Clinical,hematological, and biochemical features of Hb SC disease

Twenty-seven patients were seen and followed at our Sickle Cell Center over a period of seven years. Their clinical, hematological, and biochemical features were determined and compared to those of patients with sickle cell anemia who were concurrently investigated. The data indicate that the mild anemia of hemoglobin (Hb) SC disease is slightly microcytic and hyperchromatic. Parameters of hemolysis and the complications of chronic hemolytic anemia (cholelithiasis, leg ulcers, hepatomegaly, and cardiomegaly) are milder in Hb SC disease than in sickle cell anemia. Asplenia and its sequelae (increased platelet count and reduced serum IgM levels) are less frequent in Hb SC disease. Cerebrovascular accidents and the decreased leukocyte alkaline phosphatase scores are similar in both diseases. Thromboembolic complications, retinopathy, and renal papillary necrosis are more frequent in Hb SC disease.     

Serum opsonization of salmonella in sickle cell anemia.

Systemic salmonellosis occurs with increased frequency in sickle cell anemia. This predisposition to Salmonella infections is poorly understood. Since serum opsonizing activity is an important host defense mechanism, we studied the ability of serum from patients with sickle cell anemia and control subjects to promote phagocytosis and killing of Salmonella typhimurium by normal leukocytes. Heat-labile factors were required for opsonization of S. typhimurium by serum from control subjects, and this opsonizing capacity was deficient in 12 of 28 serums from patients with sickle cell anemia. In an effort to account for this decreased phagocytosis-promoting activity, we evaluated those serum factors known to serve as specific opsonins. Serum immunoglobulin and specific antibody levels were similar in the patients with sickle cell anemia and in the control subjects. In contrast, several complement system abnormalities were documented in patients with sickle cell disease. These abnormal findings included (1) defective alternative complement pathway function, (2) low levels of the third component of complement (C3) and (3) slightly reduced concentrations of the fourth component of complement (C4). Of these complement system abnormalities, only decreased function of the alternative pathway was significantly associated with deficient serum opsonizing activity (P < 0.01). The complement defects and associated opsonic deficiency may be manifestations of profound macrophage (reticuloendothelial system) dysfunction in sickle cell anemia. This reduction in complement-mediated serum opsonizing activity for Salmonella, in association with other consequences of abnormal reticuloendothelial system function, may predispose to salmonellosis in sickle cell anemia.     

A case of hemoglobin SC disease with cold agglutinin-induced hemolysis

Children with sickle cell disease commonly require red blood cell (RBC) transfusion. We report the first case of hemoglobin (Hb) SC disease with development of severe anemia induced by cold agglutinin hemolysis after Mycoplasma infection. Complete blood count (CBC) showed falsely decreased RBC count and hematocrit and falsely elevated MCV and MCHC. Peripheral blood smear showed RBC clumping at room temperature; this disappeared after warming to 37 degrees C. Anti C3b-C3d was present on red cells, and indirect antiglobulin test revealed a circulating cold agglutinin. Furthermore, anti-Mycoplasma pneumoniae IgM antibody was detected in serum. Careful evaluation of CBCs and peripheral blood smears is required in cases of worsening anemia among sickle cell patients and consideration should be given to cold hemagglutinin disease as an etiology.     

Antiphospholipid antibodies in sickle cell disease

Antiphospholipid antibody formation can be induced in mice by phospholipid in a hexagonal II phase but not by phospholipid in a bilayer phase. Since sickle red cell membranes have increased hexagonal II phase content, we have measured serum antiphospholipid antibody levels in 25 patients with sickle cell disease to determine whether anti-phospho-lipid antibody may similarly be induced in these patients. Seventeen of the 25 patients (68%) had increased levels of antiphospholipid antibodies. Eleven patients (65%) had IgG and six each (35%) had IgM and IgA isotypes. Antiphosphatidylethanolamine, antiphos-phatidylserine, antiphosphatidylinositol, and antiphosphatidic acid were the most frequently increased antibodies. The finding of increased antiphospholipid antibodies in these patients is compatible with the concept that antiphospholipid antibody formation is associated with structural changes in the red cell membrane and that such structural changes occur in the red cells of patients with sickle cell disease. © 1993 Wiley-Liss, Inc.     

Impaired venous hemodynamics in a minority of patients with chronic leg ulcers due to sickle cell anemia.

BACKGROUND: Chronic or recurrent leg ulceration occurs in 25% of sickle cell anemia patients, but not in the remaining 75%. Doppler studies of venous function were normal in 16 sickle cell anemia patients with leg ulcers. PATIENTS AND METHODS: Venous Duplex Ultrasound was used to study 33 sickle cell anemia patients with chronic leg ulcers. RESULTS: Six of the 33 patients had venous reflux in at least one leg. CONCLUSIONS: Venous insufficiency may contribute to the development of leg ulcers in a minority of sickle cell anemia patients. A minority of sickle cell anemia patients with chronic leg ulcers can be shown to have leg venous reflux by duplex ultrasound imaging.     

Anti-annexin V IgG and IgM antibodies in sickle cell disease patients with vaso-occlusive crisis

Vaso-occlusive crisis (VOC) is a significant cause of morbidity and mortality in sickle cell anemia (SCA) patients; however, its mechanisms are poorly understood. In view of their prothrombotic nature, we hypothesized that SCA-associated VOC may be due to the presence of anti-annexin V antibodies. Anti-annexin V antibodies were measured with ELISA in 177 VOC and 81 steady-state SCA patients. Anti-annexin V IgM and IgG concentrations were significantly higher in VOC patients than in steady-state patients and were associated with elevated VOC risk. After categorizing anti-annexin V antibodies, the adjusted odds ratio increased as the percentile value increased. Monovariate logistic regression analysis demonstrated a positive dose?Ceffect relationship for anti-annexin V IgM with VOC, with increased VOC risk seen with increased antibody titers. Multivariate logistic regression analyses confirmed the association of anti-annexin V IgM, more so than IgG, as an independent VOC risk factor. Anti-annexin V IgG antibodies correlated positively with VOC type and negatively with HbF and age of VOC onset, while anti-annexin V IgM correlated positively with VOC type, duration, frequency, site, pain severity, hospitalization, and medication, and negatively with age of VOC onset and HbS levels. High levels of anti-annexin V IgM antibodies constitute a risk factor for VOC in SCA patients.     

Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. I. Studies on nature of glomerular-bound antibody and antigen identification in a patient with sickle cell disease and immune deposit glomerulonephritis.

The nature of the glomerular-bound antibody and the putative antigen was investigated in one of the patients with sickle cell disease and immune deposit membranoproliferative glomerulonephritis by immunohistologic and glomerular antibody elution. Renal proximal tubular epithelial antigen was localized in association with immunoglobulins G (IgG), M (IgM), Clq fraction of the first component of complement (Clq) and the third component of complement (C3) in a granular pattern along the glomerular basement membrane of the patient's kidney. IgG and IgM were eluted from glomeruli. These immunoglobulins fixed to the proximal tubules of normal human kidney by direct immunofluorescence. This localization was abolished by absorption of the eluted immunoglobulins with renal tubular epithelial (RTE) antigen. The IgG eluted from the glomeruli blocked the fixation of rabbit anti-RTE antigen to normal proximal tubular brush border. These studies suggest that the nephritis in this patient was due to deposition of complexes or RTE antigen and specific antibody. An autologous immune complex nephritis may develop in some patients with sickle cell anemia secondary to RTE antigen released possibly after renal ischemia or some other phenomenon causing renal tubular damage.     

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

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

Beta s gene in Central Iran is in linkage disequilibrium with the Indian-Arab haplotype

Sickle cell anemia is not considered to be a significant disease in Iran, although the sickle cell trait is estimated to have a high incidence in the Southern provinces. Since 1977, when the presence of a mild sickle cell anemia was reported in this country, there have been no further investigations published giving precise data on the incidence and origins of the sickle cell mutation in Iran. We report here the finding of patients with the sickle cell trait, sickle cell anemia, and sickle-beta thalassemia in Central Iran. A survey of 300 individuals from a village in Southeast Esfahan revealed an incidence of the sickle cell trait of 8.33%. "Cascade screening" enabled 96 relatives in four surrounding villages to be tested, and the at-risk couples were offered counseling as a "sickle cell control program." The hematological indices and HbF levels of the affected patients were determined. The HbF levels were unusually high, ranging from 18% to 41.4%, and SS patients with the highest levels were asymptomatic. Linkage analysis revealed the betaS gene haplotype in this population to be the Indian-Arab haplotype.     

Elevated hypercoagulability markers in hemoglobin SC disease

Hemoglobin SC disease is a very prevalent hemoglobinopathy; however, very little is known about this condition specifically. There appears to be an increased risk of thromboembolic events in hemoglobin SC disease, but studies evaluating the hemostatic alterations are lacking. We describe the findings of a cross-sectional observational study evaluating coagulation activation markers in adult patients with hemoglobin SC, comparing them with those in sickle cell anemia patients and healthy controls. A total of 56 hemoglobin SC and 39 sickle cell anemia patients were included in the study, all in steady state, and 27 healthy controls. None of the patients was taking hydroxyurea. Hemoglobin SC patients had a significantly up-regulated relative expression of tissue factor, as well as elevations in thrombin-antithrombin complex and D-dimer, in comparison to controls (P<0.01). Hemoglobin SC patients had lower tissue factor expression, and thrombin-antithrombin complex and D-dimer levels when compared to sickle cell anemia patients (P<0.05). Markers of endothelial activation (soluble thrombomodulin and soluble vascular cell adhesion molecule-1) and inflammation (tumor necrosis factor-alpha) were both significantly elevated in hemoglobin SC patients when compared to controls, being as high as the levels seen in patients with sickle cell anemia. Overall, in hemoglobin SC patients, higher hemolytic activity and inflammation were associated with a more intense activation of coagulation, and hemostatic activation was associated with two very prevalent chronic complications seen in hemoglobin SC disease: retinopathy and osteonecrosis. In summary, our results demonstrate that hemoglobin SC patients have a hypercoagulable state, although this manifestation was not as intense as that seen in sickle cell anemia.     

Liver involvement in sickle cell disease

In an effort to clarify the features of hepatic dysfunction in sickle cell disease, we obtained serial tests of liver function in 100 consecutive patients with sickle cell anemia and in 30 consecutive patients with hemoglobinopathy SC during a five-year period. There were 32 patients with chronic abnormalities in tests of liver function. These abnormal tests were explained by a variety of lesions in 30 cases, and the liver disease remained unexplained in only 2 patients who declined liver biopsy. The diagnoses in these 30 patients included hepatitis, chronic passive congestion, common duct obstruction, alcoholic liver disease, pregnancy, collagen-vascular disease, and sarcoidosis. Evidence for hepatitis B infection was present in 19 of those with sickle cell anemia and in 6 of those with hemoglobinopathy SC. The bilirubin levels in sickle cell anemia appeared to have a trimodal distribution, with six patients exhibiting markedly elevated levels of indirect bilirubin suggesting a difference in bilirubin metabolism. There was no evidence of liver disease in 72 patients with sickle cell anemia, nor in 24 patients with hemoglobinopathy SC, as these patients exhibited only mild elevation of their serum indirect bilirubin levels owing to chronic hemolysis. Intrasinusoidal sickling and Kupffer cell erythrophagocytosis were nearly universal findings at liver biopsy, irrespective of the clinical disorder, and were not related to the degree of liver test abnormalities. Liver and biliary tract dysfunction in sickle cell disease have been attributed to anoxia secondary to sinusoidal obstruction by sickled erythrocytes and Kupffer cell erythrophagocytosis. However, some causes of liver disease in sickle cell patients can be explained by clinical disorders other than the hemoglobinopathy alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Erythrocyte sedimentation rate during steady state and painful crisis in sickle cell anemia

To define its diagnostic utility in sickle crisis, the erythrocyte sedimentation rates of oxygenated blood were studied in patients with sickle cell anemia and healthy normal subjects using the Guest-Westergren method. A normal range for sedimentation rate as a function of hematocrit was established in 22 normal subjects. Twenty-seven asymptomatic patients with sickle cell anemia had abnormally low sedimentation rates in relation to their hematocrits. Those low sedimentation rates were not increased by substituting plasma from healthy control subjects, which suggests that the low sedimentation rate was a cell-related phenomenon. Sedimentation rates measured in 28 patients with sickle cell anemia at the end of uncomplicated painful crisis increased to levels appropriate for their degree of anemia. In patients with sickle crisis and medical complications, the sedimentation rates were even higher. At the end of an uncomplicated painful crisis, the mean plasma fibrinogen level was significantly higher than at the onset (p less than 0.005). When red cells from patients with sickle cell anemia at the end of crisis were suspended in normal plasma from control subjects, the sedimentation rates remained high. It is concluded that the erythrocyte sedimentation rate of asymptomatic patients with sickle cell anemia is abnormally low due to cellular factors, and the increase during painful crisis is due primarily to red cell changes, modified by plasma factors.     

Zinc and copper status in patients with sickle cell anemia

Plasma zinc and copper concentrations were determined by atomic absorption spectroscopy in 57 patients with sickle cell anemia and in 45 control subjects from the Eastern Province of Saudi Arabia. Plasma zinc and copper levels in patients were found to be close to those of the control subjects. Similarly, there was a difference neither in urinary zinc level nor in the ratio Cu:Zn in patients and control subjects. This is in contrast to the situation which exists in North American Black subjects with sickle cell anemia, who are known to have zinc deficiency as well as a further decrease in zinc level during sickle cell crises. The near-normal levels of zinc and copper found in Saudi sickle cell patients therefore exclude zinc deficiency and confirm that this population exhibits a milder form of sickle cell anemia.     

Leg ulcers in patients with sickle cell disease [see comments]

During the entry examination, leg ulcers were present in 2.5% of 2,075 patients 10 years of age and older with sickle cell disease who entered into the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1986. Prevalence rates were highest among patients with sickle cell anemia and sickle cell anemia with thalassemia genotypes. Among sickle cell anemia patients free of ulcers at entry, the overall incidence was 5.73 per 100 person years in those having associated alpha-thalassemia and 9.97 for those without. Among sickle cell anemia patients with two alpha genes, the estimated incidence of leg ulcers is 2.38 per 100 person years and 6.12 per 100 person years among sickle cell anemia patients with three alpha genes (P less than .05). In both groups, the incidence was highest among those patients over 20 years of age and considerably higher among males than females (P less than .001). Leg ulcers were nonexistent in patients with sickle beta plus thalassemia and sickle hemoglobin C disease. Low steady-state hemoglobin is associated with a higher incidence of ulcer formation (P less than .0001) in sickle cell anemia patients. The protective effect of hemoglobin F is apparent at all levels of total hemoglobin among sickle cell anemia patients and those with associated alpha-thalassemia.     

Low fixed-dose hydroxyurea in severely affected Indian children with sickle cell disease

There is limited data on the efficacy of hydroxyurea (HU) in Indian sickle cell anemia patients who have severe manifestations despite high fetal hemoglobin (Hb F). Sixty sickle cell anemia children (5-18 years) with more than three episodes of vasoocclusive crises or blood transfusions per year were randomized to receive HU (n = 30) or placebo (n = 30) therapy. Fixed dose (10 mg/kg/day) of HU was administered for 18 months and the patients were followed-up monthly with clinical assessment and laboratory monitoring. In the HU group, hemoglobin (Hb) and Hb F levels increased significantly along with a significant decrease in the number of painful crises, blood transfusion requirements and hospitalizations compared to the placebo group. No major adverse events were observed in this study. In conclusion, low-fixed dose HU therapy was effective for the treatment of Indian sickle cell anemia children. However, there is a need for long-term studies to evaluate the efficacy and toxicity in a larger number of Indian sickle cell anemia patients.     

Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. II. Clinicopathologic study of seven patients.

A variety of renal structural and functional abnormalities have been associated with sickle cell disease. To define the relationship between the hemoglobinopathy and glomerular disease, clinicopathologic correlations, renal morphologic, ultrastructural immunohistologic and functional studies were performed on seven patients with clinical and laboratory evidence of glomerular disease. In addition, immunologic studies including isolation and characterization of cryoprecipitable immune complexes, and determination of immunoglobulin, total complement and complement component levels, and antibody titers to several antigens were performed in an attempt to define the etiologic and pathogenic mechanisms of the renal disease and its relationship to sickle cell anemia. Proteinuria was presnet in all patients. The nephrotic syndrome, hypertension, hematuria and renal insufficiency were found in more than one half the patients. All patients had membranoproliferative glomerulonephritis of varying degree; glomerular basement membrane splitting, electron dense deposits in the glomerulus; interstitial fibrosis, tubular atrophy and hemosiderin deposits were frequent. Immunoglobulin complement components (classif complement pathway) and renal tubular epithelial antigen were distributed in a granular pattern along the glomerular basement membranes of all patients studied by these methods. Cyroprecipitable complexes of renal tubular epithelial antigen-antibody to renal tubular epithelial antigen as well as antibody to renal epithelial antigen were detected in the circulation of some patients. There was no serologic evidence of activation of the alternate complement pathway. These studies demonstrated an immune deposit normocomplementemic nephritis associated with sickle cell anemia; they further support our hypothesis that the relationship is more then coincidental, and is mediated by glomerular deposition of immune complexes of renal tubular epithelial antigen-antibody to renal tubular epithelial antigen, the antigen possibly released after tubular damage secondary to oxygenation and hemodynamic alterations related to sickle cell disease.     

Defective release of tissue plasminogen activator in patients with sickle cell anemia

Recent studies suggest that intravascular coagulation occurs in sickle cell anemia. There is also some evidence that decreased fibrinolytic activity may be associated with the disorder. In the current study we measured tissue plasminogen activator levels (t-PA) in seven asymptomatic patients with sickle cell anemia. The mean level of releasable t-PA was only 0.01 IU/mL +/- 0.005 (SEM) as compared to 118 healthy volunteers with levels of 0.70 +/- 0.10 (SEM). Despite the small sample size, the difference between the two groups was statistically significant (P less than .001). These data suggest that defective release of t-PA may contribute to a hypercoagulable state in sickle cell anemia.     

The natural history of urate overproduction in sickle cell anemia.

Serum uric acid and uric acid excretion were studied in 95 patients with sickle cell anemia ranging in age from 17 months to 45 years to ascertain the natural history of urate overproduction. Hyperuricemia was infrequent in children with sickle cell anemia, but was found in 26 of 67 adults (39%). Thirty-six patients studied in a clinical research center had a mean urate clearance of 9.1 +/- 0.8 mL/min. Patients with sickle cell anemia were often normouricemic despite urate overproduction. Normouricemia was maintained by increased urate clearance, which was attributed to increased urate secretion. The hyperuricemic patients had decreased urate clearance with decreased pyrazinamide-suppressible urate clearance. Para-aminohippurate clearance was decreased to 634 mL/min in the hyperuricemic patients with sickle cell anemia compared with 853 mL/min in normouricemic hyperuricosuric subjects with sickle cell anemia. Hyperuricemia occurs only in patients who develop altered renal tubular function with diminished urate clearance secondary to diminished urate secretion.     

Clinical,hematologic and biosynthetic studies in sickle cell-β°-thalassemia: A comparison with sickle cell anemia

The diseases commonly confused with sickle cell anemia include sickle cellβ-thalassemia in which synthesis of β^A-chains are completely suppressed (HbS-β^O-thalassemia). We obtained hematologic measurements and studied globin biosynthesis in five patients with this disorder and compared the results with those obtained in five patients with “mild” sickle cell anemia and seven individuals with sickle cell-β-thalassemia having hemoglobin A levels of 20–30% (HbS-β⁺-thalassemia). A distinction between HbS-β^O-thalassemia and sickle cell anemia was not always possible on clinical, hematologic, or electrophoretic grounds. Thalassemia heterozygotes had hypochromia and microcytosis, not generally a feature of sickle cell anemia, although overlap of values did exist. The ratio of β to non-β, or β to β^S-chains in sickle cell anemia approximated unity, whereas patients with HbS-β^O-thalassemia had a deficit of β-chain production relative to that of the β-chain. The differentiation of HbS-β^O-thalassemia and sickle cell anemia can be best made on the basis of family or biosynthetic study. We estimated the regional prevalence of HbS-β^O-thalassemia to be 1:23,000 of the black population.     

Increased IgG molecules bound to the surface of red blood cells of patients with sickle cell anemia

We have used the complement-fixing antibody consumption ( CFAC ) test to detect small concentrations of IgG on red blood cells from patients with hemolytic anemias that are not thought to be caused by an immune mechanism. Although patients with hereditary spherocytosis, pyruvate kinase deficiency, and mechanical hemolytic anemias generally had normal concentrations of IgG bound to their red cells (less than 25 molecules IgG per red cell), we found that 39/62 (63%) patients with sickle cell anemia had elevated values. These 39 patients had a mean of 195 and a maximum of 890 molecules of IgG per red cell. None of the patients had been transfused within the previous 90 days, and some had never been transfused. Direct antiglobulin tests were positive in only two instances and autoantibodies were not found in the serum of any patient. However, eluates from the red cells of 6 of 23 patients demonstrated antibody activity against all of a panel of normal red cells by the indirect antiglobulin test. There was no correlation between the number of IgG molecules on patients' red cells and the severity of their anemia, the incidence of painful sickle cell crises, the reticulocyte count, or with blood transfusion history. We conclude that further study of immunohematologic abnormalities in patients with sickle cell anemia is warranted, especially in view of previous reports in this population of patients with red cell autoantibodies, autoimmune hemolytic anemia, hemolytic transfusion reactions without detectable alloantibodies, and an association of some episodes of pain crises with immunologically mediated red cell destruction.