P38 mitogen activated protein kinase inhibitor improves platelet in vitro parameters and in vivo survival in a SCID mouse model of transfusion for platelets stored at cold or temperature cycled conditions for 14 days.

Platelets for transfusion are stored at room temperature (20-24°C) up to 7 days but decline in biochemical and morphological parameters during storage and can support bacterial proliferation. This decline is reduced with p38MAPK inhibitor, VX-702. Storage of platelets in the cold (4-6°C) can reduce bacterial proliferation but platelets get activated and have reduced circulation when transfused.

Validation of a SCID mouse model for transfusion by concurrent comparison of circulation kinetics of human platelets, stored under various temperature conditions, between human volunteers and mice.

Background: Initial evaluation of new platelet (PLT) products for transfusion includes a clinical study to determine in vivo recovery and survival of autologous radiolabeled PLTs in healthy volunteers. These studies are expensive and do not always produce the desired results. A validated animal model of human PLTs in vivo survival and recovery used pre-clinically could reduce the risk of failing to advance product development.

Non-ionizing 405 nm Light as a Potential Bactericidal Technology for Platelet Safety: Evaluation of Bacterial Inactivation and Platelet Recovery in Severe Combined Immunodeficient Mice.

Bacterial contamination of stored platelets is a cause of transfusion-transmitted infection. Violet-blue 405 nm light has recently demonstrated efficacy in reducing the bacterial burden in blood plasma, and its operational benefits such as non-ionizing nature, penetrability, and non-requirement for photosensitizing agents, provide a unique opportunity to develop this treatment for treatment of stored platelets as a tool for bacterial reduction. Sealed bags of platelet concentrates, seeded with low-level contamination, were 405 nm light-treated (3-10 mWcm) up to 8 h.

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.

Temperature cycling during platelet cold storage improves in vivo recovery and survival in healthy volunteers.

Background: Room temperature (RT) storage of platelets (PLTs) can support bacterial proliferation in contaminated units, which can lead to transfusion-transmitted septic reactions. Cold temperature storage of PLTs could reduce bacterial proliferation but cold exposure produces activation-like changes in PLTs and leads to their rapid clearance from circulation. Cold-induced changes are reversible by warming and periodic rewarming during cold storage (temperature cycling [TC]) has been proposed to alleviate cold-induced reduction in PLT circulation.

Evaluation of Stem Cell-Derived Red Blood Cells as a Transfusion Product Using a Novel Animal Model.

Reliance on volunteer blood donors can lead to transfusion product shortages, and current liquid storage of red blood cells (RBCs) is associated with biochemical changes over time, known as 'the storage lesion'. Thus, there is a need for alternative sources of transfusable RBCs to supplement conventional blood donations. Extracorporeal production of stem cell-derived RBCs (stemRBCs) is a potential and yet untapped source of fresh, transfusable RBCs.

Automated cold temperature cycling improves in vitro platelet properties and in vivo recovery in a mouse model compared to continuous cold storage.

Background: Platelets (PLTs) stored at cold temperatures (CTs) for prolonged time have dramatically reduced bacterial growth but poor survival when infused. A previous study demonstrated that human PLTs stored with manual cycling between 4 °C (12 hr) and 37 °C (30 min) and infused into severe combined immunodeficient (SCID) mice had survivals similar to or greater than those stored at room temperature (RT). In this study, the in vitro and in vivo properties of PLTs stored in an automated incubator programmed to cycle between 5 °C (11 hr) and 37 °C (1 hr) were evaluated.

Expression of the cellular prion protein affects posttransfusion recovery and survival of red blood cells in mice.

Background: Cellular prion protein (PrP(C) ) is expressed on various cell types including red blood cells (RBCs). The PrP(C) plays a key role in the pathogenesis of prion diseases, but its physiologic function remains unclear. PrP(C) is expressed on CD34+ hematopoietic stem cells and its expression is regulated during blood cell differentiation including the erythroid line.

Reversal of hemochromatosis by apotransferrin in non-transfused and transfused Hbbth3/+ (heterozygous B1/B2 globin gene deletion) mice.

Intermediate beta-thalassemia has a broad spectrum of sequelae and affected subjects may require occasional blood transfusions over their lifetime to correct anemia. Iron overload in intermediate beta-thalassemia results from a paradoxical intestinal absorption, iron release from macrophages and hepatocytes, and sporadic transfusions. Pathological iron accumulation in parenchyma is caused by chronic exposure to non-transferrin bound iron in plasma.

Preclinical safety evaluation of human platelets treated with antimicrobial peptides in severe combined immunodeficient mice.

Background: Bacterial sepsis is a complication attributed to room temperature (RT)-stored platelets (PLTs) in transfusion medicine. Antimicrobial peptides (AMPs) are emerging as new therapeutic agents against microbes. We had previously demonstrated bactericidal activity of select synthetic AMPs against six types of bacteria in stored PLTs.

Host platelets and, in part, neutrophils mediate lung accumulation of transfused UVB-irradiated human platelets in a mouse model of acute lung injury.

We previously reported that ultraviolet light B (UVB)-treated human platelets (hPLTs) can cause acute lung injury (ALI) in a two-event SCID mouse model in which the predisposing event was Lipopolysaccharide (LPS) injection and the second event was infusion of UVB-treated hPLTs. To delineate contributions of host mouse platelets (mPLTs) and neutrophils in the pathogenesis of ALI in this mouse model, we depleted mPLTs or neutrophils and measured hPLT accumulation in the lung. We also assessed lung injury by protein content in bronchoalveolar lavage fluid (BALF).

Temperature cycling improves in vivo recovery of cold-stored human platelets in a mouse model of transfusion.

Background: Platelet (PLT) storage at room temperature (RT) is limited to 5 days to prevent growth of bacteria, if present, to high levels. Storage in cold temperatures would reduce bacterial proliferation, but cold-exposed PLTs are rapidly cleared from circulation by the hepatic Ashwell-Morell (AM) receptor, which recognizes PLT surface carbohydrates terminated by β-galactose. We cycled storage temperature between 4 and 37°C to preserve PLT function and reduce bacterial growth.

Activation of platelet protein kinase C by ultraviolet light B mediates platelet transfusion-related acute lung injury in a two-event animal model.

Background: We recently reported that infusion of ultraviolet light B (UVB)-exposed human platelets (HPs) can be the second event that mediates acute lung injury (ALI) in a two-event mouse model of transfusion-related acute lung injury (mTRALI). We have now identified changes in HPs induced by UVB light and responses of the recipient animal that mediate the mTRALI.

Study Design And Methods: Effects of UVB on HPs were monitored by flow cytometry and aggregation.

Ultraviolet B light-exposed human platelets mediate acute lung injury in a two-event mouse model of transfusion.

Background: Ultraviolet B (UVB) light has been used alone on platelet (PLT) transfusion products to prevent alloimmunization or with chemical sensitizers to reduce pathogens. Such processing can damage PLTs and potentiate their storage lesion. Transfusion-related acute lung injury (ALI) has occurred in patients whose underlying condition led to an inflamed endothelium and who were transfused with products that contained either HLA or HNA antibodies or biologic modifiers such as lipids or antigens from stored cells.

Rejuvenation improves roller pump-induced physical stress resistance of fresh and stored red blood cells.

Background: Retrospective studies on transfusion recipients suggested that transfusion of older red blood cells (RBCs) was associated with higher morbidity. Similar studies were also done on cardiac surgery patients who were placed on cardiac bypass pumps. It is possible that stored RBCs are more fragile and could be more easily damaged by these pumps, thus leading to additional morbidity.

Blood aging, safety, and transfusion: capturing the "radical" menace.

Throughout their life span, circulating red blood cells (RBCs) transport oxygen (O(2)) primarily from the lungs to tissues and return with carbon dioxide (CO(2)) from respiring tissues for final elimination by lungs. This simplistic view of RBCs as O(2) transporter has changed in recent years as other gases, for example, nitric oxide (NO), and small molecules, such as adenosine triphosphate (ATP), have been shown to either be produced and/or carried by RBCs to perform other signaling and O(2) sensing functions. In spite of the numerous biochemical and metabolic changes occurring within RBCs during storage, prior to, and after transfusion, perturbations of RBC membrane are likely to affect blood flow in the microcirculation.

Current and future cellular transfusion products.

Novel red blood cell and platelet transfusion products may be synthetic or may result from modifications to approved collection, processing, and storage procedures for existing cellular products. They must be reviewed and evaluated by the Food and Drug Administration before being legally marketed in the United States to ensure they are safe, pure, and potent. This article reviews the literature and discusses the current and future state of cellular transfusion products.

Carbon nanotubes activate blood platelets by inducing extracellular Ca2+ influx sensitive to calcium entry inhibitors.

To elucidate a mechanism of prothrombotic effects of carbon nanotubes (CNTs), we report here that multiwalled CNTs activate blood platelets by inducing extracellular Ca(2+) influx that could be inhibited by calcium channel blockers SKF 96365 and 2-APB. We also demonstrate platelet aggregating activity of different single-walled and multiwalled CNTs. In addition, we show that CNT-induced platelet activation is associated with a marked release of platelet membrane microparticles positive for the granular secretion markers CD62P and CD63.

Flow cytometric analysis of cell membrane microparticles.

Cell membrane microparticles (MPs) are phospholipid microvesicles shed from the plasma membrane of most eukaryotic cells undergoing activation or apoptosis. The presence of MPs is common in healthy individuals. However, an increase in their release is a controlled event and is considered a hallmark of cellular alteration.

Apoptotic abnormalities in differential gene expression in peripheral blood mononuclear cells from children with Fabry disease.

Aim: This study was designed to examine the effect of enzyme replacement therapy (ERT) on differential gene expression in peripheral blood mononuclear cells (PBMCs) of children with Fabry disease who had not previously been exposed to ERT.

Methods: Thirteen children with Fabry disease (age range, 6.5-17.

Adverse effects of fullerenes on endothelial cells: fullerenol C60(OH)24 induced tissue factor and ICAM-I membrane expression and apoptosis in vitro.

We studied the effects of a C60 water suspension at 4 microg/mL (nC60) and the water soluble fullerenol C60(OH)24 at final concentrations of 1-100 microg/mL on human umbilical vein endothelial cells (HUVECs) in culture. We found that a 24 hr treatment of HUVECs with C60(OH)24 at 100 microg/mL significantly increased cell surface expression of ICAM-1(CD54) (67 +/- 4% CD54+ cells vs. 19 +/- 2 % CD540 cells in control; p < 0.

Reduced erythroid cell and erythropoietin production in response to acute anemia in prion protein-deficient (Prnp-/-) mice.

Cellular prion protein (PrPc) participates in the pathogenesis of prion diseases but its normal function remains unclear. PrPc is expressed on hematopoietic cells, including erythroid precursors. We investigated the role of PrPc in erythropoiesis in vivo with phenylhydrazine-induced acute anemia.

In vivo recovery of human platelets in severe combined immunodeficient mice as a measure of platelet damage.

Background: Clinical performance of human platelet (PLT) products processed or stored under novel conditions is difficult to predict based on in vitro studies alone. Recovery and survival of radiolabeled PLTs in human subjects are used as surrogate markers for PLT efficacy in development of new products. Such experiments pose some risk to the participants, can be a financial burden on the sponsor, and may stifle innovation and development of new PLT products.

Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach.

Fabry disease is a disorder of alpha-D-galactosyl-containing glycolipids resulting from a deficiency of alpha-galactosidase A. Patients have a poorly understood vascular dysregulation. We hypothesized that disease-related perturbation by using enzyme replacement therapy in the murine model of Fabry disease would provide insight into abnormal biological processes in Fabry disease.