Assessing deviations for HPCs obtained during COVID-19 (ADHOC): Evaluating impact of the COVID-19 pandemic on cellular therapy products and processes, the BEST collaborative study.

BACKGROUND: The success of allogeneic hematopoietic stem cell transplantation is dependent on a world-wide network of collection centers providing donations that predominantly have been infused as fresh cells. The logistics chain that supports the just-in-time delivery model for stem cell and immunotherapy products was severely stressed by the COVID pandemic, and in early 2020 a number of national and international bodies recommended that cells should be cryopreserved at the collection or transplant center to avoid interruptions in their acquisition or delivery to patients who had started conditioning. STUDY DESIGN: To assess the potential consequences of such pandemic-related deviations to normal practice, we surveyed nine international laboratories to determine if the characteristics or transplant outcomes of allogeneic stem cell donations differed in the immediate periods before and after the switch to routine cryopreservation. RESULTS: Nine centers on two continents provided data for 72 HSC donations just before, and 71 just after, switching to cryopreservation for allogeneic HSC products. No statistically significant differences between the period before and after cryopreservation were noted for time from product collection to receipt, product temperature at receipt, or CD34+ cell viability at receipt. There was an indication of slower absolute neutrophil count recovery after cryopreservation was required (mean time of 15 vs. 17.6 days). DISCUSSION: While there were no apparent changes to most parameters studied, there was an indication of slower neutrophil engraftment that will need to be examined in larger, longer term studies.

Cryopreserved hematopoietic stem/progenitor cells stability program-development, current status and recommendations: A brief report from the AABB-ISCT joint working group cellular therapy product stability project team.

BACKGROUND: The AABB-ISCT Joint Working Group Stability Project Team (SPT) was assigned to roadmap a path toward standardization of cryopreserved hematopoietic stem/progenitor cell (HSPC) stability programs. HSPC stability encompasses a broad scope of conditions including non-frozen ("fresh") and cryopreserved cell products, and varying methods for storage, thaw, and administration. This report assessed current practices and focused solely on cryopreserved HSPC cell therapy products to establish preliminary recommendations for a stability program roadmap. METHODS: A survey was prepared by the SPT and distributed to ISCT and AABB members. Survey results were summarized and recommendations were outlined based on the responses from the survey. This report highlights current practices for cryopreserved HSPC stability programs, including additional considerations and recommendations. RESULTS AND DISCUSSION: Eighty-two (82) centers worldwide participated in the survey. Survey results indicate variability across programs. HSPC stability depends on multiple factors within the processing facility (e.g., cryopreservation techniques, reagents used, and storage temperature) and independent variables (e.g., donor-related factors and starting material variability). While retention of hematopoietic engraftment potential is the primary goal for cryopreserved HSPC stability, engraftment results should not be used as the sole metric for stability programs. Based on the survey results, the SPT provides recommendations for consideration. CONCLUSIONS: The SPT recommendations for best practices are not intended to replace existing standards. The survey results emphasize the need for the community to optimize best practices and consider initiating collaborative projects to improve the standardization of cryopreserved HSPC stability programs for cell therapy products.

Cryopreserved hematopoietic stem/progenitor cells stability program-development, current status and recommendations: A brief report from the AABB-ISCT joint working group cellular therapy product stability project team.

BACKGROUND: The AABB-ISCT Joint Working Group Stability Project Team (SPT) was assigned to roadmap a path toward standardization of cryopreserved hematopoietic stem/progenitor cell (HSPC) stability programs. HSPC stability encompasses a broad scope of conditions including non-frozen ("fresh") and cryopreserved cell products, and varying methods for storage, thaw, and administration. This report assessed current practices and focused solely on cryopreserved HSPC cell therapy products to establish preliminary recommendations for a stability program roadmap. METHODS: A survey was prepared by the SPT and distributed to ISCT and AABB members. Survey results were summarized and recommendations were outlined based on the responses from the survey. This report highlights current practices for cryopreserved HSPC stability programs, including additional considerations and recommendations. RESULTS AND DISCUSSION: Eighty-two (82) centers worldwide participated in the survey. Survey results indicate variability across programs. HSPC stability depends on multiple factors within the processing facility (e.g., cryopreservation techniques, reagents used, and storage temperature) and independent variables (e.g., donor-related factors and starting material variability). While retention of hematopoietic engraftment potential is the primary goal for cryopreserved HSPC stability, engraftment results should not be used as the sole metric for stability programs. Based on the survey results, the SPT provides recommendations for consideration. CONCLUSIONS: The SPT recommendations for best practices are not intended to replace existing standards. The survey results emphasize the need for the community to optimize best practices and consider initiating collaborative projects to improve the standardization of cryopreserved HSPC stability programs for cell therapy products.

Therapeutic plasma exchange practices in immune thrombocytopenia related hospitalizations: Results from a nationally representative sample.

Per the American Society for Apheresis, therapeutic plasma exchange (TPE) is a Category III indication in the management of immune thrombocytopenia (ITP). This nationally representative study evaluates TPE utilization in hospitalized adults with a primary admission diagnosis of ITP. Hospitalizations with ITP as the primary admitting diagnosis were analyzed from the 2010 to 2014 National Inpatient Sample, the largest all-payer inpatient database in the United States. Univariate and multivariable logistic regressions were used to determine clinical outcomes in ITP patients undergoing TPE. Sampling weights were applied to generate nationally representative estimates. From 2010 to 2014, there were a total of 56,149 admissions with a primary admitting diagnosis of ITP, of which 0.66% admissions (n = 372) also coded TPE. Most subjects undergoing TPE were the highest disease severity class: major (34.6%) and extreme severity (31.0%), by all-patients refined diagnoses-related groups severity of illness subclass. After multivariable analysis, underlying severity of illness remained the most significant predictor of TPE (P < .001). ITP admissions with TPE had a high rate of comorbidities (50%) and significantly longer mean length of hospital stay than those without (P < .001). TPE was reported in ~0.6% of hospitalizations with ITP as the primary diagnosis in this nationally representative sample from 2010 to 2014. TPE was performed in patients with the highest severity of underlying illness, and higher rates of comorbidities.

Bilateral aplasia of the anterior cerebral artery in the presence of its vascular source: a case report.

PURPOSE: Our goal was to investigate the cases of bilateral aplasia of the anterior cerebral artery (ACA). METHODS: The macro- and microdissection of the target human brain arteries of 388 cadaveric cases was applied under the magnifying glass. Each case was photographed and diagrammatically represented in the workbook. The length and the outer diameter of the corresponding arteries on the photos were measured using a computer software program. RESULTS: There was only one case (1/388 or 0.25%) of bilateral ACA aplasia that belonged to a male adult cadaver. Except for the variations of the posterior communicating artery on one side and the basilar artery, the instance of cerebral pathology was not recorded in this case. We compared the recent case with available literature cases. CONCLUSION: Summarizing small number of literature cases, the recent case of bilateral ACA aplasia as the fifth case discovered so far, represents a true morphological rarity.

Routine Laboratory Blood Tests Predict SARS-CoV-2 Infection Using Machine Learning.

BACKGROUND: Accurate diagnostic strategies to identify SARS-CoV-2 positive individuals rapidly for management of patient care and protection of health care personnel are urgently needed. The predominant diagnostic test is viral RNA detection by RT-PCR from nasopharyngeal swabs specimens, however the results are not promptly obtainable in all patient care locations. Routine laboratory testing, in contrast, is readily available with a turn-around time (TAT) usually within 1-2 hours. METHOD: We developed a machine learning model incorporating patient demographic features (age, sex, race) with 27 routine laboratory tests to predict an individual's SARS-CoV-2 infection status. Laboratory testing results obtained within 2 days before the release of SARS-CoV-2 RT-PCR result were used to train a gradient boosting decision tree (GBDT) model from 3,356 SARS-CoV-2 RT-PCR tested patients (1,402 positive and 1,954 negative) evaluated at a metropolitan hospital. RESULTS: The model achieved an area under the receiver operating characteristic curve (AUC) of 0.854 (95% CI: 0.829-0.878). Application of this model to an independent patient dataset from a separate hospital resulted in a comparable AUC (0.838), validating the generalization of its use. Moreover, our model predicted initial SARS-CoV-2 RT-PCR positivity in 66% individuals whose RT-PCR result changed from negative to positive within 2 days. CONCLUSION: This model employing routine laboratory test results offers opportunities for early and rapid identification of high-risk SARS-CoV-2 infected patients before their RT-PCR results are available. It may play an important role in assisting the identification of SARS-CoV-2 infected patients in areas where RT-PCR testing is not accessible due to financial or supply constraints.

Thawed solvent/detergent-treated plasma demonstrates comparable clinical efficacy to thawed plasma.

BACKGROUND: Thawed Plasma (TP), plasma thawed and refrigerated for up to 5 days, is a commonly transfused plasma product. This pilot study was conducted to determine whether Thawed Solvent/Detergent-treated Plasma stored refrigerated for up to 5-days post-thaw (T-S/D) was as efficacious as TP. STUDY DESIGN AND METHODS: This single institution retrospective cohort analysis evaluated the efficacy of T-S/D in reversing coagulopathies in comparison to TP. Utilizing the institution's electronic medical records, transfusion data were collected in adult patients who received either TP or T-S/D. The primary outcome was the incidence of subsequent transfusions within 24 hours after first dose of either type of plasma. Secondary outcomes included the number of blood products transfused within 24 hours of first-dose plasma, correction of pre-transfusion coagulation laboratory values, volume transfused, and clinical outcomes. RESULTS: TP was received by 301 patients and 137 received T-S/D during the first 32 months post-implementation of T-S/D. There was no difference in incidence of subsequent transfusions or number of blood products given. The median pre-INR of both the TP and T-S/D cohorts was 1.9, with a similar decrease in INR of 0.2 and 0.3 (p = 0.36), respectively, post plasma transfusion. There was no difference in correction of PT/aPTT, mortality, transfusion reactions, readmission rates, length of stay, or inpatient deep venous thrombosis. The median volume of T-S/D plasma transfused for the first dose was 126 mL less than TP (p = .0001). CONCLUSION: T-S/D was as efficacious as TP for the treatment of coagulopathies and the reversal of coagulation laboratory values.

Detection and Genetic Characterization of Community-Based SARS-CoV-2 Infections - New York City, March 2020.

To limit introduction of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), the United States restricted travel from China on February 2, 2020, and from Europe on March 13. To determine whether local transmission of SARS-CoV-2 could be detected, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) conducted deidentified sentinel surveillance at six NYC hospital emergency departments (EDs) during March 1-20. On March 8, while testing availability for SARS-CoV-2 was still limited, DOHMH announced sustained community transmission of SARS-CoV-2 (1). At this time, twenty-six NYC residents had confirmed COVID-19, and ED visits for influenza-like illness* increased, despite decreased influenza virus circulation.† The following week, on March 15, when only seven of the 56 (13%) patients with known exposure histories had exposure outside of NYC, the level of community SARS-CoV-2 transmission status was elevated from sustained community transmission to widespread community transmission (2). Through sentinel surveillance during March 1-20, DOHMH collected 544 specimens from patients with influenza-like symptoms (ILS)§ who had negative test results for influenza and, in some instances, other respiratory pathogens.¶ All 544 specimens were tested for SARS-CoV-2 at CDC; 36 (6.6%) tested positive. Using genetic sequencing, CDC determined that the sequences of most SARS-CoV-2-positive specimens resembled those circulating in Europe, suggesting probable introductions of SARS-CoV-2 from Europe, from other U.S. locations, and local introductions from within New York. These findings demonstrate that partnering with health care facilities and developing the systems needed for rapid implementation of sentinel surveillance, coupled with capacity for genetic sequencing before an outbreak, can help inform timely containment and mitigation strategies.

Red blood cells donated by smokers: A pilot investigation of recipient transfusion outcomes.

BACKGROUND: Current regulations do not require blood collection facilities to ask donors about cigarette smoking, and the prevalence of nicotine and its metabolites in blood products is not well established. Although smokers have higher hemoglobin (Hb) levels, smoking may adversely affect the quality of donated red blood cells through higher carboxyhemoglobin (COHb) content and premature hemolysis. STUDY DESIGN AND METHODS: Red blood cell (RBC) unit segments from 100 unique donors were tested for nicotine and its metabolite cotinine by mass spectrometry and for COHb spectrophotometrically. Outcomes were evaluated retrospectively in adult non-bleeding patients receiving single RBC units. RESULTS: Thirteen of 100 RBC segments (13%) were positive for cotinine at levels consistent with current smoking (> 10 ng/mL). The cotinine positive RBCs showed significantly greater COHb content compared to cotinine negative units (median 3.0% vs. 0.8%, p = 0.007). For patients transfused cotinine-positive units, there was no significant change in their vital signs following transfusion and no transfusion reactions were observed. However, patients transfused cotinine-positive units showed significantly reduced hematocrit and hemoglobin increments (median +1.2% and +0.4 g/dL) following transfusion compared to patients receiving cotinine negative units (median +3.6% and +1.4 g/dL) (p = 0.014). CONCLUSION: Thirteen percent of RBC units tested positive for cotinine at levels consistent with active smoking, accordant with the estimated national smoking rate of 15.5%. Cotinine-positive RBC units had greater COHb content and showed reduced hematocrit and hemoglobin increments following transfusion. These preliminary results should be validated in a larger cohort.

The impact of Daratumumab on transfusion service costs.

BACKGROUND: Daratumumab (DARA) is a human IgG1κ monoclonal antibody directed against CD38, approved for the treatment of multiple myeloma. As CD38 is expressed on RBCs, DARA can interfere with pretransfusion testing. DARA interference can be negated by denaturation of CD38 on RBCs with dithiothreitol (DTT) reagents. Because of this interference in pretransfusion testing, our hospital implemented a notification and testing/transfusion algorithm (NATTA) for pretransfusion testing and RBC product provision for DARA patients. This standardized approach combines DTT-based testing with selective genotyping and the provision of phenotypically similar RBCs for patients with clinically significant antibodies. STUDY DESIGN AND METHODS: We evaluated pretransfusion test results and transfusion requirements for 91 DARA patients in an academic medical center over 1 year to determine the incremental cost of pretransfusion testing and RBC selection. The actual costs for the NATTA approach were compared to a theoretical approach using universal genotyping with a provision of phenotypically similar RBC transfusions. RESULTS: The annual cost of testing related to DARA after NATTA implementation was $535.76 per patient. The simulated annual cost for the alternative genotyping with provision of phenotypically similar RBC transfusions approach was $934.83 per patient. CONCLUSION: In our entire cohort of DARA patients, a DTT-based testing algorithm with selective genotyping and provision of phenotypically similar RBCs only for patients with clinically significant antibodies was less expensive than a simulated model of universal genotyping and provision of phenotypically similar RBCs.

Platelet transfusion practices in immune thrombocytopenia related hospitalizations.

BACKGROUND: The role of platelet transfusions in management of Immune Thrombocytopenia (ITP) remains controversial. Current guidelines recommend that platelet transfusions in ITP be reserved for catastrophic hemorrhage or invasive surgical procedures. This study assesses the nationwide platelet transfusion practices in hospitalized children and adults with ITP. STUDY DESIGN AND METHODS: We studied hospitalizations with ITP as the primary admitting diagnosis from 2010-2014 in National Inpatient Sample (NIS), the largest all-payer inpatient database. Univariate and multivariable logistic regression analyses were used to determine factors predicting platelet transfusions. Sampling weights were applied to generate nationally representative estimates. Propensity score matching was used to perform sensitivity analyses. RESULTS: From 2010 to 2014, there were 78,376 admissions with ITP as the primary admission diagnosis (mean ± SD age: 45 ± 27 years; females 56%, children [age < 18 years] 22%) and 282,285 with ITP as one of all the admission diagnoses. Overall, 27% admissions with ITP as primary (children 4%) and 15% admissions with ITP as one of all the diagnoses documented at least one platelet transfusion. On multivariable adjustment the following factors were associated with worsening disease severity and a higher odds of platelet transfusion, adult age (adjOR = 9.03, 95% CI = 7.40-11.02), male gender (adjOR = 1.21, 95% CI = 1.11-1.31), bleeding occurrence (intracranial/gastrointestinal/genitourinary/epistaxis) (adjOR = 1.78, 95% CI = 1.61-1.96), admission to rural non-teaching hospital (adjOR = 1.85, 95% CI = 1.52-2.22), and small bed-size hospital (adjOR = 1.23, 95% CI = 1.05-1.45). Of admissions reporting platelet transfusions, only 26% reported a bleeding complication, and 11% had a major operating-room surgery/procedure. Overall, 65% of transfused patients had neither bleeding nor a major operative procedure during the hospitalization. Admissions with platelet transfusions had a significantly longer mean length of hospitalization 2.2 days (95% CI = 1.96-2.41, p < 0.001), and accrued higher mean total hospital charges; $31,150 USD (95% CI = 27,644-34,656, p < 0.001). However, platelet transfusions were not associated with in-hospital mortality (adjOR = 1.02, 95% CI = 0.73-1.45, p = 0.892). CONCLUSION: Platelets are administered to a small fraction of the hospitalized ITP patients. In a majority of these cases however, platelet usage does not appear to be concordant with the current guidelines or associated with improvement in clinical outcomes.

Validating and implementing the use of an infusion pump for the administration of thawed hematopoietic progenitor cells-a single-institution experience.

BACKGROUND: Direct thaw and administration of previously cryopreserved peripheral blood stem cell products is a commonly used practice and should be performed rapidly to reduce cellular damage caused by dimethyl sulfoxide exposure. Cells are typically thawed at the bedside and infused by gravity through a high-flow-rate central venous catheter. An existing nontunneled catheter is occasionally used instead and often results in a slower infusion rate. To ensure expedient and consistent infusions, we validated and implemented the use of an infusion pump for thawed peripheral blood stem cells. STUDY DESIGN AND METHODS: Validation was performed in two phases: in vitro simulation and in vivo clinical assessment. Total nucleated cell recovery and viability plus progenitor cell viability and potency were compared in vitro between two cryopreserved peripheral blood stem cell units that were either passed through a preset infusion pump or drained by gravity. The infusion rate, adverse events, and engraftment times were retrospectively compared between patients who received infusions by infusion pump (n = 35) and by gravity (n = 38). RESULTS: No significant differences were observed in vitro between the infusion methods for all measured variables. Overall infusion rates were similar in vivo for both groups but were significantly lower for patients who had nontunneled catheters that delivered the infusion by gravity. The time to neutrophil and platelet engraftment was similar for both groups. CONCLUSION: This is the first study to assess the use of an infusion pump for stem cell transplant. The use of an infusion pump for peripheral blood stem cell infusion is safe, provides a reliable and consistent infusion method, and can mitigate the effect of the type of venous access line used.

Congenital absence of the bilateral internal carotid artery: a review of the associated (ab)normalities from a newborn status to the eighth decade of life.

PURPOSE: Due to the fact that the internal carotid artery (ICA) is responsible for nourishing two thirds of the brain volume, our aim was to inspect the morphofunctional consequences of the bilateral lack of this artery. METHODS: In order to examine this condition, we referred to both the library archive of our Faculty of Medicine and electronic databases of anatomical and clinical reports that included the following keywords: "absence," "aplasia," or "agenesis" in combination with "internal carotid artery," "common carotid artery," or only "carotid artery." RESULT: We found 60 recorded cases of the bilateral ICA absence in the subjects of newborn status to the eighth decade of life, which had been discovered in 20 countries. The following ten parameters were described: the embryological base, terminology, history, incidence, general data, differential diagnosis, collateral circulation, the associated vascular aplasia and/or other variants, pathophysiology, and the importance in praxis. CONCLUSION: This review noted all the cases of the bilateral ICA aplasia published for the past 104 years. Although there were 11.6% of cases of the associated cerebral aneurysms and 1-4 cases of 16 other diseases, approximately one quarter of the cases was without any pathology.

Variation of some arteries of the vertebrobasilar system: case report.

A specificity of the vertebrobasilar system (VBS) is a convergent junction of paired vertebral arteries (VAs) in the basilar artery (BA) usually at the level of bulbopontine sulcus on the ventral side of the rhombencephalon. We revealed multiple VBS variations (a high junction of both VAs, absence of posterior inferior cerebellar arteries, short and ectatic BA, hypoplasia and initial duplication of the left anterior inferior cerebellar artery, and bilateral common trunks of the posterior cerebral and superior cerebellar arteries) in a 52-year-old male that routinely autopsied at the Institute of Forensic Medicine. Embryological base and morphological status of presented VBS variations is highlighted according to the literature data. Summarized variations of VBS can be classified as morphological rarity, and may be of clinical importance during angiographic studies or neurosurgical procedures.

Cryoprecipitate indications and patterns of use in the pediatric intensive care unit: inappropriate transfusions and lack of standardization.

BACKGROUND: The dosage and indications for cryoprecipitate are not well studied for any patient population. Prior observational studies have suggested that 24% to 62% of cryoprecipitate transfusions are inappropriate, and there is limited information on patterns of cryoprecipitate use in children. The purpose of this retrospective study was to explore the indications and appropriateness of the use of cryoprecipitate in critically ill children. STUDY DESIGN AND METHODS: We retrospectively reviewed the electronic medical records for cryoprecipitate ordering and utilization in the pediatric intensive care unit at a large tertiary care center during a 4.5-year period. RESULTS: For the 44 patients receiving cryoprecipitate, the only indication was for fibrinogen replacement and the most common clinical scenarios were recent cardiac surgery (39%) and disseminated intravascular coagulation in the setting of sepsis (32%). Cryoprecipitate was often transfused empirically at higher-than-recommended doses without a known pretransfusion fibrinogen level, and the majority (61%) of cryoprecipitate transfusions were deemed inappropriate according to our institutional guidelines. The indications selected for cryoprecipitate by providers during physician order entry matched the clinical scenario, assessed by chart and laboratory data review, in only 18% of patients. There was no significant difference in red blood cell usage in the 6-hour windows before and after cryoprecipitate transfusion. CONCLUSION: Our study demonstrates a lack of standardization for the use of cryoprecipitate in critically ill children, including many inappropriate transfusions at higher-than-recommended dosing. Prospective randomized clinical trials are warranted to help determine appropriate indications and efficacious cryoprecipitate dosing in the pediatric population.

A novel inflammatory role for platelets in sickle cell disease.

The severe pain, ischemia and organ damage that characterizes sickle cell disease (SCD) is caused by vaso-occlusion, which is the blockage of blood vessels by heterotypic aggregates of sickled erythrocytes and other cells. Vaso-occlusion is also a vasculopathy involving endothelial cell dysfunction, leukocyte activation, platelet activation and chronic inflammation resulting in the multiple adhesive interactions between cellular elements. Since platelets mediate inflammation as well as thrombosis via release of pro- and anti-inflammatory molecules, we hypothesized that platelets may play an active inflammatory role in SCD by secreting increased amounts of cytokines. Since platelets have been shown to contain mRNA and actively produce proteins, we also hypothesized that SCD platelets may contain increased cytokine mRNA. In this cross-sectional study, we sought to compare both the quantity of cytokines secreted and the cytokine mRNA content, between SCD and control platelets. We measured the secretion of Th1, Th2, and Th17-related cytokines from platelets in a cohort of SCD patients. We simultaneously measured platelet mRNA levels of those cytokines. Platelets from SCD patients secreted increased quantities of IL-1ß, sCD40L, and IL-6 compared to controls. Secretion was increased in patients with alloantibodies. Additionally, mRNA of those cytokines was increased in SCD platelets. Platelets from sickle cell patients secrete increased amounts of inflammatory cytokines, and contain increased cytokine mRNA. These findings suggest a novel immunological role for platelets in SCD vasculopathy, in addition to their thrombotic role, and strengthen the rationale for the use of anti-platelet therapy in SCD.