Sickle Cell-haemoglobin C Research Articles

An experimental erythrocyte rigidity index (Ri) and its correlations with Transcranial Doppler velocities (TAMMV), Gosling Pulsatility Index PI, hematocrit, hemoglobin concentration and red cell distribution width (RDW).

Brain artery velocities (Time-Averaged Maximum Mean Velocity, TAMMV) by Transcranial Doppler (TCD), hematocrit, hemoglobin, Red blood cell (RBC) Distribution Width (RDW) and RBC rigidity index (Ri), when reported together with their correlations, provide a accurate and useful diagnostic picture than blood viscosity measurements alone. Additionally, our study included a sixth parameter provided by TCD, the Gosling Pulsatility Index PI, which is an indicator of CBF (Cerebral Blood Flow) resistance. All these parameters are routine in Hematology except for values of Ri. The rigidity (Ri) of the RBC is the main rheological characteristic of the blood of Sickle Cell Anemia (SCA) patients and several pathologies. However, its quantification depends on many commercial and experimental techniques, none disseminated and predominant around the World. The difference in absorbance values of the blood, during the process of sedimentation in a microwell of a Microplate Reader, is a straightforward way of semi-quantifying the RBC rigidity Ri, since the fraction of irreversibly sickled red blood cells does not form rouleaux. Erythrocyte Rigidity Index (Ri) was calculated using initial absorbance Ainitial (6 s) and final Afinal (540 s), Ri = 1 / (Ai-Af). The Ri of 119 patients (2-17 y / o, M & F) SCA, SCC (Sickle Cell/hemoglobin C), SCD (Sickle Cell/hemoglobin D), Sβ0thal (Sickle Cell/hemoglobin Beta Zero Thalassemia) and 71 blood donors (20-65 y / o, M & F) were measured in our laboratory while the five parameters (TAMMV and PI by TCD, Hct, Hb and RDW) were obtained from medical records. The in vitro addition of hydroxyurea (HU, 50mg /dl, n = 51 patients, and n = 8 healthy donors) in the samples decreased the rouleaux adhesion strength of both donor and patients' blood samples, leading to extraordinarily high Ri values. The correlation between the studied parameters was especially significant for the direct relationships between Ri, TAMMV, and PI.

Pregnancy in sickle cell-haemoglobin C (SC) disease. A retrospective study of birth size and maternal weight gain

ObjectiveTo assess pregnancy and fetal outcomes in Jamaican subjects with sickle cell-haemoglobin C (SC) disease. Study designA retrospective chart review over 21 years (1992–2012) of all pregnancies in SC disease and a comparison group matched by gender and date of delivery in mothers with a normal haemoglobin (AA) phenotype at the University Hospital of the West Indies, Jamaica. There were 118 pregnancies in 81 patients with SC disease and 110 pregnancies in 110 in the normal comparison group. Corrections were made for repeat pregnancies from the same mother. Outcome measures included maternal weight at 20, 25, 30, 35 and 38 weeks gestation, maternal pregnancy complications, birth weight, head circumference and crown heel length and were used to analyse possible predictors of birth weight. ResultsFirst antenatal visits occurred later in women with SC disease, who also had lower haemoglobin level and lower systolic blood pressure. The prevalence of pregnancy-induced hypertension, pre-eclampsia, ante-partum or postpartum haemorrhage did not differ between genotypes. Maternal weight gain was significantly lower in SC disease and there was a significantly lower birth weight, head circumference, and gestational age. ConclusionsPregnancy in SC disease is generally benign but mothers had lower weight gain and lower birth weight babies, the difference persisting after correction for gestational age.

Newborn Screening for Sickle Cell Disease: Jamaican Experience.

To review the history of newborn screening for sickle cell disease with especial reference to Jamaica. A summary was done of the history, the development of associated laboratory technology and the implementation of newborn screening for sickle cell disease in Jamaica. Screening was initiated at Victoria Jubilee Hospital, Kingston from 1973-1981, reactivated in 1995 and extended to the University Hospital of the West Indies in 1997 and to Spanish Town Hospital in 1998. From August 2008, there was a progressive recruitment of 12 hospitals in the south and west of Jamaica which has raised the frequency of islandwide newborn coverage from 25% in 1973 to 81%. The results of this extended programme in southwest Jamaica are presented. Dried blood spots collected from the umbilical cord proved stable, cheap and efficient; mean sample collection rates were 98%, maternal contamination occurred in < 1% and caused diagnostic confusion in < 0.1%. By March 31, 2015, a total of 54 566 births have been screened, detecting 161 with homozygous sickle cell (SS) disease, 125 with sickle cell-haemoglobin C (SC) disease and 36 with sickle cell-beta thalassaemia. Of the 327 babies with clinically significant sickle cell syndromes, all except five who died within seven days of birth were confirmed by four to six weeks and recruited to local sickle cell clinics. Early detection of sickle cell disease and recruitment to clinics is known to reduce its morbidity and mortality. The methods currently detailed provide an effective and economic model of newborn screening which may be of value elsewhere.

Vitreoretinal Management and Surgical Outcomes in Proliferative Sickle Retinopathy: A Case Series

To report the outcomes of current vitreoretinal surgical management of proliferative sickle retinopathy and to compare current methods to previous studies. A retrospective, interventional case series. Fifteen eyes of 14 patients with proliferative sickle retinopathy were managed with vitreoretinal surgery over a 12-year period at a single institution. Nine patients had a sickle cell-hemoglobin C (SC) profile, 1 was sickle cell-beta(+) thalassemia (S beta(+)-thal), and 4 were sickle cell trait (AS). All 15 eyes underwent pars plana vitrectomy (PPV): 6 for vitreous hemorrhage (VH), 1 for epiretinal membrane (ERM), and an additional 8 for tractional retinal detachment (RD) and/or rhegmatogenous RD. In addition, an encircling scleral buckle (SB) was used in 2 cases. In 7 cases, 20 gauge PPV was used; 23 gauge was used in 3; and 25 gauge was used in 5. All 7 eyes with VH or ERM had improved vision postoperatively. Four of the 8 patients with traction and/or rhegmatogenous RD developed recurrent detachments and required a second operation. All retinas were attached at last follow-up, and visual acuity was 20/400 or better in all eyes. No cases of anterior segment ischemia were encountered. Anterior segment ischemia is no longer a common occurrence in eyes undergoing surgery for proliferative sickle retinopathy. Although PPV has replaced the use of SB in many situations, an encircling SB may still be used in this population when necessary. Surgery for VH and ERM generally results in favorable outcomes, but eyes undergoing surgery for traction/rhegmatogenous RD carry a more guarded prognosis.

Severe proliferative retinopathy is associated with blood hyperviscosity in sickle cell hemoglobin-C disease but not in sickle cell anemia

Little is known about the impact of blood rheology on the occurrence of retinopathy in sickle cell disease (SCD). Fifty-nine adult SCD patients in steady-state condition participated to the study: 32 with homozygous SCD (sickle cell anemia; SCA) and 27 with sickle cell hemoglobin-C disease (SCC). The patients underwent retinal examination and were categorized according to the classification of Goldberg: 1) no retinopathy (group 1), 2) non-proliferative or proliferative stage I-II retinopathy (group 2) and 3) proliferative stage III-IV-V retinopathy (group 3). Hematological and hemorheological (whole blood viscosity, RBC deformability and aggregation properties) measurements were performed for each patient. In the whole SCD group (SCA + SCC patients) and in SCC patients, the group 3 had higher platelets count than group 2 but the difference between group 3 and group 1 did not reach statistical significance. No difference was observed for the other parameters between the three groups. SCC patients from the group 3 exhibited higher whole blood viscosity than SCC patients from the group 1. No significant difference was observed between the three groups in SCA patients. This study revealed that severe sickle proliferative retinopathy is associated with blood hyperviscosity in SCC patients but not in SCA patients.

The red cell distribution width in sickle cell disease-is it of clinical value?

The red cell distribution width (RDW) has been studied during the clinical steady state in 1121 patients with homozygous sickle cell (SS) disease, 344 with sickle cell-haemoglobin C (SC) disease, 68 with sickle cell-beta+ thalassaemia, 49 with sickle cell beta 0 thalassaemia and in 130 control subjects with a normal (AA) genotype. The mean RDW was moderately increased in S beta + thalassaemia and SC disease and markedly increased in S beta 0 thalassaemia and SS disease. In SS, SC and S beta 0 thalassaemia genotypes, lower RDW values occurred in females and with alpha thalassaemia. The RDW correlated negatively with total haemoglobin, mean cell haemoglobin concentration, mean cell volume, and fetal haemoglobin (HbF) and positively with reticulocyte count in SS disease. A low RDW was associated with higher weight and less frequent dactylitis, painful crisis, acute chest syndrome, acute splenic sequestration, and hospital admissions. A low RDW in SS disease is consistent with a high total haemoglobin, high HbF, low reticulocyte count, alpha thalassaemia, and a more mild clinical course.

The prevalence of marijuana smoking in young adults with sickle cell disease: a longitudinal study

The active ingredients of marijuana may have beneficial properties in the treatment of chronic pain and inflammation and is being used by sufferers of chronic pain and arthritis in some settings. Anecdotally, marijuana is believed by some sickle cell disease (SCD) patients to improve their health. This study aimed to determine the prevalence of marijuana smoking in the Jamaica Sickle Cell Cohort Study (JSCCS) in the years 2000 and 2004. The perception that marijuana use ameliorated the complications of SCD was also investigated. All patients in the JSCCS were invited to attend an annual review, and during the 2000 and 2004 reviews, participants with homozygous sickle cell (SS) disease and sickle cell haemoglobin-C (SC) disease were asked whether they smoked marijuana, and if they smoked, whether it was used for medicinal purposes related to SCD. The authors compared smoking prevalence by gender, disease, and year of review. The association of smoking with a measure of pain frequency was also examined. The prevalence of marijuana smoking was higher among men and among SC participants. The proportion of either gender reporting smoking of marijuana increased in 2004 compared to 2000, and this use was not related to a simple measure of clinical severity of SCD. Marijuana smoking is common in adults with SCD but its usage is unrelated to clinical severity of the disease.

Fecundity and pregnancy outcome in a cohort with sickle cell‐haemoglobin C disease followed from birth

To compare pregnancy outcome in sickle cell-haemoglobin C (SC) disease with that in homozygous sickle cell (SS) disease and age-matched controls with a normal haemoglobin (AA) genotype. A cohort study followed from birth. Sickle Cell Clinic, University Hospital and other Jamaican hospitals. Ninety-five pregnancies in 43 patients with SC disease, 94 pregnancies in 52 patients with SS disease and 157 pregnancies in 68 controls. Systematic review of all pregnancies occurring in sample population. Kaplan-Meier analysis for interval to first pregnancy, and the t test, chi2 test or Fisher's exact test as appropriate; correction was made for multiple testing and multiple linear regression was used for analysis of determinants of birthweight. Age at menarche, interval to first pregnancy, outcome of pregnancy, maternal complications and possible predictors of low birthweight. Menarche was marginally delayed in SC disease compared with AA controls (median age 13.7 vs 13.0 years, P= 0.02) but age at first pregnancy was similar (median age 22.5 vs 20.1 years, P= 0.32). Pregnancy outcome in SC disease did not differ from AA controls but compared with SS disease there were marginally fewer miscarriages, more live deliveries and greater birthweight. The prevalence of pregnancy-induced hypertension, pre-eclampsia, antepartum or postpartum haemorrhage in SC disease did not differ from AA controls but the prevalence of sickle-related complications was similar to SS disease. Contrary to some claims, pregnancy outcome in SC disease is generally benign compared with SS disease.

Newborn screening for sickle cell disease in Brazil: the Campinas experience

Newborn screening for sickle cell disease commenced in 1992 in Sao Paulo State and by the end of 2000, the programme covered 78 institutions in 36 municipalities with the screening of 281,884 babies. Initially based on liquid cord blood samples, these are being replaced by dried filter paper capillary samples to ease handling and avoid diagnostic confusion from maternal contamination. The prevalence of sickle cell trait (2.0%) and HbC trait (0.6%) increased significantly between 1996 and 2000, apparently because of improved detection rather than the later introduction of institutions serving populations with higher trait frequencies. There were 29 babies with homozygous sickle cell SS disease and 26 with sickle cell-haemoglobin C (SC) disease, the latter significantly exceeding expectation and possibly attributable to a nonrandom selection of partners. Sickle cell-beta thalassaemia syndromes were proportionately more common than in Jamaica, and it is possible that this results from interaction with other Brazilian populations carrying higher beta thalassaemia gene frequencies. The frequency of abnormal haemoglobins in this population is lower than in Jamaica, but clinically significant sickle cell disease occurred once in every 5527 births, comparable with the frequencies of other significant inborn errors of metabolism.

The emerging understanding of sickle cell disease.

The emerging understanding of sickle cell disease.

Pulse oximetry in a cohort study of sickle cell disease.

Oxygen saturation was determined by pulse oximetry in a representative sample of Jamaican patients with steady-state sickle cell disease in a cohort study from birth. There were 220 with homozygous sickle cell (SS) disease and 142 with sickle cell-haemoglobin C (SC) disease aged 9-18 years, and 122 with a normal haemoglobin (AA) genotype aged 15-18 years. Pulse oximetry (SpO2) values were lower in SS disease (mean [95% confidence interval], 92.5 [92.0-93.0]) than in SC disease (96.7[96.5-96.9]) or AA controls (97.1 [96.8-97.3]). Inhalation of 100% oxygen in SS patients with O2 saturations below 90% consistently increased saturation to 99-100%. In SS disease, SpO2 correlated positively with haemoglobin and fetal haemoglobin and negatively with reticulocyte counts but not with MCHC, MCV or bilirubin level. Mean SpO2 in SS subjects with a normal alpha globin gene complement (mean [SD], 91.7 [3.9]%) was lower than in heterozygotes (93.4 [4.0]%) or homozygotes (96.1 [3.0]%) for alpha+ thalassaemia, the effects of alpha-thalassaemia not being explained by differences in haemoglobin or MCHC. In SS disease, SpO2 levels were not associated with age (within this age range), sex, number of sick clinic visits or number of hospital admissions. Higher SpO2 levels were associated with greater height and weight, more frequent painful crises and less frequent acute chest syndrome, but these associations were not significant after adjustment for haemoglobin level. Desaturation is common in steady-state SS disease and knowledge of the individual's steady-state value may be important in the interpreting low values during acute complications.

INDEX OF SUSPICION

This section of Pediatrics in Review reminds clinicians of those conditions that can present in a misleading fashion and require suspicion for early diagnosis. Emphasis has been placed on conditions in which early diagnosis is important and that the general pediatrician might be expected to encounter, at least once in a while. The reader is encouraged to write possible diagnoses for each case before turning to the discussion, which is on the following page. We invite readers to contribute case presentations and discussions. Case 1 Presentation A 4-year-old boy who has SC (sickle cell-hemoglobin C) hemoglobinopathy comes to the Resident Practice Group Clinic for a preschool evaluation. At present he has no complaints, although he has had several hospital admissions related to febrile illnesses and painful crises from his sickle cell disease. He has been receiving penicillin prophylaxis and folic acid supplementation. A complete blood count yields the following findings: white blood cell count, 27 900/mm3, with 1% band forms, 19% segmented neutrophils, 26% lymphocytes, 9% monocytes, and 45% eosinophils; hemoglobin, 10.9 g/dL; hematocrit, 31.8%; and platelet count, 464 000/mm3. Further evaluation is undertaken because of his abnormal hematologic picture, revealing two unsuspected conditions. Case 2 Presentation Twins are born after a 29-week first pregnancy to healthy parents.

Sickle cell disease: Recent advances

Diagnosis The term sickle cell disease encompasses several distinct genetic disorders, the most common of which is sickle cell anemia (homozygous sickle ceil disease or SS disease), which occurs in 1 of 450 black neonates. Somewhat less common are sickle cell-hemoglobin C (SC) disease and sickle cell-p thalassemia (S-p thalassemia, which includes both the p’ and p” variants). Sickle trait (which affects 8% of all African-Americans) is not considered a disease. The diagnosis of these conditions is based on history of disease complications, physical findings (jaundice, pallor, cardiac murmurs, splenomegaly), routine hematologic tests (hemoglobin, mean cell volume, peripheral blood smear), sickle solubility test, and hemoglobin electrophoresis or isoelectric focusing. A major advance during the past decade has been the widespread implementation in most states of neonatal screening programs, which have allowed sickle hemoglobinopathies to be diagnosed at birth and confirmed shortly thereafter. This fosters early education of parents and primary physicians. It also encourages implementation of preventive care practices, such as twice daily oral prophylactic penicillin and instructing parents to palpate the spleen. Neonatal screening programs now exist in

Influence of genotype on the natural history of untreated proliferative sickle retinopathy--an angiographic study.

The natural history of untreated proliferative sickle retinopathy (PSR) has been observed in 35 patients (40 eyes) with homozygous sickle cell (SS) disease and in 112 patients (114 eyes) with sickle cell-haemoglobin C (SC) disease over a mean follow-up period of 4.5 years (range 0.5-14.0 years). In both genotypes progression of PSR was most frequent between ages 20 and 39 years. Spontaneous regression was more common in SS disease (p = 0.01), and more likely to proceed to complete non-perfusion. In SC disease PSR tended to be stable in patients aged 40 and over, and non-perfused PSR lesions were significantly more likely to reperfuse (p = 0.01) than in SS disease. In both genotypes regression was not influenced by size or elevation of the PSR lesion. The tendency for PSR to regress in SS disease suggests that treatment is unnecessary in SS patients aged 40 and over.

Patterns of visual loss in untreated sickle cell retinopathy.

Ophthalmic assessments of 120 patients with homozygous sickle cell (SS) disease and of 222 with sickle cell haemoglobin-C (SC) disease were conducted over a period of ten years. Visual acuity loss (V.A. less than or equal to 6/18) attributable to sickle cell retinopathy occurred in 10% of untreated eyes during a mean observation period of 6.9 years. Visual loss was strongly associated with proliferative sickle retinopathy (p less than 0.001) and most commonly resulted from vitreous haemorrhage, tractional retinal detachment and epiretinal membranes. The incidence of visual loss was 31 per 1000 eye-years observation among eyes with proliferative disease compared to 1.4 per 1000 eye-years observation among eyes with non-proliferative disease.

Hemolysis in sickle cell disease as measured by endogenous carbon monoxide production. A preliminary report.

To detect and quantitate temporal variations of the hemolytic rate in sickle cell disease, the authors measured endogenous carbon monoxide (CO) production in five normal subjects, nine patients with sickle cell anemia (SS) in steady clinical state, and two patients with sickle cell-hemoglobin C (SC) disease in and out of pain crises. The red blood cell life span calculated from these data (RCLSco) ranged from 81.2 to 102.9 days (mean +/- standard deviation [SD] 88.0 +/- 9.2, coefficient of variation [CV] 10.2%) for the normal subjects and 8.0-24.7 days (mean +/- SD 12.1 +/- 5.1, CV 42.1%) for those with SS. Although the individual figures for RCLSco for the normal subjects and those with SS fell within the range previously obtained by radioisotopic techniques for the respective groups, the mean values calculated from the CO technique were slightly (though not significantly) shorter for the normal subjects and about 25% shorter for the subjects with SS (P less than 0.01). Repetitive studies were performed in four subjects with SS who were clinically stable; the temporal variability in the calculated hemolytic rate differed considerably from patient to patient (CV 3.6%, 7.0%, 17.0%, 28.0%). In two patients concurrent RCLS studies were performed by the CO technique and 51Cr tagged red blood cells. In one patient, the RCLS was similar by the two techniques, in the other, a two exponent 51Cr curve did not permit calculation of RCLS. In the two patients with SC disease there was no difference in RCLSco during and after recovery from pain crisis. Although the CO technique may overestimate the turnover of circulating heme mass, especially in the presence of hemolysis, the results of serial studies in a small number of patients with SS suggest but do not prove temporal variations in hemolytic rate in SS.

Epiretinal membranes in sickle cell disease.

Epiretinal membranes at the macula were seen in 4% of the eyes of 355 patients with homozygous sickle cell (SS) disease and sickle cell haemoglobin-C (SC) disease under the age of 60 years. The presence of proliferative sickle retinopathy (PSR), the extent of involvement of PSR, and vitreous haemorrhage all constitute risk factors for the formation of epiretinal membranes. The occlusion of PSR lesions by treatment appears to reduce the risk of epiretinal membranes being formed.

Bacteremia in sickle hemoglobinopathies

We analyzed 178 episodes of bacteremia that occurred during 13,771 patient-years of follow-up of 3451 patients with sickle hemoglobinopathies. Age-specific incidence rates of bacteremia were calculated for patients with sickle cell anemia (SS) and sickle cell-hemoglobin C (SC) disease. The incidence rate was highest among children with SS and SC younger than age 2 years. Children with SC showed an abrupt decrease after age 2 years, whereas children with SS had a gradual decline in rate from 2 to 6 years of age. The predominant pathogen in patients younger than 6 years was Streptococcus pneumoniae (66%); gram-negative organisms were responsible for 50% of bacteremias in patients 6 years and older. Urinary tract infection was present during 73% of Escherichia coli bacteremias, and 77% of Salmonella bacteremias were associated with osteomyelitis. In contrast, no focus of infection was present in 52% of pneumococcal bacteremias. The incidence of pneumococcal bacteremia in children with SS younger than age 3 years was 6.1 events/100 patient-years; the case fatality rate for pneumococcal sepsis in this age group was 24%. No hematologic or demographic variables were associated with occurrence of pneumococcal bacteremia in young children. Retrospective analysis of pneumococcal bacteremia suggests that the prophylactic use of penicillin may decrease the incidence in children younger than 3 years of age.

Haematological change in sickle cell-haemoglobin C disease and in sickle cell-beta thalassaemia: a cohort study from birth.

The haematological changes in early years following neonatal diagnosis have been observed in representative groups of children with sickle cell-haemoglobin C (SC) disease, sickle cell-beta(+) thalassaemia, and in sickle cell-beta(0) thalassaemia. Most haematological indices in SC disease were intermediate between previously published values in SS disease and in AA controls, generally being closer to values in normal children. Exceptions were microcytosis which may be genetically determined and a striking elevation of mean cell haemoglobin concentration from age 2 months to 4 years. The combination of a raised MCHC and a lowered MCV is unusual and may be characteristic of SC disease. Features in sickle cell-beta thalassaemia generally differed according to the type of beta thalassaemia gene. Sickle cell-beta(0) thalassaemia had lower levels of haemoglobin, MCHC, red cell count, MCV, and higher reticulocytes, most differences being significant before 1 year. No differences between S beta(0) thalassaemia and S beta(+) thalassaemia were apparent in HbF levels (which resembled those in SS disease) or in HbA2 levels (which exceeded those in SS disease by 1 year of age).

Sickle cell retinopathy in Jamaican children: a search for prognostic factors.

Children with homozygous sickle cell (SS) disease and with sickle cell-haemoglobin C (SC) disease, aged 6 1/2 to 8 1/2 years, were examined by fluorescein angiography/angioscopy to determine the presence of retinal nonperfusion. The haematological and clinical features of children with and without nonperfusion were compared. Retinal vessel closure was significantly correlated with low total haemoglobin, and high fetal haemoglobin, reticulocyte, and irreversibly sickled cell counts in SS disease, and with high reticulocyte count in SC disease. No relationships were apparent between vessel closure and other haematological indices or clinical events in either genotype.