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.     

Fatal splenic sequestration crisis with multiorgan failure in an adult woman with sickle cell-beta+ thalassemia

Acute splenic sequestration crisis is a potentially fatal condition mostly seen in children with sickle cell anemia (HbSS) up to 6 years of age. Sickle cell-beta thalassemia has been associated with development of splenic sequestration crisis in rare reports. There have also been rare reports of the development of fatal acute splenic sequestration crisis together with severe multiorgan failure in adult patients with sickle cell-beta thalassemia. We describe a case of fatal splenic sequestration crisis together with multiorgan failure in a 34-year-old African-American woman with sickle cell-beta thalassemia syndrome.     

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.     

Elevated platelet count and megathrombocyte number in sickle cell anemia.

Eight adult patients with sickle cell anemia were followed over a 6-mo period. During this time all patients had elevated plateletcounts, 1.7-fold (mean, 438,398 +/- 86,223), and megathrombocyte numbers, 2.3-fold (mean, 79,535 +/- 38,907), during asymptomatic periods. These data are interpreted as suggesting that the elevated platelets and megathrombocytes in asymptomatic sickle cell patients result from lack of splenic sequestration. During three crises in two patients, both megathrombocyte number and platelet count fell significantly. It is speculated that platelets may be associated with the pathology in this disease. Platelet function studies performed during crises, therefore, must take into account the number of megathrombocytes.     

Co-existince of sickle cell disease and hemidiaphragm paralysis

Sickle cell anemia is a disease caused by production of abnormal hemoglobin. Infection, acute splenic sequestration crisis, aplastic crises, acute chest syndrome, stroke, cholelithiasis, renal disease and pain are the major complications. Unilateral or bilateral diaphragm paralysis maybe seen following phrenic nerve injury and with a variety of motor-neuron diseases, myelopathies, neuropathies, and myopathies. Prominent right hemi-diaphragma elevation was observed on chest radiograph of a 14 years' old female patient with sickle cell disease. Her medical history yielded neither trauma nor intra-thoracic surgery. She didn't have either motor deficit or sensation disorder on any region of her body. Thorax CT yielded no lesion except the significantly elevated right diaphragm. Her cranial CT showed no lesion, too. Diagnosis of right hemidiaphragm paralysis was confirmed by positive Hitzenberg Sniff test on fluoroscopy. Although several pathophysiologic mechanisms are known to be involved and lead to central neurologic complications in sickle cell disease, involvement of peripheric nerves have not been reported. Here we present a 14 years' old female patient with sickle cell anemia and unilateral diaphragm paralysis, co-existence of which have not been reported so far.     

Significant bronchospasm during sickle cell painful crises is associated with a lower peripheral eosinophil count

BACKGROUND: Bronchial hyperresponsiveness and/or bronchospasm are recognized complications of sickle cell disease. OBJECTIVE: The aim of this study was to investigate the presence of bronchospasm during painful crises, using simple spirometry in patients with sickle cell disease. METHODS: A prospective, non-randomized study was undertaken in patients with homozygous sickle cell disease, who presented with increasing pain. A painful crisis was defined as any increase in bodily pains necessitating hospital admission. A 15% increase in FEV(1) following salbutamol nebulization was considered significant. RESULTS: Thirty-nine patients took part in the study. Significant bronchodilator responses were demonstrable in 48.7% of patients during painful crises. Patients with such a response had a significantly lower peripheral blood eosinophil count (mean count 0.17 x 10(9)/L vs. 0.445 x 10(9)/L, P = 0.02, confidence interval for difference between groups, 0.0, 0.39). Furthermore, the magnitudes of the bronchodilator responses were related to the degree of lowering of peripheral blood eosinophil counts (r(s) = -0.344, P = 0.037). CONCLUSION: Significant bronchospasm is demonstrable in a sizeable proportion of patients presenting with painful sickle cell crises. There seems to be a negative correlation between the magnitude of bronchospasm and the peripheral blood eosinophil count. We postulate a possible role for pulmonary sequestration of eosinophils in the pathophysiology of bronchospasm in sickle cell disease patients.     

Sickel cell anemia, the nephrotic syndrome and hypoplastic crisis in a sibship

A family is presented with five siblings, three with sickle cell anemia and two with thalassemia trait. In all three children with sickle cell anemia hypoplastic crises developed after a viral infection. Two of these children were found to have the nephrotic syndrome, as did one of their siblings with thalassemia trait.Renal biopsy in the female patient with sickle cell anemia and the nephrotic syndrome revealed focal and segmental glomerulosclerosis. The biopsies of the other two patients (one with sickle cell anemia and one with thalassemia trait) revealed minimal changes. Hemosiderosis was present only in the biopsy specimens of the two patients with sickle cell anemia. All three patients were steroidresistant. Neither the other two siblings (one with sickle cell anemia and hypoplastic crisis) nor the parents have the nephrotic syndrome.The pathogenesis of nephrotic syndrome in patients with sickle cell anemia is discussed in detail. The current hypotheses relating renal disease to the sickling process are considered. The nephrotic syndrome observed in our patients appears to be familial and unrelated to sickle cell anemia, having been found in family members without, as well as with, sickle cell anemia. The findings in this family suggest that the nephrotic syndrome found in sickle cell anemia may not be causally related, but may be fortuitous, at least in some patients.     

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.     

Splenic sequestration associated with sickle cell trait and hereditary spherocytosis.

Coexistence of sickle cell trait and hereditary spherocytosis (HS) is unusual, and only 16 cases have been reported in the literature. These patients have the same clinical and hematological features as individuals having HS alone. We report a serious complication, acute splenic sequestration crisis (ASSC), occurring in two patients with sickle cell trait and HS. One patient experienced four episodes of ASSC during an 11-year span, while the other had two episodes of this complication during a 4-year period. Red blood cell studies and membrane protein analysis confirmed the diagnosis of HS as a consequence of spectrin deficiency. Splenectomy resulted in marked clinical and hematological improvement in both patients. Histological examination of spleens following splenectomy confirmed that significant erythrostasis and sickling had indeed occurred. ASSC can occur in patients with coexistence of sickle cell trait and HS, and this potentially life-threatening complication should be considered in this condition.     

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.     

Dysfonction splénique au cours de la drépanocytose : mise au point

The spleen filters blood cells and contributes to the immune defense. The red pulp clears the blood from altered red blood cells via its unique microcirculatory network ; while the white pulp is a secondary lymphoid organ, directly connected to the bloodstream, whose specificity is the defense against encapsulated bacteria through the production of “natural” IgM in the marginal zone. Various health conditions can cause acquired impairment of the splenic function (or hyposplenism) directly and/or through therapeutic splenectomy. Hypo/asplenia is complicated by an increased susceptibility to encapsulated germ infections, but an increased risk of thrombosis and pulmonary hypertension has also been reported after surgical splenectomy. Homozygous sickle cell disease is the most common disease associated with functional asplenia. The latter appears early in childhood likely through repeated ischemic alterations caused by the sickling of red blood cells. In addition, specific complications such as hypersplenism and acute splenic sequestration can occur and may be life-threatening. We provide here an update on the role and physiology of the spleen, which will allow a better understanding of the pathophysiology of spleen damage and its consequences in sickle cell disease.     

Non hypoxia-related splenic infarct in a patient with sickle cell trait and infectious mononucleosis

Splenic infarction in patients with sickle cell trait is usually related to hypoxic conditions, while non-hypoxia-related infarcts are extremely rare. We report on a case of a 17-year-old male patient, living at sea level, who developed a severe left upper quadrant abdominal pain during the course of a febrile episode. On physical examination he had a mildly palpable but extremely painful spleen. A spleen scan revealed 2 areas of impaired radionucleide distribution. Hepatic enzymes were moderately increased and the IgM anti-EBV antibodies positive. Hemoglobin electrophoresis revealed the presence of 42% of hemoglobin S. A probable diagnosis of splenic infarction was established in a patient with sickle cell trait, during the course of infectious mononucleosis. The patient was treated symptomatically. The conditions of splenic congestion induced by the EBV infection and the high-grade fever may have contributed to splenic sequestration and subsequent infarcts.     

Red cell transfusion and alloimmunization in sickle cell disease

Red cell transfusion remains a critical component of care for acute and chronic complications of sickle cell disease. Randomized clinical trials demonstrated the benefits of transfusion therapy for prevention of primary and secondary strokes and postoperative acute chest syndrome. Transfusion for splenic sequestration, acute chest syndrome, and acute stroke are guided by expert consensus recommendations. Despite overall improvements in blood inventory safety, adverse effects of transfusion are prevalent among patients with sickle cell disease and include alloimmunization, acute and delayed hemolytic transfusion reactions, and iron overload. Judicious use of red cell transfusions, optimization of red cell antigen matching, and the use of erythrocytapheresis and iron chelation can minimize adverse effects. Early recognition and management of hemolytic transfusion reactions can avert poor clinical outcomes. In this review, we discuss transfusion methods, indications, and complications in sickle cell disease with an emphasis on alloimmunization.     

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.     

Hemoglobin S-C disease revisited: clinical study of 106 adults.

We describe the clinical features of S-C hemoglobin disease in 106 adults seen during the years 1972-2000 and followed for a mean period of 6.8 years (range 1-27 years). The median age of the patients was 50 years. Common clinical features were pain crisis (65%), avascular necrosis of the hip (23%), proliferative sickle retinopathy (34%), and splenic infarction/splenic sequestration syndrome (19%). Acute splenic sequestration crisis occurred in 10 patients and was the presenting feature in two. Obesity (19.8%), essential hypertension (20.7%), and type-2 diabetes mellitus (10.3%) were common. The frequent occurrence of these co-morbidities among patients with hemoglobin S-C disease has not been reported previously.     

Correlation of low serum IgM levels with absence of functional splenic tissue in sickle cell disease syndromes

Serum immunoglobulin concentrations were determined in 21 patients with sickle cell disease syndromes and correlated with the size and visualization of the spleen. Whereas serum immunoglobulin A (IgA) levels were elevated in all patients studied, immunoglobulins G (IgG) and M (IgM) were elevated in those patients with demonstrable increase in splenic mass. When even minimal splenic visualization could be demonstrated, serum IgM was normal. However, when there was complete absence of splenic vi-sualization, or following splenectomy, serum IgM concentration was significantly below normal. This finding of low serum IgM concentration may explain the increased susceptibility to infection observed in some groups of patients with sickle cell disease.     

Causes of death in sickle cell disease: an autopsy study

More precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality in sickle cell disease. In this study, the morphological evidence of the cause of death was studied in 306 autopsies of sickle cell disease, which were accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33-48%). The terminal infection was heralded by upper respiratory tract syndromes in 72.6% and by gastroenteritis in 13.7%. The most frequent portal of entry in children was the respiratory tract but, in adults, a site of severe chronic organ injury. Other causes of death included stroke 9.8%, therapy complications 7.0%, splenic sequestration 6.6%, pulmonary emboli/thrombi 4.9%, renal failure 4.1%, pulmonary hypertension 2.9%, hepatic failure 0.8%, massive haemolysis/red cell aplasia 0.4% and left ventricular failure 0.4%. Death was frequently sudden and unexpected (40.8%) or occurred within 24 h after presentation (28.4%), and was usually associated with acute events (63.3%). This study shows that the first 24 h after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. Close monitoring and prompt aggressive treatment are warranted.     

Interaction of sickle cell trait with hereditary spherocytosis: splenic infarcts and sequestration

The association of sickle cell trait (SCT) and hereditary spherocytosis (HS) has been reported in only 18 patients. Three of these 18 patients experienced splenic infarct or acute splenic sequestration. We report here a 46-year-old African-American male, the oldest reported case to date, who experienced episodes of hemolysis and severe left upper quadrant pain for the past 26 years. The patient had compensated hemolysis with splenomegaly. A CT scan of the abdomen revealed a large infarct in the spleen. The diagnosis of SCT was confirmed with isoelectric focusing, cation exchange and reverse-phase HPLC. The presence of a silent, interacting globin variant as the cause of hemolysis and sickling in the spleen was ruled out by sequencing of the alpha1-, alpha2- and beta-globin genes. The diagnosis of HS was established by an osmotic fragility test. The interaction of HS and SCT leads to RBC dehydration with increased MCHC and intracellular Hb S concentration presumably favoring intrasplenic sickling and resultant splenic infarcts and sequestration as seen in this case.     

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

Summary 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 beta⁰ thalassaemia and in 130 control subjects with a normal (AA) genotype. The mean RDW was moderately increased in Sbeta⁺ thalassaemia and SC disease and markedly increased in Sbeta⁰ thalassaemia and SS disease. In SS, SC and Sbeta⁰ 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.     

Monozygotic twins with sickle cell anemia and discordant clinical courses: clinical and laboratory studies.

We describe a rare set of monozygotic twins with coexistent sickle cell anemia and alpha-/alpha alpha thalassemia who have asynchronous painful crises of different frequency and severity. Studies include measurements of cell deformability and other hemorheologic tests, cell density distribution, the percentage of irreversibly sickled cells, adherence of red cells to endothelial cells, membrane heme and membrane free iron, calcium containing internal vesicles and serum antioxidants. Results of these studies, including estimates of organ damage (bone, spleen, retina), were similar except for an increase in red cell membrane free iron in the patient with more frequent and severe painful crises. The study supports the concept that non-inherited factors are important contributors to the frequency and severity of painful crises in sickle cell anemia.