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.     

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.     

Surgery in patients with hemoglobin SC disease

While surgery is commonly required for complications related to hemoglobin SC (HbSC) disease, little is known about the perioperative complications or the indications for preoperative transfusion in this group. We describe the patient characteristics, preoperative transfusion regimens, and outcome in 92 patients with HbSC and sickle-variants undergoing elective surgery. Thirty-eight percent of the patients were transfused preoperatively. Patients transfused were more likely to have been hospitalized in the year prior to the surgery and scheduled for abdominal procedures. Abdominal and ear, nose and throat procedures were the most common surgeries in our study. The overall complication rate was 18% and sickle cell-related complications occurred in 9% of patients. In patients undergoing intra-abdominal procedures, the incidence of sickle cell-related complications was significantly higher in those patients not transfused prior to their surgery (35 vs. 0%). There were two deaths. We recommend selective use of preoperative transfusion in patients with HbSC disease undergoing surgery. Transfusion appears to be beneficial in abdominal cases but is not necessary with minor procedures such as myringtomy. Am. J. Hematol. 57:101–108, 1998. © 1998 Wiley-Liss, Inc.     

Functional asplenia in hemoglobin SC disease

The incidence of functional asplenia in sickle-hemoglobin C (SC) disease has not been defined, and the use of prophylactic penicillin to prevent life-threatening septicemia in this disorder is controversial. The percentage of red blood cells with pits (pit count) is a reliable assay of splenic function in other disorders but has not been validated in hemoglobin SC disease. To address these issues, we conducted a prospective, multicenter study of splenic function in persons with hemoglobin SC disease. Baseline clinical data were recorded, and red blood cell pit counts were performed on 201 subjects, aged 6 months to 90 years, with hemoglobin SC; 43 subjects underwent radionuclide liver- spleen scanning. Pit counts greater than 20% were associated with functional asplenia as assessed by liver-spleen scan, whereas pit counts less than 20% were found in subjects with preserved splenic function. Pit counts greater than 20% were present in 0 of 59 subjects (0%) less than 4 years of age, in 19 of 86 subjects (22%) 4 to 12 years of age, and in 25 of 56 subjects (45%) greater than 12 years of age. Other subjects with hemoglobin SC, who had previously undergone surgical splenectomy, had higher pit counts (59.7% +/- 9.5%) than splenectomized subjects without hemoglobinopathy (38.5% +/- 8.8%) or with sickle cell anemia (20.5% +/- 1.9%; P < .001). Two subjects with hemoglobin SC disease (not splenectomized), ages 14 and 15 years, with pit counts of 40.3% and 41.7% died from pneumococcal septicemia. These data indicate that functional asplenia occurs in many patients with hemoglobin SC disease, but its development is usually delayed until after 4 years of age. The pit count is a reliable measure of splenic function in hemoglobin SC disease, but values indicative of functional asplenia (> 20% in our laboratory) are higher than in other disorders. The routine administration of prophylactic penicillin to infants and young children with hemoglobin SC disease may not be necessary.     

Bestatin-induced intravascular hemolysis in a patient with acute myelocytic leukemia

We encountered a patient who developed intravascular hemolysis while being treated with immunotherapy of bestatin. A 18-year-old female, diagnosed as having acute myelocytic leukemia and remained in complete remission for about 18 months by repeated consolidation therapy, was admitted to our hospital because of sudden fall of Hb concentration. Nine days prior to admission, bestatin, 30 mg daily, was resumed following a rest period of 2 weeks. Bestatin was started after the first complete remission had been achieved, Urine was dark brown with positive occult blood, but no red cells were observed. Hb was 7.9 g/dl, the number of reticulocytes 14.1%, WBC 3100/microliters with a normal classification, and platelets 6.1 x 10(4)/microliters. The serum total bilirubin was 2.3 mg/dl with a direct component of 0.8 mg/dl. Serum LDH was markedly elevated. Serum Hb was 0.12 g/dl and haptoglobin was less than 10 mg/dl. Direct and indirect Coombs' tests were both negative. Lymphocyte stimulation test by bestatin was positive. Full recovery followed the cessation of bestatin therapy and the initiation of corticosteroid therapy. It may be speculated from our case that discontinuous administration of bestatin may have been an opportune setting for developing a side effect of severe intravascular hemolysis.     

Acute myocardial infarction in hemoglobin SC disease

Although there are reports of myocardial infarction (MI) in patients with sickle cell diseases, an antemortem diagnosis of acute MI in a patient with compound heterozygous hemoglobin SC disease has not been reported. Herein, we present a patient with hemoglobin SC who suffered an acute MI. She had typical chest pain for myocardial ischemia, associated with ST elevations on the electrocardiogram (EKG) and elevations of cardiac injury markers diagnostic of infarction. The patient was treated with conventional therapies for acute coronary syndrome and also emergent red blood cell exchange. Interestingly, coronary angiography was completely normal in this patient. Potential mechanisms and management for acute MI in patients with sickle cell disease are discussed.     

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.     

The paradox of hemoglobin SC disease

Homozygous HbC gene results only in mild hemolytic anemia. In HbSC disease red cells contain equal levels of HbS and HbC. It is a paradox that HbSC exhibit a moderately severe phenotype in spite of being a mixture of HbS trait and HbC trait, neither of which has significant pathology. Why does the combination of these two Hbs result in a serious disease? The short answer is that HbC enhances, by dehydrating the SC red cell, the pathogenic properties of HbS, resulting in a clinically significant disorder, but somewhat milder that sickle cell anemia (SCA). Nevertheless, retinnitis proliferans, osteonecrosis, and acute chest syndrome have equal or higher incidence in HbSC disease compared to SCA. This pathogenic trick is accomplished by HbC inducing, by mechanisms not fully understood, an increase in the activity of K:Cl cotransport that induces the lost of K(+) and consequently of intracellular water. This event creates a sufficient increase of MCHC, so that the lower levels of HbS found in SC red cells can polymerize rapidly and effectively. This situation offers a unique opportunity: if we could inhibit the effect of HbC on K(+) transport we can cure the disease.     

Staged single-ventricle palliation in an infant with hemoglobin SC disease

Staged single-ventricle palliation is used to treat many cyanotic congenital heart diseases. Hemoglobin sickle cell disease is associated with anemia and significant vascular sickling sequelae, which increase the risk associated with single-ventricle palliation. To our knowledge, there are no reports in the English-language medical literature of single-ventricle palliation having been performed on a patient who had either sickle cell anemia or sickle cell-hemoglobin C disease. Herein, we discuss our clinical and surgical management of an infant with tricuspid atresia type IA and hemoglobin sickle cell disease who survived single-ventricle palliative procedures through the 2nd stage of a bidirectional Glenn anastomosis.     

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.     

Effects of hydroxyurea treatment for patients with hemoglobin SC disease

Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/β⁰‐thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso‐occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence‐based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ～30% of sickle cell patients within the United States. To date, only 5 publications have reported short‐term, incomplete, or conflicting laboratory and clinical outcomes of hydroxyurea treatment in a total of 71 adults and children with HbSC. We now report on a cohort of 133 adult and pediatric HbSC patients who received hydroxyurea, typically for recurrent vaso‐occlusive pain. Hydroxyurea treatment was associated with a stable hemoglobin concentration; increased fetal hemoglobin (HbF) and mean corpuscular volume (MCV); and reduced white blood cell count (WBC), absolute neutrophil count (ANC), and absolute reticulocyte count (ARC). Reversible cytopenias occurred in 22% of patients, primarily neutropenia and thrombocytopenia. Painful events were reduced with hydroxyurea, more in patients >15 years old. These multicenter data support the safety and potentially salutary effects of hydroxyurea treatment for HbSC disease; however, a multicenter, placebo‐controlled, Phase 3 clinical trial is needed to determine if hydroxyurea therapy has efficacy for patients with HbSC disease. Am. J. Hematol. 91:238–242, 2016. © 2015 Wiley Periodicals, Inc.     

Human bulbar conjunctival hemodynamics in hemoglobin SS and SC disease

The known biophysical variations of hemoglobin (Hb) S and Hb C may result in hemodynamic differences between subjects with SS and SC disease. The purpose of this study was to measure and compare conjunctival hemodynamics between subjects with Hb SS and SC hemoglobinopathies. Image sequences of the conjunctival microcirculation were acquired in 9 healthy control subjects (Hb AA), 24 subjects with SC disease, and 18 subjects with SS disease, using a prototype imaging system. Diameter (D) and blood velocity (V) measurements were obtained in multiple venules of each subject. Data were categorized according to venule caliber by averaging V and D for venules with diameters less than (vessel size 1) or greater than (vessel size 2) 15 µm. V in vessel size 2 was significantly greater than V in vessel size 1 in the AA and SS groups (P ≥ 0.009), but not in the SC group (P = 0.1). V was significantly lower in the SC group as compared to the SS group (P = 0.03). In AA and SS groups, V correlated with D (P ≤ 0.005), but the correlation was not statistically significant in the SC group (P = 0.08). V was inversely correlated with hematocrit in the SS group for large vessels (P = 0.03); however, no significant correlation was found in the SC group (P ≥ 0.2). Quantitative assessment of conjunctival microvascular hemodynamics in SS and SC disease may advance understanding of sickle cell disease pathophysiology and thereby improve therapeutic interventions. Am. J. Hematol. 88:661–664, 2013. © 2013 Wiley Periodicals, Inc.     

Molecular and cellular pathogenesis of hemoglobin SC disease.

Solution and cell studies were performed to ascertain why individuals with hemoglobin (Hb) SC have disease whereas those with Hb AS do not. The polymerization of deoxygenated mixtures containing sickle cell Hb (Hb S; alpha 2 beta 2(6)Glu leads to Val) and Hb C (alpha 2 beta 2(6)Glu leads to Lys) was investigated by measurements of delay times and solubilities. In mixtures containing more than 40% Hb S, polymerization takes place by the same mechanism as in solutions of Hb S alone, with no evidence for independent crystallization of Hb C. A detailed comparison of Hb S/Hb C and Hb S/Hb A mixtures with identical concentrations and proportions of Hb S show that there is no significant difference in the tendency of Hb C and Hb A to copolymerize with Hb S. In 50:50 Hb S/Hb C mixtures, polymerization is about 15 times more rapid than in 40:60 Hb S/Hb A mixtures at the same total Hb concentration. Measurements on density-fractionated erythrocytes show that SC cells contain a higher total Hb concentration and a more uniform distribution of reticulocytes compared to normal (AA) or sickle trait (AS) cells. The concentration distribution for C trait (AC) cells is much closer to that of SC cells than to AS or AA cells. It appears, therefore, that the presence of Hb C results in the SC cell beginning its life with an abnormally high Hb concentration. From these findings we conclude that both the larger proportion of Hb S and the higher intracellular Hb concentration contribute to the pathogenesis of Hb SC disease.