Navigating the Interplay of Sickle Cell Vasculopathy and Moyamoya Cerebrovascular Changes: A Case Report.

Sickle cell disease (SCD) is a hereditary hemoglobinopathy that can lead to progressive vasculopathy, increasing the risk of cerebrovascular complications. Moyamoya syndrome (MMS), a rare disorder characterized by stenosis of the internal carotid arteries, can occur in SCD patients due to chronic endothelial damage and inflammation. The coexistence of these conditions can result in severe cerebrovascular complications, presenting unique diagnostic and therapeutic challenges. We present a 35-year-old African American male with a complex interplay of advanced SCD and MMS, manifesting as extensive cerebrovascular disease and recurrent ischemic strokes. A CT angiogram (CTA) of the head showed diffusely decreased caliber of the right M1 segment, appearing worse compared to prior studies. CTA of the head and neck demonstrated a new cut-off of the distal right M3 segment with an asymmetric paucity of arborizing vessels within the right middle cerebral artery (MCA) distribution, consistent with progressive sickle cell vasculopathy and also demonstrated abnormal dilated collateral vessels. Further imaging with MRI exhibited multiple prior ischemic strokes in various vascular territories despite previous revascularization surgery with a left superficial temporal artery to MCA bypass. The patient's progressive cerebrovascular disease was attributed to sickle cell vasculopathy exacerbated by MMS, resulting in compromised cerebral perfusion through distinct pathological mechanisms. Management involved a multidisciplinary treatment approach, including chronic transfusions, antiplatelet therapy, surgical revascularization with extracranial-intracranial bypass, seizure management, and neuropsychiatric support. Despite maximal therapy, the patient experienced recurrent cerebrovascular events and progressive neurological deficits, highlighting the challenges in controlling these intertwined disease processes. It signifies the importance of early recognition of this rare co-occurrence and implementation of prompt multidisciplinary treatment to improve outcomes.

Genotyping and the Future of Transfusion in Sickle Cell Disease.

Patients with sickle cell disease (SCD) have a high rate of red cell alloimmunization, which increases morbidity and mortality. Reasons for this susceptibility are multifactorial, but differences in antigen frequency between donors and recipients are one of the modifiable risk factors. Here, we evaluate the benefits of red cell molecular antigen-typing for both patients with SCD and their donors and describe how results from these critical tests could be used to enhance patient safety.

Impact of universal irradiation on chronic transfusion for sickle cell disease.

BACKGROUND: Irradiation of blood products prevents transfusion-associated graft-versus-host disease, but most patients do not require this modification which could have an adverse impact on transfusion outcomes. We hypothesized that irradiation may increase transfusion requirements for patients with sickle cell disease (SCD) receiving chronic transfusion. STUDY DESIGN AND METHODS: Our pediatric hospital implemented a new policy of universal blood product irradiation in May 2018. We conducted a retrospective chart review of patients with SCD receiving chronic red blood cell (RBC) transfusion throughout the year before and after institution of this policy. The primary outcome was the change in RBC transfusion volume per patient weight transfused during the pre- vs. post- universal irradiation period. Secondary outcomes were the change in median pretransfusion laboratory values. RESULTS: Among 17 patients, 8 (47%) received more RBCs the year before irradiation and 9 (53%) received more the year after irradiation. Implementation of universal irradiation did not significantly increase transfusion volumes needed to clinically manage this population (median change +1.7 ml/kg/year, p = .54). Additionally, there were no significant changes in absolute reticulocyte count, hemoglobin, hemoglobin S%, white blood cell count, lactate dehydrogenase, total bilirubin, serum potassium, and ferritin during the two time periods. CONCLUSION: In a cohort of patients with SCD receiving simple chronic transfusion, irradiation did not impact transfusion requirements or pertinent pretransfusion laboratory values. Irradiation does not appear to have clinically significant consequences for SCD chronic transfusion management.

Hemoglobin A1c and fructosamine correlate in a patient with sickle cell disease and diabetes on chronic transfusion therapy.

In patients with sickle cell disease (SCD) and diabetes mellitus (DM), hemoglobin A1c (HbA1c ) is unreliable and the American Diabetes Association recommends monitoring long-term glycemia by measuring serum glucose, but use of serum fructosamine (SF), a measurement independent of red cell lifespan, has been reported. SF as a screen for DM in SCD, however, is not standardized and its relationship to serum glucose has not been validated. Further, screening for DM was not adequately addressed in the 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines for SCD management. Blood transfusions, an important treatment for some patients with SCD, can also impact HbA1c . We present a case of a patient with SCD and cystic fibrosis-related diabetes on monthly chronic transfusions therapy (CTT) who had well-correlated "steady state" HbA1c and SF levels over time, suggesting for the first time these markers may actually be useful when following long-term glycemic control in patients with SCD on CTT programs.

Patient and family experience with chronic transfusion therapy for sickle cell disease: A qualitative study.

BACKGROUND: There is a limited understanding of the patient and family experience of Chronic Transfusion Therapy (CTT) for prevention of complications of Sickle Cell Disease (SCD). We sought to understand patient and family experience with CTT using qualitative methods. METHODS: Fifteen parents of children < 18 years old and nine children 12-18 years old with SCD who were receiving CTT for > 1 year were interviewed using a semi-structured interview format, and interviews were analyzed using open coding methods. RESULTS: Four themes created a narrative of the patient and family experience of CTT: 1) Burden of CTT, 2) Coping with CTT, 3) Perceived benefits and risks of CTT, and 4) Decision making regarding CTT. Participants reported substantial burden of CTT, including the impact of CTT on daily life and family, distress about venous access, burden of chelation therapy, and anxiety about CTT complications. Participants described how they coped with CTT. Participants reported increased energy, decreased pain, fewer hospitalizations, and stroke prevention with CTT, but also recognized complications of CTT, though awareness was limited in adolescents. Parents described sharing in the informed decision-making process with their healthcare provider about CTT, but adolescent patient participants reported that they were not involved in this process. CONCLUSIONS: CTT is associated with significant patient and family burden. Support from family, healthcare providers and school may help individuals cope with some of this burden. These findings provide the basis for future studies to identify strategies to mitigate the burden of CTT and improve the patient experience with this therapy. Future studies should also systematically assess patient knowledge about the key components of CTT and chelation using quantitative assessments.

Outcomes in Patients with Moyamoya Syndrome and Sickle Cell Disease: A Systematic Review.

BACKGROUND: Moyamoya syndrome, a progressive, idiopathic stenosis of the internal carotid arteries, results in increased risk for both ischemic and hemorrhagic strokes. Revascularization procedures have been shown in small studies to be both safe and efficacious for these patients; however, randomized controlled trials are lacking. The goal of this systematic review is to organize the literature evaluating surgical intervention versus conservative medical management. METHODS: A systematic review was performed including studies with 3 or more participants with moyamoya syndrome in the setting of sickle cell disease and a measured outcome after either medical or surgical intervention. Relevant studies were identified using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria and a set of predetermined key words. RESULTS: Sixty-one articles were identified with 6 articles ultimately included in this review (N = 122). Of the patients, 73 (59.8%) were revascularized surgically (all indirect procedures), whereas 49 (40.2%) remained on chronic transfusion therapy. Of the patients that underwent indirect revascularization surgery, a total of 1 perioperative (1.4%) and 4 postoperative strokes (5.5%) were reported over 44 months (1 stroke per 53.3 patient-years). In comparison, an average of 46.5% of patients who were receiving chronic transfusions had major events (stroke or transient ischemic attack) while undergoing therapy (1 stroke per 13.65 patient-years, P = 0.00215). CONCLUSIONS: We present a large systematic review of the literature regarding outcomes of surgical and medical management for patients with moyamoya syndrome and sickle cell disease. The findings redemonstrate the efficacy and safety of surgical revascularization, and advocate for earlier discussion around surgical intervention.

Health literacy and knowledge of chronic transfusion therapy in adolescents with sickle cell disease and caregivers.

BACKGROUND: Patients with sickle cell disease (SCD) may require chronic transfusion therapy (CTT) for prevention of stroke or other complications. Limited health literacy (HL) is common and is associated with poor health-related knowledge and outcomes in chronic disease. We sought to assess HL and transfusion knowledge in patients with SCD on CTT and their caregivers. METHODS: A cross-sectional study of patients was conducted in outpatient hematology clinics. Forty-five pairs of adolescent patients and caregivers and 20 caregivers of pre-adolescent patients completed the Newest Vital Sign HL assessment and answered questions assessing SCD and transfusion knowledge. Community-level median income and unemployment rates were estimated from Census data. We computed the correlation of HL with knowledge and compared each to Census variables, payor status, educational attainment, and stroke. RESULTS: HL was inadequate in 22 (34%) caregivers and 31 (69%) adolescents. Adequate caregiver HL was associated with higher educational attainment but not community-level socioeconomics or payor status. Mean knowledge score was lower in adolescents than in caregivers and correlated with age in adolescents (r = 0.42, P = .004). HL correlated with knowledge (r = 0.46, P < .0001). There were no significant correlations of HL or knowledge between adolescents and their caregivers. Neither HL nor knowledge was associated with prior stroke. The greatest knowledge was demonstrated for iron overload and SCD genotype, whereas knowledge gaps existed in alloimmunization, indication for CTT, and SCD curative therapy. CONCLUSIONS: Enhanced educational resources in transfusion therapy, alloimmunization, and curative therapy are needed for patients with SCD and caregivers of all HL levels.

Iron overload in myelodysplastic syndromes (MDS).

Iron overload (IOL) starts to develop in MDS patients before they become transfusion-dependent because ineffective erythropoiesis suppresses hepcidin production in the liver and thus leads to unrestrained intestinal iron uptake. However, the most important cause of iron overload in MDS is chronic transfusion therapy. While transfusion dependency by itself is a negative prognostic factor reflecting poor bone marrow function, the ensuing transfusional iron overload has an additional dose-dependent negative impact on the survival of patients with lower risk MDS. Cardiac dysfunction appears to be important in this context, as a consequence of chronic anemia, age-related cardiac comorbidity, and iron overload. Another potential problem is iron-related endothelial dysfunction. There is some evidence that with increasing age, high circulating iron levels worsen the atherosclerotic phenotype. Transfusional IOL also appears to aggravate bone marrow failure in MDS, through unfavorable effects on mesenchymal stromal cells as well a hematopoietic cells, particularly erythroid precursors. Patient series and clinical trials have shown that the iron chelators deferoxamine and deferasirox can improve hematopoiesis in a minority of transfusion-dependent patients. Analyses of registry data suggest that iron chelation provides a survival benefit for patients with MDS, but data from a prospective randomized clinical trial are still lacking.

Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404).

BACKGROUND: Children with sickle cell anemia (SCA) have an 11% risk of stroke by the age of 18. Chronic transfusion applied in patients detected to be at risk by transcranial Doppler allows a significant reduction of stroke risk. However, chronic transfusion exposes to several adverse events, including alloimmunization and iron overload, and is not curative. Hematopoietic stem cell transplantation allows termination of the transfusion program, but its benefit has not been demonstrated. DESIGN: DREPAGREFFE (NCT01340404) is a multicenter, prospective trial enrolling SCA children younger than 15years receiving chronic transfusion due to a history of abnormal transcranial Doppler (velocities ≥200cm/s). Only those with at least one non-SCA sibling and parents accepting HLA-typing and transplantation with a genoidentical donor were eligible. Chronic transfusion was pursued in patients with no available donor, whereas others were transplanted. Comparison between the 2 arms (transfusion vs transplantation) was analyzed using both genetic randomization and propensity-score matching as a sensitivity analysis. The primary end-point was the velocity measure at 1year. Secondary endpoints were the incidence of stroke, silent cerebral infarcts and stenoses, cognitive performance in comparison with siblings, allo-immunization, iron-overload, phosphatidyl-serine, angiogenesis/hypoxia, brain injury-related factor expression, quality of life and cost. OBJECTIVES: To show that genoidentical transplantation decreases velocities significantly more than chronic transfusion in SCA children at risk of stroke. DISCUSSION: DREPAGREFFE is the first prospective study to evaluate transplantation in SCA children. It compares the outcome of cerebral vasculopathy following genoidentical transplantation versus chronic transfusion using genetic randomization and causal inference methods.

Quality of Life Outcomes in a Pediatric Thalassemia Population in Egypt.

Thalassemia is a disorder of hemoglobin (Hb) synthesis characterized by chronic hemolysis. In ß-thalassemias major (ß-TM), patients require regular transfusion at an early age due to severe anemia. Subsequently, intensive chelation therapy is initiated to mitigate the effects of the resultant iron overload. Clinical disease burden and the demanding treatment can affect health-related quality of life (HRQoL) outcomes in this population. The aim of this study was to assess HRQoL outcomes in Egyptian pediatric thalassemia patients. Patients were enrolled simultaneously from the hematology clinic at the National Research Institute in Cairo, Egypt. The Arabic version of SF36 tool was used to assess HRQoL outcomes. Socioeconomic data were collected by patient and parent interviews. Clinical data were collected by review of medical records. One hundred and thirty patients and 60 controls were enrolled, with a mean age of 5.4 ± 3.2 years and 6.3 ± 3.0, respectively. The HRQoL outcome scores were lower in all domains in the thalassemia group compared to the control group (p = 0.0001). Transfusion-dependent (TD) patients had lower HRQoL scores compared to nontransfusion-dependent (NTD) patients (p = 0.0001). Patient education and maternal education were independently associated with better HRQoL scores (p = 0.007, p = 0.028, respectively). Residents of rural areas reported lower scores compared to urban residents (p = 0.026). Thalassemia was associated with lower HRQoL scores, in all domains, compared to HRQoL in unaffected controls. Chronic transfusion independence, patient education, and maternal education were all associated with higher HRQoL scores. Psychological, social, and economic support for families with thalassemia are all essential tools to improve HRQoL outcomes.

Fanconi Syndrome Secondary to Deferasirox in Diamond-Blackfan Anemia: Case Series and Recommendations for Early Diagnosis.

Deferasirox is an oral iron chelator used to treat patients with transfusion-related iron overload. We report, from two institutions, two children with Diamond-Blackfan anemia who developed Fanconi syndrome secondary to deferasirox administration, along with a review of the literature. The current recommendation for the laboratory monitoring of patients receiving deferasirox does not include serum electrolytes or urine analysis. Thus, despite routine clinic visits and bloodwork, these two patients presented with life-threatening electrolyte abnormalities requiring hospitalization. Hence, we propose the inclusion of serum electrolytes and urine analysis as part of routine monitoring to facilitate the early diagnosis of Fanconi syndrome in the context of high doses of deferasirox therapy.

Analysis of Current Status of Chronic Red Blood Cell Transfusion / 대한수혈학회지

BACKGROUND: Chronic red blood cell (RBC) transfusion is widely practiced as part of supportive care in patients with chronic anemia. However, there were few reports on the actual situation in Korea. Therefore, we studied the current status of chronic RBC transfusion. METHODS: Among patients who received RBC transfusions at a regional hospital from January 2011 to December 2015, patients who were consistently transfused with more than 15 units of RBC for more than one year were included. We retrospectively analyzed the status of RBC transfusion, including the laboratory findings related to transfusion using medical records. RESULTS: A total of 58 patients were included in the study. The mean age of patients was 66.4 years, and there were 24 hematologic malignancies (41.4%), 20 malignant tumors (34.5%), and 14 chronic diseases (24.1%). The mean hemoglobin level at the beginning of transfusion was 7.0 g/dL, and eight patients (13.8%) showed RBC alloimmunization as the transfusion proceeded. The mean serum ferritin level at the initial phase of transfusion was 475.3 ng/mL and increased to 1,462 ng/mL during the late phase of transfusion. CONCLUSION: Since the number of elderly patients treated with chronic diseases including tumors is expected to increase significantly, patients with chronic transfusions are also expected to increase. It is necessary to research and prepare measures such as establishment of guidelines.

Immune parameter analysis of children with sickle cell disease on hydroxycarbamide or chronic transfusion therapy.

Sickle cell disease (SCD) is increasingly appreciated as an inflammatory condition associated with alterations in immune phenotype and function. In this cross-sectional study we performed a multiparameter analysis of 18 immune markers in 114 paediatric SCD patients divided by treatment group [those receiving hydroxycrabamide (HC, previously termed hydroxyurea), chronic transfusion (CT), or no disease-modifying therapy] and 29 age-matched African American healthy controls. We found global elevation of most immune cell counts in SCD patients receiving no disease-modifying therapy at steady state. Despite the decrease in percentage of haemoglobin S associated with CT therapy, the abnormal cellular immune phenotype persisted in patients on CT. In contrast, in both univariate and multivariate analysis, treatment with HC was associated with normalization of the vast majority of leucocyte populations. This study provides additional support for HC treatment in SCD, as it appears that HC decreases the abnormally elevated immune cell counts in patients with SCD.

Iron overload in adults with sickle cell disease who have received intermittent red blood cell transfusions.

OBJECTIVE: To assess the prevalence of iron overload in adults with sickle cell disease (SCD) not on a chronic transfusion protocol. DESIGN: Retrospective chart review. DATA SOURCE: University of South Alabama Comprehensive Sickle Cell Center adult outpatient clinic. RESULTS: There was no significant difference in units transfused across the four genotypes (HbSS, HbSC, HbSß(0)-thalassemia, and HbSß(+)-thalassemia). Only individuals with HbSS (n = 63) met criteria for iron overload with ferritins of ≥1500 ng/mL. Forty-eight had ferritins <1500 ng/mL, eight (13%) had ferritins ≥3000 ng/mL, and seven (11%) had ferritins ≥1500 and <3000 ng/mL. The overall prevalence of iron overload was 9.74% in SCD cohort and 23.8% in the HbSS genotype. CONCLUSIONS: Our data support that patients with HbSS are at a particularly high risk for inadvertent iron overload as compared to HbSC, HbSß(0)-thalassemia, and HbSß(+)-thalassemia. IMPLICATIONS FOR PRACTICE: This study supports the need for healthcare providers to closely monitor the number of red blood cell (RBC) transfusions, RBC units transfused, and serial baseline, steady-state ferritin levels. With closer monitoring, the clinical significance of iron overload in SCD can be established and guide the healthcare provider's management in the prevention of iron overload.

Implementation of transcranial Doppler ultrasonography screening and primary stroke prevention in urban and rural sickle cell disease populations.

BACKGROUND: Transcranial Doppler (TCD) ultrasonography identifies children with sickle cell disease (SCD) at increased risk of stroke. Initiation of chronic transfusions as primary stroke prevention in children with abnormal TCD significantly reduces stroke risk. Here, we report the results describing the implementation of TCD screening and primary stroke prevention in both urban and rural clinical practices. PROCEDURE: Retrospective chart review identified children ages 2-16 years with Hgb SS or Sß0 -thalassemia and no history of stroke followed in either the local urban or rural SCD clinics at Georgia Regents University. We defined standard of care (SOC) as having one TCD performed annually between January 2010 and December 2012 starting at age 2 years. RESULTS: A total of 195 patients were included in the evaluation of SOC screening, overall 41% achieved SOC. There was no difference in SOC between the two clinics (35% urban and 47.4% rural). The majority of patients with abnormal TCDs are on chronic transfusions (83%), and none have experienced a stroke. Monitoring of effects of transfusion was difficult with 38% and 31% of rural patients lacking documentation of Hgb S% and ferritin levels, respectively, in the past year. CONCLUSIONS: We report here data describing primary stroke prophylaxis in rural patients. SOC rates are similar between the two clinical settings. While implementation of primary stroke prevention in rural patients was difficult, rural TCD screening is feasible and can achieve SOC equal to that in an urban setting. This suggests that barriers exist in provided primary stroke prevention to all patients. Pediatr Blood Cancer 2015;62:219-223. © 2014 Wiley Periodicals, Inc.

Dosis moderadas de hidroxiurea en niños con drepanocitosis y accidente vascular encefálico. Resultados preliminares / Moderate dose of hydroxyurea in children with sickle cell disease and stroke. Preliminary results

Se trataron 20 niños con anemia drepanocítica, dos ellos con hemoglobinopatía SC y uno con S/â0 talasemia con accidente vascular encefálico o Doppler transcraneal con velocidades del flujo sanguíneo mayor de 170 cm/s. La media de seguimiento fue de 41 ± 19 meses. En los pacientes con accidente vascular encefálico se administraron 25 mg/kg/día de hidroxiurea y se realizó régimen de transfusión crónica por un año. En los niños con Doppler transcraneal patológico se administró la hidroxiurea sola en igual dosis. Hubo una disminución significativa del número de accidentes vasculares encefálicos (p <0.02) y de la velocidad del flujo sanguíneo en la arteria cerebral media derecha (p <0.003). En tres niños con velocidades de flujo muy aumentadas en el Doppler transcraneal sin accidente vascular encefálico fue necesario asociar régimen de hipertransfusión por no respuesta al tratamiento. La asociación de hidroxiurea y transfusiones de glóbulos rojos durante un año pueden ser útiles en el tratamiento y prevención del accidente vascular encefálico

Twenty children with sickle cell anemia, two with SC hemoglobinopathy and one with S/â0 thalassemia were treated, with a previous stroke or abnormal ultrasound transcranial Doppler (TCD) flow velocities more than 170 cm/s. The mean follow-up was of 41 ± 19 months. Hydroxyurea (HU) at a dose of 25 mg/kg/day associated with chronic transfusion therapy, was administrated during one year to patients with stroke. Patients with abnormal TCD received only HU at the same dose. There was a significant decrease of stroke (p <0.02) and TCD flow velocities in the right middle cerebral artery (p <0.003). It was necessary to associate chronic transfusion therapy in three children with high velocities in TCD without stroke, due to the lack of response to the treatment with HU. The combination of HU and transfusions during one year can be useful for stroke therapy and prevention