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Role of Extracellular Hemoglobin in Thrombosis and Vascular Occlusion in Patients with Sickle Cell Anemia  [PDF]
Zhou Zhou,Molly Behymer,Prasenjit Guchhait
Anemia , 2011, DOI: 10.1155/2011/918916
Abstract: Sickle cell anemia (SCA) is a common hemolytic disorder caused by a gene mutation in the β-globin subunit of hemoglobin (Hb) and affects millions of people. The intravascular hemolysis releases excessive amount of extracellular hemoglobin (ECHb) into plasma that causes many cellular dysfunctions in patients with SCA. ECHb scavenges NO which promotes crisis events such as vasoconstriction, thrombosis and hypercoagulation. ECHb and its degradation product, heme, are known to cause oxidative damage to the vessel wall and stimulate the expression of adhesive protein ligands on vascular endothelium. Our study shows that ECHb binds potently to VWF—largest multimeric glycoprotein in circulation—through the A2-domain, and significantly inhibits its cleavage by the metalloprotease ADAMTS13. Furthermore, a subpopulation of VWF multimers bound to ECHb exists in significant amount, accounting for about 14% of total plasma VWF, in SCD patients. The Hb-bound VWF multimers are resistant to ADAMTS13, and are hyperactive in aggregating platelets. Thus, the data suggest that Hb-bound VWF multimers are ultralarge and hyperactive because they are resistant to the protease. The Hb-bound VWF multimers are elevated parallely with the level of ECHb in patients' plasma, and is associated with the pathogenesis of thrombosis and vascular occlusion in SCA. 1. Introduction Sickle cell anemia (SCA) is a hemolytic disorder first described by Herrick in 1910 [1]. In 1949, Pauling and his team first demonstrated the molecular basis of SCA, showing that the disease is caused by a small difference in the molecular structure of hemoglobin, an oxygen-carrying protein in plasma [2]. In 1957, Ingram discovered that the disease was caused by a single amino acid substitution (Glutamic acid → Valine) in the β-globin subunit of hemoglobin [3]. Sickle cell anemia affects millions of people worldwide and is associated with significant morbidity and mortality. An estimated 2% of the world’s population carries genes responsible for SCA. Each year about 300,000 infants are born with SCA, including more than 200,000 cases in Africa [4]. More than 33% of deaths in SCA patients are caused by vascular occlusions and related crises, such as strokes and transient ischemic attacks [5, 6]. It is estimated that stroke alone results in 20% mortality in such patients between the ages of 5 to 10 years, with 70% of those patients having a motor deficit and significant neurocognitive deficits; 70% have a recurrent stroke within the next 3 years [7, 8]. It is known that under hypoxic conditions, deoxygenation
Role of Extracellular Hemoglobin in Thrombosis and Vascular Occlusion in Patients with Sickle Cell Anemia  [PDF]
Zhou Zhou,Molly Behymer,Prasenjit Guchhait
Anemia , 2011, DOI: 10.1155/2011/918916
Abstract: Sickle cell anemia (SCA) is a common hemolytic disorder caused by a gene mutation in the β-globin subunit of hemoglobin (Hb) and affects millions of people. The intravascular hemolysis releases excessive amount of extracellular hemoglobin (ECHb) into plasma that causes many cellular dysfunctions in patients with SCA. ECHb scavenges NO which promotes crisis events such as vasoconstriction, thrombosis and hypercoagulation. ECHb and its degradation product, heme, are known to cause oxidative damage to the vessel wall and stimulate the expression of adhesive protein ligands on vascular endothelium. Our study shows that ECHb binds potently to VWF—largest multimeric glycoprotein in circulation—through the A2-domain, and significantly inhibits its cleavage by the metalloprotease ADAMTS13. Furthermore, a subpopulation of VWF multimers bound to ECHb exists in significant amount, accounting for about 14% of total plasma VWF, in SCD patients. The Hb-bound VWF multimers are resistant to ADAMTS13, and are hyperactive in aggregating platelets. Thus, the data suggest that Hb-bound VWF multimers are ultralarge and hyperactive because they are resistant to the protease. The Hb-bound VWF multimers are elevated parallely with the level of ECHb in patients' plasma, and is associated with the pathogenesis of thrombosis and vascular occlusion in SCA.
Renal dysfunction in patients with sickle cell anemia or sickle cell trait
Sesso, R.;Almeida, M.A.;Figueiredo, M.S.;Bordin, J.O.;
Brazilian Journal of Medical and Biological Research , 1998, DOI: 10.1590/S0100-879X1998001000004
Abstract: patients with sickle cell anemia (hb ss) or sickle cell trait (hb as) may present several types of renal dysfunction; however, comparison of the prevalence of these abnormalities between these two groups and correlation with the duration of disease in a large number of patients have not been thoroughly investigated. in a cross-sectional study using immunoenzymometric assays to measure tubular proteinuria, microalbuminuria, measurement of creatinine clearance, urinary osmolality and analysis of urine sediment, we evaluated glomerular and tubular renal function in 106 adults and children with hb ss (n = 66) or hb as (n = 40) with no renal failure (glomerular filtration rate (gfr) >85 ml/min). the percentage of individuals with microalbuminuria was higher among hb ss than among hb as patients (30 vs 8%, p<0.0001). the prevalence of microhematuria was similar in both groups (26 vs 30%, respectively). increased urinary levels of retinol-binding protein or ?2-microglobulin were detected in only 3 hb ss and 2 hb as patients. urinary osmolality was reduced in patients with hb ss or with hb as; however, it was particularly evident in hb ss patients older than 15 years (median = 393 mosm/kg, range = 366-469) compared with hb as patients (median = 541 mosm/kg, range = 406-722). thus, in addition to the frequently reported early reduction of urinary osmolality and increased gfr, nondysmorphic hematuria was found in 26 and 30% of patients with hb ss or hb as, respectively. microalbuminuria is an important marker of glomerular injury in patients with hb ss and may also be demonstrated in some hb as individuals. significant proximal tubular dysfunction is not a common feature in hb ss and hb as population at this stage of the disease (i.e., gfr >85 ml/min).
Renal dysfunction in patients with sickle cell anemia or sickle cell trait  [cached]
Sesso R.,Almeida M.A.,Figueiredo M.S.,Bordin J.O.
Brazilian Journal of Medical and Biological Research , 1998,
Abstract: Patients with sickle cell anemia (Hb SS) or sickle cell trait (Hb AS) may present several types of renal dysfunction; however, comparison of the prevalence of these abnormalities between these two groups and correlation with the duration of disease in a large number of patients have not been thoroughly investigated. In a cross-sectional study using immunoenzymometric assays to measure tubular proteinuria, microalbuminuria, measurement of creatinine clearance, urinary osmolality and analysis of urine sediment, we evaluated glomerular and tubular renal function in 106 adults and children with Hb SS (N = 66) or Hb AS (N = 40) with no renal failure (glomerular filtration rate (GFR) >85 ml/min). The percentage of individuals with microalbuminuria was higher among Hb SS than among Hb AS patients (30 vs 8%, P<0.0001). The prevalence of microhematuria was similar in both groups (26 vs 30%, respectively). Increased urinary levels of retinol-binding protein or 2-microglobulin were detected in only 3 Hb SS and 2 Hb AS patients. Urinary osmolality was reduced in patients with Hb SS or with Hb AS; however, it was particularly evident in Hb SS patients older than 15 years (median = 393 mOsm/kg, range = 366-469) compared with Hb AS patients (median = 541 mOsm/kg, range = 406-722). Thus, in addition to the frequently reported early reduction of urinary osmolality and increased GFR, nondysmorphic hematuria was found in 26 and 30% of patients with Hb SS or Hb AS, respectively. Microalbuminuria is an important marker of glomerular injury in patients with Hb SS and may also be demonstrated in some Hb AS individuals. Significant proximal tubular dysfunction is not a common feature in Hb SS and Hb AS population at this stage of the disease (i.e., GFR >85 ml/min).
Fetal hemoglobin reactivation and cell engineering in the treatment of sickle cell anemia
Sandro Eridani, Andrea Mosca
Journal of Blood Medicine , 2011, DOI: http://dx.doi.org/10.2147/JBM.S14942
Abstract: al hemoglobin reactivation and cell engineering in the treatment of sickle cell anemia Review (4016) Total Article Views Authors: Sandro Eridani, Andrea Mosca Published Date February 2011 Volume 2011:2 Pages 23 - 30 DOI: http://dx.doi.org/10.2147/JBM.S14942 Sandro Eridani, Andrea Mosca Department of Biomedical Science and Technology, University of Milano, Italy Abstract: The natural history of severe hemoglobinopathies like sickle cell disease (SCD) is rather variable, depending on the circumstances, but the main influence on such variability is the level of fetal hemoglobin (HbF) in the patient's red cells. It is well known that a significant HbF level is associated with a milder course of disease and fewer complications. Therefore, attempts have been made to reactivate using various means the HbF production, which is normally switched off perinatally. A pharmacological approach has been attempted since the 1980s, ranging from drugs like 5-azacytidine and its derivative, decitabine, to a series of compounds like hydroxyurea and a number of histone deacetylase inhibitors like butyrate, which seem to act as epigenetic modifiers. Many other disparate agents have been tried with mixed results, but hydroxyurea remains the most effective compound so far available. Combinations of different compounds have also been tried with some success. Established treatments like bone marrow or cord blood transplantation are so far the only real cure for a limited number of patients with severe hemoglobinopathies. Improved chemotherapy regimens of milder toxicity than those employed in the past have made it possible recently to obtain a stable, mixed donor-recipient chimerism, with reversal of the SCD phenotype. However, great effort is directed to cell engineering, searching for an effective gene vector by which a desired gene can be transferred into new classes of vectors for autologous hemopoietic stem cells. Recent studies are also aiming at targeted insertion of the therapeutic gene into hemopoietic cells, which can also be “induced” human stem cells, obtained from somatic dedifferentiated cells. Attention in this area must be paid to the possibility of undesired effects, like the emergence of potentially oncogenic cell populations. Finally, an update is presented on improved HbF determination methods, because common international standards are becoming mandatory.
A rare case of coinheritance of Hemoglobin H disease and sickle cell trait combined with severe iron deficiency  [cached]
Michael Medinger,Elisabeth Saller,Cornelis L. Harteveld,Thomas Lehmann
Hematology Reports , 2011, DOI: 10.4081/hr.2011.e30
Abstract: We present a case of a 40-year-old female from Turkey, who was referred to our outpatient clinic for an undetermined thalassemia and sickle cell trait. At first consultation hemoglobin was decreased (71 g/L) with microcytosis (MCV 55.1 fL), and hypochromia (MCHC 239 g/L). The patient had severe iron deficiency. Brilliant cresyl blue staining showed >50% of the erythrocytes with typical Hemoglobin H (HbH) inclusions. High-performance liquid chromatography (HPLC) revealed normal levels of HbA2 and Hemoglobin F (HbF), and additionally a hemoglobin S (19%). Molecular diagnostics revealed the mutations α2 IVS-I donor site -5nt and a -- MED II deletion in the alpha gene complex and confirmed the heterozygote mutation of the beta-gene at codon 6 (HBB:c.20A>T; HbS). In conclusion, we present an extremely rare combination of HbH disease and sickle cell trait. This combination may explain the mild form of the HbH disease, with moderate anemia, splenomegaly but iron deficiency, rather than iron overload, as usually observed in HbH disease.
Safety of Pegfilgrastim (Neulasta) in Patients with Sickle Cell Trait/Anemia  [PDF]
Pashtoon Murtaza Kasi,Mrinal M. Patnaik,Prema P. Peethambaram
Case Reports in Hematology , 2013, DOI: 10.1155/2013/146938
Abstract: Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer’s website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented. 1. Background Pegfilgrastim is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and febrile neutropenia [1]. Prescribing information available on manufacturer’s website for Pegfilgrastim warns us about possible severe sickle cell crises due to the medication but do not report the actual incidence or the use in patients with sickle cell trait [2]. Caution is advised when using it in patients with sickle cell disease [3]. The heterozygous form of sickle cell anemia, sickle cell trait (SCT), is present in up to 8% of African-Americans in the United States [4, 5]. Higher prevalence of up to 25% has been reported in some populations, but it is very rare to find sickle cell disease or trait in Caucasians [6, 7]. Although considered a benign disorder, it has been associated with numerous complications and adverse events, more so when exposed to conditions that would promote sickling, for example, periods of stress or high altitude [6, 8]. Case reports ranging from pain crisis to rhabdomyolysis, renal failure, and splenic/intestinal infarction have been reported [9, 10]. With respect to administration of colony stimulating factors in
Hematological and Genetic Predictors of Daytime Hemoglobin Saturation in Tanzanian Children with and without Sickle Cell Anemia  [PDF]
Sharon E. Cox,Julie Makani,Charles R. Newton,Andrew M. Prentice,Fenella J. Kirkham
ISRN Hematology , 2013, DOI: 10.1155/2013/472909
Abstract: Low hemoglobin oxygen saturation (SpO2) is common in Sickle Cell Anemia (SCA) and associated with complications including stroke, although determinants remain unknown. We investigated potential hematological, genetic, and nutritional predictors of daytime SpO2 in Tanzanian children with SCA and compared them with non-SCA controls. Steady-state resting pulse oximetry, full blood count, transferrin saturation, and clinical chemistry were measured. Median daytime SpO2 was 97% (IQ range 94–99%) in SCA (N = 458), lower ( ) than non-SCA (median 99%, IQ range 98–100%; N = 394). Within SCA, associations with SpO2 were observed for hematological variables, transferrin saturation, body-mass-index z-score, hemoglobin F (HbF%), genotypes, and hemolytic markers; mean cell hemoglobin (MCH) explained most variability ( , Adj ). In non-SCA only age correlated with SpO2. -thalassemia 3.7 deletion highly correlated with decreased MCH (Pearson correlation coefficient 0.60, ). In multivariable models, lower SpO2 correlated with higher MCH ( -coefficient 0.32, ) or with decreased copies of -thalassemia 3.7 deletion ( -coefficient 1.1, ), and independently in both models with lower HbF% ( -coefficient 0.15, ) and Glucose-6-Phosphate Dehydrogenase genotype ( -coefficient 1.12, ). This study provides evidence to support the hypothesis that effects on red cell rheology are important in determining SpO2 in children with SCA. Potential mechanisms and implications are discussed. 1. Introduction Hemoglobin oxygen desaturation in the absence of acute illness is common in children with Sickle Cell Anemia (SCA), and is associated with higher cerebral blood flow velocities [1, 2], and with risk of complications including stroke [3]. The underlying mechanisms of hemoglobin oxygen desaturation in SCA are poorly understood but may involve the severity of anemia [4] as well as differences in hemoglobin oxygen affinity compared to hemoglobin A (HbA), with increased expression of 2.3 DPG in hemoglobin S (HbS) resulting in a right-shifted hemoglobin oxygen affinity curve and other differences in red cell physiology [5]. Other potential causes include a history of acute chest syndrome and reduced pulmonary [6] and cardiac function [7]. Coinheritance of alpha-thalassemia deletions and glucose-6-phosphate deficiency (G6PD) may affect the degree of anemia [8, 9] whilst alpha-thalassemia status modifies red cell indices [10–12] and rheology [13], as can iron status [14]. We therefore investigated potential hematological, genetic, and nutritional predictors of daytime hemoglobin oxygen saturation
The influence of socioeconomic status on the hemoglobin level and anthropometry of sickle cell anemia patients in steady state at the Lagos University Teaching Hospital
BA Animasahun, EO Temiye, OO Ogunkunle, AN Izuora, OF Njokanma
Nigerian Journal of Clinical Practice , 2011,
Abstract: Background: Sickle cell anemia (SCA) has multisystemic manifestations and is associated with severe morbidity and high mortality. It commonly affects growth leading to wasting and stunting. Aims and Objectives: This study aimed to determine the influence of socioeconomic status on the nutritional status using anthropometric measurements and steady-state hemoglobin, of children with homozygous SCA, aged 1 year to 10 years in steady state at the Lagos University Teaching Hospital. Materials and Methods: This is a cross-sectional study involving 100 children with SCA and 100 age-, sex-, and social class-matched controls that fulfilled the inclusion criteria. Social class was assessed using educational attainment and occupation of parents. Hemoglobin concentration was determined using the oxy-hemoglobin method. Results: This study demonstrated a significantly lower mean weight and weight-for-height in the SCA patients than those of controls (P < 0.001). By contrast, this study did not demonstrate any statistical significant difference in the mean height and mean body mass index of SCA patients and controls (P = 0.06) and (P = 0.12), respectively. The mean weight, height, and body mass indices of the subjects and controls were consistently below those of the NCHS standards. The magnitude of the difference from the NCHS standard was also more pronounced in the subjects, increased with advancing age and affected male subjects more than females. Progressive declines in the anthropometric attainment and hemoglobin concentration were observed from social class 1 to 4; this was statistically significant in controls (P = 0.00) but not in subjects (P > 0.1). However, SCA patients had significantly lower values than controls in each of the social classes. Conclusion: Poor socioeconomic status has an adverse effect on the nutritional status and hemoglobin of SCA patients.
Surgery in sickle cell anemia
P Fokam, AT Chiabi
Clinics in Mother and Child Health , 2004,
Abstract: Sickle cell anemia is a hemoglobin disorder with a wide range of clinical manifestations and complications. Medical treatment is the mainstay of management but surgery is indicated in some cases. The authors review the main surgical indications in sickle cell anemia as frequently encountered and review treatment guidelines.
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