Plasma Hemoglobin-Binding Capacity in Sickle Cell Disease

Studies of the capacity of plasma proteins to bind hemoglobin were madein patients with sickle cell anemia (SS), sickle cell trait (SA), hemoglobinC disease and in patients with hemolytic anemias. Hemoglobin binding wasquantitatively normal in sickle cell trait, but was greatly reduced or absentin sickle cell anemia, hemoglobin C disease and in other hemolytic disorders.These alterations have been attributed to a reduction in the level of hemoglobin-binding proteins in circulating plasma. The mechanism of this reduction was not established, but the observed changes were correlated with thepresence of increased hemolytic activity.

The binding of hemoglobin C and hemoglobin S by normal plasma wasquantitatively normal.

Submitted on October 25, 1958 Accepted on December 12, 1958     

N-Terminal Natriuretic Peptide and Ventilation-Perfusion Lung Scan in Sickle Cell Disease and Thalassemia Patients with Pulmonary Hypertension

The aim of this study was to determine the prevalence of pulmonary hypertension (PH) in sickle cell disease and thalassemia patients in relation to clinical and laboratory parameters of hemolysis and hemosidersosis, as well as plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP). The study also aimed to define the role of thromboembolic pulmonary artery (PA) obstruction in its etiology. Forty sickle cell disease and 30 thalassemia patients [15 β-thalassemia major (β-TM) and 15 β-thalassemia intermedia (β-TI)] were screened for PH defined as tricuspid regurgitant velocity (TRV) >2.5 m/sec and evaluated for PA obstruction using ventilation-perfusion lung scan (V/Q), together with measurement of their plasma levels of NT-pro-BNP. Patients were prospectively followed up for a mean of 18 ± 6.1 months. The prevalence of PH was 37.5, 40.0 and 26.7% in sickle cell disease, β-TI and β-TM patients, respectively. Pulmonary hypertension patients were older, had longer disease duration, higher serum ferritin, serum lactate dehydrogenase (LDH) and NT-pro-BNP with lower hemoglobin (Hb) levels compared to patients without PH. N-terminal pro-BNP was positively correlated with duration of illness, TRV, LDH, serum ferritin, and negatively correlated with Hb levels. The strongest predictor for TRV was serum ferritin followed by the NT-pro-BNP level. Forty-six-point-seven percent of sickle cell disease patients with PH had either high or intermediate probability V/Q scan results compared to 10% of thalassemic patients with PH who had high probability V/Q scan results. Pulmonary hypertension is highly prevalent in young sickle cell disease and thalassemia patients, where elevated serum ferritin and NT-pro-BNP are the main indicators.     

Interaction of Hemoglobin Lepore with Sickle Cell Trait and Microcythemia (Thalassemia) in a Southern Italian Family

An abnormal hemoglobin has been observed in a southern Italian familytogether with sickle cell hemoglobin and thalassemia (microcythemia). Thehematologic study has shown that all the carriers of the abnormal hemoglobinare microcythemic. The hemoglobins of these individuals have been studiedby paper, starch gel, starch block and agar gel electrophoresis. The abnormalhemoglobin has been isolated and identified by fingerprinting as HbLepore_Boston. The combination of Hb Lepore_Boston with thalassemia and sicklecell trait has been observed in members of this family. The hematologic andbiochemical implications of the Hb Lepore/thalassemia disease are discussed.

Submitted on March 23, 1964 Accepted on July 2, 1964     

Intraerythrocytic Hemoglobin Crystals in Sickle Cell-Hemoglobin C Disease

On 70 per cent of the blood smears from 60 cases of electrophoreticallyproven sickle cell-hemoglobin C disease, there is observed a misshapen erythrocyte that contains condensed hemoglobin crystals which are dark-hued,homogeneous and elongated and which have parallel sides with one end terminating in a pyramid or rounded shape. A red blood corpuscle may have multiple protuberances at varying angles to each other. The incidence of intracellular hemoglobin crystals was found to be 0-24 per 1000 red blood cells withan average of 3.2/1000. Recognition of this unusual morphology is presumptiveevidence of sickle cell-hemoglobin C and warrants examination by electrophoretic procedures.

Submitted on March 25, 1964 Accepted on May 14, 1964     

Paper electrophoresis of abnormal hemoglobins and its clinical applications; a simple semiquantitative method for the study of the hereditary hemoglobinopathies

1. Paper electrophoresis of abnormal hemoglobins is a simple and convenienttechnic for the study of the hereditary hemoglobinopathies.

2. A semiquantitative paper electrophoretic technic is described, which allows rather accurate quantitation of the various hemoglobin components byinspection alone.

3. For exact results, the more elaborate technics of elution or photoelectric scanning may be employed. The accuracy of these quantitative technics isillustrated by artificial mixture experiments.

4. The clinical applications of the method in the study of sickle cell diseaseand hemoglobin C abnormalities are discussed. Apart from the more commonhemoglobin abnormalities (such as sickle cell trait, sickle cell anemia, C trait,sickle cell-hemoglobin C disease), a patient with 100 per cent hemoglobin C(homozygous hemoglobin C disease) and a Negro patient with sickle cell-thalassemia disease were discovered. Normal adult hemoglobin (hemoglobin A) wasfound in all other hereditary and acquired anemias studied. Slightly increasedamounts of fetal hemoglobin were detected in cases of hereditary nonspherocytichemolytic disease and aregenerative anemia.

5. This technic may be used for red cell life span determinations by seriallyfollowing the disappearance of a certain hemoglobin type transfused into apatient with a different hemoglobin variety. Further applications of the technicare suggested.

6. The combination of the technics of paper electrophoresis and alkali denaturation offer an adequate, simple, and practical tool for diagnosis and investigation of hereditary hemoglobinopathies.

7. Identical apparatus and buffer may be used for serum protein electrophoresis.

Submitted on November 10, 1953 Accepted on December 3, 1953     

Sickle cell-thalassemia disease in Jamaica

Two cases of sickle cell—thalassemia disease are described in young womenof mixed Chinese and African parentage. On hemoglobin electrophoresis, acomplete suppression of hemoglobin A was found, giving a picture indistinguishable from that seen in sickle cell anemia. The findings in these twocases are contrasted with those in other examples of this disease which wehave studied in Jamaica. The importance of these findings in relation to thediagnosis of sickle cell anemia is discussed.

Submitted on June 13, 1957 Accepted on November 18, 1957     

The Effect of Hydroxyurea Therapy in Bahraini Sickle Cell Disease Patients

Hydroxyurea (HU) is used as a disease-modifying agent in sickle cell disease (SCD). Its beneficial effects have been ascribed to inhibition of the sickling process through increase of fetal hemoglobin (HbF) levels and influence on multiple factors affecting adhesion of erythrocytes to vascular endothelium. The present study investigates the effect of HU in SCD patients who were grouped on the basis of association with α- and β-thalassemia using routine laboratory methods. A retrospective cross-sectional chart-review was done of 51 adult Bahraini SCD patients attending Salmaniya Medical Complex, Bahrain. Four sub-groups of cases were identified: (i) homozygous sickle cell anemia, 24 cases; (ii) SCD with microcytosis, 16 cases; (iii) sickle α-thalassemia, seven cases; and (iv) sickle β thalassemia, four cases. Documented laboratory and clinical data included hemoglobin level (Hb), hematocrit (Hct), red cell indices, hemoglobin fractions, hospital admissions (frequency), number of inpatient-days, pain episodes (frequency) and red cell transfusion requirement (number of units). Pre- and post-treatment data were compared. Hydroxyurea treatment led to highly significant reduction of HbS % and pain crisis episodes in all patient groups. Other changes such as increases of total hemoglobin, Hct and HbF and reduction of hospital admissions, inpatient days and red cell units transfused also occurred but with less consistent levels of significance within patient sub-groups. Treatment with HU is beneficial for all subgroups of Bahraini SCD patients, without or with α- and β-thalassemia interactions.     

Transfusion-Related Chronic Liver Disease in Sickle Cell Anemia

The medical records and liver biopsies of nine sickle cell patients with chronically elevated liver function tests were retrospectively reviewed to determine the etiology of chronic liver disease. There were eight women and one man with a mean age of 30 yr. All patients had hemoglobin SS. Eight patients were referred for elevated aminotransferases and one for an elevated alkaline phosphatase. Hemosiderosis was present in all of the biopsies. Two patients had cirrhosis. Chronic hepatitis was noted in two patients, and five patients had cholestasis. Two patients had serologic markers demonstrating HBV exposure but no patients were HBsAg positive. Erythrophagocytosis, sinusoidal dilatation, and Kupffer cell hyperplasia were present in all of the liver biopsies. Transfusion-related causes were the most common significant pathologic findings in our patients, and appeared to be the etiologies of chronic liver disease in sickle cell patients.     

Pulmonary Complications of Sickle Cell Disease

The pulmonary complications of sickle cell disease are a major cause of morbidity and mortality in affected patients. The acute chest syndrome (ACS) is a leading cause of death in patients with sickle cell disease and has a multifactorial etiology. Hydroxyurea (HU), stem cell transplantation (SCT) and chronic transfusions are known to prevent the recurrence of ACS. Careful management of patients admitted for pain crises and surgery including use of incentive spirometry is critical in preventing this complication. Pulmonary hypertension is well known to be associated with sickle cell disease and patients with pulmonary hypertension have increased mortality. Asthma is also commonly seen in patients with sickle cell disease and is associated with a more complicated course. Chronic lung disease develops in a significant proportion of patients with sickle cell disease.     

The Role of Inflammation and Leukocytes in the Pathogenesis of Sickle Cell Disease

Acute and chronic vascular occlusion underlies much of the morbidity and mortality in sickle disease. Abnormal polymerization of deoxygenated hemoglobin S (HbS) resulting in stiff, non-deformable erythrocytes is central to sickle cell pathogenesis. However, a complex interplay of many factors determines the balance between adequate blood flow and vessel obstruction. Serum markers of inflammation have provided evidence for a state of chronic inflammation in sickle cell disease (SCD). Inflammation promotes endothelial adherence to sickle erythrocytes. Studies demonstrating a beneficial effect of steroid therapy for painful episodes and acute chest syndrome provide indirect evidence for the role of inflammation in this disease. Leukocytosis, in the absence of infection, is common in SCD patients and predicts for stroke, acute chest syndrome, and overall mortality. Neutrophils and monocytes have been shown to be activated in these patients. Activated leukocytes further promote vascular inflammation and vessel damage. A reduction in leukocytes, and thus inflammation, may partially explain the beneficial effects of hydroxyurea in this disease. These data provide a strong rationale for clinical studies of therapy directed at inflammation and/or leukocytes in sickle cell disease.     

Assessment of Sleep-Related Disorders in Children With Sickle Cell Disease

Sleep-related disorders (SRDs) are common in sickle cell disease, however, identification may be time-consuming. Simultaneous survey of multiple SRDs utilizing a simplified instrument would facilitate screening. A simplified questionnaire investigating SRDs [sleep-disordered breathing (SDB), restless legs syndrome (RLS), insomnia, parasomnias, and daytime effects of disrupted sleep] was administered to 2–18-year-old children with sickle cell disease. One hundred participants completed this 5–7 minute survey without difficulties: 54 awoke unrefreshed, 41 had short-term insomnia, 30 had sleep-maintenance insomnia, 21 had chronic sleep-onset insomnia, 54 had chronic habitual snoring and 11 met the criteria for RLS. Sleep-maintenance insomnia was associated with increased body mass index (BMI) (p?=?0.001), and chronic sleep-onset insomnia was associated with higher hemoglobin (Hb) levels (p?=?0.04). Survey-reported symptoms of SRDs were significantly higher than that reported in the general pediatric population. A fast and simplified SRD survey is feasible and suggests a high prevalence of SRDs in children with sickle cell disease.     

Erythropoietin Levels in Patients with Sickle Cell Disease Do Not Correlate with Known Inducers of Erythropoietin

Previous studies have suggested that erythropoietin (Epo) levels may be inappropriately low in patients with sickle cell disease compared to the extent of the related anemia they demonstrate. Here, we evaluate Epo level vs. renal function, oxygenation, and markers of inflammation for patients treated for sickle cell disease at our institution. Blood was drawn from 54 patients with sickle cell disease during routine visits to the outpatient hematology office and analyzed for hemoglobin (Hb) level, Epo, markers of inflammation, oxygenation, and renal function. Erythropoietin levels were lower than expected for patients with sickle cell disease, compared to the degree of anemia demonstrated in these patients. In addition, a correlation between Hb level and Epo was not consistently observed. Higher Epo levels were seen in patients receiving hydroxyurea (HU), but no correlation with oxygenation, hemolysis, renal function, or inflammation was observed.     

The Role of Inflammation and Leukocytes in the Pathogenesis of Sickle Cell Disease; Haemoglobinopathy

Acute and chronic vascular occlusion underlies much of the morbidity and mortality in sickle disease. Abnormal polymerization of deoxygenated hemoglobin S (HbS) resulting in stiff, non-deformable erythrocytes is central to sickle cell pathogenesis. However, a complex interplay of many factors determines the balance between adequate blood flow and vessel obstruction. Serum markers of inflammation have provided evidence for a state of chronic inflammation in sickle cell disease (SCD). Inflammation promotes endothelial adherence to sickle erythrocytes. Studies demonstrating a beneficial effect of steroid therapy for painful episodes and acute chest syndrome provide indirect evidence for the role of inflammation in this disease. Leukocytosis, in the absence of infection, is common in SCD patients and predicts for stroke, acute chest syndrome, and overall mortality. Neutrophils and monocytes have been shown to be activated in these patients. Activated leukocytes further promote vascular inflammation and vessel damage. A reduction in leukocytes, and thus inflammation, may partially explain the beneficial effects of hydroxyurea in this disease. These data provide a strong rationale for clinical studies of therapy directed at inflammation and/or leukocytes in sickle cell disease.     

Blood Transfusion in Sickle Cell Disease

Sickle cell anemia is an inherited disease that causes chronic hemolytic anemia. Its pathognomonic signs and symptoms are caused by hemoglobin (Hb) S, which results from a single nucleotide substitution in the β-globin gene that places the amino acid valine with glutamic acid at codon 6 of the β-globin chain. Hb S is an insoluble Hb that crystalizes at low oxygen tension and other precipitating conditions leading to rigidity of red cells and clumping in small blood vessels.

Patients with sickle cell disease have a variable Hb level that may range from 7.0 to 11.0 g/dL in their steady state condition. The most common cause of hospital presentation is due to acute painful crisis that results from vaso-occlusion by sickled cells. These episodes are treated with hydration and analgesia and do not require blood transfusion. Blood transfusion should be aimed to increase tissue delivery of oxygen. Hb S is known to be a low affinity Hb and so delivers oxygen at a lower partial pressure of oxygen compared to Hb A. Even with adequate pre transfusion testing and precautions, blood transfusion is never totally safe and short or long term complications may occur.

Blood transfusion in patients with sickle cell disease has only limited indications such as acute hemolytic, aplastic or sequestration crises. Chronic transfusion protocols are implemented in cases of strokes or high cerebral blood flow ultrasonic studies as a prophylactic measure. Exchange blood transfusion is used in some complications of the disease such as acute chest syndrome (ACS), priapism or peri operatively. Once it is decided to transfuse blood, the transfused blood should be Hb S negative, Rh and Kell antigen matched.     

Oxygen Saturation and Hemoglobin A Content in Patients with Sickle Cell Disease Undergoing Erythrocytapheresis

Abstract: Severe hypoxia occurs in patients with acute chest syndrome, and erythrocytapheresis has been shown to improve oxygenation. Patients with sickle cell anemia also have decreased baseline oxygen saturation values, but the effect of erythrocytapheresis on steady‐state oxygenation has not been well studied. We investigated the changes in oxygen saturation versus hematocrit, fraction of hemoglobin A, and transfusion volume during 71 prophylactic erythrocytapheresis procedures performed in 5 stable patients with sickle cell anemia. Each patient had a history of either acute chest syndrome or stroke, but no serious events occurred while enrolled in the chronic exchange program. The oxygen saturation improved from 1% to 6% during erythrocytapheresis in each of our patients (p < 0.001) regardless of preprocedure saturation level or total hematocrit. We have shown that decreased baseline oxygen saturation in sickle cell disease is related to abnormal hemoglobin S levels, and oxygen saturation can be improved with erythrocytapheresis, independent of any change in the total hematocrit.     

Artificially Induced Thyroid Suppression in Sickle Cell Disease

Depression of thyroid function in patients with hemoglobin SS diseasemight be expected to: (1) reduce tissueoxygen consumption, (2) decrease erythrocyte 2, 3-diphosphoglycerate, (3)decrease p50, (4) increase the averagelevel of erythrocyte oxygenation, and(5) increase in vivo red cell survivalwith associated improvement in anemia and possibly in musculoskeletalsymptoms. Accordingly, 150-200 mgof 6-n-propylthiouracil were administered three times a day for 143 days toa 21-yr-old male with hemoglobin SSdisease. Thyrosuppression was indicated by typical symptoms and appropriate changes in physical and biochemical parameters. Detailed hematologic follow-up, including multiplemeasurements of red cell mass, ⁵¹Crerythrocyte survival, red cell 2,3-diphosphoglycerate, and p50, showed nochange. Furthermore, musculoskeletalsymptoms continued in the patterncharacteristic of the euthyroid state.A possible explanation for the lack ofany change in clinical status may bethat decreased cardiac output, with attendant prolonged circulation time andincreased tissue oxygen demand perred cell per unit time, offset the absolute decrease in tissue oxygen consumption. The study provided an opportunity to make detailed clinicalobservations of sickle cell disease inassociation with thyroid suppression.The results suggest that thyrosuppression within the limits of symptomaticand physiologic tolerance has no therapeutic application in the clinical management of hemoglobin SS disease.

Submitted on May 9, 1972 Revised on July 3, 1972 Accepted on July 6, 1972     

Novel Sickle Cell Disease Therapies: Targeting Pathways Downstream of Sickling

Sickle cell disease is an inherited hemoglobinopathy characterized by hemolytic anemia, frequent painful episodes, poor quality of life, end organ damage and a shortened lifespan. Although the seminal event is the polymerization of the abnormal hemoglobin, the downstream pathophysiology of vaso-occlusion results from heterotypic interactions between the altered, adhesive sickle cell RBCs, neutrophils, endothelium, and platelets. Ischemia reperfusion injury, hemolysis and oxidant damage all contribute to heightened inflammation and activation of the hemostatic system. These downstream targets are the focus of emerging treatments with considerable potential to ameliorate disease manifestations. This review summarizes the progress on development of these agents.     

Detection of Sickle Cell Hemoglobin in Haiti by Genotyping and Hemoglobin Solubility Tests

Sickle cell disease is a growing global health concern because infants born with the disorder in developing countries are now surviving longer with little access to diagnostic and management options. In Haiti, the current state of sickle cell disease/trait in the population is unclear. To inform future screening efforts in Haiti, we assayed sickle hemoglobin mutations using traditional hemoglobin solubility tests (HST) and add-on techniques, which incorporated spectrophotometry and insoluble hemoglobin separation. We also generated genotype data as a metric for HST performance. We found 19 of 202 individuals screened with HST were positive for sickle hemoglobin, five of whom did not carry the HbS allele. We show that spectrophotometry and insoluble hemoglobin separation add-on techniques could resolve false positives associated with the traditional HST approach, with some limitations. We also discuss the incorporation of insoluble hemoglobin separation observation with HST in suboptimal screening settings like Haiti.     

Defining the Phenotypes of Sickle Cell Disease

The sickle cell gene is pleiotropic in nature. Although it is a single gene mutation, it has multiple phenotypic expressions that constitute the complications of sickle cell disease. The frequency and severity of these complications vary considerably both latitudinally in patients and longitudinally in the same patient over time. Thus, complications that occur in childhood may disappear, persist or get worse with age. Dactylitis and stroke, for example, occur mostly in childhood, whereas leg ulcers and renal failure typically occur in adults. It is essential that the phenotypic manifestations of sickle cell disease be defined accurately so that communication among providers and researchers facilitates the implementation of appropriate and cost-effective diagnostic and therapeutic modalities. The aim of this review is to define the complications that are specific to sickle cell disease based on available evidence in the literature and the experience of hematologists in this field.     

Patients Welcome the Sickle Cell Disease Mobile Application to Record Symptoms via Technology (SMART)

The widespread use of mobile phones among patients provides a unique opportunity for the development of mobile health intervention designed specifically for sickle cell disease, which will improve self-management as well as health care delivery. Our objective was to determine the receptiveness of patients with sickle cell disease to technology and a mobile application (app) designed for sickle cell disease. Phase I included 100 patients who completed a survey inquiring about receptiveness to technology and use of mobile devices to self-manage and communicate with providers. Phase II surveyed 17 additional patients who tested a newly developed sickle cell disease app, to report its usability and utility. In Phase I, on a 0–10 Likert scale where 0 is not comfortable, and 10 is extremely comfortable, 87.0% of participants reported >5 comfort level using a mobile device for health care management. Participants were comfortable with texting (81.0%) and emailing (77.0%) but not with social media (40.0%). Most participants (84.0%) owned computer devices (desktops, laptops, tablets, or iPads), and 92.0% owned mobile devices. In Phase II, participants reported that the app tested was useful to track pain (88.0%), and 94.0% reported that it was easy to use, practical, and useful for health self-management. All reported that the app was useful to help one communicate with providers. Following the use of our app, patients found it an extremely valuable tool for tracking pain, health management, and communicating with providers. We conclude that mobile technology might provide an appropriate venue for sickle cell disease healthcare management.