Course Of Sickle Cell Disease Research Articles

Survival of F-Reticulocytes in Sickle Cell Disease

Fetal hemoglobin, Hb F, is known to be an important factor for clinical course of sickle cell disease, as it suppresses polymerization of sickle hemoglobin. To investigate the effect of Hb F on the survival of sickle reticulocytes (young red cells) in circulation, Hb F levels in individual reticulocytes and mature erythrocytes were quantified via fluorescence image cytometry. We first examined unfractionated SS cells from 3 patients with different Hb F levels, and found that Hb F levels in reticulocyte populations were always lower than those in erythrocyte populations. This suggests that subsets of reticulocytes with lower Hb F levels are removed during maturation while those with higher Hb F levels tend to survive to become erythrocytes. The distribution of Hb F in reticulocytes was different among these patients and seems to strongly affect the survival of F-reticulocytes. We also analyzed density-separated fractions, and found that Hb F levels in reticulocytes found in the densest fraction were lower than those in lighter fractions. This suggests that reticulocytes with lower Hb F levels are susceptible to quick dehydration within their maturation period (1-2 days) in circulation.

Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia

In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P < 0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P < 0.001), and fewer underwent transfusions (48 vs. 73, P = 0.001). At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. Treatment with hydroxyurea did not cause any important adverse effects. Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.

A cautionary note regarding hydroxyurea in sickle cell disease

Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

A Cautionary Note Regarding Hydroxyurea in Sickle Cell Disease

AbstractHydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients’ drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31 %). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued. Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21 % before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

Recombinant Erythopoietin in Pediatrics: A Clinical Perspective

Recombinant human erythropoietin represents a potential therapeutic alternative to red blood cell transfusions in a number of pediatric anemias. It is effective in correcting anemia associated with chronic renal failure and may significantly reduce the morbidity associated with childhood CRF. Most exposures to allogeneic blood products in pediatrics for treatment of anemia with blood transfusions occur in neonatal intensive care units. If proven effective in treating anemia in premature babies, r-HuEPO will be responsible for a major reduction in the use of blood transfusions in clinical neonatology. Carefully designed, placebo-controlled clinical trials will be required to establish the role of r-HuEPO in anemia of prematurity. Recombinant human erythropoietin also may be useful to increase the amount of blood that can be collected before elective surgical procedures. Another potential indication is to raise the hematocrits of infants with large intracardiac shunts who develop congestive heart failure coincident with the developmental fall in hemoglobin concentration after birth. Finally, r-HuEPO may one day play a role in modifying the expression of globin genes and, thereby, ameliorate the course of sickle cell disease and beta thalassemia. Many questions surrounding the use of r-HuEPO in infancy and childhood are being addressed in ongoing clinical trials.

Newborn Experience in the Cooperative Study of Sickle Cell Disease

In 1978, the National Heart, Lung, and Blood Institute of the NIH initiated a large-scale, multiinstitutional collaborative study to investigate the clinical course of sickle cell disease from birth to death. Twenty-three institutions participate in the cooperative study, of which 19 have pediatric components. Newborn screening is performed in 18 institutions. Centers are located along the east coast, and in the South, the Midwest, and California. Both rural and urban populations are represented in the study. This Cooperative Study of Sickle Cell Disease has been described in detail. MATERIALS AND METHODS Newborn screening began in late 1978, and patient entry began in 1979. Between late 1978 and August 1986, 633 infants were found to have a hemoglobin pattern of FS and 326 were found to have FSC. A major effort was made to enroll these infants with sickle cell disease in the cooperative study. Other infants whose diseases were not diagnosed by screening but referred to the centers were also enrolled. From these two sources a total of 600 infants less than 6 months of age had been enrolled in the study as of August 1986. Diagnoses were established by cellulose acetate and citrate agar gel electrophoreses or by isoelectric focusing studies. The children have been followed up regularly at the study centers. Visits are scheduled for the ages of 2, 4, 6, 9, 12, 15, 18, 21, and 24 months and twice yearly thereafter. During the visits an interval history is obtained, a complete physical examination is performed, and developmental state is assessed.

Recruitment in the Cooperative Study of Sickle Cell Disease (CSSCD)

The Cooperative Study of Sickle Cell Disease (CSSCD) is a multiinstitutional investigation of the natural history of clinical course of sickle cell disease from birth through adulthood. The study is not a trial; rather, it involves data collection at 23 institutions in a uniform, standardized fashion on 3800 patients. Recruitment aspects that were addressed include issues related to recruitment of different age groups, ranging from newborns to pregnant women to patients over 50 years of age; the need to include mildly affected patients to ensure that the study would not reflect only a severe hospital-based population; recruitment from rural populations; and the need to screen and enter a newborn population at birth. The recruitment goal of entering 3200 patients, including 2100 patients with SS hemoglobinopathy, over a 24-month period was accomplished after 27 months.

Sickle-Cell Disease. A Handbook for the General Clinician

This is a small paperback book which is designed to be used by physicians who care for patients with sickle-cell disease. It is the first book of its kind written in Africa for Africans. Although aimed at tropical Africa, it will be of use to physicians in other parts of the world where sickle-cell disease occurs. The book consists of nine chapters and three appendices which were written by eight contributing authors including the editor, Dr. A. F. Fleming. All have academic appointments in Nigeria.The book opens with a historical introduction and an explanation of the molecular biology and the nature of inheritance of hemoglobinopathies. The mathematical basis of population genetics is presented in one page. There are three chapters on the clinical course of sickle-cell disease, one each on the pathology and radiology of the disease and laboratory diagnosis.The distinguishing feature of this booklet is its conciseness.

Glucose 6-Phosphate Dehydrogenase Deficiency and Sickle Cell Anemia: Frequency and Features of the Association in an African Community

The glucose 6-phosphate dehydrogenase (G6PD) genotype was determined in 100 male patients with homozygous sickle cell anemia (SS) by a combination of quantitative assay, cytochemical testing, and starch-gel electrophoresis. Of the 100 patients tested, 16 were found to be G6PD deficient (GdA-), AND 84 G6PD normal (22GsA and 62 GdB). This distribution of G6PD genotypes did not differ significantly from that observed in the general population. The level of G6PD activity in GdA- SS patients was nearly always higher than in G6PD-deficient subjects who did not have an associated hemolytic state, but it was nearly always lower than in G6PD-normal subjects. The clinical course of sickle cell disease, including the degree of anemia, was not milder in GdA- than in G6PD-normal patients but could not be proved to be significantly more severe. It was concluded that in this community the incidence of G6PD deficiency in sickle cell anemia was not greater than would be expected by chance, and there was no evidence that the coexistence of the GdA- gene in SS patients ameliorated their disease.

Glucose 6-phosphate dehydrogenase deficiency and sickle cell anemia: frequency and features of the association in an African community

The glucose 6-phosphate dehydrogenase (G6PD) genotype was determined in 100 male patients with homozygous sickle cell anemia (SS) by a combination of quantitative assay, cytochemical testing, and starch-gel electrophoresis. Of the 100 patients tested, 16 were found to be G6PD deficient (GdA-), AND 84 G6PD normal (22GsA and 62 GdB). This distribution of G6PD genotypes did not differ significantly from that observed in the general population. The level of G6PD activity in GdA- SS patients was nearly always higher than in G6PD-deficient subjects who did not have an associated hemolytic state, but it was nearly always lower than in G6PD-normal subjects. The clinical course of sickle cell disease, including the degree of anemia, was not milder in GdA- than in G6PD-normal patients but could not be proved to be significantly more severe. It was concluded that in this community the incidence of G6PD deficiency in sickle cell anemia was not greater than would be expected by chance, and there was no evidence that the coexistence of the GdA- gene in SS patients ameliorated their disease.

Kinetics and mechanism of deoxyhemoglobin S gelation: a new approach to understanding sickle cell disease.

We report the results of a kinetic investigation on the gelation of purified deoxyhemoglobin S. Gelation was induced by raising the temperature and was monitored by measuring both the heat absorbed, with a microcalorimeter, and the appearance of linear birefringence, with a microspectrophotometer. The kinetics are unusual. Prior to the onset of gelation there is a delay period, followed by a sigmoidal progress curve. The delay time is formally dependent on approximately the 30th power of the deoxyhemoglobin S concentration; a decrease in concentration from 23 to 22 g/dl increases the delay time by a factor of four. It is also extremely temperature dependent; a 1 degrees C temperature rise in the range 20-30 degrees C almost halves the delay time. From these results we conclude that the initial rate is controlled by the nucleation of individual fibers. We present a kinetic model that accounts for the concentration, temperature, and time dependence of the initial phase of the gelation reaction. Extrapolation of our data to physiological conditions predicts that changes in intracellular hemoglobin concentration and oxygen saturation, realizable in vivo, produce enormous changes in the delay time. The range of delay times spans both the mean capillary transit and total circulation times. This result points to the delay time as an extremely important variable in determining the course of sickle cell disease, and suggests a new approach to therapy.

Sickle States: Clinical Features in West Africans

This timely and interesting monograph deals with sickle cell disease and other inherited hemoglobinopathies found in West Africans. Much of the text is written in a clear, crisp style that effectively describes the clinical aspects of the disease in a panoramic style. The chapters dealing with sickle cell disease in infancy, childhood, and maturity, and those stressing the complications encountered by the afflicted during pregnancy and surgery are extremely comprehensive and will be of interest to physicians managing sickle cell patients with these problems. The influence of malaria on the course of sickle cell disease and its effect on the spleen is emphasized vividly. Malaria is the chief cause of morbidity and mortality in West Africans with sickle cell disease. The interrelationships of sickle cell with glucose 6-phosphate deficiency and thalassemia are also described effectively from the clinician's standpoint. Pertinent illustrations and highly informative tables accompany each clinical chapter. Rather

Effect of carbonic anhydrase inhibitors on the course of sickle-cell disease.

The inhibition of carbonic anhydrase in the mature erythrocyte has been utilized by Hilkovitz¹as a therapeutic measure in the treatment of sickle-cell disease. Evidence presented in his observations suggests that definite beneficial results may be expected when the inhibitor, acetazolamide, is administered in the recommended dosage. The logic of this procedure, as presented, is based on the knowledge that carbonic anhydrase, an enzyme present in the mature erythrocyte, catalyzes the reversible reaction. Inhibition of this reaction in sickle-cell disease could presumably affect the degree of hemoglobin reduction and diminish in vivo sickling, with a subsequent increase in erythrocyte count. His optimistic approach to the therapy of sickle-cell disease warranted further evaluation. The purpose of this communication is to present our findings after administration of comparable amounts of carbonic anhydrase inhibitors to subjects having sickle-cell disease. <h3>Clinical Material</h3> Four adult patients having sickle-cell disease were studied. Electrophoretic patterns, genetic

Observation on the genesis of crises in sickle cell anemia.

Case Reports1 June 1959OBSERVATION ON THE GENESIS OF CRISES IN SICKLE CELL ANEMIAJ. C. S. PATERSON, C. C. SPRAGUEJ. C. S. PATERSONSearch for more papers by this author, C. C. SPRAGUESearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-50-6-1502 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe periodic crises which punctuate the natural course of sickle cell anemia were separated by Singer and his colleagues17in 1950 into the following categories: (a) the "aplastic" crisis, (b) the "hyperhemolytic" crisis, and (c) "the aplastic-hyperhemolytic" crisis, in which there is both an abeyance of the delivery of cells from the marrow and an increase in the rate of hemolysis of the circulating red cells. This hematologic classification has been generally accepted, but with more emphasis put upon the "thrombotic," "infarctive" or "symptomatic" crisis, an episode of fever and pain, without any significant change in the hemoglobin level.9, 19,...Bibliography1. AndersonBusby GWT: Sickle cell anemia and pregnancy, Am. J. Obst. and Gynec. 58: 75, 1949. CrossrefMedlineGoogle Scholar2. Barcroft J: The respiratory function of the blood. Part II. Haemoglobin, 2nd Ed., 1928, Cambridge University Press, London. Google Scholar3. BauerFisher JLJ: Sickle cell disease with special regard to its nonanemic variety, Arch. Surg. 47: 553, 1943. CrossrefGoogle Scholar4. BeachamBeacham WDDW: Sickle-cell disease and pregnancy, Am. J. Obst. and Gynec. 60: 1217, 1950. CrossrefMedlineGoogle Scholar5. ConleyMartinRecinos JRMBA: Sickle cell anemia. Special report, Clin. Proc. Child. Hosp. 6: 101, 1950. Google Scholar6. Connell JH: Cerebral necrosis in sickle cell disease, J. A. M. A. 118: 893, 1942. 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The biophysics and biology of sickle-cell disease, Arch. Int. Med. 97: 145, 1956. CrossrefGoogle Scholar13. Henderson AB: Sickle cell anemia. Clinical study of fifty-four cases, Am. J. Med. 9: 757, 1950. CrossrefMedlineGoogle Scholar14. Herrick JB: Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia, Arch. Int. Med. 6: 517, 1910. CrossrefGoogle Scholar15. Huck JG: Sickle cell anaemia, Bull. Johns Hopkins Hosp. 34: 335, 1923. Google Scholar16. Singer K: The pathogenesis of sickle cell anemia. A review, Am. J. Clin. Path. 21: 858, 1951. CrossrefMedlineGoogle Scholar17. SingerMotulskyWile KAGSA: Aplastic crisis in sickle cell anemia. A study of its mechanism and its relationship to other types of hemolytic crisis, J. Lab. and Clin. Med. 35: 721, 1950. MedlineGoogle Scholar18. Tomlinson WJ: A study of the circulation of the spleen in sicklemia and sickle cell anemia, Am. J. Clin. Path. 11: 835, 1941. CrossrefGoogle Scholar19. Watson RJ: The hereditary anemias, Bull. New York Acad. Med. 30: 106, 1954. MedlineGoogle Scholar20. WatsonLichtmanShapiro RJHCHD: Splenomegaly in sickle cell anemia, Am. J. Med. 20: 196, 1956. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: New Orleans, Louisiana*Received for publication October 22, 1957.From the Department of Medicine, Tulane University Medical School, New Orleans, Louisiana.†This observation was made in the course of studies undertaken in connection with an award to Dr. G. E. Burch, Chairman of the Department of Medicine, by the John Simon Guggenheim Memorial Foundation for studies of sickle cell anemia and of methods for its treatment.Requests for reprints should be addressed to J. C. S. Paterson, M.D., Department Tropical Medicine and Public Health, The Tulane University of Louisiana, 1430 Tulane Avenue, New Orleans 12, Louisiana. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byNew Concepts in the Immunology of Sickle Cell DiseaseAbnormal neutrophil adhesion in sickle cell anaemia and crisis: relationship to blood rheologyChronic tonsillitis, tonsillectomy and sickle cell crisesInfections in Sickle Cell DiseaseGenetic ScreeningDanger lists for the anaesthetist.Sickle-cell disease and its surgical implications in the African childDanger lists for the anaesthetistThe influence of hemoglobinopathies on reproductionSICKLE-CELL DISEASE IN PREGNANCY 1 June 1959Volume 50, Issue 6Page: 1502-1507KeywordsAnemiaAplastic anemiaBone marrowFeversHemoglobin ePublished: 1 December 2008 Issue Published: 1 June 1959 PDF downloadLoading ...