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.     

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.     

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.     

Current strategies for the management of children with sickle cell disease

Children with sickle cell disease may present to doctors anywhere in the world. In developed countries, neonatal screening allows early identification and management of the disease, mostly through daily antibioprophylaxis, immunizations and education of the parents. Stroke prevention relies on the detection of high-risk patients by annual transcranial Doppler ultrasonography from 2 to 16 years of age. Annual check-ups aim to detect early organ deficiencies. The most frequent complications are pain, infections and acute anemia; they may occur in combination. Approximately 10% of children have severe sickle cell disease that may require chronic blood transfusion, hydroxyurea or hematopoietic stem cell transplantation. Comprehensive management programs have dramatically increased survival, and most patients now reach adulthood.     

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.     

Hydroxyurea therapy requires HbF induction for clinical benefit in a sickle cell mouse model

Hydroxyurea has proven clinical efficacy in patients with sickle cell disease. Potential mechanisms for the beneficial effects include fetal hemoglobin induction and the reduction of cell adhesive properties, inflammation and hypercoagulability. Using a murine model of sickle cell disease in which fetal hemoglobin induction does not occur, we evaluated whether hydroxyurea administration would still yield improvements in hematologic parameters and reduce end-organ damage. Animals given a maximally tolerated dose of hydroxyurea that resulted in significant reductions in the neutrophil and platelet counts showed no improvement in hemolytic anemia and end-organ damage compared to control mice. In contrast, animals having high levels of fetal hemoglobin due to gene transfer with a γ-globin lentiviral vector showed correction of anemia and organ damage. These data suggest that induction of fetal hemoglobin by hydroxyurea is an essential mechanism for its clinical benefits.     

In vitro antisickling activity of cromolyn sodium

The improvement in sickle cell disease (SCD) children receiving cromolyn sodium therapy prompted us to investigate its antisickling activity in vitro . The number of sickle cells was determined in deoxygenated blood samples from 15 children with severe SCD. At the eight concentrations tested, cromolyn sodium exhibited a significantly higher activity than pentoxifylline, the standard compound. Therefore cromolyn sodium would appear to be an interesting candidate for SCD therapy and deserves further in vivo investigations.     

Cromolyn sodium is effective in adult chronic asthmatics

We studied 68 chronic asthmatic patients, 18 to 76 yr of age, with a percent predicted FEV1 between 33 and 81, comparing cromolyn sodium with placebo. We used a double-blind, comparative group trial design. A 4-wk baseline period was followed by 3 months of active treatment or placebo. Patients recorded symptom severity and frequency of study drug and concomitant medication usage on daily diary cards. At each clinic visit, patients independently assessed the effectiveness of the test medication in controlling their asthma. Physicians also assessed the severity of the patients' symptoms, pulmonary function, and effectiveness of test medication at monthly intervals. Methacholine challenges were done pre- and post-treatment. Use of concomitant therapy was reduced according to a specified schedule. There was significant improvement in the severity of daytime asthma, nighttime asthma, and cough as assessed by the patients in the cromolyn sodium group. Mean use of concomitant medications decreased significantly in cromolyn sodium patients. Despite the reductions in the use of bronchodilators, pulmonary function (FEV1, FVC, FEF25-75) improved significantly in the cromolyn sodium group. Similar improvements did not occur in the control group. The physicians' assessments of symptoms showed significant improvement in favor of the cromolyn sodium group. Both physicians and patients judged cromolyn sodium to be moderately or very effective for 61% of the patients as compared to 27% (by physicians) and 24% (by patients) in the placebo group. There was no significant difference in methacholine response between the two groups, although the mean value for methacholine sensitivity in the cromolyn sodium group was significantly less at the end of the study than at baseline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary Stroke in a Woman With Sickle Cell Anemia Responsive to Hydroxyurea Therapy

The most common cause of stroke in children with sickle cell anemia is infarction due to ischemia. In adults, however, stroke is most commonly hemorrhagic in nature. Other causes of stroke in patients with sickle cell disease are very rare. In this short communication, we describe a woman with sickle cell anemia responsive to hydroxyurea (HU) therapy who had primary stroke due to paradoxical embolization caused by a large atrial septal defect. Successful management of the stroke included surgical closure of the defect with trans-esophageal echocardiographic guidance. To the best of our knowledge, this is the first patient with sickle cell anemia and stroke due to congenital heart disease who did not require open heart surgery for successful management.     

Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

Background

Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis.

Design and Methods

Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions.

Results

Results showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age.

Conclusions

Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.     

Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease

Hydroxyurea therapy reduces the rates of vaso-occlusive crisis in patients with sickle cell anaemia and recent data suggest that hydroxyurea treatment can generate nitric oxide (NO). Nitric oxide has been proposed as a novel therapy for sickle cell disease via a number of pathways. We therefore sought to determine whether hydroxyurea has NO donor properties in patients with sickle cell anaemia and explore potential mechanisms by which NO production could be therapeutic. Venous blood was collected from 19 fasting sickle cell anaemia patients, on chronic hydroxyurea therapy, at baseline and 2 and 4 h after a single morning dose of hydroxyurea, as well as 10 patients not taking hydroxyurea. The plasma and red cell NO reaction products nitrate, nitrite and nitrosylated- haemoglobin were measured using ozone-based chemiluminescent assays (using vanadium, KI and I3- reductants respectively). Consistent with NO release from hydroxyurea, baseline levels of total nitrosylated haemoglobin increased from 300 nmol/l to 500 nmol/l (P = 0.01). Plasma nitrate and nitrite levels also significantly increased with peak levels observed at 2 h. Glutathionyl-haemoglobin levels were unchanged, while plasma secretory vascular cellular adhesion molecule-1 levels were reduced in patients taking hydroxyurea (419 +/- 40 ng/ml) compared with control patients with sickle cell anaemia (653 +/- 55 ng/ml; P = 0.003), and were inversely correlated with fetal haemoglobin levels (r = -0.72; P = 0.002). These results demonstrate that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of NO. The role of NO in the induction of fetal haemoglobin and possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored.     

Treatment of acute sickle cell crises with a vasopressin analogue

Eight patients with sickle cell anemia were treated for acute painful crises with DDAVP and intravenous fluids; five were treated with placebo and the same regimen of fluid administration. Although hyponatremia was produced in both treatment groups, duration of hospitalization did not differ between them, nor did it differ from concurrent hospitalization of other patients who received conventional treatment. Safe induction of hyponatremia required intensive laboratory surveillance, and serum sodium could be lowered without use of DDAVP. These data suggest that a controlled trial hyponatremia for acute sickle cell crises should not be performed.     

Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease

Hydroxyurea improves hematologic parameters for children with sickle cell disease (SCD), but its long-term efficacy at maximum tolerated dose (MTD) has not been determined. Between 1995 and 2002, hydroxyurea therapy was initiated for 122 pediatric patients with SCD including 106 with homozygous sickle cell anemia (HbSS), 7 with sickle hemoglobin C (HbSC), 7 with sickle/beta-thalassemia (HbS/ beta-thalassemia [6 HbS/beta0, 1 HbS/beta+]), and 2 with sickle hemoglobin OArab (HbS/OArab). Median age at initiation of therapy was 11.1 years. Hydroxyurea was escalated to MTD, with an average dose of 25.4 +/- 5.4 mg/kg per day; the average duration of hydroxyurea therapy has been 45 +/- 24 months (range, 6-101 months). Hydroxyurea was discontinued for 15 (12%) children with poor compliance. Mild transient neutropenia occurred, but no hepatic or renal toxicity was noted. Hydroxyurea therapy led to significant increases in hemoglobin level, mean corpuscular volume, and fetal hemoglobin (HbF) level, whereas significant decreases occurred in reticulocyte, white blood cell, and platelet counts and serum bilirubin levels. Children with variant SCD genotypes also had hematologic responses to hydroxyurea. HbF induction has been sustained for up to 8 years without adverse effects on growth or increased numbers of acquired DNA mutations. Long-term hydroxyurea therapy at MTD is well tolerated by pediatric patients with SCD and has sustained hematologic efficacy with apparent long-term safety.     

Protective role of hemoglobin and fetal hemoglobin in early kidney disease for children with sickle cell anemia

Patients with sickle cell anemia are at risk for organ damage including kidney disease. Microalbuminuria may be an early marker of disease progression. This retrospective review analyzed laboratory and clinical findings in children with sickle cell anemia according to the presence or absence of MA during well clinic sickle cell visits. Results were analyzed in sum as well as by therapeutic intervention (not on therapy,hydroxyurea therapy, or chronic transfusion therapy). Thirty two of 144(22%) children had MA, including 20 of 82 (24%) children not on a therapeutic intervention (chronic transfusion or hydroxyurea). In children not on therapy, low hemoglobin, low fetal hemoglobin and high lactate dehydrogenase were associated with MA. Frequency of positive screens for MA for the different treatment groups were: Hydroxyurea 13%; chronic transfusion 26% and children on no treatment 24%. However,the difference between the hydroxyurea group and the chronic transfusion or no treatment groups did not reach statistical significance.Increased hemoglobin and fetal hemoglobin may provide protection against kidney disease in sickle cell anemia and should be evaluated in a randomized, prospective clinical trial.     

Inefficacy of piracetam in the prevention of painful crises in children and adolescents with sickle cell disease

Analgesia and hydration remain the only safe treatment for painful crises of sickle cell disease; hydroxyurea is effective, but the toxicity is still a problem. Piracetam is a nootropic drug that has reportedly been effective and non-toxic in sickle cell patients, but most studies were not placebo-controlled and included a small number of patients. The present study evaluated the drug in a double-blind crossed placebo-controlled clinical trial in 73 children and adolescents suffering from moderate to severe painful crises for 13 months. Information regarding frequency and severity of pain was acquired through monthly clinical evaluation, visits and house calls, and 4,300 weekly questionnaires filled out by the patients in their domiciles. A monthly pain score was calculated for each patient. Pain was the most frequent adverse manifestation of the disease stressing its significant bio-psycho-social impact. Although nearly all patients and relatives reported a better clinical course throughout the whole study, the drug was ineffective in the prevention of painful crises. This placebo effect may be ascribed to an unplanned and unsystematic 'cognitive-behavioural' management of the children. The pain score in the second semester of the study - both in the experimental and in the control groups - was significantly smaller than that in the first semester. In conclusion, piracetam was found to be ineffective in the prevention of painful crises; a powerful placebo effect due to adequate patient care was demonstrated.     

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in E-selectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyte-endothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis.     

Challenge of Managing Sickle Cell Disease in a Pediatric Population Living in Kinshasa,Democratic Republic of Congo: A Sickle Cell Center Experience

In the Democratic Republic of Congo (DRC), sickle cell disease is not yet really regarded as a health care priority. The patterns of sickle cell disease in patients living in Kinshasa, DRC are discussed and the difficulties encountered in their management are highlighted. The cross-sectional survey is of sickle cell patients and their families attending the Centre de Médecine Mixte et d’Anémie SS de Yolo (CMMASS), Kinshasa, DRC, between January and April 2009. Completed questionnaires were received from 168 respondents (111 girls; 57 boys). Seventy-one percent of the subjects were diagnosed before the age of 2 years but none in the neonatal period. Sickle cell disease was diagnosed in 54.8% of the patients after they had suffered pain crises. Of the 168 subjects, 74.0% had previously received blood transfusions. Seventy-five (45.0%) had more than three severe pain crises per year. A minority of 35.0% reported that they regularly took an antibioprophylaxis. Seventy-five (45.0%) subjects were eligible for hydroxyurea (HU) therapy but in all cases this drug was taken irregularly. Eighty-two percent of drugs were purchased by the parents. One hundred and sixty-three children (97.0%) were vaccinated according to the Expanded Programme on Immunization (EPI), 61.0% against Streptococcus pneumoniae and 16.0% against the Hepatitis B virus (HBV). No case of immunization against Hemophilus influenzae and Salmonella sp was reported. Neonatal screening programs, early educational detection programs for families, use of current method treatments and an implementation of a health insurance system for sickle cell disease will improve detection and management for these and future patients in our population.     

Diagnostic value of anemia, red blood cell morphology, and reticulocyte count for sickle cell disease.

STUDY OBJECTIVE: To determine the diagnostic value of anemia, RBC morphology, and reticulocyte count for differentiating patients with sickle cell trait from those with sickle cell disease, who have acute medical or surgical conditions and a positive sickle cell screen. DESIGN: Retrospective chart review. SETTING: A midwest urban children's hospital with 220 beds and 36,000 emergency department visits per year. PARTICIPANTS: One hundred six patients with sickle cell trait and 152 patients with sickle cell hemoglobinopathies. RESULTS: Anemia was observed significantly more often in patients with sickle cell disease compared with sickle cell trait (P less than .001) at all ages 3 months and older. However, anemia alone as a diagnostic test lacked high sensitivity and specificity in children less than 4 years old. Sensitivity approached 100% with the presence of anemia, abnormal RBC morphology, or reticulocyte count of more than 2%. CONCLUSION: Absence of anemia alone does not exclude the diagnosis of sickle cell disease in children less than 4 years old. To differentiate trait from sickle cell disease, we recommend determination of not only hemoglobin adjusted for age but also of RBC morphology and reticulocyte count on all children presenting with acute medical and surgical conditions and a positive sickle cell screen.     

Musculoskeletal manifestations of hemoglobinopathies

Patients with sickle cell disease often seek treatment for rapid periorbital swelling due to infarction of the orbital bones. Because of resulting orbital compression syndrome, treatment with corticosteroids and antibiotics is advisable. If spinal tuberculosis occurs in patients with sickle cell anemia, radiologic signs will be a combination of the two conditions. The diagnosis of juvenile rheumatoid arthritis is usually delayed in patients with sickle cell disease. Sulphasalazine is the disease-modifying drug of choice for treating juvenile rheumatoid arthritis, because it also reduces the adhesiveness of sickled red cells. TNF-alpha inhibitors may also be useful for treating these patients. A volumetric method to determine the size and special distribution of the necrotic lesions of the femoral head has been developed using magnetic resonance imaging scans. With this method it will be easier to determine which early lesions require core decompression, or which ones should be treated conservatively. Osteomyelitis can be differentiated from bone infarction with the use of segmental radionuclide bone-marrow and bone scans. Reduction in frequency of painful crises can be achieved by increasing fetal hemoglobin with the use of hydroxyurea. The treatment of the actual pain requires decisions about the analgesics that are used as well as the route of their administration. Ketorolac monotherapy is likely to fail in the presence of an initial high pain score or with involvement of four or more pain sites.     

Novel approaches to the treatment of sickle cell disease: the potential of histone deacetylase inhibitors

Sickle cell disease (SCD) is a severe genetic disorder of hemoglobin causing vaso-occlusion. Patients suffer severe anemia, strokes, renal failure, pulmonary compromise and shortened life expectancy. Over 90,000 people in the USA have SCD, and the options for therapy are limited and only partially effective. With the available therapies - hydroxyurea, blood transfusion, hydration and pain medicines - patients continue to suffer the long-term complications of the disease. This review focuses on the pathogenesis of SCD and the role of fetal hemoglobin in disrupting the polymerization of sickle hemoglobin. The authors review the compounds that induce fetal hemoglobin: hydroxyurea, which is currently US FDA approved, and the histone deacetylase inhibitors and discuss their role in the treatment of SCD and other β-hemoglobinopathies.