Exchange Blood Transfusion Research Articles

Prophylactic exchange transfusion in sickle cell disease pregnancy: a TAPS2 feasibility randomized controlled trial

AbstractSerial prophylactic exchange blood transfusion (SPEBT) is increasingly used in sickle cell disease (SCD) pregnancy, despite a lack of robust evidence. The Transfusion Antenatally in Pregnant Women with Sickle Cell Disease (TAPS2) study assessed the feasibility and acceptability of conducting a definitive randomized controlled trial of SPEBT (intervention) vs standard care (control) in this population. Women aged ≥18 years with SCD, between 6+0 and 18+6 weeks of singleton gestation, were randomized 1:1 every 6 -10 weeks throughout pregnancy in 7 hospitals in England. The main outcomes were recruitment rate (primary outcome), acceptability, and retention. Secondary outcomes were safety and maternal/infant outcomes. In total, 194 women were screened over 42 months (extended because of the pandemic), 88 were eligible, and 35 (39.8%) consented to participate; 18 participants were randomized to intervention, and 17 to control. Follow-up data were collected on all participants. Twelve patients in the intervention group received at least 1 SPEBT, of these, 11 received ≥3. The remaining patient was withdrawn from SPEBT because of transfusion reaction. Sixteen control participants required at least 1 transfusion. There were no statistically significant differences in maternal, infant, and postnatal outcomes. A trend toward a lower incidence of vaso-occlusive crisis, preterm delivery, and improved birthweight was observed in the intervention. The study achieved satisfactory recruitment and retention, confirming its acceptability to participants. TAPS2 demonstrates that it is feasible to perform a definitive international trial of SPEBT in SCD pregnancy. These trials were registered at www.ClinicalTrials.gov as #NCT03975894 and International Standard Randomized Controlled Trial Number (www.isrctn.com; #ISRCTN52684446).

Neonatal and Obstetrical Outcomes of Pregnancies Complicated by Alloimmunization.

Despite advances in the prevention of rhesus (Rh)(D) alloimmunization, alloantibodies to Rh(D) and non-Rh(D) red blood cell antigens continue to be detected in ∼4% of US pregnancies and can result in hemolytic disease of the fetus and newborn (HDFN). Recent reports on HDFN lack granularity and are unable to provide antibody-specific outcomes. The objective of this study was to calculate the frequency of alloimmunization in our large hospital system and summarize the outcomes based on antibody specificity, titer, and other clinical factors. We identified all births in a 6-year period after a positive red blood cell antibody screen result during pregnancy and summarized their characteristics and outcomes. A total of 707 neonates were born after a positive maternal antibody screen result (3.0/1000 live births). In 31 (4%), the positive screen result was due to rhesus immune globulin alone. Of the 676 neonates exposed to alloantibodies, the direct antibody test (DAT) result was positive, showing antigen-positivity and evidence of HDFN in 37% of those tested. Neonatal disease was most severe with DAT-positive anti-Rh antibodies (c, C, D, e, E). All neonatal red blood cell transfusions (15) and exchange transfusions (6) were due to anti-Rh alloimmunization. No neonates born to mothers with anti-M, anti-S, anti-Duffy, anti-Kidd A, or anti-Lewis required NICU admission for hyperbilirubinemia or transfusion. Alloimmunization to Rh-group antibodies continues to cause a majority of the severe HDFN cases in our hospital system. In neonates born to alloimmunized mothers, a positive DAT result revealing antigen-positivity is the best predictor of anemia and hyperbilirubinemia.

Hereditary TTP/Upshaw-Schulman syndrome: the ductus arteriosus controls newborn survival.

Hereditary TTP (hTTP), termed Upshaw-Schulman syndrome, is an ultra-rare disorder caused by a severe deficiency of plasma ADAMTS13 activity that allows circulation of ultra-large von Willebrand factor (UL-VWF) multimers. The greatest risk for hTTP is in their first days after birth, when 35-50% of patients will have severe hemolysis, jaundice, and thrombocytopenia. It is often fatal without effective treatment. In utero, fetal blood flowing from the pulmonary artery through the ductus arteriosus (DA) to the aorta is under low-shear-force. At birth, blood flow through the DA reverses to a left-to-right shunt, and the diameter of the DA begins to decrease due to hyper-oxygenated blood and decreased plasma prostaglandin E2. This causes turbulent circulation that unfolds UL-VWF, allowing platelet aggregation. If the DA closes promptly, hTTP newborns survive, but if it remains patent, turbulent circulation persists, triggering microvascular thrombosis. hTTP is commonly diagnosed as hemolytic disease of the fetus and newborn (HDFN) caused by anti-red cell antibodies and treated with exchange blood transfusion, which prevents kernicterus even when the diagnosis of hTTP is missed. The diagnosis of newborn-onset hTTP should be considered because HDFN does not cause severe thrombocytopenia, which might be effectively treated with recombinant ADAMTS13.

Management of Hyperparasitaemia in Severe Malaria: A Sea Change With the Availability of Artesunate.

This study aims to study the efficacy of exchange transfusion in complicated malaria with hyperparasitaemia. This is a retrospective case-control study conducted in a tertiary care referral hospital in northeastern India. A retrospective chart review was done, and 34 children with hyperparasitaemia were identified. Of these, 16 children received only antimalarial chemotherapy, and 18 received adjunct exchange blood transfusion (EBT). The data was analyzed for survival benefit as the main outcome measure. The subjects in each of the groups were comparable in terms of age, sex distribution, and mean haemoglobin at presentation. The patients treated with EBT were more ill than those who did not receive EBT; they met a greater number of WHO criteria for severe malaria (2.94 ± 1.16 vs. 1.81 ± 0.83; p=0.002) and had higher levels of parasitaemia (23.96 ± 17.55 vs. 16.14 ± 6.89; p=0.0007). The mean volume exchanged was 44.88 ± 20.49 ml/kg, against a target of 70 ml/kg due to the unavailability of fresh, compatible whole blood. There was no difference in mortality in the exchange transfusion group compared to the chemotherapy alone group (22.22% vs. 31.25%; p=0.83). In resource-limited areas, lower volumes of fresh whole blood for exchange transfusion can reduce hyperparasitaemia to a significant degree, and this may give some mortality benefit in very sick cases. Artesunate, by virtue of its rapid action, is capable of reducing hyperparasitaemia and may question the very place of blood transfusion in complicated malaria. It may also be worthwhile to accumulate more data comparing EBT against artesunate instead of quinine.

Educational Program on Nurses Knowledge about Blood Exchange Transfusion in Neonatal Care Units

Background: Exchange transfusion entails the sequential drawing and injecting of blood aliquots via peripheral or central venous and arterial lines. Notably, arterial lines—either peripheral or umbilical—should not be used for donor blood injections; rather, they should only be used for baby blood withdrawal. To ascertain the Nurses' Knowledge of Blood Exchange Transfusion in Neonatal Intensive Care Units Educational Program. Methods: Designing a quasi-experimental using (non-probability) To ascertain the impact of a training program on nurses' performance with regard to blood exchange transfusion, purposeful sampling was used. The "Statistical Package for Social Science (SPSS) software for Windows (Version 26)" is used to analyze data. Results: This result showed that 33.3%(10) of the study's nurses and 33.3%(10) of the control group's nurses were between the ages of 31 and 35.The study's findings regarding the gender of the nursing staff showed that 53.3% of the participants (19) were female. and of the fifteen participants, 63.3% were men. 50% of the participants are nurses.had a Nursing Institute (15) In terms of general years of experience, 33.3% (10) of the sample had six to ten years of experience, and 3.0% worked in the pediatric department. Conclusion: The study concluded that the nurses’ knowledge about the blood transfusion process before giving the educational program to the patients was poor, and through the intervention and giving the nursing program, their knowledge became good. The reason is due to the effectiveness of the effective programs.

Condition of the problem of organ transplantation in the USSR in 1970–1971 and ways to solve it (Yu.M. Lopukhin, A.G. Lapchinsky, V.P. Demikhov)

Aim. The article examines and analyzes the state of the problem of organ transplantation in the USSR in the early 1970s and ways to solve it with the participation of three prominent transplantologists of the Soviet Union – Yu.M. Lopukhin, A.G. Lapchinsky and V.P. Demikhov, as well as some world achievements in this field.Material and methods. Available printed works on the history of Russian and world transplantology in the 1970s, the analysis of which was carried out by historical-genetic and comparative-analytical methods.Results. Developed by Yu.M. Lopukhin together with leading surgeons and immunologists of the country the Program of scientific research on the problem of transplantation of organs and tissues included three main areas: clinical problems of transplantation of organs and body parts (limbs), including ensuring the viability of organs and tissues outside the body, the ways to overcome biological incompatibility, and also the moral and ethical issues of transplantation, and donation issues. It is shown that the methods of overcoming biological incompatibility in organ and tissue allotransplantations, which had been used for many years by A.G. Lapchinsky and V.P. Demikhov (exchange transfusion of blood between organisms of different species, cross circulation between individuals of the same species), no longer corresponded to the state of medical science, which was represented by Yu.M. Lopukhin. However, scientists who had world-class priorities for the duration of survival of experimental animals with a transplanted limb (A.G. Lapchinsky) and an additional heart and lung transplanted into the chest (V.P. Demikhov) could help in the implementation of some provisions of the Lopukhin’s Program. The preservation of organs and tissues before transplantation in a state of suspended animation was studied by A.G. Lapchinsky, and V.P. Demikhov worked at developing the methods for the extracorporeal connection of organs to the body of an intermediate host and using portable artificial hearts to maintain the vital activity of a cadaveric heart before transplantation.Conclusions. Pioneers of experimental transplantology in the USSR A.G. Lapchinsky and V.P. Demikhov, who began their research in the 1940s, still could have solved many issues of transplanting organs and body parts by the 1970s. But in presented in 1971 Program on the problem of organ and tissue transplantation, prepared under the guidance of Yu.M. Lopukhin, the emphasis was placed on immunological studies, while experimental surgeons played a minor role in it.

Alkaline Phosphatase As a Marker for Acute Complications in Sickle Cell Disease

Background: Sickle cell disease (SCD) can result in complications affecting multiple organ systems, including renal, pulmonary, and central nervous system. Alkaline phosphatases (ALP) comprise a group of isoenzymes which function to catalyze the hydrolysis of inorganic phosphate monoesters, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal-5′-phosphate. Predominantly, serum ALP is derived from the liver and bone (1). An elevation in serum ALP primarily signifies hepatobiliary disorders, wherein cholestasis and bile duct damage results in increased enzyme synthesis as a compensatory mechanism. Increased ALP levels can also be an indication of bone disease associated with increased osteoblast activity (2). ALP has been linked to the severity of the pain crisis in SCD (3), and there is also evidence that ALP is a predictor for increased mortality risk in SCD (4-6). This study aims to investigate ALP as a biomarker of SCD severity and acute organ complications (VOE). Methods: This retrospective study included 252 patients aged 18 years or older with SCD who were admitted to the University of Illinois Chicago (UIC) hospital for the management of vasoocclusive pain events (VOEs) between July 1, 2017, and June 30, 2018. The study recorded the following complications during hospitalization: acute chest syndrome, acute kidney injury, acute liver injury, thrombotic or hemorrhagic stroke, deep vein thrombosis or thromboembolism, the need for transfer to the intensive care unit, the need for exchange blood transfusion, or death during hospitalization. Data analyses were performed using the Kruskal-Wallis test, Chi-square test, linear or a stepwise ordinal logistic regression analysis. Results: The median age of this cohort was 31 years (interquartile range 26-42 years), 36% were males and 72% had hemoglobin SS/Sβ0 with 33% on hydroxyurea. In this cohort, 105 patients experienced at least one complication during at least one hospitalization(s) within the one-year study period, while 147 were hospitalized but did not experience complications during the hospitalization (Table 1). A comparison of clinical characteristics between the two cohorts revealed that patients with complications had a higher prevalence of HgbSS/Sβ0-genotype; had higher ALP, total bilirubin, and AST concentrations; Patients with complications had a greater number of hospitalizations and longer length of stay in both the median length and the total length over the study period (Table 2). In a multivariable model comparing baseline characteristics, HgbSS/Sβ0-genotype and increased ALP levels at baseline were significant predictors of complications during hospitalization, after adjusting for other variables as listed in the table (Table 3). Furthermore, in a subgroup analysis of patients with HgbSS/Sβ0-genotype, this relationship was even stronger: higher baseline ALP levels were significantly associated with acute complications during the study period (OR 7.3, 95% CI: 2.2 - 24.1, p = 0.001). Summary: Our findings suggest that SCD patients with longer hospital stay and higher numbers of admissions tend to have acute complications during hospitalization. Individuals with the HgbSS/Sbeta0 genotype and higher levels of ALP are at an increased risk of developing acute complications, which could potentially account for the increased mortality risk associated with alkaline phosphatase reported by previous literature. K. Makris, C. Mousa, E. Cavalier, Alkaline Phosphatases: Biochemistry, Functions, and Measurement. Calcif Tissue Int112, 233-242 (2023).J. Masrour Roudsari, S. Mahjoub, Quantification and comparison of bone-specific alkaline phosphatase with two methods in normal and paget's specimens. Caspian J Intern Med3, 478-483 (2012).J. I. Brody, W. N. Ryan, M. A. Haidar, Serum alkaline phosphatase isoenzymes in sickle cell anemia. JAMA232, 738-741 (1975).J. J. Feld et al., Liver injury is associated with mortality in sickle cell disease. Aliment Pharmacol Ther42, 912-921 (2015).S. A. Curtis, N. Danda, Z. Etzion, H. W. Cohen, H. H. Billett, Longitudinal Analysis of Patient Specific Predictors for Mortality in Sickle Cell Disease. PLoS One11, e0164743 (2016).V. Sachdev et al., A phenotypic risk score for predicting mortality in sickle cell disease. Br J Haematol192, 932-941 (2021).

Steady-State Von Willebrand Factor Antigen Levels Predict Low Platelet Counts and Risk for Complications in Hospitalizations for Painful Sickle Cell Vaso-Occlusive Episodes

We previously reported that a >20% decline in platelet counts from steady state to presentation predicted severe complications during hospitalization for vaso-occlusive pain crisis (VOC) in 130 adult sickle cell disease (SCD) patients. 1 Sharp platelet decline in acute chest syndrome was reported to be accompanied by large von Willebrand Factor (VWF) aggregates adherent to pulmonary vascular endothelium in SCD. 2 A prospective study of 24 SCD patients found a significant increase of VWF reactivity in VOC admissions relative to steady state, which correlated with low platelet counts and the development of acute chest syndrome. 3 We aimed to investigate the role of steady-state VWF antigen level and ADAMTS13 activity as predictors of platelet count decline and severe complications in VOC admissions. Plasma levels of VWF antigen and ADAMTS13 activity were measured 4 for 56 patients at steady-state outpatient visits (Baseline). VWF antigen was expressed as fold increase or decrease from the concentration in normal pooled plasma of 12.2 ug/ml; ADAMTS13 activity was expressed as fold of the value from normal pooled plasma which was considered 100% activity. Electronic records of VOC admission that occurred >21 days after Baseline were reviewed. Exclusion criteria included non-VOC admissions defined as elective admission for surgery, admission for accident or injury, admission for delivery of an infant, or admission with a pain score <8/10 at presentation. 5 A total of 98 qualifying admissions were identified. Severe complication during the admission was defined as having any of the following: 1) acute chest syndrome, new infiltrate on chest X-ray, or use of ventilator; 2) acute kidney injury; 6 3) acute liver injury; 7 4) thrombotic or hemorrhagic stroke; 5) venous thromboembolism including deep vein thrombosis, atrial thrombosis, and pulmonary embolism; 6) need for transfer to the intensive care unit; 7) need for exchange blood transfusion; 8) death during hospitalization. Platelet counts at presentation to the emergency room (ER) leading to the admissions under study were recorded, as well platelet counts at Baseline. The 56 patients had a median (range) age of 37 (21-66) years; 52% are female, 89% with hemoglobin SS or Sβ 0-thalassemia, and 57% on hydroxyrea (HU). Severe complication occurred in 35 (36%) of the 98 admissions involving 27 (48%) of the patients. Focusing on the first admissions, higher steady-state VWF antigen levels correlated strongly with lower ER platelet counts (ρ= -0.50, P=0.00011, Figure 1A) and higher steady-state ADAMTS13 activity correlated weakly with ER platelet counts (Spearman's ρ= 0.30, P=0.025). The ratio of VWF antigen to ADAMTS13 activity ratio also correlated strongly with lower ER platelet counts (ρ= -0.52, P=0.000052, Figure 1B). In contrast, steady-state VWF antigen level (ρ= -0.17, P=0.23), ADAMTS13 activity (ρ= 0.19, P=0.17), and VWF antigen to ADAMTS13 activity ratio (ρ= -0.23, P=0.098) showed no significant correlation with steady-state platelet counts. The correlations remained by adjusting for age, gender, Hb genotype severity, HU, and treatment of anticoagulant, aspirin, or non-steroidal anti-inflammatory drugs at VOC visits. In analyses restricted to admissions >1 year after Baseline, the correlation between steady-state VWF antigen level and ER platelet counts appeared to persist. Focusing on the 28 first admissions, steady-state VWF antigen level (ρ= -0.50, P=0.0071) and VWF antigen to ADAMTS13 activity ratio (ρ= -0.44, P=0.018) correlated negatively with ER platelet counts. Steady-state ADAMTS13 activity did not correlate with ER platelet counts in admissions that occurred >1 year after Baseline (ρ= 0.16, P=0.43). We further examined the association of steady-state VWF antigen level, ADAMTS13 activity, and their ratio with risk for severe complication in admission. Focusing on the first 56 admissions, which involved 23 complications, steady-state VWF antigen level in the top quartile (1.63) associated with risk for severe complications (OR=6.5, 95% CI 1.4-31, P=0.018, n=56), adjusting for age, gender, Hb genotype severity, and HU. Our observations suggest that steady-state VWF antigen level and the ratio of VWF antigen level to ADAMTS13 activity predict low platelet counts at presentation to VOC admissions, and that steady-state VWF antigen level in SCD patients may be a relatively stable marker for risk of severe VOC complications.

Pulmonary hypertension in sickle cell disease

Sickle cell disease (SCD) is a complex genetic disorder that has long challenged both patients and healthcare professionals. One of its chronic and debilitating complications is pulmonary hypertension (PH). SCD-associated PH is often post-capillary, secondary to left heart disease. It can also sometimes be pre-capillary with multiple and often interrelated mechanisms including obstructive remodeling of the pulmonary vascular bed secondary to hemolysis, endothelial dysfunction, thrombosis, hypoxia, or associated risk factors like portal hypertension. Screening symptomatic patients with echocardiographic signs of PH is crucial to determine those who should undergo right heart catheterization, the cornerstone exam to diagnose and categorize patients with PH. The workup following the diagnosis relies on identifying the cause of PH to personalize treatment. Ongoing efforts are made to treat this complex condition, starting with treating the underlying disease with hydroxyurea or chronic blood exchange transfusion. Robust data on the efficacy of PAH-specific therapies are lacking in this specific population. Initiation of such therapies must be made by an expert center after a case-by-case assessment of the benefit-risk ratio according to the phenotype and the mechanisms involved in the development of PH. Efforts are also poured into studying the interventional and medical therapies used on chronic thromboembolic PH for patients presenting with a thrombotic form. The management of those patients requires a multidisciplinary approach, with conjoint efforts from PH and SCD specialists.

Automated ABR screening for hearing loss and its clinical determinants among newborns with hyperbilirubinemia in National Hospital, Abuja, Nigeria.

Severe neonatal hyperbilirubinemia is a known risk factor for sensorineural hearing loss which is usually undiagnosed in our environment until school age due to a lack of routine screening programs. This cross-sectional study conducted between August 2020 and February 2021 employed a universal sampling of consecutive eligible participants after their mothers' consent. Hearing screening was conducted using an automated auditory brainstem response (AABR) device (Otoport OAE + ABR®). The proportion of AABR screening failure was assessed while associated clinical risk factors were determined using logistic regression. Statistical significance was set at 5% for all comparative analyses. One hundred and sixty newborns below 28 days of age, delivered at 34 weeks gestation and above, who had jaundice were recruited. The prevalence of screening AABR failure in at least one ear was 26.2%. Significant risk factors for AABR screening failure in addition to extreme and hazardous hyperbilirubinemia were acute bilirubin encephalopathy (ABE) (Odds Ratio (OR) =4.44, 95% CI = 3.19-6.17), birth weight below 2500 g (OR = 3.16, 95% CI = 1.48-6.77), dull tympanic membrane (TM) (OR = 5.94, 95% CI = 2.36-14.92) and exchange blood transfusion (OR = 4.84, 95% CI = 1.87-12.58). The prevalence of AABR screening failure was high, and a dull TM was its strongest predictor among late preterm and term neonates with hyperbilirubinemia. Otoscopy should be included in the care of newborn with hyperbilirubinemia and screening programs established to mitigate hearing loss among high-risk neonates in Abuja.

The effect of different dose of heparin using in peripheral arteriovenous synchronous blood exchange transfusion for neonatal hyperbilirubinemia.

To explore the optimal dosage of heparin in peripheral arteriovenous automatic synchronous exchange transfusion therapy for neonatal hyperbilirubinemia. A total of 185 neonates received peripheral arteriovenous synchronous blood exchange transfusion for hyperbilirubinemia were enrolled from pediatric department of the Ganzhou People's Hospital between January 2018 and June 2020, which were randomly divided into four groups. On the basis of exchange transfusion, different dose of heparin was pumping at the bleeding site of artery (A: no heparin; B: 100 U/h heparin; C: 200 U/h heparin; D: 300 U/h heparin). The indexes of exchange transfusion efficacy, including total bilirubin conversion rate, indirect bilirubin conversion rate, hemoglobin concentration, the platelet number and APTT value was measured before and after therapy. The sites of artery puncture, the sites and rate of vascular occlusion were counted and analyzed.

Prevalence of Red Blood Cell Alloimmunization Among Pediatric Patients with Sickle Cell Disease in Saudi Arabia

Purpose: Sickle cell disease (SCD) is a common global hereditary hemoglobin disorder. One of the main treatments of sickle cell patients is the requirement of blood transfusions. Post transfusion alloimmunization of red blood cell antigens continue to be a major risk for SCD patients. The study objective is to determine the rate, nature, and risk factors of red cell alloimmunization among pediatric SCD patients in our center and compare our results to published reports from the KSA, regional and some international countries.
 Methodology: A retrospective study drsign was adopted with record review of SCD patients at King AbdulAziz Medical City-Jeddah (KAMC-J) between 2008-2019 where blood samples were analyzed for alloimmunization using immunohematological techniques. Demographic characteristics and transfusion history were recorded. Data analysis was conducted by SPSS ver. 26. Data are summarized as frequency distribution and chi square test was used to check significance of the difference in the frequency of alloantibodies among subgroups. 
 Findings: Out of all examined sickle cell patients (n=112). Alloantibodies were detected in 21 patients (17.4%), and these were mostly single in 15 patients (71.4%) as anti-K (23.7%), anti-E (19.0%), and anti-S (9.5%). The other six patients (28.6%) had multiple alloantibodies, especially the combination of anti-C and anti-K (9.5%) and the combination of anti-C and anti-E (9.5%). Alloantibodies were significantly higher in patients who had been admitted to the hospital > 5 times annually, those who had an exchange blood transfusion, age groups > 3 years, and for those who received a larger number of blood units (p-value < 0.05).
 Recommendations: The consequences of red blood cell alloimmunization are highly significant and, therefore, extended RBC antigens to include ABO, RH (D, C, c, E, e), K, Fya, Fyb, Jka and Jkb antigens in the screening panel for donors and recipients is highly recommended to ensure better transfusion practices and avoid transfusion related complications. Our rate of alloimmunization post frequent blood transfusion is considered relatively low compared to other nations.

Nurses’ Performance in Caring of Neonates undergoing Exchange Blood Transfusion in Neonatal Intensive Care Units

: Exchange transfusion is emergency procedure for severe neonatal hyperbilirbinemia in the world. This procedure need a medical continued expertise for life-saving intervention and nursing care for preparation pre, during and post procedures

Threshold and Correlation of Total Serum Bilirubin with Screening Automated Auditory Brainstem Response Among Newborns with Hyperbilirubinemia in National Hospital Abuja

Objective To determine the total serum bilirubin (TSB) cut-off value predictive of hearing impairment among newborns with hyperbilirubinemia at the National Hospital Abuja. Setting This was a cross-sectional study conducted in the Special Care Baby Unit (SCBU) and Neonatal Intensive Care Unit (NICU) of National Hospital Abuja between August 2020 and February 2021. Methods A universal sampling of eligible participants was done, and consent was obtained from the parent. Using the TSB and results of hearing screening carried out with the Otoport advance from Otodynamics®, the proportion of automated auditory brainstem response (AABR) screening failure was determined, and the receiver’s operating characteristics (ROC) curve coordinates were used to find the threshold bilirubin level for the risk of hearing loss. The Spearman-Rho correlation assessed the relationship between TSB level and AABR findings. Results 160 newborns below 28 days of age, delivered at 34 weeks gestation and above, who had clinical jaundice were recruited. The prevalence of screening AABR failure in at least one ear was 26.2%. The correlation between TSB and AABR was weakly positive (rs = .189, p = .093) and the TSB cut-off for AABR failure was 16.3 mg/dl (sensitivity 45.5%, specificity 81%, Youden’s-J statistic = 0.265). Conclusion The TSB threshold for AABR screening failure was 16.3 mg/dl, but TSB did not correlate well with screening AABR. Serum bilirubin above 15 mg/dl in late preterm and term neonates should be actively treated with phototherapy and/or exchange blood transfusions where feasible, particularly in resource-poor settings.

Global Prevalence of Severe Neonatal Jaundice among Hospital Admissions: A Systematic Review and Meta-Analysis.

Evidence regarding the adverse burden of severe neonatal jaundice (SNJ) in hospitalized neonates in resource-constrained settings is sparse. We attempted to determine the prevalence of SNJ, described using clinical outcome markers, in all World Health Organization (WHO) regions in the world. Data were sourced from Ovid Medline, Ovid Embase, Cochrane Library, African Journals Online, and Global Index Medicus. Hospital-based studies, including the total number of neonatal admissions with at least one clinical outcome marker of SNJ, defined as acute bilirubin encephalopathy (ABE), exchange blood transfusions (EBT), jaundice-related death, or abnormal brainstem audio-evoked response (aBAER), were independently reviewed for inclusion in this meta-analysis. Of 84 articles, 64 (76.19%) were from low- and lower-middle-income countries (LMICs), and 14.26% of the represented neonates with jaundice in these studies had SNJ. The prevelance of SNJ among all admitted neonates varied across WHO regions, ranging from 0.73 to 3.34%. Among all neonatal admissions, SNJ clinical outcome markers for EBT ranged from 0.74 to 3.81%, with the highest percentage observed in the African and South-East Asian regions; ABE ranged from 0.16 to 2.75%, with the highest percentages observed in the African and Eastern Mediterranean regions; and jaundice-related deaths ranged from 0 to 1.49%, with the highest percentage observed in the African and Eastern Mediterranean regions. Among the cohort of neonates with jaundice, the prevalence of SNJ ranged from 8.31 to 31.49%, with the highest percentage observed in the African region; EBT ranged from 9.76 to 28.97%, with the highest percentages reported for the African region; ABE was highest in the Eastern Mediterranean (22.73%) and African regions (14.51%). Jaundice-related deaths were 13.02%, 7.52%, 2.01% and 0.07%, respectively, in the Eastern Mediterranean, African, South-East Asian and European regions, with none reported in the Americas. aBAER numbers were too small, and the Western Pacific region was represented by only one study, limiting the ability to make regional comparisons. The global burden of SNJ in hospitalized neonates remains high, causing substantial, preventable morbidity and mortality especially in LMICs.

Associations between neonatal jaundice and autism spectrum disorder or attention deficit hyperactivity disorder: Nationwide population based cohort study

Neonatal jaundice might result brain insults. Both autistic spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are developmental disorders, which might result from early brain injury at neonatal period. We aimed to explore the association between neonatal jaundice treated with phototherapy and the ASD or ADHD. This retrospective nationwide population cohort study was based on a nationally representative database of Taiwan, and neonates born from 2004 to 2010 were enrolled. All eligible infants were divided into 4 groups, without jaundice, jaundice with no treatment, jaundice with simple phototherapy only and jaundice with intensive phototherapy or blood exchange transfusion (BET). Each infant was follow-up until the date of incident primary outcomes, death, or 7-year-old, whichever occurred first. Primary outcomes were ASD, ADHD. Using cox proportional hazard model to analyze their associations. In total, 118,222 infants with neonatal jaundice were enrolled, including diagnosed only (7260), simple phototherapy (82,990), intensive phototherapy or BET (27,972 infants). The cumulative incidences of ASD in each group was 0.57%, 0.81%, 0.77%, and 0.83%, respectively. The cumulative incidences of ADHD in each group was 2.83%, 4.04%, 3.52% and 3.48%, respectively. Jaundice groups were significantly associated with ASD, ADHD, or either one, even after all other extraneous maternal and neonatal variables were adjusted. After stratification, the associations were still existed in subgroup with birth weights ≥2500grams and in male subgroup. Neonatal jaundice correlated with the ASD and ADHD. The associations were significant in infants of both sexes and with birth weights larger than 2500grams.

5610823 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 1B CROSSWALK-A TRIAL EVALUATING THE SAFETY OF CROVALIMAB FOR THE MANAGEMENT OF ACUTE UNCOMPLICATED VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S (HbS). HbS polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute, painful episodes called VOEs. Although most VOEs are managed at home, >70% of emergency department visits and >90% of hospitalizations for SCD are VOE-related.1,2 Additionally, acute chest syndrome is one of the most severe complications of VOEs and is a leading cause of mortality.3,4 As there are no targeted therapies for the management of VOEs, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, which represents a significant unmet medical need. Overall, accumulating nonclinical data suggest a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.5 Complement pathway activation has been described in pts with SCD at baseline, in acute pain crises, and in pts with delayed hemolytic transfusion reaction. The complement pathway can be targeted with crovalimab, which is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase 1/2 study in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.6 Aims: CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase 1b study evaluating the safety of crovalimab in managing acute uncomplicated VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0) will be enrolled (Figure). Pts must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be current. Eligible pts will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. All pts will continue with pain management and other supportive care for their VOE, and may continue concurrent SCD-directed therapies. Pts will be followed during hospitalization until discharge and will also be followed post-discharge during an observational period. The study duration for an individual pt, including the hospitalization and observational periods, will be 12 weeks. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetic, pharmacodynamic, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Protocol updates are in progress. Results: CROSSWALK-a is scheduled to be completed in September 2023. Summary: CROSSWALK-a is enrolling pts with SCD in five countries.

5610357 REDUCTION IN BLOOD TRANSFUSION BURDEN FOLLOWING INITIATION OF VOXELOTOR OR CRIZANLIZUMAB: A CASE SERIES

Background: Patients with sickle cell disease (SCD) often require blood transfusions. While transfusions may improve disease complications, resultant iron overload can lead to end-organ damage. Other transfusion complications include forming of alloantibodies and transmission of infection. Crizanlizumab and voxelotor have been shown respectively to reduce the frequency of vasoocclusive crises (VOCs) and improve anemia. This case series describes 5 patients with SCD who had a clinically significant decrease in transfusion burden following initiation of these therapies. Cases: Patient A is a 63-year-old woman with HbSBeta+thal and avascular necrosis (AVN) who was on intermittent erythrocytapheresis (apheresis) for symptomatic anemia and developed iron overload. Her serum ferritin was elevated despite chelation therapy. Upon initiation of voxelotor, the frequency of apheresis was reduced. She had a sustained improvement in her baseline hemoglobin (hgb) level as well as symptoms of anemia. Her ferritin decreased from 1253 to 714 ng/mL within 5 months and iron chelation therapy was discontinued. She had no change in acute care visits for VOCs (Table 1). Patient B is a 52-year-old woman with Hb SS, AVN and chronic pain who received intermittent simple transfusions for symptomatic anemia requiring 5 units of blood in the 12-months preceding initiation of voxelotor. She did not require any transfusions in the 12-month period following start of voxelotor. Hydroxyurea was discontinued once voxelotor was initiated due to antecedent myelosuppression at doses greater than 200mg. She had a sustained improvement in hgb as well as symptoms of anemia. She had a slight increase in acute care visits for VOCs (Table 1). Patient C is a 48-year-old man with Hb SS and retinopathy who was on monthly apheresis for many years to prevent VOCs. He had iron overload but declined iron chelation. To offset the transfusion associated iron overload, he opted to discontinue apheresis in favor of initiation of voxelotor and reinitiate hydroxyurea which had previously been discontinued. Following cessation of transfusions, he had a sustained improvement in hgb and no change in acute care visits for VOCs (Table 1). His port, placed solely for apheresis, was removed. His serum ferritin decreased from 2913 to 161 ng/mL in 18 months. Patient D is a 30-year-old man with Hb SS, AVN, chronic pain, and priapism who was on monthly apheresis for many years to prevent VOCs. He developed iron overload, however had poor compliance with chelation. After initiation of crizanlizumab for VOC prevention, the number of units utilized for apheresis was gradually tapered. Despite this, his hgb remained stable, he had no change in acute care visits for VOCs (Table 1) and reported an improvement in priapism frequency. Patient E is a 42-year-old woman with Hb SC, retinopathy, AVN, and chronic pain who received monthly apheresis for prevention of VOCs. Crizanlizumab was added for VOC prevention. She had sporadic childcare available, thus she missed some of her apheresis sessions. Despite this inadvertent decrease in transfusions, her hgb remained stable, and she had a decrease in acute care visits for VOCs (Table 1). Conclusion: In SCD patients who receive frequent simple or exchange blood transfusions for indications other than stroke prevention, tapering the amount of blood administered is possible, and should be considered when these patients are treated with crizanlizumab or voxelotor.

Serial prophylactic exchange blood transfusion in pregnant women with sickle cell disease (TAPS-2): statistical and qualitative analysis plan for a randomised controlled feasibility trial

BackgroundThere are significant knowledge gaps regarding the effectiveness of serial prophylactic exchange blood transfusion (SPEBT) for pregnant women with sickle cell disease (SCD). The protocol for the randomised feasibility trial assessing SPEBT versus usual care in women with SCD (TAPS2 trial) has previously been published. This publication outlines the statistical and qualitative analysis plan for the study.Methods and designTAPS2 is a randomised two-arm phase 2 feasibility trial with a nested qualitative study and health economic evaluation. Up to 50 pregnant women with SCD and a singleton pregnancy will be recruited and individually randomised to either SPEBT approximately every 6–10 weeks until delivery (intervention arm) or to usual care (control arm). Information will be collected on a range of feasibility and clinical outcomes.ResultsDue to the impact of COVID-19 on study recruitment, the initial study period of 24 months was extended to 48 months. Other protocol updates designed to mitigate the impact of COVID-19-related disruption included allowing for remote consent and conducting all qualitative interviews by telephone. The primary outcome for the trial is the overall recruitment rate. The number of women screened, eligible, consented, randomised and withdrawn will be summarised as a CONSORT flow diagram. Differences in clinical outcomes will additionally be presented as an initial assessment of efficacy and to inform sample size calculations for a future definitive trial. Qualitative interviews with trial participants and clinicians will be analysed using reflexive thematic analysis; data from interviews with participants who declined to participate in the trial will be extracted and incorporated into summary tables to report key findings. The health economic analysis plan is not covered by this update.ConclusionThe publication of this analysis plan is designed to aid transparency and to reduce the potential for reporting bias.Trial registrationNIH registry (www.clinicaltrials.gov), registration number NCT03975894 (registered 05/06/19); ISRCTN (www.isrctn.com), registration number ISRCTN52684446 (retrospectively registered 02/08/19).

Targeted next-generation sequencing identifies eighteen novel mutations expanding the molecular and clinical spectrum of PKLR gene disorders in the Indian population.

Pyruvate kinase deficiency (PKD) is an autosomal recessive condition, caused due to homozygous or compound heterozygous mutation in the PKLR gene resulting in non-spherocytic hereditary hemolytic anemia. Clinical manifestations in PKD patients vary from moderate to severe lifelong hemolytic anemia either requiring neonatal exchange transfusion or blood transfusion support. Measuring PK enzyme activity is the gold standard approach for diagnosis but residual activity must be related to the increased reticulocyte count. The confirmatory diagnosis is provided by PKLR gene sequencing by conventional as well as targeted next-generation sequencing involving genes associated with enzymopathies, membranopathies, hemoglobinopathies, and bone marrow failure disorders. In this study, we report the mutational landscape of 45 unrelated PK deficiency cases from India. The genetic sequencing of PKLR revealed 40 variants comprising 34 Missense Mutations (MM), 2 Nonsense Mutations (NM), 1 Splice site, 1 Intronic, 1 Insertion, and 1 Large Base Deletion. The 17 novel variants identified in this study are A115E, R116P, A423G, K313I, E315G, E318K, L327P, M377L, A423E, R449G, H507Q, E538K, G563S, c.507 + 1 G > C, c.801_802 ins A (p.Asp268ArgfsTer48), IVS9dsA-T + 3, and one large base deletion. In combination with previous reports on PK deficiency, we suggest c.880G > A, c.943G > A, c.994G > A, c.1456C > T, c.1529G > A are the most frequently observed mutations in India. This study expands the phenotypic and molecular spectrum of PKLR gene disorders and also emphasizes the importance of combining both targeted next-generation sequencing with bioinformatics analysis and detailed clinical evaluation to elaborate a more accurate diagnosis and correct diagnosis for transfusion dependant hemolytic anemia in a cohort of the Indian population.