Chronic Blood Transfusion Research Articles

Iron Overload in Patients With Heavily Transfused Sickle Cell Disease-Correlation of Serum Ferritin With Cardiac T2* MRI (CMRTools), Liver T2* MRI, and R2-MRI (Ferriscan®).

The treatment of sickle cell disease (SCD) is mainly supportive, except for a minority, who receive bone marrow transplantation (BMT). Serum ferritin (SF) is routinely available but is notoriously unreliable as a tool for iron-overload assessment since it is an acute-phase reactant. Although blood transfusion is one of the most effective ways to deal with specific acute and chronic complications of SCD, this strategy is often associated with alloimmunization, iron overload, and hemolytic reactions. This study, thus, aims to evaluate iron overload in patients with SCD on chronic blood transfusions and specifically, correlate SF with the current standard of care of iron-overload assessment using MRI-based imaging techniques. Amongst a historic cohort of 58 chronically transfused patients with SCD, we were able to evaluate 44 patients who are currently alive and had multiple follow-up testing. Their mean age (±SD) was 35 (9) years and comprised of 68.2% of women. The studied iron-overload parameters included cardiac T2* MRI, liver iron concentration (LIC) by Liver T2* MRI, and serial SF levels. Additionally, in a smaller cohort, we also studied LIC by FerriScan© R2-MRI. Chronic blood transfusions were necessary for severe vaso-occlusive crisis (VOC) (38.6%), severe symptomatic anemia (38.6%), past history of stroke (15.9%), and recurrent acute chest syndrome (6.9%). About 14 (24%) patients among the original cohort died following SCD-related complications. Among the patients currently receiving chelation, 26 (96%) are on Deferasirox (DFX) [Jadenu® (24) or Exjade® (2)], with good compliance and tolerance. However, one patient is still receiving IV deferoxamine (DFO), in view of the significantly high systemic iron burden. In this evaluable cohort of 44 patients, the mean SF (±SD) reduced marginally from 4,311 to 4,230 ng/ml, mean Liver T2* MRI dropped from 12 to 10.3 mg/gm dry weight, while the mean cardiac T2*MRI improved from 36.8 to 39.5 ms. There was a mild to moderate correlation between the baseline and final values of SF ng/ml, r = 0.33, p = 0.01; Cardiac T2* MRI ms, r = 0.3, p = 0.02 and Liver T2* MRI mg/kg dry weight, r = 0.6, p < 0.001. Overall, there was a positive correlation between SF and Liver T2* MRI (Pearson's r = 0.78, p < 0.001). Cardiac T2*MRI increased with the decreasing SF concentration, showing a negative correlation which was statistically significant (Pearson's r = −0.6, p < 0.001). Furthermore, there was an excellent correlation between SF ng/ml and LIC by FerriScan© R2-MRI mg/g or mmol/kg (Spearmen's rho = −0.723, p < 0.008) in a small subset of patients (n = 14) who underwent the procedure. In conclusion, our study demonstrated a good correlation between serial SF and LIC by either Liver MRI T2* or by FerriScan© R2-MRI, even though SF is an acute-phase reactant. It also confirms the cardiac sparing effect in patients with SCD, even with the significant transfusion-related iron burden. About 14 (24%) patients of the original cohort died over the past 15 years, indicative of a negative impact of iron overload on disease morbidity and mortality.

Red Blood Cell Alloimmunization Rates and Related Factors of Patients with Thalassemia in Shiraz, Iran.

The development of antibodies against red blood cell (RBC) antigens is one of the most significant adverse effects of chronic blood transfusions. This study aimed to estimate the frequency and causes of RBC immunization in patients with major thalassemia. The findings could help determine the limitation of current practices and help future developments in the selection of suitable blood units for the transfusion support of patients with thalassemia. The alloimmunization rate was detected in 52 of 650 patients with major thalassemia (8%). The most frequent antibodies were against K (50%), D (26%), and E (15.4%). Sex, age, and splenectomy did not have any impact on the immunization rate. Immunization was lower in patients who had received only leuko-reduced blood units. It is recommended that antibody screening before the first transfusion and extended RBC matching particularly for the most frequent antigens (ABO/Rh/Kell) should be performed for patients with thalassemia.

CHRONIC KIDNEY DISEASE IN BRAZILIAN ADULTS WITH SICKLE CELL DISEASE: RESULTS FROM THE REDS-III MULTICENTER COHORT STUDY

Chronic kidney disease (CKD) has a significant impact on sickle cell disease (SCD) morbidity and mortality. Early identification of individuals at highest risk of developing CKD may allow therapeutic intervention to prevent worse outcomes. This study aimed to evaluate the prevalence and risk factor for CKD among adults with SCD in Brazil. Participants in the REDS-III multicenter SCD cohort with more severe genotypes [sickle cell anemia (SCA) = hemoglobin (Hb) SS, Hb Sβ0-thalassemia, Hb Sβ+-thalassemia with mutations associated with severe phenotype] aged ≥18 years at time of enrollment with at least two serum creatinine values were analyzed. Participants were enrolled between 2013-2015 and were prospectively followed and monitored for the occurrence of clinical complication, including death, for up to three years. The estimated glomerular filtration rate (eGFR) was calculated using the JSCCS-GFR Equation. The CKD stage was defined according to the K/DOQI. For participants with multiple eGFR measures, we use the two most recent values to define CKD; for those who presented different CKD stages, we used the mean value to define the outcome. Because albuminuria status was not known in all participants, those with CKD stage 2 or higher were compared to those with eGFR≥90. The association among the characteristics and the presence of CKD stage 2 or higher were assessed using binary logistic regression model. 497 (65.7%) participants were receiving hydroxyurea (HU) therapy, 105 (13.9%) were treated with chronic blood transfusion (CBT), and 69 (9.1%) were under both therapies. Among the 756 participants, 569 (75.3%) had eGFR≥90, 175 (23.1%) had stage-2, six (0.79%) had stage-3, and six (0.79%) had ESRD. Participants with CKD stage 2 or higher were significantly older and predominantly male when compared with those with eGFR≥90. There was no association between CKD stage 2 or higher and HU or CBT. Participants with CKD stage 2 or higher had a 2.3 (95%CI: 1.4–3.7) times higher odds for death when compared to those with eGFR≥90. Male sex (OR: 34.7; 95%CI: 20.3–62.5), higher age (OR: 1.03; 95%CI: 1.01–1.05), higher diastolic blood pressure (OR: 1.03; 95%CI: 1.002–1.05), lower Hb (OR: 0.704; 95%CI: 0.59–0.83), and lower reticulocytes (OR: 0.91; 95%CI: 0.86–0.96) levels were significantly associated with stage 2 or higher in the final multivariate model. We observed a higher odds for mortality in participants with CKD stage 2 or higher when compared to those with eGFR≥90. This highlights the importance of early detection and implementation of preventative therapies. We also observed a significant independent association between lower levels of Hb and reticulocytes with CKD stage 2 or higher. These data might reflect a state of hypoproliferative anemia in participants with CKD stage 2 or higher likely due to deficiency of erythropoietin. In this study, CKD stage 2 or higher was more prevalent in men than in women, and male sex was the strongest independent predictor of CKD stage 2 or higher in the final model. This finding might be used to target individuals at highest risk for CKD in prevention campaigns. CKD stage 2 or higher was observed in one-quarter of adults with SCA. Older age, male sex, higher diastolic blood pressure, lower hemoglobin, and lower reticulocytes levels were significantly associated with occurrence of CKD stage 2 or higher, which, in turn, significantly increased the risk of mortality.

Prevalence and Outcome of Cholelithiasis in Children with Sickle Cell Disease at King Saud Medical City, Saudi Arabia

BACKGROUND: Sickle cell disease (SCD) is one of the common hereditary blood diseases in Saudi Arabia. The hepatobiliary system is one of the common organs to be affected either directly from the sickling process or indirectly as a result of chronic hemolysis and multiple blood transfusions. Cholelithiasis is one of the common complications of sickle cell anemia. OBJECTIVES: To assess the prevalence of cholelithiasis in children with SCD treated at King Saud Medical City (KSMC); Pediatric Hospital in Saudi Arabia and describe the outcome, management, and clinical profile of children with SCD and cholelithiasis. MATERIALS AND METHODS: This is a retrospective descriptive study conducted at a single tertiary health care center, KSMC, Pediatric Hospital, Riyadh from 2012 to 2019 on 277 patients aged &lt;14 years. Medical records of all pediatric patients with SCD included in the study were identified and reviewed. RESULTS: From total of 277 patients, 87 (31.4%) had cholelithiasis. Forty three (49.4%) of them were female and 44 (50.6%) were male. From 87 patients who developed cholelithiasis, 15 patients aged &lt;5 years old, 50 aged (5–10 years), and 22 aged &gt;10 years. According to the genotype of sickle cell (SS), the occurrence of cholelithiasis were (75.9% in SS, 23% in S/BETA 0 and 1.1% in S/BETA+). The majority were symptomatic (59.8%) compared to asymptomatic (40.2%) and 26 patients (29.9%) were complicated. In our study, we found that complications for the gallstones were acute calcular cholecystitis, chronic cholecystitis, direct hyperbilirubinemia, transaminitis, and acute pancreatitis. CONCLUSION: The prevalence of cholelithiasis in our study was significant. The large majority of patients were symptomatic. Cholecystectomy must be strongly recommended in symptomatic patients.

Awareness and accessibility of Hepatitis B vaccination among undergraduate clinical students of a tertiary institution in South Eastern Nigeria

Hepatitis B virus Infection is a chronic Infection with increasing incidence and worldwide prevalence. It is a leading cause of liver failure and hepatocellular carcinoma. Healthcare personal, chronic blood transfusion, unprotected sex, etc are some major risk factor of contracting the disease. It can be prevented by vaccination. This study was carried out among undergraduate Clinical students of college of Health Science, Nnamdi Azikiwe University (CHS-NAU), Nnewi it was a cross-sectional descriptive study using the convenience sampling method. Pretested self-administered questionnaires were distributed and the data analyzed using the statistical package for social science (SPSS) Version 20.0. A total of 178 questionnaires were distributed with a response rate of 100% (178). The study showed a high level of knowledge of HBV vaccination and consider attitude towards the need for vaccination but poor compliance to update due to busy schedule, cost, and level of study. HBV vaccination is low among the students of a CHS-NAU as in other parts of Nigeria and Africa with similar reasons. Good Policy enactment and implementation can help bridge the gap between the awareness, attitude and accessibility of vaccine.

Nomogram to predict postoperative infectious complications after surgery for colorectal cancer: a retrospective cohort study in China

BackgroundPostoperative infectious complications (ICs) after surgery for colorectal cancer (CRC) increase in-hospital deaths and decrease long-term survival. However, the methodology for IC preoperative and intraoperative risk assessment has not yet been established. We aimed to construct a risk model for IC after surgery for CRC.MethodsBetween January 2016 and June 2020, a total of 593 patients who underwent curative surgery for CRC in Chengdu Second People’s Hospital were enrolled. Preoperative and intraoperative factors were obtained retrospectively. The least absolute shrinkage and selection operator (LASSO) method was used to screen out risk factors for IC. Then, based on the results of LASSO regression analysis, multivariable logistic regression analysis was performed to establish the prediction model. Bootstraps with 300 resamples were performed for internal validation. The performance of the model was evaluated with its calibration and discrimination. The clinical usefulness was assessed by decision curve analysis (DCA).ResultsA total of 95 (16.0%) patients developed ICs after surgery for CRC. Chronic pulmonary diseases, diabetes mellitus, preoperative and/or intraoperative blood transfusion, and longer operation time were independent risk factors for IC. A prediction model was constructed based on these factors. The concordance index (C-index) of the model was 0.761. The calibration curve of the model suggested great agreement. DCA showed that the model was clinically useful.ConclusionSeveral risk factors for IC after surgery for CRC were identified. A prediction model generated by these risk factors may help in identifying patients who may benefit from perioperative optimization.

Stroke in Pediatric Sickle Cell Disease in Sub-Saharan Africa: Systematic Review and Estimated Prevalence

Background: Most people with sickle cell disease (SCD) live in Sub-Saharan Africa (SSA); many do not survive to adulthood (Grosse et al. Am J Prev Med 2011). Stroke is a common complication of SCD in the region (Ohene-Frempong et al.Blood 1998), yet the region's burden of pediatric SCD stroke is unknown. This systematic review aims to describe what is known, and to estimate the number of children affected by SCD stroke in SSA.Methods: Systematic reviews using Pubmed, Embase, and Web of Science were performed for all studies reporting pediatric SCD stroke prevalence data. Keyword search strategy included these or related terms: “stroke” or “brain” and “sickle cell” and “Africa” or each country in SSA available in English or French. Publication dates were selected between 1980 and December 13, 2016. Using pre-selected inclusion criteria, titles and abstracts were screened and full-text articles were reviewed. For publications meeting inclusion criteria, extracted data included: study and participant characteristics, number of patients with stroke, diagnostic criteria, imaging, management, recurrence. The number of children affected by SCD stroke in SSA was estimated based on current estimates of national population and S allele frequency (Piel et al. Lancet 2013) and the stroke prevalence in the extracted studies. The stroke prevalence in SSA was estimated based on both fixed-effect analysis and random-effect analysis.Results: After duplicates were removed, 133 individual articles remained. Ten full text articles met review selection criteria, including one in French. In all, papers reported data from seven countries in the region, including four reports from Nigeria. Cross-sectional SCD clinic-based data, with a sample size of 6,289 patients, reported pediatric stroke prevalence of 2.9-16.9%. Diagnostic criteria of stroke varied by site and were limited by access to brain imaging, which was reported in only half of the included studies. Treatment for stroke included packed red blood cell transfusion, exchange transfusion, or hyperhydration. Secondary stroke prevention with chronic blood transfusion or hydroxyurea was offered at two of 10 sites. Recurrence data was limited by variable study follow-up and limited reporting times. Using available sickle gene frequencies by country, estimated births affected by SCD per country in SSA, and a linear- or random-effects model, pediatric stroke prevalence in SSA was projected as 279,908 (95% CI: 240,335-319,481) and 561,746 (347,472-775,056), respectively. Estimates do not include stroke- or disease-associated mortality.Conclusion: This meta-analysis estimates prevalence of pediatric SCD stroke in SSA, underscoring the region's high stroke burden. Multiple clinic-based cross-sectional studies reported stroke prevalence comparable to data from high income countries prior to implementation of standardized prevention strategies. Accuracy is limited by different approaches to stroke diagnosis, paucity of population-based data on disease prevalence and mortality, regional variation in disease prevalence and severity, and overall high rates of early death in children with SCD. Available data would skew towards surviving patients, leading to possible underreporting of people at risk for SCD stroke. Improved diagnostic specificity with standardized criteria and imaging would be useful for identification of strokes. Understanding the large numbers affected by SCD stroke is critical for focusing public health efforts to introduce preventive measures to reduce stroke risk and to implement rehabilitative strategies. Adopting standardized primary and secondary stroke prevention measures in SSA may decrease the burden of SCD-associated stroke.This work was supported by funding from the National Institutes of Health (5R21HD089791, PIs Idro, Green). DisclosuresNo relevant conflicts of interest to declare.

Community Survey of Knowledge of Thalassemia

Background:The patient demographics at the Northern California Comprehensive Thalassemia Center (NCTC) at UCSF Benioff Children's Hospital Oakland (BCHO), show 475 patients with the largest ethnic groups being: 14% Chinese, 10% Laotian, 6% South Asian Indian, 5% Vietnamese, 5% Filipino and only 5% Italian. 54% of all patients receive chronic blood transfusions, 22% receive period transfusions. Among the transfusion-dependent patients, 59% are South East or East Asian, 17% South Asian, 7% are from the Middle East and 9% are Italian. The NCTC patient demographics reflect the changes in US migration over the past 40 years, where the number of Asian immigrants has increased by 21.4%. In 2009, California had 32.8% of the total Asian immigrants in the U.S, which reflects the largest immigrant group affected by thalassemia in the NCTC population.California's statewide newborn screening data shows that Asians have the highest rates of thalassemia syndromes, where the prevalence of Hemoglobin EE in Southeast Asians is 792 per 100,000 and Hemoglobin H disease is 404 per 100,000 in Asians. Despite this, there has been a lack of thalassemia education and outreach to the at-risk minority groups. While it is easy to assert the lack of outreach has to do with language barriers and mistrust of Western medicine from the immigrant population, community based interventions suggest larger more significant challenges.Methods:We developed a community survey designed to gauge general community knowledge of thalassemia and where they seek health care information. Responses were gathered from 91 subjects to date. The first group was high school students ranging from 15-18, and the second group was adults at a community church. In conjunction with the survey, both groups also participated in a thalassemia educational session.Results:The participants were predominantly of Chinese ethnicity (77%) and 50% were born outside of United States. High school students comprised 57% of the subjects, while 20% were older than 45 years. The survey demonstrated that the base knowledge of thalassemia is low. A large majority of participants (71%) had never heard of thalassemia, while 42% were unsure if their friends or family have thalassemia. However, 66% of the participants had heard of anemia. Half of the participants (51% ) were unsure if it would be useful for them to know their carrier status. Significantly, 41% believed, or were uncertain, that their community would discriminate against thalassemia carriers. Furthermore, after being informed that their child could be at risk for a serious blood disease, 36% still did not want to get tested before having a child, and 40% did not want their family members tested. One-third (33%) of participants were not comfortable with sharing their own health issues with family, and 58% did not seek medical information from family members. Physicians were the main source of medical information for 84% of participants. A majority (57%) of the participants wanted to receive more information about thalassemia from their health care providers.Conclusion:These data show that the awareness of thalassemia in the Asian immigrant population is very low, although most had some familiarity with anemia. The disinterest and uncertainty to seek more information about thalassemia could be related to the potential consequence of discrimination within the community. These findings suggest that there are internal barriers within a community and extended families with not only to the understanding of thalassemia but to the willingness to share and discuss knowledge about the genetic disease. As a result, outreach efforts will require a shift in the framework of how thalassemia is presented to the community. Perhaps, labeling thalassemia as a genetic disease could have cultural and social implications for the community, which can create resistance to outreach efforts. Using basic education approaches, community members can first be engaged through the relatable condition anemia, which can be used to scaffold a connection to thalassemia. This approach also highlights the importance of working with primary care providers because they are the main source of medical information for the community, and can initiate conversation about testing for thalassemia and genetic counseling. DisclosuresNo relevant conflicts of interest to declare.

Cognitive, Brain and Intracranial Artery Involvement in Beta Thalassemia

Background: Brain involvement in beta thalassemia is scarcely known so far, and available data show different degrees of abnormalities in terms of neuroradiologic findings and cognitive impairment, mainly showing asymptomatic white matter lesions in transfusion dependent thalassemia (TDT; Karimi et al, Ann Hematol 2016) or in non transfusion dependent thalassemia (NTDT; Karimi et al, Ann Hematol 2012 ; Pazgal et al, Thrombosis Research 2016), arterial stenosis in NTDT (Musallam et al, EJH 2011) and a general impairment in cognitive function in TDT (Elalfy et al, Hematology 2017). To our knowledge there are no studies investigating neuroimaging and cognitive function in both groups of patients, comparing results to healthy subjects.Methods: In our observational study thalassemic patients from 4 major Centers in the South of Italy, aged more than 16 years, both Transfusion Dependent (TDT) and Not Transfusion Dependent (NTDT), and healthy volunteers underwent 3T brain MRI including a FLAIR sequence and intracranial time-of-flight MR-angiography. Three neuroradiologists blinded of clinical data evaluated the MR-exams reporting the presence of artery stenosis and aneuryms and the presence of white matter signal abnormalities graded according to the Fazekas score; the number and the size of parenchymal lesions (<0.5cm, 0.5-1.5cm, >1.5cm) were recorded. Both patients and controls were administered the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) to detect cognitive ability, and results were analyzed by a team of blinded psychologists and psychiatrists. Clinical and laboratory data were collected to correlate neurologic and psychometric findings with disease history and severity.Results: Seventy-four thalassemic patients (46/74 females, mean-age 35.2±11.4 years, range 16-66; 51 TDT and 23 NTDT; mean hemoglobin 9.3±1.4 g/dl, range 7.5-12; 41 splenectomized; 34 on prophylactic aspirin) and 56 healthy controls (36/56 females, mean-age 34.2±11.7 years, range 17-66) were enrolled. No intracranial artery stenosis was detected. Patients and controls did not differ regarding the incidence rate of aneurysms (9.46% vs 9.67%). White matter lesions (WML) were found both in patients and controls, but the prevalence (35/74; 47.30% vs 28/56; 50.0%), the number (4.1 vs 4.6), the size and the Fazekas score did not differ between the groups. Compared to controls, patients presenting WML tend to be younger (35.32y compared to 39.89y, p= 0.033). No differences in WML were found between TDT and NTDT, nor between patients on aspirin and others, and splenectomy was associated with an increased lesion burden only in TDT (mean 5.56 versus 1.53, p= 0.048); in splenectomized patients on aspirin the number and prevalence of WML was lower compared to those splenectomized not on prophylaxis, but the difference did not reach the statistical significance. Patients with WML did not differ from others in terms of comorbidities, hemoglobin, platelets, erythroblasts, ferritin, hemolysis markers and chelation therapies. The presence of WML did not correlate with cognitive impairment as measured by the Intelligence Quotient (IQ) derived from the WAIS-IV test, both in patients and in controls. IQ in patients was significantly lower than controls, and this finding remained significant after correction for education (IQ: 82.75±11.11 in patients, 93.96±SD13.22 in controls, p=0.032), regardless of the presence of WML, that was again comparable.Conclusions: Beta-thalassemia and chronic blood transfusion treatment do not seem to imply significant brain and intracranial artery changes, although cognitive function seems to be affected. Further analysis are required to clarify if the general cognitive impairment derives from functional changes in cerebral connectivity, or if it is one of the effect of the chronic course of the disease. DisclosuresNo relevant conflicts of interest to declare.

Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy.

Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as “Epileptic Heart” and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the “Epileptic Heart” could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.

The combined use of electrocardiography, echocardiography and cardiac magnetic resonance imaging in left atrium evaluation among beta-thalassemia patients

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Beta-thalassemia major (β-TM) patients are subjected to iron overload as a consequence of chronic blood transfusions. The redundant iron affects, among other organs, the heart resulting in myocardial dysfunction. Iron deposition does not only affect ventricular myocardium but atrial myocardium as well. According to current practice, the overall myocardial iron status is estimated by calculating T2* at the middle section of the ventricular septum using cardiac magnetic resonance imaging (CMR). Current CMR technology limits the direct estimation of atrial iron status. Purpose The current study evaluates left atrial function by novel echocardiographic techniques and correlates these findings with CMR data. Methods 37 β-TM patients (mean age 41.17 years (SD = 8.33), 51.4% male), were subjected to electrocardiography, echocardiography and CMR imaging and P wave axis, PR segment duration, left atrial volume index (LAVI), left atrial strain at reservoir phase (LASr) and T2* were measured. Results No correlation between T2* and LASr (r = 0.253, p = 0.131) or T2* and LAVI (r = 0.044, p = 0.796) were found. However, a correlation was found between the echocardiographic parameters LAVI and LASr (r = -0.676, p &amp;lt;0.001). P wave axis did not correlate with any other parameter, while PR segment duration was correlated with LASr (r = -0.399, p = 0.015). Regression analysis revealed correlation between LAVI and LASr (r2 = 0.457, p &amp;lt;0.001). Conclusions The current study suggests that despite the undisputed contribution of CMR in left ventricular iron load estimation, it may be less accurate in atrial iron status estimation. Considering the limitations of current CMR technology regarding the iron status of the thin atrial and right ventricular walls, our study highlights the role of speckle tracking in combination with CMR imaging for a more comprehensive evaluation of β-TM patients. Correlation table P axis PR segment T2* LAVI LASr P axis 0,151 (p = 0,373) 0,112 (p = 0.,508) -0,140 (p = 0,410) -0,117 (p = 0,489) PR segment 0,151 (p = 0,373) 0,051 (p = 0,766) 0,278 (p = 0,096) -0,399 (p = 0,015) T2* 0,112 (p = 0.,508) 0,051 (p = 0,766) 0,044 (p = 0,796) 0,253 (p = 0,131) LAVI -0,140 (p = 0,410) 0,278 (p = 0,096) 0,044 (p = 0,796) -0,676 (p &amp;lt;0,001) LASr -0,117 (p = 0,489) -0,399 (p = 0,015) 0,253 (p = 0,131) -0,676 (p &amp;lt;0,001) T2*: obtained by cardiac magnetic resonance imaging LAVI left atrial volume index (ml/m2) LASr left atrial strain at reservoir phase Abstract Figure. Correlation between LASr and T2*

Синдром анемии-полицитемии – современные подходы к диагностике и антенатальной коррекции

Twin anemia polycythemia sequence (TAPS) is a specific complication of the monochorionic multiple birth, which is based on chronic feto-fetal blood transfusion over placental vascular anastomoses, and the main clinical symptom is discordant fetal hemoglobin level in the absence amniotic fluid imbalance. Currently, there is no generally recognized consensus on the optimal treatment tactics. Dynamic observation, labor, intrauterine blood transfusion, selective fetocide, fetoscopic laser coagulation of placental vascular anastomoses are applied, although the latter is recognized by the majority of researchers as the most promising method for treating TAPS. There are disagreements in estimating the frequency of perinatal morbidity and mortality during pregnancy, complicated by the development of TAPS, and their real value has not yet been completely defined. Key words: intrauterine transfusion, Solomon method, monochorionic twins, twin anemia polycythemia sequence, fetoscopic laser coagulation

Reactive Oxygen Species-Triggered Dissociation of a Polyrotaxane-Based Nanochelator for Enhanced Clearance of Systemic and Hepatic Iron.

Chronic blood transfusions are used to alleviate anemic symptoms in thalassemia and sickle cell anemia patients but can eventually result in iron overload (IO) and subsequently lead to severe oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat transfusional IO, but the use of the iron chelator is hindered by nonspecific toxicity and poor pharmacokinetic (PK) properties in humans, resulting in the need to administer the drug via long-term infusion regimens that can often lead to poor patient compliance. Herein, a nanochelator system that uses the characteristic IO physiological environment to dissociate was prepared through the incorporation of DFO and reactive oxygen species (ROS)-sensitive thioketal groups into an α-cyclodextrin-based polyrotaxane platform (rPR-DFO). ROS-induced dissociation of this nanochelator (ca. 10 nm) into constructs averaging 2 nm in diameter significantly increased urine and fecal elimination of excess iron in vivo. In addition to significantly improved PK properties, rPR-DFO was well-tolerated in mice and no adverse side effects were noted in single high dose or multiple dose acute toxicity studies. The overall features of rPR-DFO as a promising system for iron chelation therapy can be attributed to a combination of the nanochelator's improved PK, favorable distribution to the liver, and ROS-induced dissociation properties into constructs <6 nm for faster renal elimination. This ROS-responsive nanochelator design may serve as a promising alternative for safely prolonging the circulation of DFO and more rapidly eliminating iron chelates from the body in iron chelation therapy regimens requiring repeated dosing of nanochelators.

Positive effects of ultrasound-guided peripheral IV insertion on pediatric sickle cell anemia/thalassemia patients receiving automated red cell exchange procedures or chronic transfusion therapy.

Peripheral vascular access and venipuncture are major causes of distress and anxiety for children and their parents. This is especially difficult for patients with hemoglobinopathies (thalassemia major and sickle cell disease) who require chronic blood transfusions. These patients require peripheral venous access for regular blood transfusions and (in the case of sickle cell disease) for automated red cell exchange procedures. Peripheral intravenous (PIV) catheters are much preferred to central venous lines as they carry far fewer risks. However, when patients experience multiple unsuccessful attempts to initiate a PIV, it can be traumatizing and cause anxiety for future visits. Establishing therapeutic trust and ensuring a smooth experience are of paramount importance for these chronic patients who require regular blood transfusions. The purpose of this study was to determine whether ultrasound-guided PIV insertion decreases PIV-associated pain and anxiety, and whether the number of attempts and amount of time spent accessing PIVs in children with difficult peripheral intravenous (DPIV) access is reduced. This was a pilot study with both retrospective and prospective components. Hemoglobinopathies are relatively rare in our population and our study cohort was small (N = 18). We identified four DPIV access patients. We recorded each time these patients had a PIV inserted as an encounter. We found that while there was a small amount of time gained by using ultrasound-guided PIV insertion, patient and parent satisfaction was significantly improved.

Increase in Fetal Hemoglobin Levels in Pediatric Patients with Sickle Cell Disease after Vitamin D Replacement

Background: High fetal hemoglobin (HbF) levels reduce mortality and morbidity in sickle cell disease (SCD). Results from a prior clinical trial to assess safety of high dose vitamin D and our unbiased genomic analyses identifying a vitamin D regulated protein as a HbF inducer suggests that vitamin D replacement may increase HbF levels in SCD patients. To test this hypothesis, we performed a single center retrospective chart review investigating the impact of vitamin D replacement on HbF levels in our pediatric SCD population. Methods: We reviewed electronic medical records of pediatric patients with SCD with one or more serum vitamin D level who used vitamin D replacement from January 2007 to March 2020. SCD patients on chronic blood transfusion were excluded. Our cohort contained 81 SCD patients (ages: 2.3-19.9 years; 40 males) 71 HbSS, 6 HbSC, 3 HbSβ0, and1 Hb S-δβ. Vitamin D deficiency was defined as vitamin D levels &amp;lt; 30 ng/ml. All subjects were on hydroxyurea, with stable MCV (mean 96 fL at baseline and 95.6 fL during the study period). The patients received a median vitamin D dose of 2002 IU/day for a median of 229 days with a median follow-up of 365 days after replacement. Statistical analyses: Vitamin D deficient and non-deficient SCD patients data was compared at baseline by t test (for continuous variables with normal distribution), Wilcoxon test (for continuous variables with non-normal distribution), chi2 test (for categorical variables), and Fisher exact test (for categorical variables with small sample size). Linear relationships between vitamin D levels and HbF, CBC, BMI, and age were assessed using scatter plots and correlation coefficients (r value). Non-normal variables were log transformed to achieve normal distribution. A linear mixed effect (MLE) models were run to analyze linear relationship of variables of time dependent variables, including variable number of clinic visits and variable follow-up time. All models had 'vitamin D level" as an exposure variable; hydroxyurea and folic acid use as covariates, and one of the following as an outcome variable: HbF, hemoglobin, MCV, MCHC, reticulocyte count, WBC count, and platelet count. We performed mediation analysis to determine if HbF or MCV were intermediate variables for the effect of vitamin D on reticulocyte count. All LME models and scatter plots were created separately for the period of vitamin D replacement and a one-year follow-up period after cessation of vitamin D replacement to capture any lag period in HbF induction and sustained effect of vitamin D replacement. Results: The LME model, adjusting for hydroxyurea and folic acid, indicated that HbF increased by 0.68 percentage points with every 10 ng/ml rise in vitamin D levels during the vitamin D replacement period (p=0.04) and continued to rise after replacement, exhibiting a 2.2 percentage point rise per 10 ng/mL increase above replacement HbF levels during a 12 month follow-up period (p=0.005) (Figure 1, Table 1). WBC and absolute reticulocyte count (ARC) decreased significantly following vitamin D replacement according to the LME models (p&amp;lt;0.05) (Table 1). Reduction in ARC was due to HbF induction as per the mediation analysis. Conclusion: SCD patients have a 56.4-96.4 % prevalence of vitamin D deficiency reported in the literature. Several studies have shown that vitamin D deficiency is associated with increased morbidity and mortality in SCD patients. However, vitamin D screening and replacement are not routinely implemented in clinical practice. Our study is the first to analyze the effect of vitamin D replacement on HbF levels as a primary objective using longitudinal panel data. Our findings strongly suggest that vitamin D replacement can increase HbF levels and reduce laboratory markers such as ARC and WBC, whose elevation is associated with clinical severity. Disclosures Sheehan: Emmaus: Research Funding; Novartis: Research Funding; Global Blood Therapeutics: Research Funding.

Lentiviral Mediated Gene Therapy for Pyruvate Kinase Deficiency: A Global Phase 1 Study for Adult and Pediatric Patients

Introduction: Pyruvate Kinase Deficiency (PKD) is a rare inherited hemolytic anemia that is caused by mutations in the PKLR gene leading to decreased red cell pyruvate kinase (RPK) activity and impaired erythrocyte metabolism. The disorder is characterized by anemia, reticulocytosis, splenomegaly and iron overload, and may be life-threatening in severely affected individuals. PKD represents a significant unmet medical need as current therapies are palliative and limited to chronic blood transfusions, iron chelation therapy, and splenectomy. The side effects of these supportive treatments include iron overload, end-organ damage and increased infection risks. AG-348, an allosteric activator of RPK, is under evaluation in clinical trials, predominantly in less severely-afflicted transfusion-independent patients. Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed in selected cases and resulted in transfusion independence, suggesting that the disorder may be reversed when an adequate level of hematopoietic stem and progenitor cells (HSPCs) harboring a corrected PKLR gene engraft in the bone marrow (BM). The therapeutic efficacy of allogeneic transplant is limited by the availability of a suitable donor and transplant-associated toxicities. Preclinical studies conducted in a clinically relevant PKD murine model have demonstrated the safety and efficacy of Lin- BM cells transduced with the therapeutic lentiviral vector, PGK-coRPK-WPRE, in ameliorating the PKD phenotype. More specifically, transplantation of transduced cells resulted in increased erythrocyte survival, decreased reticulocytosis, and improvement in the secondary manifestations of hemolytic anemia, including splenomegaly and hepatic iron overload. Based on compelling preclinical data, a global Phase 1 clinical trial RP-L301-0119 (clinicaltrials.gov#NCT04105166) is underway to evaluate the feasibility and safety of lentiviral mediated gene therapy in adults and pediatric subjects with severe PKD. Methods: 6 subjects with severe PKD (defined as having a history of severe and/or transfusion-dependent anemia despite prior splenectomy) will be enrolled in the Phase 1 study; the first 2 subjects will be adults (age ≥18-&amp;lt;50 years), followed by 2 older pediatric subjects (age ≥12-17 years) once initial safety has been established. Subsequently, 2 younger pediatric subjects (age ≥8-11 years) will be enrolled. Peripheral blood (PB) hematopoietic stem cells are collected on two consecutive days via apheresis after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. CD34+ HSPCs are enriched, transduced with PGK-coRPK-WPRE lentiviral vector (LV), and cryopreserved. Following final release testing of the investigational product (IP), RP-L301, myeloablative conditioning with therapeutic drug monitoring (TDM)-guided busulfan is administered over 4 days. RP-L301 is then thawed and infused. Patients are followed for safety assessments, including replication competent lentivirus (RCL) and insertion site analysis (ISA), and for efficacy parameters including PB and BM genetic correction, decrease in transfusion requirements, clinically significant improvement in anemia, and reduction of hemolysis. Results: An adult female PKD subject (age 31 years) with significant anemia and transfusion requirement has received treatment as of July 2020. Mobilization and apheresis procedures were performed successfully and busulfan conditioning was administered at the target area under the curve (AUC). IP consisted of 3.9×106 CD34+ cells/kg body weight, with a mean vector copy number (VCN) of 2.73. Safety and preliminary efficacy results will be available at the time of presentation. Conclusions: Efficacy in pre-clinical models indicates promising potential for clinical gene therapy in severe PKDHematopoietic stem cell mobilization using G-CSF and plerixafor appears feasible and effective in adult PKD patientsIP was successfully manufactured to meet the required specifications for the Phase 1 clinical study and administered without short-term infusion related complications Disclosures Navarro: Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: SN has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents &amp; Royalties, Research Funding. Sevilla:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Glader:Agios Pharmaceuticals, Inc.: Consultancy. Beard:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from this company., Patents &amp; Royalties, Research Funding. Rao:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Segovia:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from the Company., Patents &amp; Royalties, Research Funding.

Effect of Sickle Cell Related Therapies on Growth in Children with Sickle Cell Disease: Evidence from the Displace Study

Introduction Reduced growth and delayed maturation have been previously described in children with sickle cell disease (SCD) due to multifactorial causes including chronic anemia and increased hemolysis. Interventions that decrease anemia and inflammation may have a beneficial effect on growth in children with SCD. Previous studies have demonstrated that children with SCD treated with hydroxyurea (HU) and chronic red cell transfusion therapy (CRCT) experience linear growth and increase in body mass index (BMI) compared to their counterparts not on therapy. Unfortunately, most of these studies were limited due to small sample size, cross-sectional study design or were conducted from single or a few center(s). DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) is a large, NHLBI (National Heart, Lung, and Blood Institute) funded consortium to improve stroke prevention implementation in SCD. DISPLACE includes the largest database of children with SCD from 28 different centers in the US. These data allow for an optimal assessment of growth in children with SCD on different disease modifying therapies. Using the DISPLACE database, we conducted a cross-sectional sub-study to evaluate how HU and CRCT affect growth in children over time. Methods The DISPLACE study collected data on 5,247 children aged 2-19 years with SCD from 28 centers in the US between 2012-2016. The majority of children have data collected from at least five years of continuous care. At baseline and annually thereafter, all children had routine standard of care anthropometric measurements including height and weight, vital signs, laboratory tests including complete blood count and chemistries and SCD-related therapies including chronic blood transfusion therapy and hydroxyurea therapy. Body mass index was converted to z-scores (zBMI) based on the Centers for Disease Control guide for age and sex. Children were categorized based on the zBMI score as underweight, normal, and overweight/obese. Our inclusion criteria included children with documented results of weight, height, vital signs, clinical and laboratory tests at baseline. Children who do not have sufficient data for evaluation (at least one missing anthropometric measurement or laboratory value) were excluded. Results Of the 3,305 children included in the study, 19.8%, 66.1%, 14.2% were underweight, normal, and overweight/obese at their initial (baseline) visit respectively. Children who were overweight/obese had a significantly higher hemoglobin level (p&amp;lt;0.0001) and significantly lower reticulocyte count (p = 0.0334) at baseline than normal and underweight children. Children who are overweight/obese had a significantly higher systolic and diastolic blood pressure compared to those who are normal or underweight (p = 0.0079 and p = 0.0003 respectively). A higher proportion of children who were overweight/obese were on CRCT at baseline compared to children with normal or underweight zBMI (p = 0.0002). The proportion of children on HU therapy at baseline was similar across zBMI categories (p = 0.2412). The multivariable adjusted model showed that the baseline hemoglobin levels were associated with the odds of being underweight (OR 0.93, 95% CI: 0.86 - 0.99), or overweight/obese (OR: 1.26, 95% CI: 1.17 - 1.36) compared with normal zBMI. At baseline, blood transfusion was associated with being overweight/obese versus normal (OR: 1.85, 95% CI: 1.31 - 2.60). After two years of therapy, there was a statistically significant increase in median zBMI from baseline among children initiating blood transfusion versus controls, (p = 0.0481), but the zBMI difference in hydroxyurea therapy versus controls remain same. (p=0.3925). Conclusion In our US-based study, the majority of children with SCD (70%) had normal zBMI. As baseline hemoglobin is associated with zBMI, that may predict who is at risk for being underweight or overweight. In addition, patients treated with CRCT are more likely to be overweight and have higher blood pressure. These findings suggest that individuals on CRCT should be monitored and may need lower calories than those not on disease modifying therapies. Disclosures Kanter: bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees.

Comparison of Magnetic Resonance Imaging T2 Results in Beta-Thalassemia Patients Treated by Deferasirox or Combination of Deferoxamine and Deferiprone

Background: Iron extra load is an anticipated and lethal consequence of chronic blood transfusion in major beta-thalassemia patients; therefore it is necessary to use an efficient iron chelator drug to stimulate the evacuation of the surplus iron from the body. This trial was performed to compare myocardial and hepatic magnetic resonance imaging T2 (MRI T2*) results of beta-thalassemia patients treated by Deferasirox or combination of Deferoxamine and Deferiprone. Material and Methods: In this clinical trial, 44 patients who were on combination therapy with Deferiprone and Deferoxamine and complied with the inclusion criteria were randomized to either case (Deferasirox) or control (combined therapy) groups. Twenty-two patients in the case group received Deferasirox. For 22 patients in the control group, prior treatment with Deferiprone and Deferoxamine was continued. Myocardial and hepatic MRI T2* results were assessed before and after the study. Moreover, serum ferritin level (SFL) was evaluated every 3 months. Results: SFL at the start of the study did not differ significantly in two groups (2158.1± 1012.2 μg/L in the control group vs. 2145.5±1121.4 μg/L in the case group) (P=0.08). SFL at the end of the study did not differ significantly in two groups (2204.4±1143.5 μg/L in the control group vs. 2347.2±1236.6 μg/L in the case group), either (P=0.12). In each group, myocardial and hepatic MRI T2 at the start and at the end of the trial did not differ significantly (P&gt;0.1). Conclusion: Myocardial and hepatic MRI T2*results were better in the control (combination therapy) group than those in the case (Deferasirox) group. Major beta-thalassemia patients replied to combined treatment better than Deferasirox.

Iron Administration Affects Cardiac Calcium Channel Expression in Mice: The Role of Cardiac Calcium Channel Expression in The Heart of Iron Overload Mice Model

BACKGROUND: Iron-overload cardiomyopathy (IOC) is a major comorbidity in patients with chronic repetitive blood transfusion due to myocardial iron uptake that facilitated by calcium channels. As cardiac compensatory mechanism to IOC, we hypothesized the cardiac calcium channels expression would be increased and involved in cardiomyopathy progressivity. This study was aimed to investigate the gene expression of calcium channels in the heart of the iron overload mice model.METHODS: Mice were divided into three groups according to iron administration doses 0, 0.1, and 0.3 mg/day. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured for the representation of cardiovascular outcomes. The heart tissues were harvested. Further mRNA levels of L-type calcium channels (LTCCs) and T-type calcium channels (TTCCs) were examined using semi-quantitative PCR. The expressions of cardiac calcium channels and blood pressure among the three groups were compared.RESULTS: The expressions of TTCCs in the two iron-injected groups were higher than the control group (p=0.018). The expressions of LTCCs were not different (p=0.413) among groups. SBP, DBP, and MAP of the iron-injected group were lower than the control group (p=0.025, p=0.011, and p=0.008, respectively).CONCLUSION: Iron administration affects the expression of TTCCs but not the LTCCs, accompanied by decreasing of systolic and diastolic blood pressure.KEYWORDS: cardiomyopathy, iron overload, L-type calcium channel, T-type calcium channel.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.