Heritability of Protein and Metabolite Biomarkers Associated with COVID-19 Severity: A Metabolomics and Proteomics Analysis.

Objectives: Prior studies have characterized protein and metabolite changes associated with SARS-CoV-2 infection; we hypothesized that these biomarkers may be part of heritable metabolic pathways in erythrocytes.

Methods: Using a twin study of erythrocyte protein and metabolite levels, we describe the heritability of, and correlations among, previously identified biomarkers that correlate with COVID-19 severity. We used gene ontology and pathway enrichment analysis tools to identify pathways and biological processes enriched among these biomarkers.

Red blood cells contain enzymatically active GPx4 whose abundance anticorrelates with hemolysis during blood bank storage.

The antioxidant function of the phospholipid hydroperoxide glutathione peroxidase (GPx4) is vital for the homeostasis of many cell types, from neoplastic cells to normal erythroid precursors. However, some functional proteins in erythroid precursors are lost during the development of red blood cells (RBCs); whether GPx4 is maintained as an active enzyme in mature RBCs has remained unclear. Our meta-analyses of existing RBC proteomics and metabolomics studies revealed the abundance of GPx4 to be correlated with lipid-anchored proteins.

Pooled platelet concentrates provide a small benefit over single-donor platelets for patients with platelet refractoriness of any etiology.

Background: At our institution, patients with platelet refractoriness (of any etiology) are sometimes switched from apheresis platelets to pooled platelets before human leukocyte antigen (HLA)-matched units become available.

Study Design And Methods: Seven patients were analyzed. Platelet counts were available from 57 single-unit transfusions (26 pooled, 31 apheresis).

β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer's disease pathology.

Alzheimer's disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism.

Retrospective cohort studies of repeat donors reveal donor-dependent variability in the recovery of transfused platelets.

Background: The in vivo recovery of transfused platelets is variable and often unpredictable. Although many recipient-dependent factors are well described, donor-dependent variables remain poorly understood.

Study Design And Methods: To explore donor-dependent variables we conducted 2 retrospective studies of platelet transfusion outcomes in repeat donors.

Piloting and implementation of quality assessment and quality control procedures in RBC-Omics: a large multi-center study of red blood cell hemolysis during storage.

Background: The major aims of the RBC-Omics study were to evaluate the genomic and metabolomic determinants of spontaneous and stress-induced hemolysis during RBC storage. This study was unique in scale and design to allow evaluation of RBC donations from a sufficient number of donors across the spectrum of race, ethnicity, sex, and donation intensity. Study procedures were carefully piloted, optimized, and controlled to enable high-quality data collection.

Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016.

The US Food and Drug Administration (FDA) held a workshop on red blood cell (RBC) product regulatory science on October 6 and 7, 2016, at the Natcher Conference Center on the National Institutes of Health (NIH) Campus in Bethesda, Maryland. The workshop was supported by the National Heart, Lung, and Blood Institute, NIH; the Department of Defense; the Office of the Assistant Secretary for Health, Department of Health and Human Services; and the Center for Biologics Evaluation and Research, FDA. The workshop reviewed the status and scientific basis of the current regulatory framework and the available scientific tools to expand it to evaluate innovative and future RBC transfusion products.

Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells.

Each year over 90 million units of blood are transfused worldwide. Our dependence on this blood supply mandates optimized blood management and storage. During storage, red blood cells undergo degenerative processes resulting in altered metabolic characteristics which may make blood less viable for transfusion.

The heritability of hemolysis in stored human red blood cells.

Background: The transfusion of red blood cells (RBCs) with maximum therapeutic efficacy is a major goal in transfusion medicine. One of the criteria used in determining stored RBC quality is end-of-storage hemolysis. Between donors, a wide range of hemolysis is observed under identical storage conditions.

Heritability of glutathione and related metabolites in stored red blood cells.

Red blood cells (RBCs) collected for transfusion deteriorate during storage. This deterioration is termed the "RBC storage lesion." There is increasing concern over the safety, therapeutic efficacy, and toxicity of transfusing longer-stored units of blood.

The heritability of metabolite concentrations in stored human red blood cells.

Background: The degeneration of red blood cells (RBCs) during storage is a major issue in transfusion medicine. Family studies in the 1960s established the heritability of the RBC storage lesion based on poststorage adenosine triphosphate (ATP) concentrations. However, this critical discovery has not been further explored.

The concentration of glutathione in human erythrocytes is a heritable trait.

Glutathione (GSH) is a ubiquitous, redox-active, small molecule that is critical to cellular and organism health. In red blood cells (RBCs), the influence of the environment (e.g.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP.

Human thrombomodulin knock-in mice reveal differential effects of human thrombomodulin on thrombosis and atherosclerosis.

Objective: We sought to develop a murine model to examine the antithrombotic and antiinflammatory functions of human thrombomodulin in vivo.

Methods And Results: Knock-in mice that express human thrombomodulin from the murine thrombomodulin gene locus were generated. Compared with wild-type mice, human thrombomodulin knock-in mice exhibited decreased protein C activation in the aorta (P<0.

An analysis of mobile whole blood collection labor efficiency.

Background: Labor efficiency is desirable in mobile blood collection. There are few published data on labor efficiency. The variability in the labor efficiency of mobile whole blood collections was analyzed.

Hematocrit and C-reactive protein predict treatment response times in ADAMTS13-deficient thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) syndromes are a heterogeneous group of microvascular syndromes that are typically treated with plasma exchange and other adjunctive therapies. Important pathogenic factors, such as ADAMTS13 deficiency, define distinct subsets of TMA. New treatments for TMA are being explored that are hypothesized to bring about remission more quickly.

Successful use of maternal blood in the management of severe hemolytic disease of the fetus and newborn due to anti-Kp(b).

Background: The incidence of hemolytic disease of the fetus and newborn (HDFN) has decreased since the introduction of Rh immunoglobulin prophylaxis in Rh(D)-negative pregnant women. Thus, the relative incidence of rare alloantibody-related HDFN has increased. The lack of available maternally matched red blood cells for transfusion in these cases may create management difficulties.

Severe autoimmune neutropenia associated with acute autoimmune hepatitis.

A 49-year-old previously healthy female presented with acute hepatitis and severe neutropenia. A diagnosis of type 1 autoimmune hepatitis was made based on the histological appearance of a liver core biopsy, positive anti-smooth muscle antibodies, and positive anti-neutrophil cytoplasmic antibody (atypical ANCA). Hemogram revealed mild leukopenia with severe neutropenia (absolute neutrophil count 256/mm(3)), normal hemoglobin and mild thrombocytopenia (115000/mm(3)).

Elevated procalcitonin and C-reactive protein as potential biomarkers of sepsis in a subpopulation of thrombotic microangiopathy patients.

Thrombotic microangiopathy (TMA) comprises a group of microvascular thrombosis syndromes associated with multiple pathogenic factors. Deficient activity of ADAMTS13 is a pathogenic factor in a subset of TMA patients that provides a strong rationale for plasma exchange treatment. However, the subset of TMA patients with normal ADAMTS13 activity remains a heterogeneous group of patients in which the appropriate treatment is not well understood.

Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site.

The function of von Willebrand factor (VWF) is regulated by proteolysis, which limits its multimeric size and ability to tether platelets. The importance of ADAMTS13 metalloprotease in VWF regulation is demonstrated by the association between severe deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura (TTP). However, ADAMTS13 activity levels do not always correlate with the clinical course of TTP, suggesting that other proteases could be important in regulating VWF.

Value of ADAMTS13 activity and inhibitor in the postmortem diagnosis of thrombotic thrombocytopenic purpura.

Background And Objectives: Thrombotic thrombocytopenic purpura (TTP) is a clinical diagnosis that can be difficult to establish in severely ill patients. We report a case of fulminant TTP in a woman who died before receiving plasma exchange. An autopsy plasma sample was analyzed for ADAMTS13 activity and inhibitor for correlation with the diagnosis of TTP.

Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008).

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP.

A comparative labor productivity analysis of blood collection centers.

Background: Blood center labor benchmarking data may be helpful to optimize staffing and to establish productivity targets. Data were gathered and labor productivity was analyzed among blood donor centers of different sizes collecting different product mixes.

Study Design And Methods: Blood collection volumes and blood center labor data were obtained from eight blood centers: six regional centers, one mobile collection operation, and our hospital-affiliated center.