Hydroxyurea-induced splenic regrowth in an adult patient with severe hemoglobin SC disease

Hydroxyurea has been extensively used in patients with sickle cell anemia and severe sickle cell-hemoglobin C (SC) disease to reduce the severity of their diseases. We report here our experience with an adult patient with severe SC disease who developed symptomatic splenomegaly requiring splenectomy while being treated with hydroxyurea. This case suggests that hydroxyurea might restore some splenic function in functionally asplenic patients with sickle cell anemia or SC disease, but also raises the clinical concern that hydroxyurea may induce splenic regrowth, resulting in symptomatic splenomegaly. With the increasing use of hydroxyurea in the management of SS disease or other hemoglobinopathies, the importance of spleen monitoring must be further emphasized in these patients.     

Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease [see comments]

Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.     

Pathology of Berkeley sickle cell mice: similarities and differences with human sickle cell disease

Because Berkeley sickle cell mice are used as an animal model for human sickle cell disease, we investigated the progression of the histopathology in these animals over 6 months and compared these findings to those published in humans with sickle cell disease. The murine study groups were composed of wild-type mixed C57Bl/6-SV129 (control) mice and sickle cell (SS) mice (alpha-/-, beta-/-, transgene +) of both sexes and between 1 and 6 months of age. SS mice were similar to humans with sickle cell disease in having erythrocytic sickling, vascular ectasia, intravascular hemolysis, exuberant hematopoiesis, cardiomegaly, glomerulosclerosis, visceral congestion, hemorrhages, multiorgan infarcts, pyknotic neurons, and progressive siderosis. Cerebral perfusion studies demonstrated increased blood-brain barrier permeability in SS mice. SS mice differed from humans with sickle cell disease in having splenomegaly, splenic hematopoiesis, more severe hepatic infarcts, less severe pulmonary manifestations, no significant vascular intimal hyperplasia, and only a trend toward vascular medial hypertrophy. Early retinal degeneration caused by a homozygous mutation (rd1) independent from that causing sickle hemoglobin was an incidental finding in some Berkeley mice. While our study reinforces the fundamental strength of this model, the notable differences warrant careful consideration when drawing parallels to human sickle cell disease.     

Epidemiological and clinical study of sickle cell disease in France,French Guiana and Algeria

Abstract: The main clinical and haematological features of sickle cell patients were compared in 618 French, 50 Guianese and 87 Algerian patients. In homozygous sickle cell patients, the proportion of icteric subjects rises with age in all centres; the prevalence of splenomegaly reaches a peak in children from 1 to 5 years and then decreases; jaundice and splenomegaly are more often noted in Algerian and Guianese than French patients. The prevalence of painful crisis is comparable in the 3 centres. In 465 French SS children, having a mean age of 7.3 ± 5.9 years, the prevalence of a past history of meningitis is 7.3%, of septicaemia 4.1% of osteomyelitis 8.8%. These percentages do not differ significantly between countries. Prevalence of a past history of cerebrovascular accident is 3.2% in French SS patients; 1.2% in SC, 3.8% in Sβ thalassaemia. A past history of acute splenic sequestration was noted significantly more often in SS (11.75%) and Sβ thalassaemia (14.3%) than SC (3.6%) in French children (p < 0.05). Proportions of subjects transfused at least once do not differ between countries; SS children are more transfused (64%) than SC (15.6%) and Sβ thalassaemic (66%) (p < 10–4). Haemoglobin and reticulocyte counts do not differ significantly between countries. In conclusion, no major differences were detected between French, Guianese and Algerian homozygous sickle cell patients: this may be due to the fact that France is in itself a mosaic of ethnic origins.     

Fibrocongestive splenomegaly in sickle cell disease: a distinct clinicopathological entity in the Eastern province of Saudi Arabia

Sickle cell disease displays a unique progression in the Eastern province of Saudi Arabia, where splenomegaly with hypersplenism is noted with high frequency in the adolescent and adult patients. The late persistence of splenomegaly although likely reflects the milder progression of sickle cell disease in this region; nevertheless, it predisposes the patients to increased morbidity. The present study documents the characteristic clinicopathological features of splenomegaly associated with sickle cell disease in the Al-Hassa region of Eastern province Saudi Arabia. Forty-four cases of sickle cell disease patients in whom splenectomy was performed during 1999-2003 were studied. The hemoglobinopathy profiles of the patients (age range 5-42 years) comprised sickle cell anemia (8 cases), sickle cell anemia with high fetal hemoglobin (23 cases), and sickle cell-beta degrees thalassemia (13 cases). All patients had manifestations of hypersplenism and 39 patients experienced episodes of minor-type sequestration crisis. Splenectomy was effective in ameliorating the hematological abnormalities in all cases, without any major complications in the follow-up period. The splenectomy specimens showed moderate-to-marked enlargement in most cases, with histological features of fibrocongestive splenomegaly and prominent Gandy-gamma body formations. Micro-infarcts in 27 cases and gross infarctions in 9 cases were evident. The relationship of persistent splenomegaly with higher fetal hemoglobin levels and splenic hypofunction is examined along with the significance of splenectomy in these cases.     

Endotoxinaemia in sickle cell disease

Fifty-nine children with sickle cell anaemia (HbSS) or associated haemoglobinopathies were studied prospectively using a chromogenic Limulus amoebocyte lysate assay to detect circulating endotoxin. The 41 children with HbSS (mean age 8 years 9 months) had more serious disease than the 18 with HbSC disease (n = 14) or HbS-beta-thalassaemia (n = 4) (mean age 7 years 2 months), with a greater degree of splenomegaly, lower haemoglobin, and higher white cell counts, platelet counts and bilirubin values (P less than 0.05 for all). Twenty-nine children with HbSS had evidence of poor reticuloendothelial function, with red cell pitting of greater than or equal to 2%. Three of these 29 had low levels of endotoxin in plasma (0.12-0.24 endotoxin units (EU)/ml); two were clinically well, one had a painful crisis. Eight of 18 children with other sickle haemoglobinopathies had greater than or equal to 2% pitted red cells; none was endotoxinaemic. Therefore, in 37 patients with reticuloendothelial dysfunction, three were endotoxinaemic; all had sickle cell anaemia. Although not statistically significant, this suggests that endotoxinaemia may occur predominantly in patients with reticuloendothelial dysfunction, and is compatible with the hypothesis that systemic endotoxinaemia can derive from the intestine especially when reticuloendothelial function is depressed.     

A long-term study of patients with chronic natural killer cell lymphocytosis

Chronic natural killer cell lymphocytosis is a persistent state of natural killer (NK) cell (CD3-CD16/CD56+) excess in the peripheral blood that is not associated with clinical lymphoma. In 16 consecutive patients (median age 60.5 years, range 7-77), males were overrepresented (M:F 7:1) and the median absolute NK cell count was 4.09 x 10(9)/l (range 1.2-16.6). Bone marrow examination was performed in 14 patients and showed atypical granulomata in two; chromosome studies in seven patients were normal. Clonal T-cell receptor gene rearrangement was not found in any of 12 patients evaluated. At presentation, seven patients (44%) had no clinical symptoms or signs and the others had vasculitic skin lesions (three patients), non-neutropenic fever (three patients), recurrent neutropenic infection (two patients), musculoskeletal symptoms (two patients), peripheral neuropathy (two patients), aphthous ulcers (one patient), and splenomegaly (one patient). Five patients had anaemia, five had neutropenia, and two had thrombocytopenia. After a median follow-up of 5.1 years (range 0-10.2) from immunophenotypic diagnosis or 5.7 years (range 0.1-14.1) from documentation of absolute lymphocytosis, vasculitic glomerulonephritis developed in one patient, accelerated splenomegaly developed in a patient receiving myeloid growth factor treatment, and severe aplastic anaemia developed in one patient. Treatment with nonsteroidal anti-inflammatory drugs or immunosuppressive agents was variably successful.     

Reduced levels of T-cell subsets CD4+ and CD8+ in homozygous sickle cell anaemia patients with splenic defects

T-lymphocyte subsets were studied in two patient groups: (1) 50 patients with homozygous sickle cell anaemia (SCA) (mean age 12 (range 3-32) years old) in good health at the time of the study who showed no infectious complication. (2) 50 patients (mean age 13 (range 4-29) years old) with normal haemoglobin rate. The global response revealed a significant increase in levels of CD3+ (P=0.04) and CD8+ (P=0.04) cells when compared with the control group, there was no significant difference in levels of CD4+ cells (P=0.05) between the two groups. However, there was a relationship between T-cell subpopulation levels and spleen status. The average values of T-cell subsets (CD4+ and CD8+) in patients with SCA-induced splenic defects (asplenic, splenomegaly or splenectomized patients) were significantly reduced when compared to SCA patients with normal spleens and the control groups. These data show that T-cell activity was reduced in patients with splenic defects. A correlation between splenic status and a perturbed host defence system in patients with SCA suggests that monitoring T-cell subsets might have prognostic value in the course of sickle cell disease.     

Sickle cell β-thalassaemia compared with sickle cell anaemia in Algeria

Clinical, haematological and biochemical features in 42 subjects with S-beta thalassaemia (31 subjects with S-beta° thalassaemia and 11 subjects with S-beta⁺ thalassaemia); and in 42 with homozygous sickle cell disease were compared. Persistent splenomegaly was more common and painful crises less common in the S-beta thalassaemia group. Total Hb was higher and reticulocyte count lower in S-beta⁺ thalassaemia than in S-beta° thalassaemia or SS disease. Microcytosis was marked in the S-beta thalassaemia group while the MCV was normal in sickle cell anaemia. Hb F was significantly higher in the S-beta° thalassaemia group, without any influence on the severity of the disease. Many features suggest that sickle cell thalassaemia is more severe in Algeria than in Negro subjects and similar to the disease in Italian patients.     

Sickle cell beta-thalassaemia compared with sickle cell anaemia in Algeria

Clinical, haematological and biochemical features in 42 subjects with S-beta thalassaemia (31 subjects with S-beta thalassaemia and 11 subjects with S-beta+ thalassaemia); and in 42 with homozygous sickle cell disease were compared. Persistent splenomegaly was more common and painful crises less common in the S-beta thalassaemia group. Total Hb was higher and reticulocyte count lower in S-beta+ thalassaemia than in S-beta thalassaemia or SS disease. Microcytosis was marked in the S-beta thalassaemia group while the MCV was normal in sickle cell anaemia. Hb F was significantly higher in the S-beta thalassaemia group, without any influence on the severity of the disease. Many features suggest that sickle cell thalassaemia is more severe in Algeria than in Negro subjects and similar to the disease in Italian patients.     

Effect of blood transfusion on iron status in sickle cell anaemia

The iron status of 31 patients with sickle cell anaemia (Hb SS) and balanced globin chain synthesis was studied. Twelve patients (group I) had never been transfused; 14 had received up to 4 units of blood in the past (group II) and five had been hypertransfused for 6 months to 2 years (group III). The hypertransfused group had significantly higher MCV and MCH than the nontransfused one, and significantly lower total iron binding capacity and higher serum ferritin concentration than either groups I or II. The serum ferritin concentration was lower than normal in eight patients (five in group I and three in group II), and higher than normal in seven patients (four in group III and three in group II). The remaining 16 patients had normal serum ferritin concentrations. Our results indicate that iron overload is uncommon in adults with Hb SS who have not been transfused, and that a proportion of patients have lower than normal serum ferritin concentrations. Transfused patients, even 6 months after the last transfusion, show increased haemoglobin content of red cells, which may have an adverse effect on the frequency and severity of sickle crises.     

Massive splenic infarction in Saudi patients with sickle cell anemia: a unique manifestation

Splenic infarcts are common in patients with sickle cell anemia (SCA), but these are usually small and repetitive, leading ultimately to autosplenectomy. Massive splenic infarcts on the other hand are extremely rare. This is a report of our experience with 8 (4 males and 4 females) cases of massive splenic infarction in patients with SCA. Their ages ranged from 16 to 36 years (mean 22 years). Three presented with left upper quadrant abdominal pain and massive splenic infarction on admission, while the other 5 developed massive splenic infarction while in hospital. In 5 the precipitating factors were high altitude, postoperative, postpartum, salmonella septicemia, and strenuous exercise in one each, while the remaining 3 had severe generalized vasoocclusive crises. Although both ultrasound and CT scan of the abdomen were of diagnostic value, we found CT scan more accurate in delineating the size of infarction. All our patients were managed conservatively with I.V. fluids, analgesia, and blood transfusion when necessary. Diagnostic aspiration under ultrasound guidance was necessary in two patients to differentiate between massive splenic infarction and splenic abscess. Two patients required splenectomy during the same admission because of suspicion of secondary infection and abscess formation, while a third patient had splenectomy 2 months after the attack because of persistent left upper quadrant abdominal pain. In all the 3 histology of the spleen showed congestive splenomegaly with massive infarction. All of our patients survived. Two patients subsequently developed autosplenectomy while the remaining 3 continue to have persistent but asymptomatic splenomegaly. Massive splenic infarction is a rare and unique complication of SCA in the Eastern Province of Saudi Arabia, and for early diagnosis and treatment, physicians caring for these patients should be aware of such a complication.     

Splenic Red Cell Pooling in Hairy Cell Leukaemia

The splenic red cell volume has been measured directly by an isotope method with quantitative scanning in 10 patients with leukaemic reticuloendotheliosis (hairy cell leukaemia). The volume ranged between 211 and 726 ml (mean 410 ml, SD 158) and this constituted 15–48% (mean 28.1%, SD 9.5) of the total circulating red cell volume. This is an exceptionally large pool when compared with that found in myeloproliferative and lymphoproliferative disorders with the same degree of splenomegaly. It is consistent with the histological features which show marked red cell accumulation in the splenic cord areas. The red cell pooling in the spleen thus appears to be a significant factor in the anaemia and there was fairly good correlation between the percentage of improvement in the anaemia and the percentage of red cell volume contained in the spleen. By direct measurement of the splenic red cell pool, it is possible to predict the extent to which splenectomy will benefit the anaemia and this may also provide an indirect measure of the extent of bone marrow dysfunction in the causation of the anaemia.     

The Clinical Features of Haemoglobin SC Disease in Jamaica

S ummary . The clinical and haematological features of 90 Jamaican patients with haemoglobin SC disease are reviewed. Mean haemoglobin levels indicated mild anaemia although individual haemoglobin levels were often within the normal range. The clinical features were qualitatively similar to those of homozygous sickle cell disease (SS disease) although they were generally less frequent and of lesser severity. Ocular pathology was an exception, occurring more frequently in SC disease than in SS disease even in age–sex-matched groups. There is some evidence that the higher haemoglobin level in SC disease may be aetiologically related to retinal vascular disease.     

Blood film features of sickle cell–haemoglobin C disease

Summary. The blood films of patients with sickle cell-haemoglobin C disease (SC) were compared with those of patients with related haemoglobinopathies in order to establish the most characteristic features. The blood films from SC patients generally permitted the distinction from sickle cell anaemia (SS) but not necessarily from haemoglobin C disease (CC) or C/β thalassaemia. About half of the SC films showed characteristic SC poikilocytes and a minority also had some cells containing haemoglobin C crystals. In addition, SC differed from SS in having fewer classical sickle cells and nucleated red cells, more irregularly-contracted cells and less polychromasia and evidence of hyposplenism.     

A comparison of sickle cell syndromes in Northern Greece

Haematological and clinical characteristics have been examined in 30 patients with homozygous sickle cell (SS) disease, 28 with sickle cell-beta zero thalassaemia, and 21 with sickle cell-beta+ thalassaemia. The latter could be divided into three groups on their molecular basis and HbA levels, four subjects with an IVS-2 nt 745 mutation having 3-6% HbA (designated S beta+ thalassaemia type I), 14 subjects with an IVS-1 nt 110 mutation having 8-15% HbA (designated S beta+ thalassaemia type II), and three subjects with an IVS-1 nt 6 mutation having 20-25% HbA (designated S beta+ thalassaemia type III). Comparisons were conducted between SS disease, S beta zero thalassaemia, and S beta+ thalassaemia type II. Compared to SS disease, both thalassaemia syndromes had higher HbA2 levels and red cell counts and lower mean cell haemoglobin content (MCHC), mean cell volume (MCV) and MCH, and S beta zero thalassaemia had higher HbF and reticulocyte counts. Compared to S beta zero thalassaemia, S beta+ thalassaemia had a higher haemoglobin and MCHC. Clinically, persistence of splenomegaly was more common in S beta zero and S beta+ thalassaemia type II compared to SS disease. Few significant differences occurred between SS disease, S beta zero and S beta+ thalassaemia type II in Northern Greece suggesting that the 8-15% HbA in the latter condition was insufficient to modify the clinical course.     

Sickle cell disease: the Lebanese experience

Sickle cell disease (SCD), the commonest single gene disorder worldwide, is an inherited disease that has different clinical and hematological manifestations in different populations. The objective of this study is to describe the characteristics of the Lebanese SCD population. This was a retrospective study that included information on 387 patients with either sickle cell anemia (SS) or sickle beta-thalassemia (ST). The mean (+/-SD) age was 17.9 years (+/-12.5), and the mean (+/-SD) follow-up was 9.3 +/- 6.9 years. Fifty percent of the patients were males and SS/ST distribution was 3 : 1. The disease was clustered in two geographic areas in North and South Lebanon. Nearly, all patients were Muslims and 56% were the offspring of consanguineous parents. The prevalence of splenomegaly beyond 6 years of age among SS patients was 28.9%. The prevalence rates of stroke, leg ulcers and priapism were 4.1%, 1.4%, and 0.8%, respectively. Comparing the SS and the ST patients, there were no statistically significant differences in the prevalence of all clinical manifestations except for splenomegaly (SS: 28.9%, ST: 54.9%, P-value < 0.001) and splenectomy (SS: 16.1%, ST: 35.7%, P-value < 0.001). In contrast to Northern American populations and similar to some Mediterranean populations, Lebanese SCD patients have a higher prevalence of persistent splenomegaly. The relatively low incidence of thrombotic complications deserves further investigation. The study's limitations include those of any other retrospective study and the fact that not all Lebanese centers caring for inherited hemoglobin disorders were included. However, the results of this first large scale national survey indicate that preventive efforts should target the Northern and Southern regions of Lebanon to decrease the number of new off springs afflicted with this disease similar to what has been successfully achieved with Thalassemia, another hemoglobinopathy that is highly prevalent in the country.     

Case report: splenic infarction and acute splenic sequestration in adults with hemoglobin SC disease.

While acute splenic sequestration and splenic infarction are commonly observed in infants and young children with sickle cell anemia, they are rarely experienced by adult hemoglobin S homozygotes because the recurrent splenic infarction that takes place during childhood is typically followed by scarring, atrophy, and splenic fibrosis. Both acute splenic sequestration and splenic infarction do remain relatively common in adults with the other sickle hemoglobinopathies. These episodes are almost certainly a consequence of the persistently enlarged and distensible spleens that often remain present in these conditions. In this report, the authors describe two adult patients with hemoglobin SC disease: one who developed acute splenic sequestration and one with splenic infarction. In neither case was there a history of recent air travel or exposure to altitude. The clinical course of these two syndromes is presented, and the hematologic, radiologic, and pathologic manifestations are discussed. Because they can sometimes be difficult to distinguish from one another, and because a failure to identify acute splenic sequestration can be catastrophic, these two entities must be included in the differential diagnosis for any hemoglobin SC patient who present with an unexplained fall in hemoglobin, left upper quadrant pain, unexplained fever, or symptomatic splenomegaly.     

Comparison of Sickle Cell-β° Thalassaemia with Homozygous Sickle Cell Disease

Clinical and haematological features in 41 patients with sickle cell-beta0 thalassaemia (Sbeta0 thalassemia) and in 123 age--sex matched controls with homozygous sickle cell (SS) disease were compared. Persistence of splenomegaly was more common and fetal loss less common in Sbeta0 thalassemia but other clinical features were similar in the two genotypes. Total haemoglobin, Hb A2, PCV, CCV, and red cell count were significantly higher and MCV, MCH, MCHC, and ISC counts significantly lower in Sbeta0 thalassaemia. Proportional reticulocyte counts were significantly lower in Sbeta0 thalassaemia but there was no difference in absolute reticulocyte counts. Persistence of splenomegaly and low ISC counts are compatible with decreased intravascular sickling which may result from the lower mean cell haemoglobin S concentration in Sbeta0 thalassaemia. If beneficial effects of a low MCHC can be confirmed then a carefully monitored trial of iron deficiency in SS disease may be a logical experimental procedure.     

Sickle cell disease in Madhya Pradesh,Central India: A comparison of clinical profile of sickle cell homozygote vs. sickle-beta thalassaemia individuals

Background and objectives: The clinical manifestation in sickle cell disease (SCD) patients varies from one individual to another due to factors like the presence of alpha-thalassaemia mutation, foetal haemoglobin, and β-globin gene haplotype. The present study enumerates the clinical profile of sickle cell anaemia patients from Central India.

Methods: Seven hundred seventy-six SCD patients from Jabalpur and surrounding districts (Madhya Pradesh) in central India were registered with the sickle cell clinic of NIRTH, Jabalpur. The present study reveals recorded signs and symptoms of genetically confirmed sickle cell anaemia (404) and sickle beta thalassaemia (92) patients.

Results: Majority of the patients were from scheduled caste communities (47.9%) and Gond tribal community (13.8%). Splenomegaly was the most common clinical manifestation observed (71.4%). Overall, 63.5% patients had a history of blood transfusion. The most frequent signs and symptoms observed were Pallor, Icterus, Joint pain, Fever, and Fatigue. Majority of the patients revealed onset of disease prior to attaining the age of 3 years (sickle cell anaemia 44.3% and sickle beta thalassaemia 35.9%). Mean haemoglobin levels among SCA individuals were marginally higher than SBT patients. On the other hand, mean foetal haemoglobin levels among SBT individuals showed the reverse trend. Notably, the present study reports the first incidence of priapism recorded in Central India.

Conclusions: The study revealed a high prevalence of SCD among scheduled caste, backward caste, and tribal communities. Dissemination of study findings, screening, pre-marriage counselling, and pre-natal diagnosis are fundamental to preventing or lowering of birth of sickle cell anaemia children in the affected populations.