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1
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Özer Ö, Doğan L, Baysal Z, Basir H, Çıftçı AT, Eröz P, Güçlü ES. Evaluation of peripheral blood inflammatory biomarkers in sickle cell disease with and without retinopathy. Graefes Arch Clin Exp Ophthalmol 2024; 262:3787-3796. [PMID: 38976013 PMCID: PMC11608169 DOI: 10.1007/s00417-024-06569-9] [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: 05/22/2024] [Revised: 06/18/2024] [Accepted: 06/24/2024] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND The aim of this study was to evaluate the clinical significance of blood-cell associated inflammation markers in patients with sickle cell disease (SCD) and sickle cell retinopathy (SCR). METHODS Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), systemic immune inflammation index (SIII), systemic inflammation response index (SIRI), systemic inflammation modulation index (SIMI) and aggregate systemic inflammation index (AISI) were calculated. This study included 45 healthy controls (Group 1) and 100 SCD (Group 2). Patients in Group 2 were then divided into two groups: without SCR (Group 3) and with SCR (Group 4), and patients with SCR (Group 4) were further divided into two groups: non-proliferative sickle cell retinopathy (NPSCR) (Group 5) and proliferative sickle cell retinopathy (PSCR) (Group 6). RESULTS The mean values for NLR, PLR, SIII, SIRI, AISI, and SIMI were significantly higher in Group 2 compared to Group 1 (p = 0.011 for NLR, p = 0.004 for SIII, and p < 0.001 for others). Furthermore, AISI and SIMI parameters demonstrated statistically significant discriminatory power to distinguish Group 5 from Group 6 (p = 0.0016 and p = 0.0006, respectively). CONCLUSION Given the critical role of inflammatory mechanisms in the pathogenesis of SCD and its related complications, the assessment of blood-cell-associated inflammatory markers may present a pragmatic and advantageous approach to the clinical oversight and therapeutic intervention of SCD.
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Affiliation(s)
- Ömer Özer
- Department of Ophthalmology, Niğde Ömer Halisdemir University, Niğde, 51240, Turkey.
| | - Levent Doğan
- Department of Ophthalmology, Niğde Ömer Halisdemir University, Niğde, 51240, Turkey
| | - Zeki Baysal
- Department of Ophthalmology, Niğde Ömer Halisdemir University, Niğde, 51240, Turkey
| | - Hakan Basir
- Clinic of Internal Medicine, Gülnar State Hospital, Mersin, Turkey
| | - Ali Türker Çıftçı
- Department of Biostatistics and Medical Informatics, Niğde Ömer Halisdemir University, Niğde, Turkey
| | - Pınar Eröz
- Clinic of Ophthalmology, Tarsus State Hospital, Mersin, Turkey
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2
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Argueta DA, Tran H, Goel Y, Nguyen A, Nguyen J, Kiven SB, Chen C, Abdulla F, Vercellotti GM, Belcher JD, Gupta K. Mast cell extracellular trap formation underlies vascular and neural injury and hyperalgesia in sickle cell disease. Life Sci Alliance 2024; 7:e202402788. [PMID: 39242155 PMCID: PMC11381676 DOI: 10.26508/lsa.202402788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/09/2024] Open
Abstract
Sickle cell disease (SCD) is the most common inherited monogenetic disorder. Chronic and acute pain are hallmark features of SCD involving neural and vascular injury and inflammation. Mast cells reside in the vicinity of nerve fibers and vasculature, but how they influence these structures remains unknown. We therefore examined the mechanism of mast cell activation in a sickle microenvironment replete with cell-free heme and inflammation. Mast cells exposed to this environment showed an explosion of nuclear contents with the release of citrullinated histones, suggestive of mast cell extracellular trap (MCET) release. MCETs interacted directly with the vasculature and nerve fibers, a cause of vascular and neural injury in sickle cell mice. MCET formation was dependent upon peptidylarginine deiminase 4 (PAD4). Inhibition of PAD4 ameliorated vasoocclusion, chronic and acute hyperalgesia, and inflammation in sickle mice. PAD4 activation may also underlie neutrophil trap formation in SCD, thus providing a novel target to treat the sequelae of vascular and neural injury in SCD.
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Affiliation(s)
- Donovan A Argueta
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Huy Tran
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - Yugal Goel
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Aithanh Nguyen
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - Julia Nguyen
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - Stacy B Kiven
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - Chunsheng Chen
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - Fuad Abdulla
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - Gregory M Vercellotti
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - John D Belcher
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
| | - Kalpna Gupta
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA
- Division of Hematology, Oncology, and Transplantation, School of Medicine, University of Minnesota, Twin Cities, Minneapolis, MN, USA
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3
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Gingell L, Hrinczenko B. Characterizing the Immature Immunophenotype of Sickle Cell Disease Monocytes. Cureus 2024; 16:e60703. [PMID: 38899253 PMCID: PMC11186669 DOI: 10.7759/cureus.60703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Sickle cell disease (SCD) is marked by episodic vaso-occlusive crisis (VOC). Recurrent VOC creates a pro-inflammatory state that induces phenotypic alterations in innate immune cells. Monocytes are of particular interest to VOC pathophysiology because they are especially malleable to inflammatory signaling. Indeed, inflammatory disease states such as chronic obstructive pulmonary disease (COPD), obesity and atherosclerosis are known to influence monocyte development and alter monocyte subpopulations. In this study, we describe SCD monocyte subsets by performing immunophenotypic flow cytometric, enzymatic, and morphologic analysis on peripheral blood. Herein, we add to the growing body of evidence suggesting aberrant monocyte populations underpin VOC pathophysiology. We found that SCD monocytes possess an immature phenotype as demonstrated by 1) decreased CD4 positivity (p < .01), 2) low α-naphthyl butyrate esterase (ANBE) expression, and 3) naïve morphologic features. We additionally found an increase in CD14+CD16-CD4- monocytes (p < .01), a subset associated with the impaired immune response of post-trauma patients. Interestingly, we also found a large proportion of CD14+CD4-HLA-DR- monocytes which, under normal circumstances, are exclusively found in neonates (p < .01). Finally, we report an increase in nonclassical monocytes (CD14dimCD16+), a subset recently shown to have a critical role in prevention and recovery from VOC.
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Affiliation(s)
- Luke Gingell
- Medical School, Michigan State University, Grand Rapids, USA
| | - Borys Hrinczenko
- Hematology/Oncology, Michigan State University, East Lansing, USA
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4
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Plasma microparticles of sickle patients during crisis or taking hydroxyurea modify endothelium inflammatory properties. Blood 2021; 136:247-256. [PMID: 32285120 DOI: 10.1182/blood.2020004853] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/05/2020] [Indexed: 12/29/2022] Open
Abstract
Microparticles (MPs) are submicron extracellular vesicles exposing phosphatidylserine (PS), detected at high concentration in the circulation of sickle cell anemia (SS) patients. Several groups studied the biological effects of MPs generated ex vivo. Here, we analyzed for the first time the impact of circulating MPs on endothelial cells (ECs) from 60 sickle cell disease (SCD) patients. MPs were collected from SCD patients and compared with MPs isolated from healthy individuals (AA). Other plasma MPs were purified from SS patients before and 2 years after the onset of hydroxyurea (HU) treatment or during a vaso-occlusive crisis and at steady-state. Compared with AA MPs, SS MPs increased EC ICAM-1 messenger RNA and protein levels, as well as neutrophil adhesion. We showed that ICAM-1 overexpression was primarily caused by MPs derived from erythrocytes, rather than from platelets, and that it was abolished by MP PS capping using annexin V. MPs from SS patients treated with HU were less efficient to induce a proinflammatory phenotype in ECs compared with MPs collected before therapy. In contrast, MPs released during crisis increased ICAM-1 and neutrophil adhesion levels, in a PS-dependent manner, compared with MPs collected at steady-state. Furthermore, neutrophil adhesion was abolished by a blocking anti-ICAM-1 antibody. Our study provides evidence that MPs play a key role in SCD pathophysiology by triggering a proinflammatory phenotype of ECs. We also uncover a new mode of action for HU and identify potential therapeutics: annexin V and anti-ICAM-1 antibodies.
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5
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Sickle cell disease clinical phenotypes in Nigeria: A preliminary analysis of the Sickle Pan Africa Research Consortium Nigeria database. Blood Cells Mol Dis 2020; 84:102438. [PMID: 32504882 DOI: 10.1016/j.bcmd.2020.102438] [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: 02/25/2020] [Revised: 04/07/2020] [Accepted: 04/07/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND/OBJECTIVE Sickle cell disease (SCD) is a monogenic disease with multiple phenotypic expressions. Previous studies describing SCD clinical phenotypes in Nigeria were localized, with limited data, hence the need to understand how SCD varies across Nigeria. METHOD The Sickle Pan African Research Consortium (SPARCO) with a hub in Tanzania and collaborative sites in Tanzania, Ghana and Nigeria, is establishing a single patient-consented electronic database with a target of 13,000 SCD patients. In collaboration with the Sickle Cell Support Society of Nigeria, 20 hospitals, with paediatric and adult SCD clinics, are participating in patient recruitment. Demographic and clinical information, collected with uniform case report forms, were entered into Excel spreadsheets and uploaded into Research Electronic Data Capture software by trained data clerks and frequency tables generated. RESULT Data were available on 3622 patients enrolled in the database, comprising 1889 (52.9%) females and 1434 (39.6%) children ≤15 years. The frequencies of Hb SS, Hb SC and Hb Sβ thalassemia in this data set were 97.5%, 2.5% and 0% respectively. Sixty percent, 23.8%, 5.9%, 4.8% and 2.5% have had bone pain crisis, dactylitis, acute chest syndrome, priapism and stroke respectively. The most frequent chronic complications were: leg ulcers (6.5%), avascular necrosis of bone (6.0%), renal (6.3%) and pulmonary hypertension (1.1%). Only 13.2% had been hospitalized while 67.5% had received blood transfusion. CONCLUSION These data on the spectrum of clinical phenotypes of SCD are useful for planning, improving the management of SCD across Nigeria and provide a foundation for genomic research on SCD.
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6
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Valdez JM, Datta YH, Higgins JM, Wood DK. A microfluidic platform for simultaneous quantification of oxygen-dependent viscosity and shear thinning in sickle cell blood. APL Bioeng 2019; 3:046102. [PMID: 31803859 PMCID: PMC6881198 DOI: 10.1063/1.5118212] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/01/2019] [Indexed: 01/13/2023] Open
Abstract
The pathology of sickle cell disease begins with the polymerization of intracellular hemoglobin under low oxygen tension, which leads to increased blood effective viscosity and vaso-occlusion. However, it has remained unclear how single-cell changes propagate up to the scale of bulk blood effective viscosity. Here, we use a custom microfluidic system to investigate how the increase in the stiffness of individual cells leads to an increase in the shear stress required for the same fluid strain in a suspension of softer cells. We characterize both the shear-rate dependence and the oxygen-tension dependence of the effective viscosity of sickle cell blood, and we assess the effect of the addition of increasing fractions of normal cells whose material properties are independent of oxygen tension, a scenario relevant to the treatment of sickle patients with blood transfusion. For untransfused sickle cell blood, we find an overall increase in effective viscosity at all oxygen tensions and shear rates along with an attenuation in the degree of shear-thinning achieved at the lowest oxygen tensions. We also find that in some cases, even a small fraction of transfused blood cells restores the shape of the shear-thinning relationship, though not the overall baseline effective viscosity. These results suggest that untransfused sickle cell blood will show the most extreme relative rheologic impairment in regions of high shear and that introducing even small fractions of normal blood cells may help retain some shear-thinning capability though without addressing a baseline relative increase in effective viscosity independent of shear.
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Affiliation(s)
- José M Valdez
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Yvonne H Datta
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - John M Higgins
- Center for Systems Biology and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA and Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - David K Wood
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA
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7
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Teixeira RS, Arriaga MB, Terse-Ramos R, Ferreira TA, Machado VR, Rissatto-Lago MR, Silveira-Mattos PS, Boa-Sorte N, Ladeia AMT, Andrade BB. Higher values of triglycerides:HDL-cholesterol ratio hallmark disease severity in children and adolescents with sickle cell anemia. ACTA ACUST UNITED AC 2019; 52:e8833. [PMID: 31618296 PMCID: PMC6799940 DOI: 10.1590/1414-431x20198833] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/26/2019] [Indexed: 01/01/2023]
Abstract
Dyslipidemia has been described in sickle cell anemia (SCA) but its association with increased disease severity is unknown. Here, we examined 55 children and adolescents with SCA as well as 41 healthy controls to test the association between the lipid profiles in peripheral blood and markers of hemolysis, inflammation, endothelial function, and SCA-related clinical outcomes. SCA patients exhibited lower levels of total cholesterol (P<0.001), low-density lipoprotein cholesterol (LDL-c) (P<0.001), and high-density lipoprotein cholesterol (HDL-c) (P<0.001), while displaying higher triglyceride (TG) levels and TG/HDL-c ratio values (P<0.001). TG/HDL-c values were positively correlated with lactate dehydrogenase (P=0.047), leukocyte count (P=0.006), and blood flow velocity in the right (P=0.02) and left (P=0.05) cerebral artery, while being negatively correlated with hemoglobin levels (P<0.04). Acute chest syndrome (ACS) and vaso-occlusive events (VOE) were more frequent in SCA patients exhibiting higher TG/HDL-c values (odds ratio: 3.77, P=0.027). Multivariate logistic regression analysis confirmed independent associations between elevated TG/HDL-c values and SCA. Thus, children and adolescents with SCA exhibited a lipid profile associated with hemolysis and inflammatory parameters, with increased risk of ACS and VOE. TG/HDL-c is a potential biomarker of severity of disease.
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Affiliation(s)
- R S Teixeira
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil.,Departamento de Pediatria, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - M B Arriaga
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brasil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, BA, Brasil
| | - R Terse-Ramos
- Departamento de Pediatria, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - T A Ferreira
- Departamento de Pediatria, Faculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brasil
| | - V R Machado
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil
| | - M R Rissatto-Lago
- Departamento de Ciências da Vida, Universidade Estadual da Bahia, Salvador, BA, Brasil
| | - P S Silveira-Mattos
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brasil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, BA, Brasil
| | - N Boa-Sorte
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil.,Departamento de Ciências da Vida, Universidade Estadual da Bahia, Salvador, BA, Brasil
| | | | - B B Andrade
- Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil.,Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brasil.,Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Fundação José Silveira, Salvador, BA, Brasil.,Universidade Salvador, Laureate International Universities, Salvador, BA, Brasil
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8
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Lu X, Galarneau MM, Higgins JM, Wood DK. A microfluidic platform to study the effects of vascular architecture and oxygen gradients on sickle blood flow. Microcirculation 2018; 24. [PMID: 28129479 DOI: 10.1111/micc.12357] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 01/23/2017] [Indexed: 01/22/2023]
Abstract
Our goal was to develop a model of the microvasculature that would allow us to quantify changes in the rheology of sickle blood as it traverses the varying vessel sizes and oxygen tensions in the microcirculation. We designed and implemented a microfluidic model of the microcirculation that comprises a branching microvascular network and physiologic oxygen gradients. We used computational modeling to determine the parameters necessary to generate stable, linear gradients in our devices. Sickle blood from six unique patients was perfused through the microvascular network and subjected to varying oxygen gradients while we observed and quantified blood flow. We found that all sickle blood samples fully occluded the microvascular network when deoxygenated, and we observed that sickle blood could cause vaso-occlusions under physiologic oxygen gradients during the microvascular transit time. The number of occlusions observed under five unique oxygen gradients varied among the patient samples, but we generally observed that the number of occlusions decreased with increasing inlet oxygen tension. The model system we have developed is a valuable tool to address fundamental questions about where in the circulation sickle-cell vaso-occlusions are most likely to occur and to test new therapies.
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Affiliation(s)
- Xinran Lu
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Michelle M Galarneau
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN, USA
| | - John M Higgins
- Department of Pathology, Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.,Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - David K Wood
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA
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9
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Increased Vasoocclusive Crises in "O" Blood Group Sickle Cell Disease Patients: Association with Underlying Thrombospondin Levels. Mediterr J Hematol Infect Dis 2017; 9:e2017028. [PMID: 28512557 PMCID: PMC5419181 DOI: 10.4084/mjhid.2017.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 03/23/2017] [Indexed: 11/08/2022] Open
Abstract
Objectives To explore the incidence of vaso-occlusive crisis (VOC) in Blood Group “O” sickle cell disease (SCD) patients, and correlate it with the blood group and thrombospondin (TSP) levels. Methods In 89 consecutive SCD patients, blood samples were obtained for von Williebrand factor (vWF:Ag) antigen, collagen binding activity (CBA), ristocetin binding activity (RCo), blood group typing, C-reactive protein (CRP), high performance liquid chromatography (HPLC), Serum TSP 1 and TSP 2 levels, complete blood counts (CBC), lactic dehydrogenase (LDH) levels, liver function (LFT) and renal function tests (RFT) during VOC episodes and in steady state conditions. Results In steady state SCD patients (n=72), “O” blood group patients (n=37) showed a significantly higher median serum TSP 1 and TSP 2 levels as compared to non-O blood group patients [n=35] [p <0.05, Mann-Whitney test]; with an inverse relation between vWF:Ag, Factor VIII:C and TSP levels. Furthermore, the serum TSP 1 and TSP 2 levels were significantly higher in patients presenting with acute VOC [n=17], as well as in those with repeated VOC’s (group 1, n=16), especially amongst blood group “O” patients [p, <0.05, Mann-Whitney test]. Conclusions The study demonstrates an inverse relation between TSP and vWF levels, in blood group “O” SCD patients, with an upregulation of the TSP levels. Expectedly, during active VOC crisis, the TSP 1 and TSP 2 levels were significantly elevated.
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10
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Hoppe C, Jacob E, Styles L, Kuypers F, Larkin S, Vichinsky E. Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial. Br J Haematol 2017; 177:620-629. [PMID: 28369718 PMCID: PMC5435522 DOI: 10.1111/bjh.14580] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 12/06/2016] [Indexed: 12/21/2022]
Abstract
Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.
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Affiliation(s)
- Carolyn Hoppe
- Department of Hematology-Oncology, UCSF Benioff Children’s Hospital Oakland, Oakland, CA
| | - Eufemia Jacob
- School of Nursing, University of California Los Angeles, CA
| | | | - Frans Kuypers
- Children’s Hospital Oakland Research Institute, Oakland, CA
| | - Sandra Larkin
- Children’s Hospital Oakland Research Institute, Oakland, CA
| | - Elliott Vichinsky
- Department of Hematology-Oncology, UCSF Benioff Children’s Hospital Oakland, Oakland, CA
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11
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Mathew R, Huang J, Wu JM, Fallon JT, Gewitz MH. Hematological disorders and pulmonary hypertension. World J Cardiol 2016; 8:703-718. [PMID: 28070238 PMCID: PMC5183970 DOI: 10.4330/wjc.v8.i12.703] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 09/07/2016] [Accepted: 10/09/2016] [Indexed: 02/06/2023] Open
Abstract
Pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate, is known to occur in a number of unrelated systemic diseases. Several hematological disorders such as sickle cell disease, thalassemia and myeloproliferative diseases develop PH which worsens the prognosis. Associated oxidant injury and vascular inflammation cause endothelial damage and dysfunction. Pulmonary vascular endothelial damage/dysfunction is an early event in PH resulting in the loss of vascular reactivity, activation of proliferative and antiapoptotic pathways leading to vascular remodeling, elevated pulmonary artery pressure, right ventricular hypertrophy and premature death. Hemolysis observed in hematological disorders leads to free hemoglobin which rapidly scavenges nitric oxide (NO), limiting its bioavailability, and leading to endothelial dysfunction. In addition, hemolysis releases arginase into the circulation which converts L-arginine to ornithine, thus bypassing NO production. Furthermore, treatments for hematological disorders such as immunosuppressive therapy, splenectomy, bone marrow transplantation, and radiation have been shown to contribute to the development of PH. Recent studies have shown deregulated iron homeostasis in patients with cardiopulmonary diseases including pulmonary arterial hypertension (PAH). Several studies have reported low iron levels in patients with idiopathic PAH, and iron deficiency is an important risk factor. This article reviews PH associated with hematological disorders and its mechanism; and iron homeostasis and its relevance to PH.
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12
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Wun T. The Role of Inflammation and Leukocytes in the Pathogenesis of Sickle Cell Disease. Hematology 2016; 5:403-12. [DOI: 10.1080/10245332.2000.11746536] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Affiliation(s)
- Ted Wun
- Division of Hematology and Oncology, Department of Internal Medicine, UC Davis School of Medicine and the VA Northern California Health Care System, Sacramento, CA, USA
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13
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Adly AA, Ismail EA, Andrawes NG, Mahmoud MM, Eladawy R. Soluble Fas/FasL ratio as a marker of vasculopathy in children and adolescents with sickle cell disease. Cytokine 2016; 79:52-8. [PMID: 26765484 DOI: 10.1016/j.cyto.2015.12.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 12/12/2015] [Accepted: 12/29/2015] [Indexed: 01/19/2023]
Abstract
OBJECTIVES Sickle cell disease (SCD) is characterized by chronic inflammation due to ischemic tissue damage, accentuated during acute complications. Fas and its ligand (FasL) are members of tumor necrosis factor receptor superfamily and a major pathway for induction of apoptosis. Fas/FasL interactions may be related to augmentation of inflammatory response. We assessed the levels of sFas and sFasL in 35 children and adolescents with SCD compared with 35 healthy controls in relation to hemolysis, iron overload, sickle vasculopathy including kidney disease. METHODS SCD patients, in steady state and asymptomatic for pulmonary hypertension, were studied stressing on hydroxyurea therapy, serum ferritin, urinary albumin creatinine ratio (UACR), high-sensitivity C-reactive protein (hs-CRP) and sFas/sFasL levels. RESULTS sFas/sFasL ratio was significantly higher in patients compared with controls. sFas/sFasL ratio was elevated in patients with pulmonary hypertension, nephropathy and those who had history of frequent sickling crisis or serum ferritin ⩾2500. SCD patients treated with hydroxyurea had lower sFas/sFasL ratio than untreated patients. sFas/sFasL ratio was positively correlated to transfusion index, white blood cells, hs-CRP, serum ferritin and UACR. The cutoff value of sFas/sFasL at 8.75pg/mL could differentiate SCD patients with and without nephropathy while the cutoff value at 22pg/mL could differentiate SCD patients with and without pulmonary hypertension risk with high sensitivity and specificity. CONCLUSION sFas/sFasL ratio may be considered as a marker for vascular dysfunction in SCD patients and is related to inflammation, iron overload and albuminuria level. Thus, it may be a reliable method to assess renal impairment in SCD.
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Affiliation(s)
- Amira A Adly
- Department of Pediatric, Faculty of Medicine, Ain Shams University, Egypt
| | - Eman A Ismail
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Egypt.
| | - Nevine G Andrawes
- Department of Pediatric, Faculty of Medicine, Ain Shams University, Egypt
| | - Mai M Mahmoud
- Department of Pediatric, Faculty of Medicine, Ain Shams University, Egypt
| | - Rasha Eladawy
- Department of Pediatric, Faculty of Medicine, Ain Shams University, Egypt
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A Survey of the Pain Management of Acute Painful Crisis among Patients with Sickle Cell Disease at Two Centres in Jamaica. W INDIAN MED J 2014; 63:252-7. [PMID: 25314283 DOI: 10.7727/wimj.2013.333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 02/12/2014] [Indexed: 11/18/2022]
Abstract
OBJECTIVES The aim of this survey was to establish the pain management approaches to acute painful crisis (APC) in sickle cell patients at two healthcare facilities and to compare with available guidelines. METHODS A multi-centre observational survey of the management of APC in sickle cell patients was conducted. Data were collected at the Sickle Cell Unit (SCU), Tropical Medicine Research Institute (TMRI) and Accident and Emergency Department (A&E), University Hospital of the West Indies. RESULTS One hundred episodes of uncomplicated APC involving 81 patients managed at the SCU clinic and 64 episodes at the A&E in a total of 28 patients were included in the data set. Drugs used at the SCU included oral morphine, codeine and paracetamol and intramuscular diclofenac. At the A&E, parenteral morphine and pethidine were most commonly used. At the SCU, the mean time to initiation of analgesics was 38 minutes (IQR 25 to 50 minutes); at the A&E, this was 111 minutes (IQR 50 to 150 minutes). At the SCU, the mean duration of stay (DOS) was 2.9 hours (IQR 1.9 to 3.8 hours) with 94% of the patients being discharged home. At the A&E, the mean DOS was 13.0 hours (IQR 8.3 to 16.9 hours) with 93% of the patients being discharged home. The A&E patient group contained multiple high frequency presenters. Documentation of pain severity scores was inconsistent. CONCLUSION The findings of the survey indicate that the management of APC at the two centres is substantially different. Further study is required to investigate patient satisfaction, centre preference and analgesic therapy efficacy.
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15
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Dinan D, Epelman M, Guimaraes CV, Donnelly LF, Nagasubramanian R, Chauvin NA. The current state of imaging pediatric hemoglobinopathies. Semin Ultrasound CT MR 2014; 34:493-515. [PMID: 24332202 DOI: 10.1053/j.sult.2013.05.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The hemoglobinopathies are a group of genetic disorders with a broad spectrum of clinical manifestations and radiologic findings. The imaging of pediatric hemoglobinopathies, which is influenced by concomitant hemosiderosis and the sequela of chelation therapy, has evolved over the years along with ever-improving technology. This article reviews and illustrates the most common radiographic and cross-sectional imaging findings of the 2 best known and clinically relevant hemoglobinopathies in pediatric patients, sickle cell disease and β-thalassemia.
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Affiliation(s)
- David Dinan
- Department of Medical Imaging, Nemours Children's Hospital, Orlando, FL
| | - Monica Epelman
- Department of Medical Imaging, Nemours Children's Hospital, Orlando, FL.
| | | | | | | | - Nancy A Chauvin
- Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, PA
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16
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Hoppe CC. Inflammatory Mediators of Endothelial Injury in Sickle Cell Disease. Hematol Oncol Clin North Am 2014; 28:265-86. [DOI: 10.1016/j.hoc.2013.11.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Abstract
P-selectin on endothelial cell surfaces is central to impaired microvascular blood flow in sickle cell disease (SCD). Restoration of blood flow is expected to provide therapeutic benefit for SCD patients, whatever the mechanism of action of the treatment. Long-term oral administration of a P-selectin-blocking agent potentially improves blood flow and averts acute painful vaso-occlusive crises in patients with SCD. This review focuses on the pathophysiology of the impairment of microvascular blood flow in SCD with an emphasis on the role of P-selectin and summarizes the status of development of antiselectin therapies as a means of improving microvascular flow.
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18
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Venkataraman A, Adams RJ. Neurologic complications of sickle cell disease. HANDBOOK OF CLINICAL NEUROLOGY 2014; 120:1015-25. [PMID: 24365368 DOI: 10.1016/b978-0-7020-4087-0.00068-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Sickle cell disease (SCD) is a group of genetic blood disorders that vary in severity, but the most severe forms, primarily homozygous sickle cell anemia, are associated with neurologic complications. Over the last 90 years it has become established that some patients will develop severe arterial disease of the intracranial brain arteries and suffer brain infarction. Smaller infarctions and brain atrophy may also be seen and over time there appear to be negative cognitive effects in some patients, with or without abnormal brain imaging. Focal mononeuropathies and pneumococcal meningitis are also more common in these patients. Brain infarction in children can largely be prevented screening children beginning at age 2 years and instituting regular blood transfusion when the Doppler indicates high stroke risk (>200cm/sec). Iron overload and the uncertain duration of transfusion are disadvantages but overall this approach, tested in a randomized clinical trial, reduced first stroke by over 90%. Secondary stroke prevention has not been subjected to a randomized controlled trial except for one recently stopped comparison of regular transfusions compared to hydroxuyrea (results favored transfusion). The usual stroke prevention agents (such as aspirin or warfarin) have not been rigorously tested. Magnetic resonance imaging and positron emission tomography give evidence of subtle and sometimes overt brain injury due to stroke in many adults, but a preventive strategy for adults with SCD has not been developed. Bone marrow transplantation is the only cure, but some non-neurologic symptoms can be controlled in adults with hydroxuyrea.
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Affiliation(s)
- Akila Venkataraman
- Pediatric Neurology and Epilepsy Division, Lutheran Medical Center, Brooklyn, NY, USA
| | - Robert J Adams
- South Carolina Stroke Center of Economic Excellence and Medical University of South Carolina Stroke Center, Charleston, SC, USA.
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19
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Caracas MDS, Jales SP, Neto LHJ, da Silva Castro JC, Suganuma LM, Fonseca GHH, Gualandro SFM, de Siqueira JTT. Temporomandibular joint arthritis in sickle cell disease: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 115:e31-5. [DOI: 10.1016/j.oooo.2012.05.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 05/12/2012] [Accepted: 05/18/2012] [Indexed: 11/25/2022]
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20
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Kaul DK, Fabry ME, Suzuka SM, Zhang X. Antisickling fetal hemoglobin reduces hypoxia-inducible factor-1α expression in normoxic sickle mice: microvascular implications. Am J Physiol Heart Circ Physiol 2012; 304:H42-50. [PMID: 23125209 DOI: 10.1152/ajpheart.00296.2012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Chronic inflammation is a salient feature of sickle cell disease (SCD) and transgenic-knockout sickle (BERK) mice. Inflammation is implicated in the activation of hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions. We hypothesize that, in SCD, inflammation coupled with nitric oxide (NO) depletion will induce expression of HIF-1α, a transcription factor with wide-ranging effects including activation of genes for vasoactive molecules. To this end, we have examined the expression of HIF-1α in normoxic BERK mice expressing exclusively human α- and β(S)- globins, and evaluated the effect of fetal hemoglobin (HbF) in BERK mice (i.e., <1.0%, 20%, and 40% HbF). HbF exerts antisickling and anti-inflammatory effects. Here, we show that HIF-1α is expressed in BERK mice under normoxic conditions, accompanied by increased expression of its vasoactive biomarkers such as VEGF, heme oxygenase-1 (HO-1), and serum ET-1 levels. In BERK mice expressing HbF, HIF-1α expression decreases concomitantly with increasing HbF, commensurately with increased NO bioavailability, and shows a strong inverse correlation with plasma NO metabolites (NOx) levels. Reduced HIF-1α expression is associated with decreased HO-1, VEGF, and ET-1. Notably, arteriolar dilation, enhanced volumetric blood flow, and low blood pressure in normoxic BERK mice all show a trend toward normalization with the introduction of HbF. Also, arginine treatment reduced HIF-1α, as well as VEGF expression in normoxic BERK mice, supporting a role of NO bioavailability in HIF-1α activation. Thus HIF-1α expression in normoxic sickle mice is likely a consequence of chronic inflammation, and HbF exerts an ameliorating effect by decreasing sickling, increasing NO bioavailability, and reducing inflammation.
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Affiliation(s)
- Dhananjay K Kaul
- Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
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21
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22
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23
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Gavins FNE, Russell J, Senchenkova EL, De Almeida Paula L, Damazo AS, Esmon CT, Kirchhofer D, Hebbel RP, Granger DN. Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S. Blood 2011; 117:4125-33. [PMID: 21304105 PMCID: PMC3087535 DOI: 10.1182/blood-2010-08-301366] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Accepted: 01/06/2011] [Indexed: 12/17/2022] Open
Abstract
The microvasculature assumes an inflammatory and procoagulant state in a variety of different diseases, including sickle cell disease (SCD), which may contribute to the high incidence of ischemic stroke in these patients. This study provides evidence for accelerated thrombus formation in arterioles and venules in the cerebral vasculature of mice that express hemoglobin-S (β(s) mice). Enhanced microvascular thrombosis in β(s) mice was blunted by immunologic or genetic interventions that target tissue factor, endothelial protein C receptor, activated protein C, or thrombin. Platelets from β(s) mice also exhibited enhanced aggregation velocity after stimulation with thrombin but not ADP. Neutropenia also protected against the enhanced thrombosis response in β(s) mice. These results indicate that the cerebral microvasculature is rendered vulnerable to thrombus formation in β(s) mice via a neutrophil-dependent mechanism that is associated with an increased formation of and enhanced platelet sensitivity to thrombin.
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MESH Headings
- Anemia, Sickle Cell/complications
- Anemia, Sickle Cell/genetics
- Anemia, Sickle Cell/metabolism
- Animals
- Blood Platelets/metabolism
- Bone Marrow Transplantation
- Cerebral Arteries/metabolism
- Disease Models, Animal
- Hemoglobin, Sickle/genetics
- Hemoglobin, Sickle/metabolism
- Intracranial Thrombosis/etiology
- Intracranial Thrombosis/genetics
- Intracranial Thrombosis/metabolism
- Male
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Mutant Strains
- Microcirculation/physiology
- Neutrophils/metabolism
- Platelet Aggregation/physiology
- Protein C/metabolism
- Thrombin/metabolism
- Thromboplastin/metabolism
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Affiliation(s)
- Felicity N E Gavins
- Wolfson Neuroscience Laboratories, Faculty of Medicine, Imperial College, London, UK.
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24
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Knight-Perry J, DeBaun MR, Strunk RC, Field JJ. Leukotriene pathway in sickle cell disease: a potential target for directed therapy. Expert Rev Hematol 2011; 2:57-68. [PMID: 21082995 DOI: 10.1586/17474086.2.1.57] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Sickle cell disease (SCD) is characterized by recurrent episodes of vaso-occlusion, resulting in tissue ischemia and end-organ damage. Inflammation is critical to the pathogenesis of vaso-occlusion and has been associated with SCD-related morbidity and mortality. Despite the impact of inflammation, no directed anti-inflammatory therapies for the treatment or prevention of vaso-occlusive events currently exist. Among individuals with SCD, asthma is a comorbid inflammatory condition that increases the risk of pain episodes, acute chest syndrome and death. Inflammation associated with asthma could augment the proinflammatory state of SCD, increasing episodes of vaso-occlusion. Leukotrienes are inflammatory mediators that play a prominent role in the pathogenesis of asthma and have been associated with SCD-related morbidity. Targeting inflammatory mediators, such as leukotrienes, is a promising approach for the development of novel therapies for the treatment of SCD. This review will examine the relationship between inflammation and vaso-occlusion, with particular focus on the leukotriene pathway.
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Affiliation(s)
- Jessica Knight-Perry
- Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA
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25
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Abstract
Heme is an essential molecule in aerobic organisms. Heme consists of protoporphyrin IX and a ferrous (Fe(2+)) iron atom, which has high affinity for oxygen (O(2)). Hemoglobin, the major oxygen-carrying protein in blood, is the most abundant heme-protein in animals and humans. Hemoglobin consists of four globin subunits (alpha(2)beta(2)), with each subunit carrying a heme group. Ferrous (Fe(2+)) hemoglobin is easily oxidized in circulation to ferric (Fe(3+)) hemoglobin, which readily releases free hemin. Hemin is hydrophobic and intercalates into cell membranes. Hydrogen peroxide can split the heme ring and release "free" redox-active iron, which catalytically amplifies the production of reactive oxygen species. These oxidants can oxidize lipids, proteins, and DNA; activate cell-signaling pathways and oxidant-sensitive, proinflammatory transcription factors; alter protein expression; perturb membrane channels; and induce apoptosis and cell death. Heme-derived oxidants induce recruitment of leukocytes, platelets, and red blood cells to the vessel wall; oxidize low-density lipoproteins; and consume nitric oxide. Heme metabolism, extracellular and intracellular defenses against heme, and cellular cytoprotective adaptations are emphasized. Sickle cell disease, an archetypal example of hemolysis, heme-induced oxidative stress, and cytoprotective adaptation, is reviewed.
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Affiliation(s)
- John D Belcher
- Department of Medicine, Division of Hematology, Oncology and Transplantation, Minneapolis, Minnesota 55455, USA
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26
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Juncos JP, Grande JP, Croatt AJ, Hebbel RP, Vercellotti GM, Katusic ZS, Nath KA. Early and prominent alterations in hemodynamics, signaling, and gene expression following renal ischemia in sickle cell disease. Am J Physiol Renal Physiol 2010; 298:F892-9. [PMID: 20107113 DOI: 10.1152/ajprenal.00631.2009] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Acute ischemic insults to the kidney are recognized complications of human sickle cell disease (SCD). The present study analyzed in a transgenic SCD murine model the early renal response to acute ischemia. Renal hemodynamics were profoundly impaired following ischemia in sickle mice compared with wild-type mice: glomerular filtration rate, along with renal plasma flow and blood flow rates, were markedly reduced, while renal vascular resistances were increased more than threefold in sickle mice following ischemia. In addition to these changes in renal hemodynamics, there were profound disturbances in renal signaling processes: phosphorylation of members of the MAPK and Akt signaling proteins occurred in the kidney in wild-type mice after ischemia, whereas such phosphorylation did not occur in the kidney in sickle mice after ischemia. ATP content in the postischemic kidney in sickle mice was less than half that observed in wild-type mice. Examination of the expression of candidate genes uncovered changes that may predispose to increased sensitivity of the kidney in sickle mice to ischemia: increased expression of inducible nitric oxide synthase and decreased expression of endothelial nitric oxide synthase, and increased expression of TNF-alpha. Inducibility of anti-inflammatory, cytoprotective genes, such as heme oxygenase-1 and IL-10, was not impaired in sickle mice after ischemia. We conclude that the kidney in SCD is remarkably vulnerable to acute ischemic insults. We speculate that such sensitivity of the kidney to ischemia in SCD may underlie the occurrence of acute kidney injury in patients with SCD and may set the stage for the emergence of chronic kidney disease in SCD.
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Affiliation(s)
- Julio P Juncos
- Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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27
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Driss A, Asare K, Hibbert J, Gee B, Adamkiewicz T, Stiles J. Sickle Cell Disease in the Post Genomic Era: A Monogenic Disease with a Polygenic Phenotype. GENOMICS INSIGHTS 2009. [DOI: 10.4137/gei.s2626] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
More than half a century after the discovery of the molecular basis of Sickle Cell Disease (SCD), the causes of the phenotypic heterogeneity of the disease remain unclear. This heterogeneity manifests with different clinical outcomes such as stroke, vaso-occlusive episodes, acute chest syndrome, avascular necrosis, leg ulcers, priapism and retinopathy. These outcomes cannot be explained by the single mutation in the beta-globin gene alone but may be attributed to genetic modifiers and environmental effects. Recent advances in the post human genome sequence era have opened the door for the identification of novel genetic modifiers in SCD. Studies are showing that phenotypes of SCD seem to be modulated by polymorphisms in genes that are involved in inflammation, cell–cell interaction and modulators of oxidant injury and nitric oxide biology. The discovery of genes implicated in different phenotypes will help understanding of the physiopathology of the disease and aid in establishing targeted cures. However, caution is needed in asserting that genetic modifiers are the cause of all SCD phenotypes, because there are other factors such as genetic background of the population, environmental components, socio-economics and psychology that can play significant roles in the clinical heterogeneity.
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Affiliation(s)
- A. Driss
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - K.O. Asare
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - J.M. Hibbert
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - B.E. Gee
- Department of Clinical Pediatrics, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - T.V. Adamkiewicz
- Department of Family Medicine, Morehouse School of Medicine, Atlanta, Georgia, USA
| | - J.K. Stiles
- Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA
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28
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Abstract
The phenotypic heterogeneity of sickle cell disease continues to puzzle clinicians and investigators more than half a century after the elucidation of its molecular basis. Although advances have been made in understanding the influences of globin gene-related factors such as alpha-thalassemia (thal) and high Hb F determinants, these are far from providing a satisfactory explanation to the variation and clinical diversity of sickle cell disease in many cases. The sequencing of the human genome and the development of novel technologies such as high throughput genotyping and analysis of gene expression through cDNA microarrays has made it possible to investigate this diversity with these approaches and identify novel genetic modifiers of sickle cell disease. This brief review focuses on the recent advances in our understanding of the impact of non globin genetic modifiers on the phenotypic diversity of the disease.
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Affiliation(s)
- Abdullah Kutlar
- Sickle Cell Center, Medical College of Georgia, Augusta, Georgia 30912-3680, USA.
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29
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Blum A. The possible role of red blood cell microvesicles in atherosclerosis. Eur J Intern Med 2009; 20:101-5. [PMID: 19327596 DOI: 10.1016/j.ejim.2008.06.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2007] [Revised: 05/01/2008] [Accepted: 06/09/2008] [Indexed: 11/28/2022]
Abstract
The tendency of sickle cells to adhere to the endothelium reflects the surface features not only of the red cells but also of the endothelial cells. Sickle cell disease is a prototype of a condition where the erythrocyte is under stress, ischemic, oxidative, or shear stress, that causes changes in the erythrocyte morphology. This change leads eventually to enhanced erythrocyte-endothelial cell adhesion. Reactive oxygen species generated by cytokine-activated inflammatory cells oxidize lipoproteins such as LDL and lipoprotein(a) within the vessel wall, facilitating uptake of these particles by activated macrophages and smooth muscle cells, with conversion into lipid-laden foam cells. Notably, the membranes of sickle RBCs have undergone excessive cytoskeletal protein thiol oxidation, and sickle RBCs are abnormally prone to vesiculation during mechanical stress in vitro and apparently in vivo. This abnormality was successfully reproduced in normal RBCs by causing stress conditions using PMS-induced stimulation of intracellular superoxide generation, a process similar to that occurring in sickle RBCs. It could be that the generation of reactive oxygen species in atherosclerosis activates red blood cells, and microvesicles of red blood cells are formed, enhancing the activation of the vascular endothelium and leading to vascular inflammation and atherogenesis.
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Affiliation(s)
- Arnon Blum
- Cardiovascular Department, Translational Branch, NHLBI, National Institutes of Health, USA.
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30
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Bao B, Prasad AS, Beck FWJ, Snell D, Suneja A, Sarkar FH, Doshi N, Fitzgerald JT, Swerdlow P. Zinc supplementation decreases oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell disease patients. Transl Res 2008; 152:67-80. [PMID: 18674741 DOI: 10.1016/j.trsl.2008.06.001] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2008] [Revised: 06/02/2008] [Accepted: 06/04/2008] [Indexed: 11/18/2022]
Abstract
Zinc deficiency is common in adult sickle-cell disease (SCD) patients. We previously demonstrated that zinc supplementation to adult SCD patients decreased the incidences of infections and hospital admissions. We hypothesize that zinc supplementation improves T-helper cell function and decreases vascular endothelial cell activation, oxidative stress, and nuclear factor-kappa B (NF-kappaB)-DNA binding in mononuclear cells (MNCs) in SCD patients. To test this hypothesis, 36 SCD patients were recruited and randomly divided into 2 groups. One group (n = 18) received 25-mg zinc orally thrice a day for 3 months. The other group (n = 18) received placebo. The results indicate that the zinc-supplemented group had decreased incidence of infections compared with the placebo group. After zinc supplementation, red blood cell, hemoglobin (Hb), hematocrit, (Hct), plasma zinc, and antioxidant power increased; plasma nitrite and nitrate (NOx), lipid peroxidation products, DNA oxidation products, and soluble vascular cell adhesion molecule-1 decreased in the zinc-supplemented group, compared with the placebo group. Zinc-supplemented patients exhibited significant decreases in lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) and IL-1beta mRNAs, and TNF-induced nuclear factor of kappaB-DNA binding in MNCs, compared with the placebo group. Ex vivo addition of zinc to MNCs isolated from the placebo subjects decreased TNF-alpha and IL-1beta mRNAs. Zinc supplementation also increased relative levels of IL-2 and IL-2Ralpha mRNAs in phytohemagglutinin-p-stimulated MNCs. These results suggest that zinc supplementation may be beneficial to SCD patients.
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Affiliation(s)
- Bin Bao
- Department of Internal Medicine, Division of Hematology/Oncology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
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31
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Lionnet F, Bachmeyer C, Stankovic K, Tharaux PL, Girot R, Aractingi S. Efficacy of the endothelin receptor blocker bosentan for refractory sickle cell leg ulcers. Br J Haematol 2008; 142:991-2. [PMID: 18671710 DOI: 10.1111/j.1365-2141.2008.07206.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Noronha JFA, Costa FF, Saad STO, Lorand-Metze IGH, Grotto HZW. Evaluation of reticulated platelets in patients with sickle cell diseases. Thromb Res 2007; 121:259-67. [PMID: 17521711 DOI: 10.1016/j.thromres.2007.04.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2006] [Revised: 03/28/2007] [Accepted: 04/11/2007] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND PURPOSE Reticulated platelet (RP) count provides an estimate of thrombopoiesis. The objective was to evaluate RP in patients in different stages of sickle cell disease (SCD) and to determine the relationship between interleukin-6 (IL-6), interleukin-3 (IL-3) and thrombopoietin (TPO) and RP count and degree of activation. METHODS Eighty-nine adult patients with SCD were studied: 38 were in the steady state, 27 in hemolytic crisis (HC) and 24 in vaso-occlusive crisis (VOC). RPs and activated platelets were analyzed by flow cytometry. Soluble P-selectin, IL-6, IL-3 and thrombopoietin (TPO) levels were measured by ELISA tests. RESULTS The patients in VOC had a higher absolute number of RPs and CD62P+ platelets than did the control group or patients in the steady state. A significant correlation was observed between the absolute number of CD62P+ platelets and RPs in patients in the steady state, HC and VOC. In the steady-state group of patients, the level of soluble P-selectin was found to be dependent on the RP values. IL-3 and TPO serum levels were higher in patients in the steady state, HC and VOC than in the control group. IL-6 serum levels were higher in HC and VOC patients than in the control group and higher in patients in the steady state than in the VOC group. CONCLUSION Our results suggest that PRs contribute to the vaso-occlusive process in sickle cell disease. Increased interleukin serum levels probably indicate that inflammatory process is involved in the vascular-occlusive phenomenon. However, it appears that these inflammatory mediators do not have an effect on thrombopoiesis in sickle-cell-disease patients.
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Affiliation(s)
- J F A Noronha
- Department of Clinical Pathology, School of Medical Sciences, State University of Campinas, Campinas, Brazil.
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Kutlar A. Sickle cell disease: a multigenic perspective of a single gene disorder. ACTA ACUST UNITED AC 2006; 10 Suppl 1:92-9. [PMID: 16188647 DOI: 10.1080/10245330512331390069] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- Abdullah Kutlar
- Medical College of Georgia, Sickle Cell Center, Augusta, GA, USA
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34
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Canalli AA, Costa FF, Saad STO, Conran N. Granulocytic adhesive interactions and their role in sickle cell vaso-occlusion. ACTA ACUST UNITED AC 2006; 10:419-25. [PMID: 16273736 DOI: 10.1080/10245330500141259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Recent research has high-lighted the importance of leukocytes in sickle cell disease (SCD). Here we summarize evidence to show that the granulocytes may play a role in SCD due to their increased numbers and adhesive properties, facilitating their participation in the vaso-occlusive process.
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35
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Abstract
The endothelium is a highly metabolically active organ that is involved in many physiological processes, including the control of vasomotor tone, barrier function, leukocyte adhesion and trafficking, inflammation, and hemostasis. Endothelial cell phenotypes are differentially regulated in space and time. Endothelial cell heterogeneity has important implications for developing strategies in basic research, diagnostics and therapeutics. The goals of this review are to: (i) consider mechanisms of endothelial cell heterogeneity; (ii) discuss the bench-to-bedside gap in endothelial biomedicine; (iii) revisit definitions for endothelial cell activation and dysfunction; and (iv) propose new goals in diagnosis and therapy. Finally, these themes will be applied to an understanding of vascular bed-specific hemostasis.
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Affiliation(s)
- W C Aird
- Division of Molecular and Vascular Medicine, Department of Medicine, and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Hwa C, Sebastian A, Aird WC. Endothelial biomedicine: its status as an interdisciplinary field, its progress as a basic science, and its translational bench-to-bedside gap. ENDOTHELIUM : JOURNAL OF ENDOTHELIAL CELL RESEARCH 2005; 12:139-51. [PMID: 16291517 DOI: 10.1080/10623320500192016] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The endothelium, a layer of endothelial cells lining the luminal surface of all blood vessels, functions as a highly metabolically active organ spatially distributed throughout the body. Despite enormous advances in our understanding of endothelial cell biology, little awareness of this organ reaches clinical practice. The present study aims to document the extent and scope of the bench-to-bedside gap in endothelial biomedicine, and to offer hypotheses to explain the gaping chasm. A PubMed search using keywords "endothelial cells" and "endothelium" yielded over 90,000 publications, increasing exponentially over the past decade. A Scirus search without date restriction returned journal results for the endothelium not greatly fewer than for the epithelium. A survey of representative vascular biology meetings revealed a high percentage of talks related to the endothelium. The number of grants awarded by the National Institutes of Health for studies in endothelial cell biology continues to steadily increase. At the bedside, however, few clinicians give consideration to the health of the endothelium. A survey of the major medical textbooks revealed a paucity of index entries for "endothelial cells" or "endothelium." The endothelium does not offer itself for inspection, palpation, percussion, and/or auscultation. No convenient blood tests measure endothelial function. The authors propose to explain the bench-to-bedside gap in endothelial biomedicine as a function of (1) historical constraints, (2) the unseen and diffuse nature of the cell layer, (3) the complexity of the system, and (4) its adaptability. Until the bench-to-bedside gap closes, the enormous potential of the endothelium as a diagnostic, preventive, and therapeutic target will remain largely untapped.
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Affiliation(s)
- Charlotte Hwa
- Division of Molecular and Vascular Medicine, Department of Medicine, and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 023215, USA
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Abstract
Sickle cell disease is a congenital haemoglobinopathy with a high incidence of perioperative complications. Traditional anaesthetic management, based largely on extrapolation from biochemical models, has emphasized avoidance of red cell sickling to prevent exacerbations of the disease. This historical review outlines the evolution of the traditional approach to sickle cell pathology, assesses the validity of this model, describes the emergence of the concept of the disease as one defined by chronic inflammatory vascular damage, and outlines the practical implications of this new approach.
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Affiliation(s)
- P G Firth
- Nuffield Department of Anaesthetics, The John Radcliffe, Headley Way, Headington, Oxford OX3 9DU, UK.
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Abstract
Sickle cell anaemia (SCA) is the most common cause of childhood stroke, occurring with the highest frequency before the age of 6 years. Despite the relative frequency of stroke in SCA, few predictors of risk exist. Anaemia, leucocytosis, hypertension, silent infarction, and history of acute chest syndrome are well-documented risk factors for ischaemic stroke in SCA. Recent data suggest that other environmental and genetic factors, many unrelated to SCA, influence the development of cerebrovascular disease. Non-invasive assessment of individual stroke risk using transcranial Doppler ultrasonography has provided a means of selecting and prophylactically treating SCA children at highest risk. With the ultimate goal of preventing stroke, the information gained from the studies reviewed here may lead to improved prediction of stroke so that clinical trials to assess risk-based therapy may be carried out on selected children with SCA.
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Affiliation(s)
- Carolyn Hoppe
- Department of Hematology/Oncology, Children's Hospital and Research Center at Oakland, Oakland, CA 94609, USA.
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Kutlar A. Sickle cell disease: a multigenic perspective of a single-gene disorder. Med Princ Pract 2005; 14 Suppl 1:15-9. [PMID: 16103709 DOI: 10.1159/000086180] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2004] [Accepted: 04/19/2005] [Indexed: 11/19/2022] Open
Abstract
Although significant progress has been made in our understanding of sickle cell disease (SCD) and in the development of new therapies, many questions are still unanswered, and a cure remains elusive. This is particularly evident in the clinical heterogeneity of the disease. Studies have shown the importance of high hemoglobin F determinants and alpha-thalassemia as modifiers of disease severity, but these alone do not explain the diversity that is seen. This paper focuses on recent advances on the effect of nonglobin genetic modifiers on the SCD phenotype. The roles of polymorphic variants of (1) methylenetetrahydrofolate reductase gene in the pathogenesis of avascular necrosis, (2) factor V R485K and risk of venous thrombosis, and (3) UDP glucuronosyltransferase-1 polymorphism on serum bilirubin levels in SCD are discussed. Mention is made of genetic polymorphisms that might predispose to stroke. The application of gene expression profiling to the study of SCD is very promising and some preliminary data are provided.
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Affiliation(s)
- Abdullah Kutlar
- Sickle Cell Center, Medical College of Georgia, Augusta, GA 30912, USA.
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Abstract
The endothelium is a highly dynamic cell layer that is involved in a multitude of physiologic functions, including the control of vasomotor tone, the trafficking of cells and nutrients, the maintenance of blood fluidity, and the growth of new blood vessels. Over the past several decades, advances in basic research of the endothelium have far outstripped those in the clinic. One explanation for this growing bench-to-bedside chasm relates to the inflexible and largely outdated nature of the present-day medical infrastructure. The constraints of medical subspecialization have created a conceptual blind spot, namely, the inability to appreciate the endothelium for what it is: a cell layer that is teeming with life, every bit as active as any other organ in the body. The overall goal of this review is to bring the endothelium "to life" and to argue that future breakthroughs in biomedicine are contingent on acceptance of the endothelium as a bona fide organ system.
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Affiliation(s)
- William C Aird
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Schnog JB, Mac Gillavry MR, van Zanten AP, Meijers JCM, Rojer RA, Duits AJ, ten Cate H, Brandjes DPM. Protein C and S and inflammation in sickle cell disease. Am J Hematol 2004; 76:26-32. [PMID: 15114593 DOI: 10.1002/ajh.20052] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Reduced activity of naturally occurring anticoagulants (NOAC) protein C and protein S may contribute to vaso-occlusion in sickle cell disease (SCD). We studied whether protein C and S are related to clinical vaso-occlusion, hematological markers of disease severity (hemoglobin levels, leukocyte counts, and percentage of fetal hemoglobin), and inflammation in SCD. Protein C activity, protein S (free and total) antigen, endothelial activation markers (soluble vascular cell adhesion molecule-1 [sVCAM-1], von Willebrand antigen [vWF]), and high sensitive C-reactive protein (hsCRP) levels were measured in 30 HbSS and 20 HbSC patients and in race-matched HbAA controls. NOAC levels were reduced in patients, and endothelial activation markers and hsCRP were elevated (except vWF in HbSC patients). Protein C activity and vWF levels were lower in HbSC patients who experienced painful crises compared to HbSC patients who were clinically asymptomatic. No other differences were observed between patients who did and did not experience vaso-occlusive events (painful crises, stroke, acute chest syndromes) or leg ulcers. A significant positive correlation between total protein S with hemoglobin levels and a significant negative correlation between total and free protein S and sVCAM-1 were detected in HbSS patients. Except perhaps for protein C in relation to painful crises in HbSC patients, these markers were not associated with the occurrence of clinical events. The protein S, hemoglobin, and sVCAM-1 associations may suggest decreased endothelial protein S production due to the more severe endothelial perturbation in HbSS patients with lower hemoglobin levels.
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Affiliation(s)
- J B Schnog
- Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands.
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Abstract
Sickle red cells express adhesion molecules including integrin alpha4beta1, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins leading to its activation. Monocytes also activate endothelium by releasing proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Sickle monocytes also express increased surface CD11b and cytoplasmic cytokines TNFalpha and IL-1beta indicating activated state. Polymorphonuclear leukocytes (PMNs) are also activated with reduced L-selectin expression, enhanced CD64 expression and elevated levels of sL-selectin, sCD16 and elastase resulting in increased adhesiveness to the endothelium. Platelets are also activated and secrete thrombospondin (TSP) and cytokine IL-1. They also form platelet- monocytes aggregates causing endothelial cell P-selectin expression. Endothelial cell activation by these multiple mechanisms leads to a loss of vascular integrity, expression of leukocyte adhesion molecules, change in the surface phenotype from antithrombotic to prothrombotic, excessive cytokine production and upregulation of HLA molecules. Furthermore, contraction of these activated endothelial cells leads to exposure of extracellular matrix proteins, such as TSP, laminin, and fibronectin and their participation in adhesive interactions with bridging molecules from the plasma such as von Willebrand factor (vWf) released from endothelial cells, ultimately culminating in vasoocclusion and local tissue ischemia, the pathognomonic basis of vasoocclusive crisis.
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Affiliation(s)
- Anil Pathare
- Department of Hematology, College of Medicine, Sultan Qaboos University, Muscat, Sultanate of Oman.
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Wood KC, Hebbel RP, Granger DN. Endothelial cell P-selectin mediates a proinflammatory and prothrombogenic phenotype in cerebral venules of sickle cell transgenic mice. Am J Physiol Heart Circ Physiol 2004; 286:H1608-14. [PMID: 14704223 DOI: 10.1152/ajpheart.01056.2003] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Whereas the adhesion of leukocytes and erythrocytes to vascular endothelium has been implicated in the vasooclusive events associated with sickle cell disease, the role of platelet-vessel wall interactions in this process remains undefined. The objectives of this study were to: 1) determine whether the adhesion of platelets and leukocytes in cerebral venules differs between sickle cell transgenic (betaS) mice and their wild-type (WT) counterparts (C57Bl/6) under both resting and posthypoxic conditions, and 2) define the contributions of P-selectin to these adhesion processes. Animals were anesthetized, and platelet and leukocyte interactions with endothelial cells of cerebral postcapillary venules were monitored and quantified using intravital fluorescence microscopy in WT, betaS, and chimeric mice produced by transplanting bone marrow from WT or betaS mice into WT or P-selectin-deficient (P-sel(-/-)) mice. Platelet and leukocyte adhesion to endothelial cells in both unstimulated and posthypoxic betaS mice were significantly elevated over WT levels. Chimeric mice involving bone marrow transfer from betaS mice to P-sel(-/-) mice exhibited a profound attenuation of both platelet and leukocyte adhesion compared with betaS bone marrow transfer to WT mice. These findings indicate that betaS mice assume both an inflammatory and prothrombogenic phenotype, with endothelial cell P-selectin playing a major role in mediating these microvascular responses.
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Affiliation(s)
- Katherine C Wood
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA
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Firth PG, Tsuruta Y, Kamath Y, Dzik WH, Ogilvy CS, Peterfreund RA. Transfusion-related acute lung injury or acute chest syndrome of sickle cell disease? — A case report. Can J Anaesth 2003; 50:895-9. [PMID: 14617585 DOI: 10.1007/bf03018735] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE To describe how to differentiate transfusion-related acute lung injury from acute chest syndrome of sickle cell disease. CLINICAL FEATURES A neurosurgical patient with sickle cell disease received two units of packed red blood cells postoperatively. Four hours later she developed progressive respiratory distress, diffuse geographical airspace disease and bilateral pulmonary edema. The patient recovered sufficiently to be transferred from the intensive care unit within four days. The temporal relationship to transfusion, features on computerized tomographic scan, and the rapid resolution of severe edema point to a diagnosis of transfusion related acute lung injury. Granulocyte or human leukocyte antigen antibodies in donor plasma may confirm a diagnosis of transfusion injury. CONCLUSION The clinician should appreciate that erythrocyte transfusion to prevent or treat acute chest syndrome may cause transfusion related acute lung injury, a condition that mimics, exacerbates or possibly triggers the syndrome it was intended to treat.
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Affiliation(s)
- Paul G Firth
- Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA.
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Shet AS, Aras O, Gupta K, Hass MJ, Rausch DJ, Saba N, Koopmeiners L, Key NS, Hebbel RP. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood 2003; 102:2678-83. [PMID: 12805058 DOI: 10.1182/blood-2003-03-0693] [Citation(s) in RCA: 412] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Blood microparticles (MPs) in sickle cell disease (SCD) are reportedly derived only from erythrocytes and platelets. Yet in SCD, endothelial cells and monocytes are activated and abnormally express tissue factor (TF). Thus, sickle blood might contain TF-positive MPs derived from these cells. With the use of flow cytometry to enumerate and characterize MPs, we found total MPs to be elevated in crisis (P =.0001) and steady state (P =.02) in subjects with sickle cell disease versus control subjects. These MPs were derived from erythrocytes, platelets, monocytes, and endothelial cells. Erythrocyte-derived MPs were elevated in sickle crisis (P =.0001) and steady state (P =.02) versus control subjects, as were monocyte-derived MPs (P =.0004 and P =.009, respectively). Endothelial and platelet-derived MPs were elevated in sickle crisis versus control subjects. Total TF-positive MPs were elevated in sickle crisis versus steady state (P =.004) and control subjects (P <.0001) and were derived from both monocytes and endothelial cells. Sickle MPs shortened plasma-clotting time compared with control MPs, and a TF antibody partially inhibited this procoagulant activity. Markers of coagulation were elevated in patients with sickle cell disease versus control subjects and correlated with total MPs and TF-positive MPs (P <.01 for both). These data support the concept that SCD is an inflammatory state with monocyte and endothelial activation and abnormal TF activity.
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Affiliation(s)
- Arun S Shet
- Vascular Biology Center, University of Minnesota Medical School, Minneapolis, USA.
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46
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Perelman N, Selvaraj SK, Batra S, Luck LR, Erdreich-Epstein A, Coates TD, Kalra VK, Malik P. Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood 2003; 102:1506-14. [PMID: 12714517 DOI: 10.1182/blood-2002-11-3422] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Sickle cell disease (SCD) results in chronic hypoxia and secondarily increased erythropoietin concentrations. Leukocytosis and activated monocytes are also observed in SCD in absence of infection or vaso-occlusion (steady state), the reasons for which are unknown. We found that erythroid cells produced placenta growth factor (PlGF), an angiogenic growth factor belonging to the vascular endothelial growth factor (VEGF) family, and its expression was induced in bone marrow CD34+ progenitor cells in the presence of erythropoietin. Furthermore, the steady state circulating PlGF levels in subjects with severe SCD (at least 3 vaso-occlusive crises [VOCs] per year) were 18.5 +/- 1.2 pg/mL (n = 9) compared with 15.5 +/- 1.2 pg/mL (n = 13) in those with mild SCD (fewer than 3 VOCs per year) and 11.3 +/- 0.7 pg/mL (n = 9) in healthy controls (P <.05), suggesting a correlation between PlGF levels and SCD severity. In addition, PlGF significantly increased mRNA levels of the proinflammatory cytochemokines interleukin-1beta, interleukin-8, monocyte chemoattractant protein-1, and VEGF in peripheral blood mononuclear cells (MNCs) of healthy subjects (n = 4; P <.05). Expression of these same cytochemokines was significantly increased in MNCs from subjects with SCD at steady state (n = 14), compared with healthy controls. Of the leukocyte subfractions, PlGF stimulated monocyte chemotaxis (P <.05, n = 3). Taken together, these data show for the first time that erythroid cells intrinsically release a factor that can directly activate monocytes to increase inflammation. The baseline inflammation seen in SCD has always been attributed to sequelae secondary to the sickling phenomenon. We show that PlGF contributes to the inflammation observed in SCD and increases the incidence of vaso-occlusive events.
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Affiliation(s)
- Natalya Perelman
- Division of Hematology-Oncology, Childrens Hospital Los Angeles, CA 90027, USA
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Belcher JD, Bryant CJ, Nguyen J, Bowlin PR, Kielbik MC, Bischof JC, Hebbel RP, Vercellotti GM. Transgenic sickle mice have vascular inflammation. Blood 2003; 101:3953-9. [PMID: 12543857 DOI: 10.1182/blood-2002-10-3313] [Citation(s) in RCA: 172] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Inflammation may play an essential role in vaso-occlusion in sickle cell disease. Sickle patients have high white counts and elevated levels of serum C-reactive protein (CRP), cytokines, and adhesion molecules. In addition, circulating endothelial cells, leukocytes, and platelets are activated. We examined 4 transgenic mouse models expressing human alpha- and sickle beta-globin genes to determine if they mimic the inflammatory response seen in patients. These mouse models are designated NY-S, Berk-S(Antilles), NY-S/S(Antilles) (NY-S x Berk-S(Antilles)), and Berk-S. The mean white counts were elevated 1.4- to 2.1-fold (P </=.01) in the Berk-S(Antilles), NY-S/S(Antilles), and Berk-S mice, but not in the NY-S mice compared with controls. Serum amyloid P-component (SAP), an acute-phase response protein with 60% to 70% sequence homology to CRP, was elevated 8.5- to 12.1-fold (P </=.001) in transgenic sickle mice. Similarly, serum interleukin-6 (IL-6) was elevated 1.6- to 1.9-fold (P </=.05). Western blots, confirming immunohistochemical staining, showed vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and platelet-endothelial cell adhesion molecule (PECAM) were up-regulated 3- to 5-fold (P </=.05) in the lungs of sickle mice. Ribonuclease protection assays (RPAs) demonstrated VCAM mRNA also was elevated in sickle mice 1.2- to 1.4-fold (P </=.01). Nuclear factor kappaB (NF-kappaB), a transcription factor critical for the inflammatory response, was elevated 1.9-fold (P </=.006) in NY-S sickle mouse lungs. We conclude that transgenic sickle mice are good models to study vascular inflammation and the potential benefit of anti-inflammatory therapies to prevent vaso-occlusion in sickle cell disease.
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Affiliation(s)
- John D Belcher
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis 55455, USA.
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Weiner DL, Hibberd PL, Betit P, Cooper AB, Botelho CA, Brugnara C. Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in pediatric patients with sickle cell disease. JAMA 2003; 289:1136-42. [PMID: 12622584 DOI: 10.1001/jama.289.9.1136] [Citation(s) in RCA: 119] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
CONTEXT Vaso-occlusion is central to the painful crises and acute and chronic organ damage in sickle cell disease. Abnormal nitric oxide-dependent regulation of vascular tone, adhesion, platelet activation, and inflammation contributes to the pathophysiology of vaso-occlusion. Nitric oxide may have promise as a mechanism-of-disease-based therapy for treatment of vaso-occlusion. OBJECTIVE To explore the efficacy and safety of inhaled nitric oxide (INO) for treatment of vaso-occlusive crisis in pediatric patients. DESIGN Prospective, double-blind, placebo-controlled, randomized clinical trial with enrollment between September 1999 and October 2001. SETTING Urban, tertiary care children's hospital in the United States. PARTICIPANTS Twenty patients aged 10 to 21 years with sickle cell disease and severe acute vaso-occlusive crisis. INTERVENTION Patients were randomly assigned to receive INO (80 ppm with 21% final concentration of inspired oxygen; n = 10), or placebo (21% inspired oxygen; n = 10) for 4 hours. MAIN OUTCOME MEASURES Change in pain at 4 hours of inhalation compared with preinhalation pain, measured on a 10-cm visual analog scale (VAS); secondary outcome measures were pain over 6 hours, parenteral narcotic use over 24 hours, duration of hospitalization, blood pressure, oxygen saturation, and methemoglobin concentration. RESULTS Preinhalation VAS pain scores were similar in the INO and placebo groups (P =.80). The decrease in VAS pain scores at 4 hours was 2.0 cm in the INO group and 1.2 cm in the placebo group (P =.37). Repeated-measures analysis of variance for hourly pain scores showed a 1-cm/h greater reduction in the INO group than the placebo group (P =.02). Morphine use over 6 hours was significantly less in the INO group (mean cumulative use, 0.29 vs 0.44 mg/kg; P =.03) but was not different over 4 hours (0.26 vs 0.32 mg/kg; P =.21) or 24 hours (0.63 vs 0.91 mg/kg; P =.15). Duration of hospitalization was 78 and 100 hours in the INO and placebo groups, respectively (P =.19). No INO toxicity was observed. CONCLUSIONS Results of this exploratory study suggest that INO may be beneficial for acute vaso-occlusive crisis. These preliminary results warrant further investigation.
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Affiliation(s)
- Debra L Weiner
- Pediatric Emergency, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA.
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Girgis RE, Qureshi MA, Abrams J, Swerdlow P. Decreased exhaled nitric oxide in sickle cell disease: relationship with chronic lung involvement. Am J Hematol 2003; 72:177-84. [PMID: 12605389 DOI: 10.1002/ajh.10284] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
A deficiency in airway nitric oxide (NO) could contribute to pulmonary vaso-occlusion in sickle cell disease (SCD). We measured the fractional expired concentration of NO (FE(NO)) by chemiluminescence during a slow vital capacity maneuver against a positive pressure of 16 cm H(2)O at an expiratory flow rate of 50 mL/sec in 44 stable ambulatory adults with SCD and 30 healthy controls. A history of acute chest syndrome was present in 29 patients, and 22 complained of dyspnea. Mean +/- SD FE(NO) was significantly reduced in the SCD group compared with controls (14.8 +/- 8.4 vs. 24.9 +/- 13.5 ppb, P < 0.001). SCD patients with dyspnea had lower FE(NO) than those without dyspnea (10.1 +/- 5.7 vs. 19.6 +/- 8 ppb, P < 0.001) and those with a history of ACS had lower values than those no episodes of ACS (13.0 +/- 8.3 vs. 18.4 +/- 7.6 ppb, P < 0.05). There was a weak correlation between FE(NO) and percent-predicted DLCO (r = 0.4, P = 0.02) among the SCD patients. We conclude that exhaled NO is reduced in adults with SCD, and this may play a role in the pathogenesis of acute chest syndrome and chronic sickle cell lung disease.
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Affiliation(s)
- Reda E Girgis
- Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine, Detroit, Michigan, USA.
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50
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Affiliation(s)
- Donald E Wesson
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
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