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Left ventricular (LV) and right ventricular (RV) function were evaluated at rest and during exercise using radionuclide ventriculography in 10 patients, aged 19-53 years, with sickle-cell anemia (SCA). Seven patients were in New York Heart Association functional class I and 3 were in class II. The resting LV ejection fraction (EF) was normal in 9 patients and the resting RVEF was normal in 4. LV dilation and high cardiac output were observed in 6 patients at rest. The LVEF during exercise was normal in all 10 patients, whereas only 2 patients had normal RVEF at rest and during exercise. The LVEF was lower in patients with SCA at rest (54 +/- 4% versus 61 +/- 6%, p less than 0.001) and exercise (66 +/- 4% versus 74 +/- 6%, p less than 0.001) than in 42 age-matched normal subjects. Rest thallium-201 images from 9 patients showed abnormal RV uptake in 8 and normal LV uptake in 8. Thus, in adult patients with SCA, LV function was normal during exercise in all patients and at rest in all but 1 patient. The LVEF, however, was lower than that in age-matched normal subjects. RV function was abnormal in most patients at rest and during exercise. RV thallium-201 uptake suggested pressure or volume overload (or both), most likely due to pulmonary vaso-occlusive complications of the disease.

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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.

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The effects of an ionic contrast agent (meglumine iothalamate) and a nonionic contrast medium (iopamidol) on the sickling phenomenon were studied in vitro. The findings indicate that, at the same concentration of contrast agent in the blood, iopamidol causes significantly less sickling than meglumine iothalamate. This indicates that nonionic contrast agents are preferable for diagnostic studies in patients with sickle cell anemia.

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A 63-year-old man of italian origin with severe heterozygous beta-thalassemia whose clinical condition deteriorated after splenectomy is described. The alpha/beta synthesis ration in the peripheral blood was 3.02 +/- 0.56 and in the bone marrow 1.43. The free alpha-chain pool comprised 73% of the total radioactive alpha-globin in the peripheral blood and 68% in the bone marrow. RBC membranes isolated from erythrocytes incubated in the presence of 14C-leucine were practically devoid of nascent beta-chains with an alpha/beta ratio of 5.12 +/- 1.47, significantly higher than that present in the corresponding hemolysate. RBC membranes from this patient, compared to control membrane preparations, showed increased proteolytic activity directed against tetrameric hemoglobin and beta-hemoglobin chains, with concomitant decreased catabolism of alpha-hemoglobin chains. RBC membranes from individuals with mild beta-thalassemia trait and from transfused patients with homozygous beta-thalassemia degraded alpha-hemoglobin chains more efficiently than those from the patient described. The data suggest that decreased degradation of the alpha-chain by RBC membranes from this patient might lead to progressive accumulation of this polypeptide and expansion of the free alpha-chain pool, which, in turn, may be responsible for the severity of the clinical picture.

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Membrane protein synthesis in human immature erythroid cells was studied by incubating the cells with 35S-methionine in vitro. The radioactive precursor amino acid was incorporated into membrane protein in a linear fashion for approximately 60 min, after which there was only a slight increase in incorporation. Intracellular protein synthesis, in contrast, was linear for periods up to 2 h. Analysis of isolated membranes by polyacrylamide gel electrophoresis in sodium dodecyl sulphate showed that peripheral blood reticulocytes synthesized two proteins in the 4.5 region (MW=50-60000 D) and a third protein coinciding with band 6 (glyceraldehyde-3-phosphate dehydrogenase). Separation of reticulocytes into different age groups on stractan II gradients showed more immature reticulocytes synthesize a wider range of membrane proteins, extending from bands 4.1 to 8. When nucleated red cells were present in the incubations, synthesis of band 3 was also observed. Earlier erythroid precursor present in erythropoietic BFU-E cultures synthesized spectrin in addition to the other membrane proteins. The data indicate that human red cell membrane protein synthesis follows a programmed pattern and that as the erythroid elements mature they lose the capacity to synthesize certain membrane proteins.

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The influence of heme containing alpha A and beta S globin chains on the rate of synthesis of globin subunits has been studied in a human cell-free system derived from sickle reticulocytes. The autologous lysate system produced measurable amounts of nascent protein as equal amounts of alpha and nonalpha chains, which were released as soluble globin. The addition of either alpha A or beta S hemoglobin chains in concentrations between 10(-5)M and 10(-8)M did not alter either the rate of total globin synthesis or the alpha/beta synthesis ratio. The results suggest that the presence of free hemoglobin chains within the cell does not in itself affect the rate of globin chain synthesis and that other mechanisms within the cell are more important in coordinating the synthesis of equal amounts of alpha and nonalpha globin chains. One cannot conclude that there is no effect on chain initiation, since in the mammalian systems very littl chain initiation occurs.

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Four patients with sickle cell disease noted the development of urinary retention during an acute painful crisis. The acute urinary retention resolved with improvement in the painful sickle cell crisis. No evidence of anatomic urologic defect, systemic neurologic abnormality, or infection was documented in these patients. Patients with sickle cell disease in painful crisis should be observed for signs of acute urinary retention.

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Serum immunoglobulin concentrations were measured for 44 patients who had sickle cell syndromes and for 19 normal black individuals. Most patients who had sickle cell syndrome had significantly elevated IgA levels. In addition, patients who had sickle cell anemia had elevated IgG levels, and patients who had sickle-beta-Thalassemia or other sickle combinations (SC, SD, SO) had significantly elevated IgM levels. None of these patients had a monoclonal gammopathy. The elevated immunoglobulin levels could be the result of chronic reticuloendothelial stimulation by chronic extravascular hemolysis or by potentiation by the inflammation secondary to cholecystitis and cholelithiasis. The reason patients with sickle cell anemia do not have increased IgM levels could be due to their functional asplenia.

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Proteolytic activity in the mature human erythrocyte was localized to the cell membrane. This activity, which could not be ascribed to contaminating leukocytes in the suspension, was totally absent from the soluble portion of the cell and was more active against hemoglobin subunits than against tetrameric hemoglobin molecules. Pulse-chase experiments confirmed that the membrane proteolytic activity was more active in degrading beta chains that alpha chains. The activity could be extracted from erythrocyte cell membranes, but not from membrane-free hemolysate, by exposure to 0.75-M KSCN. The activity of the protease was dependent on time and temperature and did not require ATP or an energy-generating system for activity.

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The symptoms of thromboembolism in sickle cell anemia patients with acute chest syndromes are difficult to differentiate from the similar symptoms of painful thoracic crises and infectious pulmonary episodes. Furthermore, the chronic pulmonary abnormalities in sickle cell disease frequently contribute to the confusing results of noninvasive diagnostic procedures usually employed in evaluating pulmonary thromboembolism. In this study the chronic pulmonary status of asymptomatic sickle cell patients was defined, and this information was used in the evaluation of patients with acute chest syndromes suggestive of pulmonary thromembolism. Sixteen asymptomatic sickle cell patients were prospectively studied by chest roentgenography, spirometry, arterial gas analyses, and radioisotopic lung scans. There was an appreciable degree of preexisting chronic restrictive lung disease with mild to moderate arterial hypoxemia and abnormal lung scans in more than half of the patients. These prospective baseline data were incorporated into the diagnostic evaluation of four of these patients who later developed an acute chest syndrome suggestive of pulmonary thromboembolism. Determination of the cause of the chest pain was greatly faciliated by the existence of the baseline pulmonary data. In another patient persistence of abnormal studies following a presumed thromboembolic episode aided diagnostic evaluation when another episode of chest pain occurred. The findings indicate that comprehensive pulmonary studies in sickle cell patients while in an asymptomatic state will provide baseline data which aid the evaluation of possible pulmonary thromboembolism in acute chest syndromes without resorting to high-risk invasive studies.

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The role of the human erythrocyte membrane in degrading hemoglobin and hemoglobin subunits was investigated by determined the total radioactivity (cpm) of the nascent alpha and beta globin chains attached to the membrane after labeling of intact cells with 14C-leucine. In conditions characterized by balanced globin synthesis (normal and sickle cell anemia), the total radioactivity of membrane-attached alpha globin is always less than membrane-attached beta globin (alpha/beta = 0.60 +/- 0.10) despite the equal synthesis of alpha and beta chains in the hemolysate. In conditions characterized by unbalanced globin synthesis (alpha-thal and beta-thal traits) the cpm of membrane-attached alpha are also less than those of membrane-attached beta. Attachment of globin chains to the membrane is not related to the net ionic charge of individual chains, but the amount of attachment is related to the relative size of the free intracellular alpha chain pool. The alpha/beta ratio of less than 1 is not due to selective attachment of nascent beta chains or selective destruction of nascent alpha chains. The data indicate that part of the discrepancy between membrane and hemolysate alpha/beta radioactivities seen in the conditions studied is due to different rates of entry into the membrane and catabolism of newly labeled globin polypeptide chains by it.

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A factor V inhibitor arose in a 79-year-old man within 1 month of an operation for a fractured leg. Absorption studies with solid-phase antibodies to human immunoglobulins showed the inhibitory activity to be primarily in the IgG class, but also in the IgA class, of immunoglobulins. This is the first report of an IgA immunoglobulin with factor V inhibitory activity. While the inhibitor was present, and at a time when no circulating Factor V activity was detectable, the patient developed septicemia and disseminated intravascular coagulation. The mechanism sustaining disseminated intravascular coagulation despite the absence of circulation factor V activity remains unexplained. The factor V inhibitor disappeared within 5 months of its initial detection. Possible origins of factor V inhibitors are discussed.

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