW. Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development. Front Physiol 2014; 5:415. [PMID: 25389409 PMCID: PMC4211382 DOI: 10.3389/fphys.2014.00415] [Citation(s) in RCA: 207] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Accepted: 10/08/2014] [Indexed: 12/13/2022] Open
Abstract
Hemolysis, which occurs in many disease states, can trigger a diverse pathophysiologic cascade that is related to the specific biochemical activities of free Hb and its porphyrin component heme. Normal erythropoiesis and concomitant removal of senescent red blood cells (RBC) from the circulation occurs at rates of approximately 2 × 106 RBCs/second. Within this physiologic range of RBC turnover, a small fraction of hemoglobin (Hb) is released into plasma as free extracellular Hb. In humans, there is an efficient multicomponent system of Hb sequestration, oxidative neutralization and clearance. Haptoglobin (Hp) is the primary Hb-binding protein in human plasma, which attenuates the adverse biochemical and physiologic effects of extracellular Hb. The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD163. Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization. When Hb is released from RBCs within the physiologic range of Hp, the potential deleterious effects of Hb are prevented. However, during hyper-hemolytic conditions or with chronic hemolysis, Hp is depleted and Hb readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric Hb. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein able to bind heme with high affinity. Hx sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion. In the present review we discuss the components of physiologic Hb/heme detoxification and their potential therapeutic application in a wide range of hemolytic conditions.
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Affiliation(s)
- Dominik J Schaer
- Division of Internal Medicine, University of Zurich Zurich, Switzerland
| | - Francesca Vinchi
- Department of Molecular Biotechnology and Health Sciences, University of Torino Torino, Italy
| | - Giada Ingoglia
- Department of Molecular Biotechnology and Health Sciences, University of Torino Torino, Italy
| | - Emanuela Tolosano
- Department of Molecular Biotechnology and Health Sciences, University of Torino Torino, Italy
| | - Paul W Buehler
- Division of Hematology, Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration Bethesda, MD, USA
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