Scheduled Transfusion Research Articles

Extensive red blood cell matching considering patient alloimmunization risk.

Red blood cell (RBC) transfusions pose a risk of alloantibody development in patients. For patients with increased alloimmunization risk, extended preventive matching is advised, encompassing not only the ABO-D blood groups but also the most clinically relevant minor antigens: C, c, E, e, K, Fya, Fyb, Jka, Jkb, S and s. This study incorporates patient-specific data and the clinical consequences of mismatching into the allocation process. We have redefined the MINimize Relative Alloimmunization Risks (MINRAR) model to include patient group preferences in selecting RBC units from a finite supply. A linear optimization approach was employed, considering both antigen immunogenicity and the clinical impact of mismatches for specific patient groups. We also explore the advantages of informing the blood bank about scheduled transfusions, allowing for a more strategic blood distribution. The model is evaluated using historical data from two Dutch hospitals, measuring shortages and minor antigen mismatches. The updated model, emphasizing patient group-specific considerations, achieves a similar number of mismatches as the original, yet shifts mismatches among patient groups and antigens, reducing expected alloimmunization consequences. Simultaneous matching for multiple hospitals at the distribution centre level, considering scheduled demands, led to a 30% decrease in mismatches and a 92% reduction in shortages. The reduction of expected alloimmunization consequences by incorporating patient group preferences demonstrates our strategy's effectiveness for patient health. Substantial reductions in mismatches and shortages with multi-hospital collaboration highlights the importance of sharing information in the blood supply chain.

Comparison of Alloimmunization in Pregnant People with Sickle Cell Disease Receiving Chronic Versus on-Demand Transfusions: A Multinational Study

Introduction Despite exceptional maternal morbidity and mortality risk, people with sickle cell disease (SCD) lack firm indications for chronic transfusion therapy (CTT) during pregnancy. Alloimmunization may cause hemolytic transfusion reactions and can limit the safety of future blood transfusions; thus it is a rationale for restricting CTT during pregnancy. Little data quantifies this risk. The 2020 American Society of Hematology (ASH) Guidelines for SCD TransfusionSupport recommend CTT in some pregnancies, but adoption in clinical practice is unknown. This study's purpose is to use a large two-center SCD pregnancy cohort to describe alloimmunization rates in SCD pregnancies treated with CTT vs on-demand transfusion (ODT) and to determine the fraction of SCD pregnancies meeting the ASH Guideline to initiate CTT in pregnancy. Methods We reviewed SCD pregnancies delivered at Mt. Sinai Hospital, Toronto (1990-2017) and Johns Hopkins Hospital (2000-2021). We collected data on transfusions and SCD complications before and during pregnancy, delivery, and fetal outcomes. Analyses classified subjects and pregnancies as receiving CTT or ODT. We defined CTT as pregnancies treated with scheduled, prophylactic transfusions; ODT as pregnancies transfused as-needed, including no transfusions. Sinai routinely matched transfusions for Rh and K antigens while Hopkins matched Rh only. Both centers provided extended matching if an alloantibody was detected. The first analysis included singleton pregnancies to primigravida subjects. We compared new alloantibody development, SCD complications, and pregnancy outcomes in CTT vs. ODT groups and in genotype stratified groups. We used Chi-squared and Wilcoxon rank-sum tests for categorical and continuous variables; p < .05 was significant. The second analysis included all cohort pregnancies and identified which met criteria for CTT per ASH Transfusion Guidelines which advise CTT for (A) severe SCD complications before or during pregnancy here defined by acute chest syndrome (ACS) or pain requiring acute care in the year before or during pregnancy, any history of venous thromboembolism (VTE), stroke, or multi-organ failure or (B) features of high-risk pregnancy, defined by multiple gestation, pre-eclampsia, gestational hypertension, cardiac comorbidities, or preterm labor history. Results Among 145singleton, primigravida pregnancies, more received ODT than CTT (119 ODT vs 26 CTT). Among ODT subjects 46/119 received at least one transfusion during pregnancy. CTT subjects had more severe SCD than ODT subjects before pregnancy (Table 1). During pregnancy, SCD severity did not differ (Table 2). Before pregnancy, 18 subjects were alloimmunized and did not differ by treatment group (6/26 CTT vs 12/119 ODT, p=0.07). During pregnancy, six subjects developed an alloantibody and did not differ by treatment group (1/26 CTT vs 5/119 ODT, p=0.93). Half (3/6) had a history of alloimmunization before pregnancy (1 CTT vs 2 ODT, p=0.27) and three did not (0 CTT vs 3 ODT, p=0.27). All subjects with new antibodies during pregnancy and historic alloimmunization developed anti-K antibodies (1 CTT, 2 ODT) at both sites. Those without alloimmunization history developed anti-Jkantibodies (3 ODT) at Sinai. In the secondary analysis, we included 299 pregnancies to 203 subjects. Among them, 249 pregnancies (83%) met at least one ASH Guideline criteria for initiating CTT. This included all CTT pregnancies (61/61, 39 subjects) and 79% of ODT pregnancies (188/238, 164 subjects), 46% of which received at least one transfusion during pregnancy (86/188). Conclusions In this SCD pregnancy cohort, alloimmunization rates were low and did not differ between those treated with CTT versus ODT. As alloimmunization events were inconsistent with institutional matching practices, new antibody development may be attributable to transfusions from outside hospitals or pregnancy-associated alloimmunization. Antigen matching per ASH Transfusion Guidelines avoids C, E, K and Jk alloimmunization. Scheduled transfusions may reduce emergency transfusion which increases alloimmunization risk. Finally, all CTT and 79% of ODT pregnancies met ASH Guideline criteria for CTT in pregnancy, however the cohort predates ASH Guideline publication. Guideline adherence may lead to increased use of CTT during pregnancy. More discriminating tools are needed to inform CTT use in SCD pregnancy.

Pharmacokinetics (PK) of Deferasirox in Transfusion Dependent Thalassemia

Iron overload is a major cause of organ dysfunction and death in transfusion-dependent thalassemia (TDT) and advances in iron chelation are urgently needed. The iron chelator, deferasirox, is widely used in TDT, however, many patients accumulate iron despite taking maximum recommended doses and many experience dose-limiting toxicity, including renal and liver failure. There is high inter-individual variability in the plasma concentrations of patients taking comparable deferasirox doses and low exposure correlates with inadequate chelation response. The cause of variable drug levels remains unknown, in part because prior deferasirox PK studies primarily include limited sample sizes and/or homogenous patients. There is an urgent unmet need to determine (1) what patient characteristics contribute to the observed variability in deferasirox-plasma concentrations, and (2) how dosing strategies can be tailored to achieve optimal therapeutic plasma-drug concentrations in all patients. We initiated a 2 year, single center observational pharmacokinetic (PK) pilot study to describe the PK of deferasirox in a diverse group of TDT patients from 2 years old through adulthood with a goal accrual of 50 patients. Our aim is to develop a population PK (popPK) model of deferasirox that will be evaluated in a future prospective study to individualize dosing and optimize exposure. The eligibility criteria are broad to capture a diverse population. Patients are eligible if they: 1) have a diagnosis of TDT, 2) are taking deferasirox, and 3) are able to provide informed consent (or have a guardian provide informed consent). For quantification of plasma deferasirox concentrations, 0.5 ml of whole blood are collected prior to transfusions at 4 regularly scheduled transfusion visits. Samples are then analyzed by a validated high performance liquid chromatography assay. Baseline labs, liver iron concentration and information on concomitant chelators are collected at the start of the study and labs, fed/fasted state, time and dose of last deferasirox, deferasirox regimen, and concomitant chelators are collected at each study visit. The planned analysis is to use nonlinear mixed effect modeling to calculate drug exposure and develop the popPK model. We have enrolled 39 patients with TDT, including 27 patients with beta thalassemia major, 10 patients with hemoglobin E beta thalassemia, 12 patients with hemoglobin H constant spring and one patient with beta thalassemia intermedia. Median age is 28 years old, with a range from 6 - 63 years old. Pre-study iron status also varied considerably, with median liver iron concentration 4.5 mg/g (range 1.5 -30 mg/g) and median ferritin 1500 ug/L (range 460 - 5600 ug/L). Thirty one patients have completed the study and 141 samples have been collected. Initial analysis of the first 15 patients who completed the study show a wide range of steady state plasma-deferasirox concentrations, consistent with prior reports. The means for the 4 samples collected per patient were calculated and found to have a median of 36.3 ug/ml with a range of 13.4 - 56.0 ug/ml. For the individual sample collections, the range of plasma deferasirox concentrations was even greater (0.18 - 99.9 ug/ml). These results need to be analyzed further to account for the dosing regimen, iron burden and other individual patient characteristics. In this study, we also collected genomic DNA from the buffy coat to evaluate the impact of single nucleotide polymorphisms in enzymes involved in drug metabolism and distribution. Once all data is collected, we will evaluate whether patient age, weight, laboratory values, fed/fasted state, concomitant chelators or pharmacogenomics impact deferasirox serum concentrations and can inform individualized deferasirox dosing. This study is unique, unlike prior deferasirox PK studies which collected intensive PK, we are using sparse sampling to collect real world data on deferasirox at steady state in TDT patients. Our hope is that this study will enable safer more effective dosing of deferasirox in patients with TDT.

Erythrocyte Disorders Mimicking Congenital Dyserythropoietic Anemia Based on Bone Marrow Pathology Exposed By Genetic Evaluation

Congenital dyserythropoietic anemias (CDAs) are a rare group of heterogeneous genetic diseases characterized by hemolysis, ineffective erythropoiesis predisposing to iron overload, and the pathologic finding of bi- and multinucleated erythroblasts in the bone marrow (BM). With the identification of causative genetic mutations over the last two decades, the current classification includes the following types with the causative gene in parenthesis: Ia ( CDAN1), Ib ( CDIN1); II ( SEC23B); IIIa ( KIF23), IIIb ( RACGAP1); IV ( KLF1) ; and XLTD ( GATA1). Clinical presentation can vary widely even within the same type, ranging from mild cases of anemia to severe cases in which patients are subject to lifelong transfusion dependency. The CDA registry (CDAR) in North America (NCT02964494) was established to allow natural history studies on patients with CDA. Participants without a genetic diagnosis are offered whole genome sequencing (WGS) for patients and parents and may elect to provide samples to the CDAR biorepository to support collaborative mechanistic studies. Currently 169 subjects from 73 different families are enrolled in CDAR (85 patients, 84 unaffected family members). After genetic evaluation, 13 patients were found to be affected not by CDA, but rather by other causes of hereditary hemolytic anemia with secondary dyserythropoiesis. Three patients were diagnosed with pyruvate kinase deficiency (PKD). Patient (pt) 1 had a history of chronic anemia requiring sporadic transfusions since birth and was diagnosed with CDA-II based on BM studies. WGS revealed that the patient was heterozygous for a known PKLR pathogenic variant c.1022G>C p.(Gly341Ala)and for a novel variant of uncertain significance (c.695-3C>G).PK activity assay confirmed the diagnosis of PKD and the patient is now treated with the PK activator mitapivat. Pt 2 had severe transfusion dependent anemia since birth and iron overload. The patient underwent splenectomy at the age of 4 with mild improvement of symptoms. He was diagnosed with CDA II based on BM pathology. Genetic testing was performed and he was found to be compound heterozygous for 2 pathogenic variants in PKLR: c.644dup p.(Arg216fs) and c.994_1003dup p.(Val335fs). Pt 3 had a history of anemia and jaundice since birth; she has not had frequent transfusions but was splenectomized at age 17. The patient was found to be homozygous for c.1436G>A p.(Arg510Gln), a known pathogenic variant in PKLR. Four patients were diagnosed with HBB pathogenic variants causing frameshift and transcription of an elongated β-globin chain, i.e. unstable hemoglobinopathy. Pt 4 was first diagnosed with CDA II at 12 years of age based on BM studies performed due to chronic hemolytic anemia. After enrolling in CDAR, WES revealed heterozygous HBB p.(Lys96Asnfs*63). Pts 5, 6, and 7 are all symptomatic participants from the same family (mother and children). The mother (Pt 5) had frequent transfusion requirement, misdiagnosed in childhood as CDA IV due to BM dyserythropoiesis and the finding of high fetal hemoglobin. Her children had a similar phenotype requiring episodic transfusions initially, transitioning to scheduled transfusions by 8 y.o. WES in pt 5 revealed heterozygous HBB c.348_349delinsG (Hb Grand Junction) with follow-up HBB sequencing confirming that the children also carry the same variant . Three more patients were diagnosed with SPTA1 variants causing RBC membrane disorders. Pt 8 was found to have homozygous c.4339-99C>T (alpha-LEPRA) and heterozygous c.4347G>T p.(Lys1449Asn) with a phenotype of hereditary spherocytosis. Pts 9 and 10 are sisters, who presented with chronic, transfusion-dependent anemia since birth. They were diagnosed with CDA-II based on binucleated erythroblasts in BM studies performed in early childhood. They had splenectomy at 5 years of age and became transfusion-independent but continued to have mild anemia and reticulocytosis. WGS performed for them and their parents revealed a novel homozygous intronic variant in SPTA1 c.5834-18A>G. Phenotypic analysis was compatible with hereditary spherocytic pyropoikilocytosis. Hemolytic anemias with stress erythropoiesis may mimic the clinical presentation and pathologic findings of CDAs, making the phenotypic diagnosis challenging. Including genetic evaluation in the diagnostic workup of these patients can improve accuracy, timing of diagnosis, and management by specific therapy, if available.

A retrospective study for association between post-transfusion hemoglobin S level and pre-transfusion hemoglobin S level at the next scheduled transfusion.

Patients with sickle cell disease (SCD) frequently undergo prophylactic red blood cell (RBC) exchange transfusion and simple transfusion (RCE/T) to prevent complications of disease, such as stroke. These treatment procedures are performed with a target hemoglobin S (HbS) of ≤30%, or a goal of maintaining an HbS level of <30% immediately prior to the next transfusion. However, there is a lack of evidence-based instructions for how to perform RCE/T in a way that will result in an HbS value <30% between treatments. To determine whether targets for post-treatment HbS (post-HbS) or post-treatment HCT (post-HCT) can help to maintain an HbS <30% or <40% between treatments. We performed a retrospective study of patients with SCD treated with RCE/T at Montefiore Medical Center from June 2014 to June 2016. The analysis included patients of all ages, and data including 3 documented parameters for each RCE/T event: post-HbS, post-HCT, and follow-up HbS (F/u-HbS), which is the pre-treatment HbS prior to the next RCE/T. Generalized linear mixed model was used for estimating the association between post-HbS or post-HCT levels and F/u-HbS <30%. Based on our results, targeting post-HbS ≤10% was associated with higher odds of having events of F/u-HbS <30% between monthly treatments. Targeting post-HbS ≤15% was associated with higher odds of events of F/u-HbS < 40%. As compared to post-HCT ≤30%, a post-HCT >30%-36% did not contribute to more F/u-HbS <30% or HbS <40% events. For patients with SCD undergoing regular RCE/T for stroke prevention, a post-HbS ≤10% can be used as a goal to help maintain an HbS <30% for 1 month, and a post-HbS ≤15% allowed patients to maintain HbS <40%.

Appropriateness of packed red blood cells transfusions in chronic anemic patients in the emergency department: the TRANSFUS-ED retrospective analysis

Patients suffering from chronic anemia can benefit from scheduled transfusions of packed red blood cells (PRBCs), while urgent transfusions have specific indications. These patients frequently seek medical attention in the emergency department (ED), where they can be inappropriately transfused, but research in this field is limited. This study aimed to assess the appropriateness of PRBCs transfusions in chronic anemic patients in the ED. A retrospective analysis was performed on patients who accessed the ED of the Azienda Ospedaliera di Padova (Padova, Italy) between 2016 and 2019 and received PRBCs transfusions. Patients aged ≥ 18 years old and with chronic anemia were included, while those with acute anemia or admitted to the hospital after the transfusion were excluded. Chronic anemia was defined as satisfying one of the following in the past medical history: diagnosis of chronic anemia; two or more previous blood samplings demonstrating anemia; periodic transfusions. As primary outcome, the appropriateness of transfusions was assessed according to the American Association of Blood Banks (AABB) 2016 criteria, using the recommended threshold of 7 g/dL for hemodynamically stable adults and 8 g/dL for patients with pre-existing cardiovascular disease. Out of 1153 transfusions, 344 transfusions were included in the study. According to our criteria, 139 (40.4%) patients were inappropriately transfused, resulting in a total estimated cost of 54,528.71 € in the study period. This study showed that transfusions in chronic anemic patients are recurrent events in the ED and are frequently inappropriate. A possible explanation could be the lack of a well-structured primary care network granting periodic transfusions in ambulatory centers. In the future, implementing and improving chronic anemic patients’ access to transfusion services through dedicated pathways could reduce the burden on the ED and also decrease costs.

Workflow Improvement after Implementing Remote Blood Allocation Devices at an Academic Medical Center Blood Bank

Abstract Introduction/Objective Patients with hematological cancer routinely receive red blood cell (RBC) transfusions in the outpatient infusion clinical setting as part of their clinical therapy. Typically, RBCs are delivered to the outpatient infusion clinic via the pneumatic tube (P-tube). However, due to the recent expansion of the hospital footprint and the new location of the transfusion services, the P-tube encountered challenges that impacted the reliability of the delivery of RBC, which can delay patient care and affect patient satisfaction. This study’s purpose is to evaluate the pre-and post-implementation of the Haemobank-20 (HB20), remote blood storage and dispensing device, by reviewing the turn-around time (TAT) and the number of orders fulfilled outside of the transfusion service. Methods/Case Report Blood products are stocked to the HB in the infusion center. An electronic transfusion schedule is reviewed the night before scheduled transfusions to ensure appropriate inventory. When a patient is ready for the transfusion, the clinical nurse will use the device to retrieve blood products for the patient from the HB20. The average timed delivery time from the transfusion service to the outpatient infusion center is about 11 minutes. Data was retrospectively gathered from a 10-month interval before and after HB20 implementation to evaluate the number of orders fulfilled by the HB20. Results (if a Case Study enter NA) The HB has helped maintain nurse-to-patient ratios, reduced traffic at the blood bank issue window, and significantly sped up the turnaround time of RBCs from 11 minutes to less than 60 seconds. Before HB implementation, staff at the blood bank received 2853 units of RBCs through the blood bank window. This has been decreased by 61.2 percent to 1136 RBCs. Conclusion Implementing the Haemobank-20 in the outpatient infusion center has successfully reduced the turnaround time and the workload within the Transfusion Services. The current results study demonstrate that the remote blood-release system is safe and helpful in improving the efficiency of blood issue for patients in remote outpatient locations.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a prospective, longitudinal cohort study

SummaryBackgroundWorldwide, haemoglobin E β-thalassaemia is the most common genotype of severe β-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia.MethodsIn this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality.Findings109 patients (54 [50%] male; 55 [50%] female) were recruited and followed up for a median of 18 years (IQR 14–20). Median age at recruitment was 13 years (range 8–21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45–not reached). Median survival was worse among male patients (hazard ratio [HR] 2·51, 95% CI 1·16–5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90–24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01–1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 μg/L (vs concentration ≤1300 μg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival.InterpretationPatients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival.FundingWellcome Trust, Medical Research Council, US March of Dimes, Anthony Cerami and Ann Dunne Foundation for World Health, and Hemoglobal.

Pretransfusion Hemoglobin F Level in Thalassemia Patients: Effect of Well-Balanced Versus Poor Transfusion

Background: Thalassemia is a common condition in Iraq. More than ten thousand patients registered in Iraq. If well-balanced hypertransfusion regimen to maintain pretransfusion hemoglobin level above the internationally agreed 9.0 gm/ dL could suppress the patients‘ bone marrow and shutdown the hematopoiesis to the extent of not producing any hemoglobin F. Patients and Methods: One hundred well-balanced transfusion-dependant thalassemia patients were evaluated for Hemoglobin F level prior to their scheduled transfusions. Hemoglobin level must have been more than 9.0 gm/ dL to qualify the patient to be entered into this group. All such patients must have showed minimal skeletal changes of thalassemia. Another hundred patients with frank features of thalassemia and poor history of blood transfusion were also enrolled in the study. We aimed at knowing whether HbF is significantly different in the two groups. It could indicate that patients‘ bone marrow could be totally turned off and no abnormal hemoglobin will be allowed to be produced. Results: Seventy nine percent of our enrolled transfusion-dependent thalassemia patients who fulfilled the criteria and were well managed showed correction of their HbF level to near zero! Thirty five percent of the poorly transfused patients also corrected their abnormal HbF level. Conclusions: This study showed that marrow micromilieu could be manipulated in patients with thalassemia in such a way so as to totally shutdown production of abnormal hemoglobin F as a result of provision of normal hemoglobin through blood transfusion. The fact that even one third of poorly transfused patients could show the same results indicates that any degree of transfusion support will have its impact on the marrow.

Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial

For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial. HOPE is an international, randomised, double-blind, placebo-controlled, phase 3 trial done at 60 clinical sites in Canada, Egypt, France, Italy, Jamaica, Kenya, Lebanon, Netherlands, Oman, Turkey, the USA, and the UK. Patients (aged 12-65 years) with confirmed sickle cell disease, a haemoglobin concentration of 5·5-10·5 g/dL at enrolment, and who had between one and ten vaso-occlusive crisis events in the previous 12 months were enrolled. Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded. Patients were randomly assigned (1:1:1) to receive either once-daily oral voxelotor 1500 mg, voxelotor 900 mg, or placebo for 72 weeks. Randomisation was done centrally by use of an interactive web response system, stratified by baseline hydroxyurea use (yes vs no), age group (adolescents [12 to <18 years] vs adults [18 to 65 years]), and geographic region (North America vs Europe vs other). The primary endpoint (already reported) was the proportion of patients who achieved a haemoglobin response at week 24. In this final analysis, we report prespecified long-term efficacy assessments by intention to treat, including changes in haemoglobin concentrations from baseline to week 72, changes in the concentration of haemolysis markers (absolute and percentage reticulocytes, indirect bilirubin concentrations, and lactate dehydrogenase concentrations) from baseline to week 72, the annualised incidence of vaso-occlusive crises, and patient functioning, as assessed with the Clinical Global Impression of Change (CGI-C) scale. Safety was assessed in patients who received at least one dose of treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT03036813. Between Dec 5, 2016, and May 3, 2018, 449 patients were screened, of whom 274 were randomly assigned to the voxelotor 1500 mg group (n=90), the voxelotor 900 mg group (n=92), or the placebo group (n=92). At week 72, the adjusted mean change in haemoglobin concentration from baseline was 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group, 0·5 g/dL (0·3 to -0·8) in the voxelotor 900 mg group, and 0·0 g/dL (-0·3 to 0·3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p<0·0001), and between the voxelotor 900 mg group and the placebo group (p=0·014). Significant improvements in markers of haemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]). The proportion of patients in the voxelotor 1500 mg group who were rated as "moderately improved" or "very much improved" at week 72 with the CGI-C was significantly greater than in the placebo group (39 [74%] of 53 vs 24 [47%] of 51; p=0·0057). Serious adverse events unrelated to sickle cell disease were reported in 25 (28%) of 88 patients in the voxelotor 1500 mg group, 20 (22%) of 92 patients in the voxelotor 900 mg group, and 23 (25%) of 91 patients in the placebo group. Grade 3 or 4 adverse events were infrequent (ie, occurred in <10% of patients); anaemia occurred in five or more patients (two [2%] patients in the voxelotor 1500 mg group, seven [8%] patients in the voxelotor 900 mg group, and three [3%] patients in the placebo group). Of all 274 patients, six (2%) deaths occurred during the study (two deaths in each treatment group), all of which were judged as unrelated to treatment. Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease. Global Blood Therapeutics.

Hemoglobin D in a Patient with Sickle Cell Disease (Genotype HbSS).

A 29-year-old Saudi Arabian male with known sickle cell disease presented to the hematology clinic at Vanderbilt University Medical Center for follow-up and disease management. The patient had a complex past medical history including frequent pain crises requiring hospitalization, chronic kidney disease, and cholangitis. He was reported to be homozygous for hemoglobin S (HbS)2, a β-globin variant caused by a point mutation at codon 6, which results in the substitution of valine for glutamine. Under some circumstances, HbS can polymerize within red blood cells (RBCs), forming rigid, sickle-shaped cells that produce many of the secondary complications of the disease. At Vanderbilt University Medical Center, the patient had been undergoing simple RBC transfusion therapy. As part of the routine laboratory tests performed before each scheduled transfusion, the patient's HbS concentration was measured with cation-exchange high performance liquid chromatography (HPLC) on a Bio-Rad Variant HPLC analyzer (Fig. 1). During the daily review of hemoglobin HPLC chromatograms, the clinical chemistry team noted that an additional hemoglobin variant …

Measuring the impact of ambulatory red blood cell transfusion on home functional status: study protocol for a pilot randomized controlled trial

BackgroundRed blood cell (RBC) transfusion is frequently employed in both ambulatory and hospital environments with the aim of improving patient functional status. In the ambulatory setting, this practice is particularly common in patients with malignancy due to anemia associated with their cancer therapy. Increasingly, the efficacy of this US$10.5 billion per year practice has been called into question. While it is often standard of care for patients with chemotherapy-induced anemia to receive ambulatory RBC transfusions, it is unclear to what extent such transfusions affect home functional status. It is also unclear whether or not changes in functional status in this population can be objectively quantified using wearable activity monitors. We propose to directly measure the impact of outpatient RBC transfusions on at-home functional status by recording several physiological parameters and quantifiable physical activity metrics, e.g., daily energy expenditure and daily total step count, using the ActiGraph wGT3X-BT. This device is an accelerometer-based wearable activity monitor similar in size to a small watch and is worn at the waist. Study participants will wear the device during the course of their daily activities giving us quantifiable insight into activity levels in the home environment.Methods/designThis will be a randomized crossover pilot clinical trial with a participant study duration of 28 days. The crossover nature allows each patient to serve as their own control. Briefly, patients presenting at a tertiary medical center’s Ambulatory Infusion Center (AIC) will be randomized to either: (1) receive an RBC transfusion as scheduled (transfusion) or (2) abstain from the scheduled transfusion (no transfusion). After an appropriate washout period, participants will crossover from the transfusion arm to the no-transfusion arm or vice versa. Activity levels will be recorded continuously throughout the study using an accelerometry monitor. In addition to device data, functional status and health outcomes will be collected via a weekly telephone interview. The primary outcome measure will be daily energy expenditure. Performance metrics, such as step count changes, will also be evaluated. Additional secondary outcome measures will include daily sedentary time and Patient-reported Outcomes Measurement Information System (PROMIS) Global 10 Survey scores.DiscussionThis trial will provide important information on the feasibility and utility of using accelerometry monitors to directly assess the impact of RBC transfusion on patients’ functional status. The results of the study will inform the merit and methods of a more definitive future trial evaluating the impact of ambulatory RBC transfusions in the target population.Trial registrationClinicalTrials.gov, identifier: NCT02835937. Registered on 15 July 2016.

Variation in Serial TCD Velocity Measurements in the TCD with Transfusions Changing to Hydroxyurea (TWiTCH) Trial

▪Introduction: The multicenter phase 3 randomized clinical trial TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307) investigated whether hydroxyurea could maintain TCD velocities and prevent stroke in children with sickle cell anemia and abnormal TCD velocities. The trial was stopped early after reaching the primary endpoint, when the average TCD velocity in the alternative (hydroxyurea) arm was found to be non-inferior and even slightly better (138 versus 143 cm/sec) than the standard (transfusion) arm. A planned secondary analysis was to determine the variation in serial TCD velocity measurements for individual study participants, to document the normal TCD velocity fluctuations that occur and to inform the need for frequent TCD evaluations in this clinical setting.Methods: All TCD examinations collected in TWiTCH were analyzed for the maximum time-averaged mean velocity (TAMV) measured in the main intracranial arteries. TCD studies were performed by certified examiners using identical non-imaging instruments, no more than one week before a scheduled transfusion or phlebotomy procedure. Measurements on the index side, defined as the cerebral hemisphere with the higher mean arterial velocity at baseline assessment, were used for these statistical analyses. TCD values were analyzed according to four phases of the trial: (1) screening with three monthly TCD examinations performed at Weeks -8, -4, and 0 before randomization; (2) initial treatment period (hydroxyurea dose escalation with overlap transfusions or transfusions only) with three quarterly TCD measurements at Weeks 12, 24, and 36; (3) steady-state treatment period (hydroxyurea only or transfusions only) with four quarterly TCD measurements at Weeks 48, 60, 72, and 84; and (4) study exit with three monthly TCD examinations performed at Weeks 96, 100, and 104 or during the accelerated close-out period. The within-patient variance and standard deviation of the TAMV values were found using a linear mixed model, which was calculated using SAS Version 9.3.Results: TAMV measurements on the index side from 1458 TCD examinations on 121 randomized patients formed the overall dataset. TAMV values ≥170 cm/sec were identified in 140 measurements on 40 children (9.6% of TCD values) and exceeded 200 cm/sec in 1.8% of examinations (26 values, 8 children) during the study treatment phase. The within-patient TCD variation, representing fluctuation of repeated TCD measurements in the same study participant, was 12.0 cm/sec for the entire cohort during the initial screening phase (363 TCD measurements). In the initial treatment phase, TCD variation in the hydroxyurea arm (180 values, 60 children) was 10.5 cm/sec, similar to 10.2 cm/sec on the transfusion arm (183 values, 61 children). In the steady-state treatment phase, the TCD variation in the hydroxyurea arm was 10.2 cm/sec (207 values, 57 children), compared to 12.3 cm/sec on the transfusion arm (212 values, 58 children). In the final exit phase, TCD variation in the hydroxyurea arm was 9.8 cm/sec (155 values, 58 children), similar to 10.2 cm/sec on the standard arm (155 values, 57 children). TCD variation was greater with higher baseline TCD velocity and shorter transfusion duration, but was not affected by age or gender. For example, participants with baseline TCD velocity of <170 cm/sec had a post-randomization measurement variation of 10.8 cm/sec, while those ≥170 cm/sec had higher variation (13.7 cm/sec, p=0.001).Conclusions: The TWiTCH trial provides prospective data regarding the biological variation in serial TCD values that occurs in children with previous abnormal TCD examinations but no severe vasculopathy. The observed within-patient variation in TCD velocities was consistently 10-14 cm/sec, with higher variation observed in children with higher baseline TCD velocities. This fluctuation can be expected with serial TCD examinations and should be considered before making treatment decisions based on a single TCD measurement. Since comparison of entry and exit TCD values in the TWiTCH trial documented that hydroxyurea at maximum tolerated dose was non-inferior to transfusions, frequent TCD examinations may not be warranted. DisclosuresWare:Bayer Pharmaceuticals: Consultancy; Addmedica: Research Funding; Global Blood Therapeutics: Consultancy; Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding; Nova Laboratories: Consultancy. Heeney:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Sancilio and Company: Consultancy, Research Funding. Thompson:Baxalta (now part of Shire): Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mast: Research Funding; Eli Lily: Research Funding; Celgene: Research Funding; Amgen: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Research Funding.

A diagnostic nomogram for delayed hemolytic transfusion reaction in sickle cell disease.

Diagnosis of delayed hemolytic transfusion reactions (DHTR), one of the most dreaded complications of transfusion in patients with sickle cell disease (SCD), is challenging and not straightforward. Current diagnostic approaches are complex and not consensual; they are based on assessment of hemoglobin (Hb) drop and enhanced hemolysis, features also seen during classical vaso-occlusive events. In this observational study, we tested the hypothesis that the rate of decline in HbA after an index transfusion is a surrogate marker for the destruction of transfused RBC, which could be used diagnostically. We examined 421 transfusion episodes (in 128 patients of a French referral center for SCD) for which an Hb electrophoresis was obtained within 1 week following an index transfusion and repeated within 2 months (before a subsequent scheduled transfusion or during an acute complication). Chart review found DHTR to be present in 26 cases (6.2%), absent in 389 cases (92.4%), and possible in six cases (1.4%). As expected, DHTR was associated with accelerated hemolysis (increased serum bilirubin and lactic dehydrogenase concentrations) and a decline in total Hb as compared to the early post-transfusion value. However, the decline in HbA concentration appeared more effective in segregating between patients without DHTR and others. We propose a diagnostic nomogram for DHTR based on Hb A as a biologic marker of the survival of transfused RBCs. Am. J. Hematol. 91:1181-1184, 2016. © 2016 Wiley Periodicals, Inc.

A Survey on Transfusion Status in Orthopedic Surgery at a Trauma Center.

Increased costs and mortality associated with inappropriate blood transfusions have led to investigations about blood request and blood transfusion techniques. We investigated the transfusion status in patients who underwent orthopedic surgery in Poursina Hospital (Rasht, Iran) to optimizing blood usage and determine if a scheduled transfusion program for every orthopedic surgery could improve blood transfusion management. In this descriptive-prospective study, all orthopedic surgeries in Poursina Hospital, Rasht, between April to June 2013 were reviewed. All patient information was recorded, including: demographics, type of surgery, hemoglobin level, cross-match test, duration of surgery, and blood loss, and transfusion. Based on the one-way ANOVA and independent samples test analysis, cross-match to transfusion ratio and transfusion possibility, the transfusion index, and maximal surgical blood order schedule were calculated to determine blood transfusion status. Among 872 selected orthopedic surgery candidates, 318 of them were cross-matched and among those, 114 patients received a blood transfusion. In this study, the cross-match to transfusion ratio was 6.4, transfusion possibility 36.47%, transfusion index 0.6, and maximal surgical blood order schedule 0.9. We found that blood ordering was moderately higher than the standard; so it is highly recommended to focus on the knowledge of evidence based on transfusion and standard guidelines for blood transfusion to avoid over-ordering.

Can the interval between antibody identifications be increased for alloimmunized patients?

New alloantibody formation is unpredictable in patients who have been previously alloimmunized. Pretransfusion testing is designed to detect these antibodies while antibody identification (ABI) techniques are designed to identify the specificity of the antibody. Pretransfusion testing intervals are prescribed by regulatory and accrediting agencies, intervals for ABI in alloimmunized patients are not. Our institution evaluated the safety of increasing the interval from every 72 hours to 14 days. The current 72-hour interval was chosen at our institution to align with AABB Standard 5.14.3.2, which requires a pretransfusion specimen drawn within 3 days of the scheduled transfusion for potentially immunized patients. Over 2 years, all ABI entries in the laboratory information system were screened. All cases of alloimmunized patients with an additional antibody specificity that developed within 14 days of a previous ABI were reviewed and confirmed by four transfusion medicine physicians. Initially, 8948 entries were screened. Thirty patients were identified to have formed 33 newly identified clinically significant alloantibodies within 14 days. After further categorization, only 13 antibodies (0.15% of all ABIs, 0.47% of alloimmunized patients examined) were deemed to be newly formed clinically significant antibodies that would have led to a change in transfusion practice. Retrospective analysis of ABI results over a 2-year period revealed that 0.47% of previously alloimmunized patients that have samples for pretransfusion testing develop a new clinically significant alloantibody in 14 days or less. While there would be significant resource advantages to increasing the duration between repeat ABI, it does not outweigh the risk of a potential hemolytic transfusion reaction.

Age-dependent pathophysiology of acute chest syndrome in children with sickle cell disease.

Age-dependent pathophysiology of acute chest syndrome in children with sickle cell disease.

SCD-Biochip: A Functional Assay for Red Cell Adhesion in Sickle Cell Disease

Vaso-occlusion, a hallmark of sickle cell disease (SCD), is caused by abnormal adhesion of blood cells to the endothelium. Analyses of RBC-endothelial interactions are technically challenging, which has limited the widespread use of these evaluations clinically or as a research tool. Here, we present a microfluidic device (SCD-Biochip) that allows serial quantitative and qualitative examination of RBC adhesion and deformability to endothelium associated protein-immobilized microchannels (fibronectin, FN, and laminin, LN), in a closed preprocessing-free system (Fig. 1A).15 µL of surplus blood, after clinical lab tests had been completed, was taken from subjects with HbSS (transfused, non-transfused, and with high or low levels of HbF), HbSC, HbSBeta-thalassemia and from control subjects (HbAA). Samples were injected, without processing, on to FN- and LN-immobilized microchannels. This was followed by wash steps at or above the physiological flow velocities of post-capillary venules (0-10 mm/s). Adhered RBCs were then quantified. We observed a statistically significant difference in RBC adherence per unit area to FN (Fig. 1B), after 0.8 mm/s flow velocity (low wash), amongst RBCs from subjects with HbSS (90±84.0, n=26), with compound heterozygous HbSC or Sβthalassemia (21±6.8, n=4), or with normal hemoglobin (HbAA, 4±3, n=10, Mann-Whitney, p<0.05). Strikingly, this test was sensitive to physiological changes that were not well-reflected in routine lab tests (e.g., adherence to FN did not differ between samples from transfused or non-transfused HbSS patients (77±62, n=6, compared with 88.1±82.6, n=17, P=0.75, respectively), despite routine scheduled transfusions of HbAA-containing RBCs in the former. Samples from HbSS subjects with a low HbF were more likely to be highly adherent to FN than were samples from subjects with a high HbF (5/7 with <8% HbF compared with 1/10 ≥8% HbF, p=0.035). Increased adherence of HbSS- (707±904.8, n=7), compared with HbAA-containing RBCs (9±6, n=7), to LN at low wash was also seen. Of interest, a single sample from an HbSS subject with acute pain showed an adherence to FN and LN of 250 and 2176, respectively.Qualitatively, HbSS-containing RBCs showed decreased adherence to FN at increased flow rates; adhered RBCs decreased from 90±84 (n=25) at low flow wash to 69±52 (n=13) at 3.3 mm/s (intermediate flow) and 36±48.2 (n=11) at 41.7 mm/s (high flow). Analyses revealed deformable HbAA- and HbSS-containing RBCs, but only HbSS-containing samples also had a significant population of non-deformable RBCs. We analyzed single cell deformation and detachment in the presence of physiological fluid flow. Deformable HbAA- and HbSS-containing RBCs detached at relatively low flow rates (6.11±0.48 n=3, and 9.3±1.44 n=6, respectively), compared to non-deformable HbSS-containing RBCs (40±6.97 n=5). Deformable HbAA- or HbSS-containing RBCs displayed a single adhesion pivot point, compared to non-deformable HbSS-containing RBCs, which showed multiple adhesion sites. At highest flow (41.7mm/s), 75±17% (n=9) of adhered RBCs were non-deformable on FN. Of note, flow evaluations revealed two characteristic RBC profiles in HbSS subjects: either one in which adherent non-deformable cells predominated at all flow rates or one in which less adherent deformable cells comprised >50% of the RBC population.The SCD-Biochip evaluates, simply and with small blood sample volumes, complex biophysical properties of adhesion and deformability, which reflect clinical phenotypes, including hemoglobin composition. This adaptable technology may give important biophysical insights into disease pathophysiology when widely applied in SCD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Transcranial doppler velocity and brain MRI/MRA changes in children with sickle cell anemia on chronic transfusions to prevent primary stroke

Chronic transfusions help prevent primary stroke in children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities. However, the effects of transfusions on TCD velocities and brain MRI/MRA findings are incompletely described. We reviewed TCD and brain MRI/MRA results in 27 children with SCA and abnormal TCD velocities receiving transfusions to prevent primary stroke. All TCDs were performed by a single examiner, immediately prior to a scheduled transfusion. We also examined the effects of laboratory and clinical parameters on TCD responses to transfusion therapy. For the whole cohort, the average pre-transfusion HbS on transfusions was 31.7 ± 12.3%. The most significant decline in TCD velocities occurred within 10 months of starting transfusions. Follow-up TCD values trended upward with increasing pre-transfusion %HbS levels while on treatment. Half of the children had persistent conditional/abnormal TCD velocities despite transfusions and 28% had new/progressive stenosis on MRA, but none had primary stroke during 73 patient-years of follow-up. For children with SCA and abnormal TCD velocities, transfusions lower TCD velocities and help prevent stroke, but do not always result in normal velocities or protect against progression of cerebral vasculopathy. Improved adherence to transfusion goals may improve on-treatment TCD velocities.