Reduction of anti-A and anti-B isoagglutinin titers of group O whole blood units employing an ABO antibody immune adsorption column.

BACKGROUND: Massive hemorrhage is a leading cause of death from trauma. There is growing interest in group O whole blood transfusions to mitigate coagulopathy and hemorrhagic shock. Insufficient availability of low-titer group O whole blood is a barrier to routine use. We tested the efficacy of the Glycosorb® ABO immunoadsorption column to reduce anti-A/B titers in group O whole blood. METHODS: Six group O whole blood units were collected from healthy volunteers, and centrifuged to separate platelet poor plasma. Platelet-poor plasma was filtered through a Glycosorb® ABO antibody immunoabsorption column, then reconstituted to prepare post-filtration whole blood. Anti-A/B titers, CBC, free hemoglobin, and thromboelastography (TEG) assays were performed on pre-and post-filtration whole blood. RESULTS: Mean( ± SEM) anti-A (224 ± 65 pre vs 13 ± 4 post) and anti-B (138 ± 38 pre vs 11 ± 4 post) titers were significantly reduced (p = 0.004) in post-filtration whole blood. No significant changes were detected in CBC, free hemoglobin, and TEG parameters on day 0. Free hemoglobin increased throughout storage (48 mg/dl ± 24 Day 0 vs 73 ± 35 Day 7 vs 96 ± 44 Day 14; p = 0.14). CONCLUSIONS: The Glycosorb® ABO column can significantly reduce anti-A/B isoagglutinin titers of group O whole blood units. Glycosorb® ABO could be employed to provide whole blood with lower risk of hemolysis and other consequences of infusing ABO incompatible plasma. Preparation of group O whole blood with substantially reduced anti-A/B would also increase the supply of low-titer group O whole blood for transfusion.

Red Blood Cell Transfusion: 2023 AABB International Guidelines.

Importance: Red blood cell transfusion is a common medical intervention with benefits and harms. Objective: To provide recommendations for use of red blood cell transfusion in adults and children. Evidence Review: Standards for trustworthy guidelines were followed, including using Grading of Recommendations Assessment, Development and Evaluation methods, managing conflicts of interest, and making values and preferences explicit. Evidence from systematic reviews of randomized controlled trials was reviewed. Findings: For adults, 45 randomized controlled trials with 20 599 participants compared restrictive hemoglobin-based transfusion thresholds, typically 7 to 8 g/dL, with liberal transfusion thresholds of 9 to 10 g/dL. For pediatric patients, 7 randomized controlled trials with 2730 participants compared a variety of restrictive and liberal transfusion thresholds. For most patient populations, results provided moderate quality evidence that restrictive transfusion thresholds did not adversely affect patient-important outcomes. Recommendation 1: for hospitalized adult patients who are hemodynamically stable, the international panel recommends a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (strong recommendation, moderate certainty evidence). In accordance with the restrictive strategy threshold used in most trials, clinicians may choose a threshold of 7.5 g/dL for patients undergoing cardiac surgery and 8 g/dL for those undergoing orthopedic surgery or those with preexisting cardiovascular disease. Recommendation 2: for hospitalized adult patients with hematologic and oncologic disorders, the panel suggests a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (conditional recommendations, low certainty evidence). Recommendation 3: for critically ill children and those at risk of critical illness who are hemodynamically stable and without a hemoglobinopathy, cyanotic cardiac condition, or severe hypoxemia, the international panel recommends a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (strong recommendation, moderate certainty evidence). Recommendation 4: for hemodynamically stable children with congenital heart disease, the international panel suggests a transfusion threshold that is based on the cardiac abnormality and stage of surgical repair: 7 g/dL (biventricular repair), 9 g/dL (single-ventricle palliation), or 7 to 9 g/dL (uncorrected congenital heart disease) (conditional recommendation, low certainty evidence). Conclusions and Relevance: It is good practice to consider overall clinical context and alternative therapies to transfusion when making transfusion decisions about an individual patient.

Considerations for immune effector cell therapy collections: a white paper from the American Society for Apheresis.

BACKGROUND AIMS: This white paper was developed to provide leukapheresis guidance for the collection of mononuclear cells from adult and pediatric patients who are destined for immune effector cell (IEC) therapies for commercial and research applications. Currently, there is considerable variability in leukapheresis processes and limited published information regarding best practices relevant to new cellular therapies, especially IECs. Herein the authors address critical leukapheresis questions in five domains to help guide consistent collection processes and ensure high-quality products. The first four domains are onboarding, pre-collection, collection and post-collection, with protocol feasibility, preparation, care and follow-up of the patient/donor at each step, respectively, and technical considerations during collection. The fifth domain of quality assurance focuses on ensuring product potency, purity, safety and auditing. METHODS: The American Society for Apheresis (ASFA) Clinical Applications Committee (IEC Therapy Subcommittee) was charged by the society's board of directors with working collaboratively with other ASFA committees and organizations, including the Foundation for the Accreditation of Cellular Therapy, Association for the Advancement of Blood and Biotherapies, American Society for Transplantation and Cellular Therapy, National Marrow Donor Program and International Society for Cell & Gene Therapy, to develop guidelines regarding leukapheresis collection of cells destined for the manufacture of IEC therapies. After a review of the literature and discussion with members of the involved committees and various institutions, a draft guidance was created and circulated for comment and revision. RESULTS: Critical aspects of apheresis that could affect the quality and quantity of the leukapheresis product were identified. These areas were then discussed and reviewed. After consensus, the best practice guidelines were proposed and accepted. CONCLUSIONS: In the current era of rapid growth of IEC therapies, it is important to address critical leukapheresis steps to provide high-quality products and more consistent practices and to eliminate redundant efforts.

Transfusion therapy of neonatal and paediatric patients: They are not just little adults.

Patient blood management (PBM) strategies are needed in the neonate and paediatric population, given that haemoglobin thresholds used are often higher than recommended by evidence, with exposure of children to potential complications without meaningful benefit. A literature review was performed on the following topics: evidence-based transfusions of blood components and pharmaceutical agents. Other topics reviewed included perioperative coagulation assessment and perioperative PBM. The Transfusion and Anaemia Expertise Initiative (TAXI) consortium published a consensus statement addressing haemoglobin (Hb) transfusion threshold in multiple subsets of patients. A multicentre trial (PlaNeT-2) reported a higher risk of bleeding and death or serious new bleeding among infants who received platelet transfusion at a higher (50 000/µl) compared to a lower (25 000/µl) threshold. Recent data support the use of a restrictive transfusion threshold of 25 000/µl for prophylactic platelet transfusions in preterm neonates. The TAXI-CAB consortium mentioned that in critically ill paediatric patients undergoing invasive procedures outside of the operating room, platelet transfusion might be considered when the platelet count is less than or equal to 20 000/µl and there is no benefit of platelet transfusion when the platelet count is more than 50 000/µl. There are limited controlled studies in paediatric and neonatal population regarding plasma transfusion. Blood conservation strategies to minimise allogenic blood exposure are essential to positive patient outcomes neonatal and paediatric transfusion practices have changed significantly in recent years since randomised controlled trials were published to guide practice. Additional studies are needed in order to provide practice change recommendations.

Factor V activity in apheresis platelets: Implications for management of FV deficiency.

BACKGROUND: Allogeneic platelet (PLT) infusion is a strategy to raise Factor V (FV) levels in patients with congenital FV deficiency. However, since FV is labile in vitro, we hypothesized that FV activity could be low in PLT units. STUDY DESIGN AND METHODS: FV activity was tested using a prothrombin time-based platform in the supernatant and platelet lysate (PL) of apheresis PLT units (16 units stored in PLT additive solution with acetate and phosphate [PAS-C] and 10 units stored in plasma only), on post-collection days 3-6. Statistical analysis was performed using Student's t test (P < .05). RESULTS: FV activity was severely diminished in PAS-C PLTs (N = 16) supernatant (3.70% ± 1.02%) and PL (3.26% ± 1.02%). FV activity in plasma-only PLTs (N = 10) was lower in both supernatant (44.55% ± 6.46%) and lysate (39.67% ± 6.33%) relative to normal plasma levels, but both were significantly higher (P < .0001) compared to PAS-C PLTs. In a separate set of experiments, FV activity in PAS-C PLTs examined serially over storage time (N = 3 for these experiments) showed that FV levels were reduced by day 3 and not significantly different by day 5 of storage (Day 3 supernatant 5.03% ± 1.41%; Day 5 supernatant: 3.10% ± 0.57%; P = .2; Day 3 lysate: 3.89% ± 1.03%; Day 5 lysate: 2.61% ± 0.41%; P = .4). CONCLUSION: Plasma should be considered over PLTs as first-line therapy for non-complex FV deficiency-associated hemorrhage. If PLTs are considered for transfusion, plasma-only PLT units should be preferentially utilized, as PAS-C PLT have near-absent FV activity.

Optimization of repeat plerixafor dosing for autologous peripheral blood stem-cell collection.

INTRODUCTION: Peripheral CD34+ cells may be mobilized using filgrastim alone or in combination with chemotherapy. The addition of plerixafor can be efficacious, though guidelines for repeat dosing are lacking. MATERIAL AND METHODS: This quality improvement project was initiated to generate guidelines for repeat plerixafor dosing after retrospective evaluation of data in adult patients undergoing autologous peripheral blood stem cell mobilization and collection. RESULTS: Analysis included 195 patients: 119 (61 %) with multiple myeloma and 76 (39 %) with lymphoma. Patients given at least one dose of plerixafor (n = 109) were further divided: Group 1) (A) goal of 3 × 10E6/kg and day 1 peripheral blood CD34+ count < 30 × 10E6/L, vs (B) ≥ 30 × 10 E6/L; Group 2) (A) goal of 6 × 10E6/kg and day 1 peripheral blood CD34+ count < 50 × 10E6/L or < 50 % of collection goal after day 1, vs (B) ≥ 50 % of collection goal after day 1. Ninety five percent of cases in Group 1B and 88 % of cases in Group 2B did not receive additional plerixafor doses and all of them achieved their collection goals. In contrast, those in Groups 1A and 2A required additional plerixafor dosing and some mobilizations/collections were futile. CONCLUSION: Based on these data, with consideration of collection goal, peripheral blood CD34+ count, and CD34+ cell bag count on collection day 1, we have generated institutional guidelines for collection initiation and repeat plerixafor dosing. Long term, we predict these guidelines will optimize pharmacy, apheresis, and stem cell processing resources while improving the patient experience.

The report from ASFA COVID-19 taskforce: Considerations and prioritization on apheresis procedures during the SARS-CoV-2 coronavirus disease (COVID-19) pandemic.

Since vaccination for SARS-CoV-2 coronavirus started, the trajectory of patient numbers infected with the virus has improved once; however, variants of SARS-CoV-2 have emerged and more people have been infected; therefore, pandemic status is still far from resolution. Government and social efforts to prevent coronavirus infection continue in most states in the US and globally even after the Centers for Disease Control and Prevention declared some restriction relief for fully vaccinated people in March 2021. Healthcare institutions and various professional organizations have developed guidelines or policies to prevent the spread of these coronaviruses in the setting of apheresis. In this report, the issues that apheresis services may encounter under the current COVID-19 (SARS-CoV-2 coronavirus disease) pandemic will be discussed with potential strategies that can be adapted for efficient and optimum use of apheresis resources.

Surprises in the t-J Model: Implications for Cuprates.

Many strongly correlated systems, such as the cuprate superconductors, have the interesting physics of low dimensionality and hence enhanced fluctuation effects. We perform an analysis of the t-J model in the slave boson formulation which accounts for strong correlations, focusing on fluctuation effects that have hitherto not received the attention they deserve. We find several interesting results including the instability of the d-wave superconducting state to internal phase fluctuations giving way to a time reversal broken d+is^{*} superconductor at low doping. This offers an explanation for some recent experimental findings in the cuprate superconductors, including the observation of nodeless superconductivity at low doping. We also suggest further experiments that can validate our claims. On a broader perspective, this work points to the importance of considering fluctuation effects in other two-dimensional strongly correlated systems opening up a plethora of possibilities.

Immunohistochemical expression of vitamin D receptor and forkhead box P3 in classic Hodgkin lymphoma: correlation with clinical and pathologic findings.

BACKGROUND: Expression of forkhead box P3 (FOXP3), a key regulator of T-cell function, in the tumor immune microenvironment is related to survival in classic Hodgkin lymphoma (CHL). Vitamin D receptor (VDR), a transcription factor agonists have been shown to induce FOXP3 expression in T-cells and enhance recruitment of these cells to the inflammatory sites. VDR expression is CHL has been described. However, there is no data on expression of VDR in context of quantity of FOXP3 positive cells in CHL. METHODS: We examined and correlated immunohistochemical expression of VDR and FOXP3 along with clinical and pathology findings in 29 cases of CHL. RESULTS: VDR was expressed in Hodgkin Reed-Sternberg (HRS) cells and background lymphocytes and FOXP3 was expressed in background lymphocytes. 82% of CHL cases, regardless of the subtype, expressed VDR and in majority of the cases, VDR expression was directly proportional to the quantity of FOXP3 expressing lymphocytes in the tumor microenvironment. In cases with higher clinical stage (III/IV), only 28.5% of cases diffusely expressed VDR and FOXP3 compared to 71.4% showing focal positivity. Whereas in cases with lower clinical stages (I/II), the expression pattern of VDR and FOXP3 was almost similar (41.6% diffuse versus 33.3% focal). Interestingly, focal VDR and FOXP3 expression pattern was significantly higher among males. Mixed cellularity cases showed predilection for focal VDR and FOXP3 expression (80% cases); whereas nodular sclerosis subtype had focal and diffuse VDR and FOXP3 expression patterns in similar proportion. Cases with diffuse VDR and FOXP3 expression were less likely to have bone marrow involvement. Epstein Barr virus- encoded small RNA (EBER) positive cases were predominantly focally positive (80%) for VDR and FOXP3. CONCLUSIONS: In summary, quantity of FOXP3 positive T-cells in CHL microenvironment seems to correlate with VDR expression. Clinical stage show a trend of inverse correlation with expression of VDR and quantity of FOXP3 positive T-cells. These findings suggest that VDR could be a possible prognostic and therapeutic target in CHL.

Disease detection methodologies in relapsed B-cell acute lymphoblastic leukemia: Opportunities for improvement.

BACKGROUND: Accurate disease detection is integral to risk stratification in B-cell acute lymphoblastic leukemia (ALL). The gold standard used to evaluate response in the United States includes morphologic evaluation and minimal residual disease (MRD) testing of aspirated bone marrow (BM) by flow cytometry (FC). This MRD assessment is usually made on a single aspirate sample that is subject to variability in collection techniques and sampling error. Additionally, central nervous system (CNS) assessments for ALL include evaluations of cytopathology and cell counts, which can miss subclinical involvement. PROCEDURE: We retrospectively compared BM biopsy, aspirate, and FC samples obtained from children and young adults with relapsed/refractory ALL to identify the frequency and degree of disease discrepancies in this population. We also compared CNS FC and cytopathology techniques. RESULTS: Sixty of 410 (14.6%) BM samples had discrepant results, 41 (10%) of which were clinically relevant as they resulted in a change in the assignment of marrow status. Discrepant BM results were found in 28 of 89 (31.5%) patients evaluated. Additionally, cerebrospinal fluid (CSF) FC identified disease in 9.7% of cases where cytopathology was negative. CONCLUSIONS: These results support further investigation of the role of concurrent BM biopsy, with aspirate and FC evaluations, and the addition of FC to CSF evaluations, to fully assess disease status and response, particularly in patients with relapsed/refractory ALL. Prospective studies incorporating more comprehensive analysis to evaluate the impact on clinical outcomes are warranted.

Immunohematologic aspects of alloimmunization and alloantibody detection: A focus on pregnancy and hemolytic disease of the fetus and newborn.

Alloimmunization to non-ABO, red blood cell (RBC) antigens remains one of the most clinically-relevant complexities faced by blood banking practitioners. In the setting of transfusion therapy, these antibodies raise risks for incompatibilities, while for pregnant patients they can mediate deadly forms of hemolytic disease of the fetus and newborn. As such, a thorough understanding of pathways that lead to alloimmunization, as well as the tools used by blood banks to detect alloantibodies, is critical to transfusion practice. In this review, in which alloimmunization in the setting of pregnancy will be emphasized, we will review: 1) the clinical impacts of RBC alloantibodies in the peri-partum period; 2) the current pathophysiologic mechanisms thought to influence non-ABO antigen alloimmunization; 3) the strengths and weaknesses of laboratory tools used in aiding alloimmunization detection; and 4) future directions of the transfusion community related to alloimmunization impacting pregnancy.

A study of PD-L1 expression in intravascular large B cell lymphoma: correlation with clinical and pathological features.

Intravascular large B cell lymphoma (IVLBCL) is a rare, aggressive, extranodal large B cell lymphoma characterised by growth of tumour cells within the lumen of vessels, particularly capillaries. Programmed cell death ligand 1 (PD-L1) is a cell surface glycoprotein that interacts with programmed death 1 (PD-1) on the T cell surface, leading to modulation of the immune response. PD-L1 is a targetable immune check-point molecule that is expressed on neoplastic cells in various cancers, including a subset of lymphomas. We correlated the expression of PD-L1 with clinical and pathological findings in this rare disease. Eleven cases of IVLBCL were identified in the archives of Laboratory of Pathology at the National Cancer Institute, NIH. A panel of immunostains (CD20, CD3, CD5, PD-L1) was performed. The cases were classified as the classic form or the variant associated with haemophagocytic syndrome (HPS) based on published 2017 WHO criteria. Three cases (27.3%) were HPS variant and eight cases (72.7%) were the classic form. Five (45.5%) of 11 cases were CD5-positive; two of three (66%) were HPS variants and three of eight (37.5%) were classic form. Overall, four of nine evaluable cases (44.4%) were positive for PD-L1, three of which were classic. Only one CD5-positive case was PD-L1-positive, a classic variant. In summary, a subset of IVLBCL express PD-L1. Although limited, these data suggest that PD-L1 is expressed in both the so-called classic form as well as the HPS variant. PD-L1 is expressed irrespective of CD5 expression. Finally, detection of PD-L1 expression in a subset of IVLBCL lymphoma cases may identify patients who might benefit from targeted immunotherapy.

Efficacy and Safety of Direct Acting Antiviral Therapy for Chronic Hepatitis C in Thalassemic Children.

OBJECTIVES: There is limited data on the efficacy and safety of directly acting antiviral therapy (DAA) for chronic hepatitis C in pediatric population. The aim was to assess the efficacy and safety of DAA in chronic hepatitis C ß-thalassemic major pediatric patients. METHODS: Prospective study was conducted from September 2015 to January 2017. All ß-thalassemic major chronic hepatitis C pediatric patients with age between 5 and 14 years were included in this study. Data related to demography, laboratory parameters, hepatitis C viral load, genotype and outcome of antiviral therapy was analyzed. DAA was planned according to EASL guidelines 2015 for chronic hepatitis C therapy in adults. OBSERVATIONS: Fourteen ß-thalassemic major patients (median age was 9.5 y, 12 male) were studied. All patients were of genotype 3, received DAA (sofosbuvir 400 mg+daclatasvir 80 mg) for 12 weeks. The median viral load was 2.5×10 IU/mL. End of treatment response and sustained virological response at 12 weeks was achieved in all the patients. Serum alanine aminotransferase, aspartate aminotransferase, ferritin, and albumin significantly reduced after DAA. CONCLUSIONS: DAA in adult dosage are safe and effective for treatment of chronic hepatitis C (genotype 3) in pediatric ß-thalassemic major population.

A new paradigm in facial reanimation for long-standing palsies?

BACKGROUND: A chance observation of return of excellent facial movement, after 18 months following the first stage of cross-face nerve grafting, without free functional muscle transfer, in a case of long-standing facial palsy, lead the senior author (RBA) to further investigate clinically. PATIENTS AND METHODS: This procedure, now christened as cross-face nerve extension and neurotization, was carried out in 12 patients of very long-standing facial palsy (mean 21 years) in years 1996-2011. The mean patient age and duration of palsy were 30.58 years and 21.08 years, respectively. In patients, 1-5 a single buccal or zygomatic branch served as a donor nerve, but subsequently, we used two donor nerves. The mean follow-up period was 20.75 months. RESULTS: Successive patients had excellent to good return of facial expression with two fair results. Besides improved smile, patients could largely retain air in the mouth without any escape and had improved mastication. No complications were encountered except synkinesis in 1 patient. No additional surgical procedures were performed. CONCLUSION: There is experimental evidence to suggest that neurotization of a completely denervated muscle can occur by the formation of new ectopic motor end plates. Long-standing denervated muscle fibres eventually atrophy severely but are capable of re-innervation and regeneration, as validated by electron microscopic studies. In spite of several suggestions in the literature to clinically validate functional recovery by direct neurotization, the concept remains anecdotal. Our results substantiate this procedure, and it has the potential to simplify reanimation in longstanding facial palsy. Our work now needs validation by other investigators in the field of restoring facial animation.

Low-level laser (light) therapy (LLLT) for treatment of hair loss.

OBJECTIVE: Alopecia is a common disorder affecting more than half of the population worldwide. Androgenetic alopecia, the most common type, affects 50% of males over the age of 40 and 75% of females over 65. Only two drugs have been approved so far (minoxidil and finasteride) and hair transplant is the other treatment alternative. This review surveys the evidence for low-level laser therapy (LLLT) applied to the scalp as a treatment for hair loss and discusses possible mechanisms of actions. METHODS AND MATERIALS: Searches of PubMed and Google Scholar were carried out using keywords alopecia, hair loss, LLLT, photobiomodulation. RESULTS: Studies have shown that LLLT stimulated hair growth in mice subjected to chemotherapy-induced alopecia and also in alopecia areata. Controlled clinical trials demonstrated that LLLT stimulated hair growth in both men and women. Among various mechanisms, the main mechanism is hypothesized to be stimulation of epidermal stem cells in the hair follicle bulge and shifting the follicles into anagen phase. CONCLUSION: LLLT for hair growth in both men and women appears to be both safe and effective. The optimum wavelength, coherence and dosimetric parameters remain to be determined.