US20190388467A1 - Methods for managing adverse events in patient populations requiring transfusion - Google Patents

Methods for managing adverse events in patient populations requiring transfusion Download PDF

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US20190388467A1
US20190388467A1 US16/312,119 US201716312119A US2019388467A1 US 20190388467 A1 US20190388467 A1 US 20190388467A1 US 201716312119 A US201716312119 A US 201716312119A US 2019388467 A1 US2019388467 A1 US 2019388467A1
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blood
patient
oxygen
oxygen reduced
stored blood
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Angelo D'Alessandro
Rafael Cordero
Andrew Dunham
Philip Keegan
Tatsuro Yoshida
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Hemanext Inc
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New Health Sciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/38—Removing constituents from donor blood and storing or returning remainder to body, e.g. for transfusion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/02—Blood transfusion apparatus
    • A61M1/0272—Apparatus for treatment of blood or blood constituents prior to or for conservation, e.g. freezing, drying or centrifuging

Definitions

  • the present disclosure relates to improvements in the field of transfusion medicine.
  • DHTR delayed hemolytic transfusion reaction
  • SIRS systemic inflammatory response syndrome
  • TRALI transfusion related acute lung injury
  • TAM transfusion related immunomodulation
  • Pat. No. 6,162,396 to Bitensky et al. discloses anaerobic storage bags for blood storage that comprise an oxygen impermeable outer layer, a red blood cell (RBC) compatible inner layer that is permeable to oxygen, and having an oxygen scrubber placed between the inner and outer layers.
  • RBC red blood cell
  • Oxidative damage during storage has been implicated as a major contributor to packed red blood cell (pRBC) membrane damage, as suggested by the accumulation of markers of lipid peroxidation, such as isoprostane, and oxidized structural and functional proteins, such as band 3, glyceraldehyde 3-phosphate dehydrogenase and hemoglobins (see Wither et al., “Hemoglobin oxidation at functional amino acid residues during routine storage of red blood cells,” Transfusion , (56)2: 421-426, (2016) (“Wither 2016”); and Reisz 2016).
  • Increasing amounts of cytokines during storage duration can also play a role in storage lesion development with potential clinical implications for a negative transfusion outcome.
  • Certain patient populations are more susceptible to storage lesions than others. Without limiting patient populations, these patient population include massively or chronically-transfused recipients, such as trauma or cancer patients, or patients suffering from hemoglobinopathies (e.g., sickle cell disease). Among these more sensitive populations are, as non-limiting examples, trauma patients and cancer patients. Associated with the adverse clinical outcomes is the accumulation of biologic response modifiers (BRMs) that include cytokines that mediate inflammation, regulate cell growth, regulate angiogenesis and modulate t-helper cell function.
  • BRMs biologic response modifiers
  • interleukin 17 IL-17
  • eotaxin CCL11
  • basic FGF bFGF
  • macrophage inflammatory protein 1a MIP-1a
  • monocyte chemotactic protein 1 MCP-1
  • platelet-derived growth factor PDGF
  • tumor necrosis factor alpha TNF- ⁇
  • VEGF vascular endothelial growth factor
  • HETEs hydroxyeicosatetraenoic acid
  • thromboxanes See Behrens et al., “Accumulation of biologic response modifiers during red blood cell cold storage,” Transfusion 49(Suppl3):10A (2009) (hereby incorporated by reference in its entirety).
  • cytokines accumulate during blood storage and these accumulated cytokines can be associated with negative outcomes when given perioperatively to cancer patients. See Benson et al., “Accumulation of Pro-Cancer Cytokines in the Plasma Fraction of Stored Packed Red Cells,” J Gastrointest Surg. 16:460-468 (2012) (hereby incorporated by reference in its entirety).
  • D' Alessandro 2013 concluded that oxygen reduced storage elevated oxidative stress may impair the RBC antioxidant capacity by limiting glucose metabolism through the Pentose Phosphate Pathway, which in turn generates reducing equivalents (NADPH) necessary to modulate the redox poise (e.g. recycling of oxidized glutathione).
  • NADPH reducing equivalents
  • 13 C-glucose (position 1,2 and 3) is spiked at the beginning of the storage, providing a method to trace and compare the actual fluxes of glucose oxidation through glycolysis (which generates high energy phosphate compounds) and the pentose phosphate pathway (to fuel antioxidant cascades), as determined by calculating isotopologue ratios of lactate+2 and +3, as well as, the energy metabolism in both anaerobic and aerobically stored cells throughout the storage period.
  • PPP pentose phosphate pathway
  • EMP Embden-Meyerhof-Parnas Pathway
  • Lactate emerges through oxidative PPP (without back-reaction, gluconeogenesis) and will be lacking 13 C at position 1 (which is released in the form of CO2 when glucose is metabolized through the PPP), while lactate produced directly from glucose via EMP will have either all three carbons with 13 C or none at all.
  • flux through PPP can be estimated using a metabolic model. Since ribose-5-P enters Adenine nucleotide pool (AXP) pathway, we are able to deduce further insights into ATP degradation and re-synthesis. See Reisz 2016.
  • AXP Adenine nucleotide pool
  • Transfusion therapy ranges from the treatment of trauma and replacement of blood during surgery, to cancer therapies, and to treatments of genetic diseases like sickle cell anemia and thalassemia.
  • Transfusion therapy ranges from the treatment of trauma and replacement of blood during surgery, to cancer therapies, and to treatments of genetic diseases like sickle cell anemia and thalassemia.
  • a determination of blood groups and immunologic incompatibilities little progress has been made in understanding the changes underlying blood storage lesions or identifying patients at risk of complications from transfusion therapies. To date, recommendations for optimal methods and selections of patient populations has received little attention.
  • the present disclosure provides for, and includes, a method of reducing the risk of an inflammatory response in a patient and in need of a blood transfusion comprising providing oxygen reduced stored blood having reduced levels of at least one inflammatory factor when compared to non-oxygen reduced stored blood stored for an identical storage period wherein said patient has an increased risk of an inflammatory response.
  • the present disclosure provides for, and includes, a method for reducing oxidative stress in a human patient in need of a blood transfusion comprising providing oxygen reduced stored blood for transfusion into a human patient in need of a blood transfusion having an increased risk for transfusion mediated oxidative stress, wherein said oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has an increased risk of oxidative stress.
  • the present disclosure provides for, and includes, a method for reducing cardiac, renal and gastrointestinal ischemia reperfusion injury in a patient in need of a blood transfusion comprising providing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period for transfusion to a human patient in need of a blood transfusion and having an increased risk for cardiac, renal and gastrointestinal ischemia reperfusion injury.
  • the present disclosure provides for, and includes, a method for reducing the risk of an adverse event in a hemoglobinopathy patient in need of a blood transfusion comprising providing oxygen reduced stored blood for transfusion into a hemoglobinopathy patient in need of a blood transfusion, wherein the oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein the patient has an increased risk of oxidative stress.
  • the present disclosure provides for, and includes, a method for reducing delayed hemolytic transfusion reactions in a patient in need of a blood transfusion comprising providing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein the patient has an increased risk of a delayed hemolytic transfusion reaction.
  • FIGS. 1 to 20 present the results of studies of stored blood (in this aspect, packed red blood cells) having an initial oxygen saturation of 20% or less prior to being stored for a storage period (oxygen reduced stored blood) compared to conventionally stored blood (normoxic) and blood that has been fully oxygenated prior to storage (hyperoxygenated or hyperoxic) according to aspects of the present disclosure.
  • FIG. 1 is a graph presenting the percent SO 2 over 42 days of conventionally stored normoxic (solid line) and hyperoxic ( - - - - ) blood and anaerobically stored blood with an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 2 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of Leukotriene B4 of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 3 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of Thromboxane B2 of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial with an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIGS. 4A and 4B are graphs presenting the results of an experiment according to the present disclosure, comparing the levels of hydroxyeicosatetraenoic acid (HETE) of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 4A presents the levels of HETE in supernatant over a period of 42 days.
  • FIG. 4B presents the levels of HETE in oxygen reduced stored blood over a period of 42 days.
  • FIG. 5 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of NADPH of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 6 is a graph presenting the results of an experiment according to the present disclosure, comparing NADPH/NADP + of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 7 is a graph presenting the results of an experiment according to the present disclosure, comparing the total NADPH and NADP + reservoirs of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 8 is a graph presenting the results of an experiment according to the present disclosure, comparing the total NADP and NAD + reservoirs of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 9 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of methylenetetrahydrofolate of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 10 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of glutamate of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 11 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of reduced glutathione (GSH) of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • GSH reduced glutathione
  • FIG. 12 is a graph presenting the results of an experiment according to the present disclosure, comparing the GSH/GSSG ratio of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 13 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of cysteine of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 14 is a graph presenting the results of an experiment according to the present disclosure, comparing the levels of urate of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 15 is a graph presenting the results of an experiment according to the present disclosure, comparing the EMP flux of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 16 is a graph presenting the results of an experiment according to the present disclosure, comparing ATP synthesis in conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 17 is a graph presenting the results of an experiment according to the present disclosure, comparing Cys152 dioxidation of glyceraldehyde 3-phosphate dehydrogenase in conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial percent SO 2 of 5%.
  • FIGS. 18A and 18B are graphs presenting the results of an experiment according to the present disclosure, comparing the phosphorylation of PIP to PIP3 in conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 19 is a graph presenting the results of an experiment according to the present disclosure, comparing histidine 93 of hemoglobin beta subunit oxidation in conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • FIG. 20 is a graph presenting the results of an experiment according to the present disclosure, comparing methemoglobin levels of conventionally stored normoxic (solid line) and hyperoxic ( - - - ) and oxygen reduced stored blood with an initial an initial percent SO 2 of 20, 10, 5, and ⁇ 3%.
  • pre-existing conditions include, but are not limited to diabetes, ischemic heart disease, systemic inflammatory syndrome brought on by trauma or infection, multiple organ failure brought on by trauma or infection, smoke inhalation, and chronic pulmonary obstructive disease such as systemic inflammation due to infection, autoimmune diseases, and diabetes.
  • Oxygen reduced stored blood and methods provided herein can provide new and unexpected reductions in levels of inflammatory factors, improved protection from oxidative damage, reduced levels of microparticles, and/or other changes during storage thereby providing improvements and safety or other advantages to certain populations of patients in need of transfusion therapy.
  • the present methods include those that provide for, and include, reductions in morbidity and adverse events in certain patients identifiable as having pre-existing conditions associated with increased risk.
  • FIG. 1 Improvements and clinical benefits to oxygen reduced stored blood compared to conventional storage Changed blood Date of Improvement Molecule/path SO2 Clinical (day) way range Benefit 2 7 14 21 28 35 42 Change ⁇ FIG. 1 SO 2 does not ⁇ 3-20 Maintain steady X X X X X X X N/A FIG. 1 increase during redox storage environment; prevent increase in oxidative stress due to increased O 2 content 2 Reduced ⁇ 3-20, Reduced levels of X X X X below FIG. 2 Leukotriene leukotriene B4, a detection B4 highly pro- inflammatory BRM 3 Reduced ⁇ 3-5 Reduction in X X X X X X X 1/2.1 at FIG.
  • B2 is an end product, and more stable form of unstable thromboxane A2, and a potent BRM for platelet activator and smooth muscle contraction.
  • 4 Reduced ⁇ 3-20 HETEs are pro- X X X X X X 1/5x 14 d
  • Reduced ⁇ 3-10 HETEs are pro- X X X X 1/5 at FIG.
  • Glutamate is a at 42 d precursor for GSH synthesis 12 Higher GSH 5-20 Higher anti- X X X X X X 2x at day FIG. 11 levels oxidant capacity; 7, 2.1x at lower level of 42 d oxidative stress 13 Higher 5-10 Higher anti- X X X X X X X X X X X X X X X X X X X X at day FIG. 12 GSH/GSSG oxidant capacity; 7 d and ratio lower level of 42 d oxidative stress 14 Increased 5-20 Higher GSH X X X 2. 1x at FIG.
  • the present disclosure provides for, and includes, method for reducing the risk of an inflammatory response in a human patient in need of a blood transfusion comprising providing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period for transfusion to a human patient in need of a blood transfusion wherein said patient has an increased risk for an inflammatory response (see e.g., Table 1).
  • the oxygen reduced stored blood has a reduced level of at least one inflammatory factor.
  • initial oxygen saturation refers to the oxygen saturation of the blood prior to initiation of storage at 1 to 6° C.
  • the initial oxygen saturation of venous blood at collection and processing to red cell concentrate is about 50% and during the storage period, due to permeability of conventional storage bags, increases to fully saturated over a period of one to two weeks (see e.g., FIG. 1 ).
  • oxygen reduced stored blood will prevent, or mitigate the pro-inflammatory effect of blood transfusion, especially on patients with pre-existing, inflammatory pathologies.
  • oxygen reduced stored blood can prevent new pathologies such as transfusion related acute lung injury (TRALI) and systemic inflammatory response syndrome (SIRS)
  • TRALI transfusion related acute lung injury
  • SIRS systemic inflammatory response syndrome
  • Methods of the present disclosure provide for, and include, identifying a patient at risk of an inflammatory response, and providing the identified patient oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period.
  • providing oxygen reduced stored blood includes, without limitation, whole blood as provided in paragraph [00128], and red blood cells as provided at paragraphs[00129] and [00130].
  • Oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period can be prepared with lower levels of oxygen. As provided by the present disclosure, certain improvements are evident beginning at an initial saturation level of 20%. As used herein, improvements and benefits to the selected patients provided in the present disclosure are relative to (e.g., compared to) non-oxygen reduced stored blood stored for an identical storage period. Importantly, these differences become more pronounced as the storage period increases and as the initial oxygen saturation prior to storage is reduced.
  • oxygen reduced stored blood having an initial oxygen saturation of 20% or less as identified in paragraph [0047] and stored for at least 2 days has reduced leukotriene B4.
  • oxygen reduced stored blood of the present disclosure further includes reduced thromboxane B2.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4, reduced thromboxane B2, and reduced HETEs.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4 and reduced HETEs.
  • oxygen reduced stored blood as identified in paragraphs [00128], [00129], and [00130], further includes reduced leukotriene B4, thromboxane B2, and HETEs.
  • oxygen reduced stored blood suitable for reducing risks of an inflammatory response include oxygen reduced stored blood having reduced leukotriene B4, thromboxane B2, and HETEs.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes reduced methemoglobin, reduced oxidation of beta-hemoglobin at residue H93, increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH), increased GSH, increased ATP, increased DPG, increased NADPH reservoir, reduced PIP to PIP3 ratio, increased methylene THF, increased glutamate, increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio), increased urate, and increased cysteine.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes reduced methemoglobin.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased GSH.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased ATP.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased DPG.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased NADPH reservoir.
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes reduced PIP to PIP3 ratio. In another aspect, the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased methylene THF. In another aspect, the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased glutamate. In another aspect, the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio). In another aspect, the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased urate. In another aspect, the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased cysteine.
  • GSSG GSH to glutathione disulfide
  • the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased urate. In another aspect, the oxygen reduced stored blood suitable for reducing risks of an inflammatory response further includes increased cysteine.
  • oxygen reduced stored blood having an initial oxygen saturation of 10% or less as identified, for example, in paragraph [0048] and stored for at least 2 days has reduced leukotriene B4.
  • oxygen reduced stored blood of the present disclosure further includes reduced thromboxane B2.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4, reduced thromboxane B2, and reduced HETEs.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4 and reduced HETEs.
  • the oxygen reduced stored blood as identified, for example, in paragraphs [0052] and [0054], further includes reduced leukotriene B4, thromboxane B2, and HETEs.
  • Oxygen reduced stored blood suitable for reducing risks of an inflammatory response include oxygen reduced stored blood having reduced leukotriene B4, thromboxane B2, and HETEs.
  • oxygen reduced stored blood having an initial oxygen saturation of 5% or less as identified in paragraph [0049] and stored for at least 2 days has reduced leukotriene B4.
  • oxygen reduced stored blood of the present disclosure further includes reduced thromboxane B2.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4, reduced thromboxane B2, and reduced HETEs.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4 and reduced HETEs.
  • the oxygen reduced stored blood as identified in paragraphs [0052] and [0054] further includes reduced leukotriene B4, thromboxane B2, and HETEs.
  • Oxygen reduced stored blood suitable for reducing risks of an inflammatory response include oxygen reduced stored blood having reduced leukotriene B4, thromboxane B2, and HETEs.
  • oxygen reduced stored blood having an initial oxygen saturation of 3% or less, for example, as identified in paragraph [0050] and stored for at least 2 days has reduced leukotriene B4.
  • oxygen reduced stored blood of the present disclosure further includes reduced thromboxane B2.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4, reduced thromboxane B2, and reduced HETEs.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced leukotriene B4 and reduced HETEs.
  • the oxygen reduced stored blood as identified, for example, in paragraphs [0052] and [0054], further includes reduced leukotriene B4, thromboxane B2, and HETEs.
  • Oxygen reduced stored blood suitable for reducing risks of an inflammatory response include oxygen reduced stored blood having reduced leukotriene B4, thromboxane B2, and HETEs.
  • Methods of the present disclosure provide for, and include, identifying a patient having an increased risk of an inflammatory response and providing the identified patient oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period. Methods also provide for providing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period for transfusion to a person having an increased risk of an inflammatory response. Also included are methods comprising transfusing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period to a patient having an increased risk of an inflammatory response. As discussed, as the storage period is increased, the improvements and benefits to the patients having an increased risk of an inflammatory response of transfusing oxygen reduced stored blood increase relative to blood stored using conventional methods.
  • providing oxygen reduced stored blood having an initial oxygen saturation of 20% or less include providing oxygen reduced stored blood having an initial oxygen saturation of 10% or less.
  • Methods of providing oxygen reduced stored blood having an initial oxygen saturation of 20% or less further include providing oxygen reduced stored blood having an initial oxygen saturation of 5% or less.
  • Methods of providing oxygen reduced stored blood having an initial oxygen saturation of 20% or less further include providing oxygen reduced stored blood having an initial oxygen saturation of 3% or less.
  • the inflammatory factor is a protein. In an aspect, the inflammatory factor is a cytokine. In some aspects according to the present disclosure, the at least on inflammatory factor is at least one eicosanoid inflammatory mediator. Also provided herein, are reductions in at least one eicosanoid inflammatory mediator and at least one inflammatory cytokine. In an aspect according to the present disclosure, the oxygen reduced stored blood has been stored at least two days and provides for reduced levels of inflammatory factors. In an aspect, the inflammatory factors that are reduced include thromboxane B2 and hydroxyeicosatetraenoic acid (HETE). In a further aspect, the reduced levels of inflammatory factors include a biologic response modifier, such as RANTES, Eoxtaxin 1, soluble CD40-ligand (SCD40L), or combinations thereof.
  • RANTES thromboxane B2
  • HETE hydroxyeicosatetraenoic acid
  • the reduced levels of inflammatory factors include a biologic response modifier, such as RAN
  • methods of the present disclosure provide for, and include, providing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period to patients having an increased risk of an inflammatory response.
  • a patient having an increased risk of an inflammatory response is a surgery patient requiring a tissue perfusion bypass.
  • a patient having an increased risk of an inflammatory response is a patient having chronic vascular inflammation.
  • a patient having an increased risk of an inflammatory response is a patient having chronic inflammatory bowel disease.
  • a patient having an increased risk of an inflammatory response is a patient having chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a patient having an increased risk of an inflammatory response is patient having sickle cell disease.
  • a patient having an increased risk of an inflammatory response is a patient having thalassemia.
  • the patient has ⁇ -thalassemia.
  • the patient in need has ⁇ -thalassemia.
  • a patient having an increased risk of an inflammatory response is a patient having organ failure.
  • a patient having an increased risk of an inflammatory response is a patient having systemic inflammatory response syndrome (SIRS).
  • a patient having an increased risk of an inflammatory response is a patient having diabetes mellitus.
  • a patient having an increased risk of an inflammatory response is a patient having Behcet's disease.
  • a patient having an increased risk of an inflammatory response is a patient having rheumatoid arthritis.
  • a patient having an increased risk of an inflammatory response is patient having smoke inhalation.
  • a patient having an increased risk of an inflammatory response is patient having ischemic heart disease.
  • a patient having an increased risk of an inflammatory response has sickle cell and ⁇ -thalassemia.
  • a patient having an increased risk of an inflammatory response has diabetes and COPD.
  • a patient having an increased risk of an inflammatory response has sickle cell disease and SIRS.
  • a patient having an increased risk of an inflammatory response has diabetes and ischemic heart disease.
  • a patient having an increased risk of an inflammatory response has MODS and SIRS.
  • a patient having an increased risk of an inflammatory response has COPD and ischemic heart disease.
  • a patient having an increased risk of an inflammatory response is a trauma victim with an autoimmune disease. It will be appreciated by one of ordinary skill in the art that individual patients are evaluated for each of the risks separately. That is, the methods provided for refer to each individual risk, not as a list of risks for selection of a risk factor therefrom.
  • methods of the present disclosure provide greater benefit to patients having more than one underlying condition that are aggravated by transfused blood having increased levels of inflammatory factors.
  • a patient having an increased risk aggravating a preexisting condition has sickle cell and ⁇ -thalassemia.
  • a patient having an increased risk of aggravating a preexisting condition has diabetes and COPD.
  • a patient having an increased risk of aggravating a preexisting condition has sickle cell disease and SIRS.
  • a patient having an increased risk of aggravating a preexisting condition has diabetes and ischemic heart disease.
  • a patient having an increased risk of aggravating a preexisting condition has MODS and SIRS.
  • a patient having an increased risk of aggravating a preexisting condition COPD and ischemic heart disease is a patient at risk of an underlying condition that is aggravated by transfused blood having increased levels of inflammatory factors.
  • a patient at risk of aggravating an underlying condition is a patient with hemolytic anemia from sickle cell and/or thalassemia has anemia worsened by DHTR after therapeutic transfusion.
  • a patient at risk of aggravating an underlying condition is a patient with systemic inflammation resulting from obesity and diabetes has increased inflammatory response worsened after blood transfusion.
  • a patient at risk of aggravating an underlying condition is a patient suffering from SIRS due to trauma or infection, has worsened inflammatory response after receiving transfusion.
  • a patient at risk of aggravating an underlying condition is a patient with ischemic heart disease who receives a transfusion during surgery can have increased tissue damage as the result of transfusion of reactive oxygen species and inflammatory biomolecules.
  • oxygen reduced stored blood of the present disclosure provides for reduced levels of inflammatory factors beginning at least as early as day two of a storage period.
  • “aggravated” refers to increased inflammation of a pre-existing inflammatory condition.
  • a patient having aggravated response is a patient having an underlying low grade inflammatory condition arising from diabetes, an autoimmune disease, or trauma.
  • Methods of the present disclosure provide for, and include, for providing oxygen reduced stored blood to a patient having chronic vascular inflammation.
  • chronic vascular inflammation is a co-morbidity associated with several degenerative disorders such as sickle cell disease, hematological cancers, diabetes, and heart disease.
  • red blood cells can initiate or propagate pro-inflammatory signals through release of membrane microparticles containing bioactive kinases and other signaling molecules.
  • These microparticles can be taken up by circulating monocytes, stimulating release of TNF- ⁇ , IL-1 ⁇ , and IL-6; furthermore, uptake of RBC secreted microparticles also promotes monocyte-endothelial adhesion.
  • Methods of the present disclosure provide for, and include, for providing oxygen reduced stored blood to a patient having chronic inflammatory bowel disease.
  • a patient with chronic inflammatory bowel disease such as ulcerative colitis and Crohn's disease, is characterized by chronically activated intestinal inflammation as the result of elevated recruitment of neutrophils from the circulatory environment to the intestinal lumen. See Nielsen et al., “Activation of neutrophil chemotaxis by leukotriene B4 and 5-hydroxyeicosatetraenoic acid in chronic inflammatory bowel disease,” Scandinavian Journal of Clinical and Laboratory Investigation 47(6):605-611 (1987) (Nielsen et al. (1987) (hereby incorporated by reference in its entirety)).
  • neutrophils Upon recruitment, neutrophils secrete inflammatory cytokines and chemokines that promote recruitment of additional immune cells, further exacerbating the inflammatory response.
  • initial and continued activation and recruitment of neutrophils in IBD is, in part, the result of hydroxyeicosatetraenoic acids (HETE).
  • HETE hydroxyeicosatetraenoic acids
  • oxygen reduced stored blood contains lower concentrations of HETE acids (see e.g., FIG. 4 ).
  • oxygen reduced stored blood has reduced levels of leukotriene B4 (see e.g., FIG. 2 ), which has been shown to be elevated in patients suffering from ulcerative colitis.
  • Patients with a chronic IBD, such as ulcerative colitis and Crohn's disease that received a transfusion of oxygen reduced stored blood have a reduced exposure to HETE acids and leukotriene B4, decreasing activation and recruitment of neutrophils into the circulatory environment, and potentially decreasing the risk of secondary inflammation of the intestinal wall.
  • Methods of the present disclosure provide for, and include, for providing oxygen reduced stored blood to a patient having chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • People who suffer from chronic obstructive pulmonary disease (COPD) develop persistent bacterial colonization of the airways (termed chronic colonization). See Monso et al., “Bacterial infection in chronic obstructive pulmonary disease.
  • Methods of the present disclosure provide for, and include, for providing oxygen reduced stored blood to a patient having sickle cell disease.
  • Development of vascular occlusive events which are the main cause of the morbidity and mortality in sickle cell disease, results from the chronically inflamed vascular environment characterized by elevated levels of inflammatory cytokines, such as TNF ⁇ , as well as increased numbers of circulating white blood cells, such as neutrophils and monocytes.
  • circulating neutrophils are activated due to exposure to hydroxyeicosatetraenoic (HETEs) acids, as well as leukotriene B4.
  • HETEs hydroxyeicosatetraenoic
  • Leukotriene B4 hydroxyeicosatetraenoic
  • the present disclosure provides that oxygen reduced stored blood has reduced levels of HETE acids and leukotriene B4 (see e.g., FIG. 4 and FIG. 2 ) relative to conventionally stored blood.
  • Transfusion of oxygen reduced stored blood can be more efficacious at resolving the vascular crises, as well as further preventing the development of later crises, by decreasing the patient exposure to pro-immune activating molecules.
  • Methods of the present disclosure provide for, and include, for providing oxygen reduced stored blood to a patient having thalassemia.
  • a patient with ⁇ - or ⁇ -thalassemia major is unable to produce functional hemoglobin molecules, resulting in severe anemia and necessitating transfusion of red blood cells (RBCs).
  • RBCs red blood cells
  • a result of requiring regular (i.e., chronic) transfusions people with thalassemia can suffer from delayed hemolytic transfusion reaction (DHTR) which is characterized by a rapid decrease in hematocrit following therapeutic transfusion.
  • DHTR can be initiated as a response to sudden eryptosis, leading to rapid removal of the circulating red cells by macrophages and monocytes.
  • eryptosis is also promoted when red cells no longer have sufficient levels of ATP, which also occurs during conventional storage.
  • ATP Trigger's syndrome
  • anaerobic stored blood products for chronic therapeutic transfusions for people with ⁇ - or ⁇ -thalassemia can have a decreased risk of developing DHTR due to the increased protection from oxidative damage, and superior preservation of intracellular energy (ATP), and a further potential benefit of decreasing the frequency at which transfusions are required.
  • ATP intracellular energy
  • Methods of the present disclosure provide for, and include, providing oxygen reduced stored blood to a patient having systemic inflammatory response syndrome (SIRS).
  • SIRS systemic inflammatory response syndrome
  • a patient is deemed to have systemic inflammatory response syndrome (SIRS) if two of the following criteria are met: body temperature higher than 38° C. or lower than 36° C., heart rate faster than 90 beats per minute (BPM), respiratory rate greater than 20 breaths per minute, arterial CO 2 tension of less than 32 mmHg, and abnormal white cell (either above 12,000 cells/ ⁇ L or below 4,000 cells/ ⁇ L. See Lang, E.
  • SIRS System for erythrocyte death
  • an infectious agent such as bacterial infections, influenza, infective endocarditis, as well as non-infectious sources, such as severe burns, autoimmune disorders, hemorrhagic shock, hematologic malignancy, and chemical exposure.
  • a patient currently suffering from SIRS can have the condition exacerbated if the patient also receives a blood transfusion, due to the presence of inflammatory biomolecules and cytokines within the blood unit.
  • oxygen reduced stored blood has decreased levels of inflammatory factors, such as hydroxyeicosatetraenoic acids (HETEs), and leukotriene B4 (see e.g., FIG. 2 and FIG. 4 ).
  • HETEs hydroxyeicosatetraenoic acids
  • leukotriene B4 see e.g., FIG. 2 and FIG. 4 .
  • a patient with SIRS can be provided with a transfusion of oxygen reduced stored blood can provide a reduced exposure to HETE acids and leukotriene B4, decreasing activation and recruitment of circulating neutrophils into the circulatory environment, and decreasing the risk of long-term organ system damage.
  • Behcet's Disease also known as Behcet's syndrome
  • Behcet's syndrome is a rare, chronic, autoinflammatory disorder of unknown origin. Its manifestations are thought to be caused by vasculitis resulting in damage to blood vessels throughout the body, and is characterized by oral or skin lesions, ocular inflammation, arthritis, and gastrointestinal lesions.
  • Current research suggests viral, bacterial, genetic and environmental factors may play a role in the development of Behcet's Disease, but no specific cause has been established and no triggers have been identified.
  • leukotrienes which are potent activators of circulating white blood cells, such as neutorphils. See Lang. et al., “Oxidative Stress and Suicidal Erythrocyte Death,” Antioxidants Redox Signaling 21(1):138-153 (2014).
  • oxygen reduced stored blood contains lower concentrations leukotriene B4 and HETEs (see e.g., FIG. 2 and FIG. 4 ).
  • a patient with Behcet's disease that received a transfusion of oxygen reduced stored blood can have a reduced exposure to HETE acids and leukotriene B4, decreasing activation and recruitment of circulating neutrophils into the circulatory environment, and potentially decreasing the risk of complications and secondary morbidities associated with chronic systemic inflammation.
  • Methods of the present disclosure provide for, and include, providing oxygen reduced stored blood to a patient having rheumatoid arthritis.
  • Rheumatoid arthritis is a chronic autoimmune disease that characteristically involves the small joints of the hands and feet. As the disease progresses, a patients' cartilage and bone will begin to degrade in the synovial space of the joint, characterized by hyperplastic, invasive tissue containing large amounts of immunocompetent cells, such as T lymphocytes, memory B lymphocytes, and macrophages.
  • Leukotrienes are inflammatory lipids that are among the most potent endogenous chemotactic agents for leukocytes yet identified, and are strongly implicated in the recruitment of immune cells to the synovial tissue in rheumatoid arthritis. See Wellen, K. E. et al., “Inflammation, stress, and diabetes,” The Journal of clinical investigation. 115(5): 1111-1119 (2005) (hereby incorporated by reference in its entirety). For a patient with rheumatoid arthritis, a transfusion of blood has the potential to exacerbate their condition as a result of transfusing the accumulation of inflammatory biomolecules and cytokines within conventionally stored blood units.
  • oxygen reduced stored blood has lower concentrations of inflammatory factors, such as leukotriene B4 and HETEs (see e.g., FIG. 2 and FIG. 4 ). Therefore, patients with rheumatoid arthritis can be provided a transfusion of oxygen reduced stored blood that will avoid being exposed to powerful, exogenous pro-inflammatory molecules, thereby allowing for a reduced risk of aggravating or worsening the severity of the arthritic condition.
  • inflammatory factors such as leukotriene B4 and HETEs
  • Methods of the present disclosure provide for, and include, providing oxygen reduced stored blood to a patient having smoke inhalation.
  • Damage to the lungs and respiratory tract is one of the leading causes of death associated with fires.
  • the lung injury process is activated by toxins in the smoke's gas and particle components and perpetuated by a resulting lung inflammation.
  • This inflammatory process becomes self-perpetuating through the activation of a large number of inflammatory cascades, and increased plasma levels of inflammatory cytokines. See Park, G. Y. et al. “Prolonged airway and systemic inflammatory reactions after smoke inhalation,” Chest. 123(2):475-480 (2003) (hereby incorporated by reference in its entirety).
  • oxygen reduced stored blood can introduce decreased levels of inflammatory molecules, such as HETE and leukotriene B4 (see e.g., FIG. 2 and FIG. 4 ).
  • oxygen reduced stored blood can be used to prevent further exacerbation of the elevated inflammatory response from smoke inhalation, and provide superior patient outcomes and recoveries.
  • Methods of the present disclosure provide for, and include, a method of reducing the risk of an inflammatory response in a human patient in need of multiple blood units (e.g., more than 4) or massive transfusion (10 or more units).
  • the selected patients requiring a massive transfusion with oxygen reduced stored blood reduces or does not aggravate a pre-existing inflammatory state.
  • a trauma patient requiring multiple units or a massive transfusion is a patient with pre-existing disease who is pre-disposed to low-grade chronic systemic inflammation.
  • the human patient has diabetes mellitus, Behcet's disease, rheumatoid arthritis, COPD, smoke inhalation and atherosclerosis.
  • Patients with these conditions can have existing primed inflammatory leukocytes prior to the event requiring RBC transfusion.
  • Infusion of HETEs, leukotrienes and thromboxanes in transfused RBC on already primed immune system will increase risk of morbidities such as multiple organ dysfunction (MODS), SIRS, and TRALI. Further, higher transfusion volume proportionally increases the dose and exaggerates the effects.
  • MODS multiple organ dysfunction
  • TRALI TRALI
  • higher transfusion volume proportionally increases the dose and exaggerates the effects.
  • patients can be provided with oxygen reduced stored RBC as a transfusion, having reduced infusion of HETEs, leukotrienes and thromboxanes and reduce the probability of morbidity.
  • a patient having an increased risk of an inflammatory response is a patient having one or more conditions that are aggravated by increased levels of inflammatory factors.
  • a patient having an increased risk of aggravating an existing inflammatory response is a patient having chronic vascular inflammation.
  • a patient having an increased risk aggravating an inflammatory response is a patient having chronic inflammatory bowel disease.
  • patients having a combination of underlying conditions are also provided for, and included, are patients having a combination of underlying conditions.
  • methods of the present disclosure provide greater benefit to patients having more than one underlying condition that are aggravated by transfused blood having increased levels of inflammatory factors.
  • the present disclosure provides for, and include, reductions in adverse events following transfusion of oxygen reduced stored blood to a patient at risk of an inflammatory response.
  • the patient receiving a transfusion of oxygen reduced stored blood has a reduced risk of a delayed hemolytic reaction.
  • TRALI transfusion related acute lung injury
  • TRALI presents clinically with rapid onset of dyspnea (labored breathing) and tachypnea (abnormally rapid breathing). Additionally, patients can also present with fever, cyanosis, and hypotension. Clinical examination of the patients can reveal pulmonary crackles (auditory “crackling” when the patient is breathing) independent of signs of congestive heart failure. Chest X-Rays can reveal evidence of bilateral pulmonary edema not associated with heart failure, and bilateral patchy infiltrates which can progress to Acute Respiratory Distress Syndrome (ARDS).
  • ARDS Acute Respiratory Distress Syndrome
  • the present methods provide for a reduction of risk through at least the presentation of reduced levels of inflammatory factors, including, but not limited to leukotriene, 8-isoprostane, thromboxane, hydroxyeicosatetraenoic acid (HETE), and combinations thereof.
  • the present methods include reduced or ameliorated (not increased) levels of cytokines.
  • increases in the storage period provide further improvements of methods of the present disclosure when compared to conventionally stored blood.
  • the present disclosure provides for, and includes, a reduction in adverse events following transfusion by providing oxygen reduced stored blood to a patient at risk of an inflammatory response.
  • methods of the present disclosure provides for a reduced incidence of systemic inflammatory response syndrome (SIRS).
  • SIRS systemic inflammatory response syndrome
  • a patient is deemed to have SIRS if two of the following criteria are met: body temperature higher than 38° C. or lower than 36° C., heart rate faster than 90 BPM, respiratory rate greater than 20 breaths per minute, arterial CO 2 tension of less than 32 mmHg, and abnormal white cell (either above 12,000 cells/ ⁇ L or below 4,000 cells/ ⁇ L.
  • SIRS can develop as the result of an infectious agent such as bacterial infection, influenza, infective endocarditis, as well as non-infectious sources, such as severe burns, autoimmune disorders, hemorrhagic shock, hematologic malignancy, and chemical exposure.
  • infectious agent such as bacterial infection, influenza, infective endocarditis, as well as non-infectious sources, such as severe burns, autoimmune disorders, hemorrhagic shock, hematologic malignancy, and chemical exposure.
  • a patient currently suffering from SIRS can have the condition aggravated if the patient also receives a blood transfusion, due to the presence of inflammatory biomolecules and cytokines within the blood unit.
  • oxygen reduced stored blood can be provided that has decreased levels of inflammatory factors, such as hydroxyeicosatetraenoic acid (HETE), and leukotriene B4 (see e.g., FIG. 2 and FIG. 4 ). Therefore, a patient with SIRS that receives a transfusion of oxygen reduced stored blood will have a reduced exposure to HETEs and leukotriene B4, decreasing activation and recruitment of circulating neutrophils into the circulatory environment, and potentially decreasing the risk of long-term organ system damage.
  • HETE hydroxyeicosatetraenoic acid
  • leukotriene B4 see e.g., FIG. 2 and FIG. 4 .
  • MODS refers to the development of potentially reversible physiologic derangement involving two or more organ systems not involved in the primary insult that resulted in the patient's hospitalization. Clinically, MODS is scored based on physiological measurements made from 6 key organ systems, with higher scores indicating a lower level of organ function. See Table 2.
  • Systemic inflammation can develop as the result of an infectious agent such as bacterial infections, influenza, infective endocarditis, as well as non-infectious sources, such as severe burns, autoimmune disorders, hemorrhagic shock, hematologic malignancy, and chemical exposure.
  • an infectious agent such as bacterial infections, influenza, infective endocarditis, as well as non-infectious sources, such as severe burns, autoimmune disorders, hemorrhagic shock, hematologic malignancy, and chemical exposure.
  • a patient with MODS originating from systemic inflammation can benefit from a transfusion of oxygen reduced stored blood by having a reduced exposure to HETE acids and leukotriene B4, decreasing activation and recruitment of circulating neutrophils into the circulatory environment, and potentially decreasing the risk of long-term organ system damage.
  • Oxidative stress is associated with a wide range of disease states resulting from the reaction of oxygen and metal catalysts as described by the Fenton or Haber-Weiss reactions.
  • One pervasive source of oxidative stress is the combination of oxygen and metals in our bodies, generally iron, that allow the generation of hydroxyl radical and superoxide followed by a series of oxidation products.
  • the body has a series of controls in place. For example, the presence of reducing thiols such as cysteine or glutathione provides a reversible means to reduce oxidizing compounds. The oxidized forms of these thiols are reduced enzymatically to maintain a defense against oxidative damage. Under extreme stress or conditions of chronic oxidative stress the ability of the body to regenerate the thiols becomes compromised.
  • Thalassemia and sickle cell disease are chronic diseases during which the patients are exposed to oxidative damage due to the instability of the hemoglobin in their red blood cells.
  • the degrading hemoglobin allows iron to react freely with oxygen generating the reactive species mentioned.
  • Resulting degradation of the antioxidant pool is significant; for example, the glutathione levels in ⁇ -thalassemia patients has been documented to be only 35% of the level of normal subjects. See Kalpravidh, et al., “Glutathione Redox System in ⁇ -Thalassemia/Hb E Patients,” The Scientific World Journal 2013, article ID 543973 (2013) (hereby incorporated by reference in its entirety).
  • Oxidative stress is a major cause of vasculopathy which has been implicated in stroke, pulmonary hypotension and leg ulcers.
  • Methods of the present disclosure provide for, and include, for providing oxygen reduced stored blood to a patient having ischemic heart disease.
  • Ischemic heart disease is characterized by a narrowing of the blood vessels that provide blood, oxygen, and nutrients to the heart muscle. As the disease progresses, the heart muscle can begin to die, leading to loss of cardiac function and, ultimately, a myocardial infarction.
  • Surgical intervention to re-establish blood flow either through angioplasty and stent deployment, or through a vascular bypass graft. In both cases, the return of blood flow to the site of injury can result ischemia/reperfusion (I/R) injury leading to new myocardial damage.
  • I/R ischemia/reperfusion
  • I/R injury can result in the exposure of cells to reactive oxygen species which can stimulate cellular autophagy.
  • reactive oxygen species which can stimulate cellular autophagy.
  • Xia, Y. et al. “Activation of volume-sensitive Cl— channel mediates autophagy-related cell death in myocardial ischaemia/reperfusion injury,” Oncotarget (2016) and Yousefi, B. et al., “The role of leukotrienes in immunopathogenesis of rheumatoid arthritis,” Modern rheumatology/the Japan Rheumatism Association 24(2): 225-235 (2014) (hereby incorporated by reference in their entireties).
  • red blood cells stored conventionally undergo oxidative damage during storage which can pose a significant health risk to ischemic heart disease patients undergoing surgical interventions.
  • Transfusion of red blood cells with oxidative damage can exacerbate the I/R injury, leading to further damage to the heart tissue.
  • Providing oxygen reduced stored blood provides superior anti-oxidative protection, as evidenced by increased NADPH reservoirs (see e.g., FIG. 5 , FIG. 6 , and FIG. 7 ), elevated levels of cysteine (see e.g., FIG. 13 ), elevated ratios of GSH to GSSG (see e.g., FIG. 12 ).
  • these red blood cells have a decreased risk for inducing I/R injury to patients with already weakened or deteriorated cardiac function.
  • Methods of the present disclosure provide for, and include, for providing oxygen reduced stored blood to a patient having diabetes.
  • a patient with diabetes is at severe risk for long-term vascular complications as the result of prolonged hyperglycemia.
  • Reactive oxygen species have been shown to be generated as the result of glucose auto-oxidation, polyol pathway activation, prostanoid synthesis, and protein glycation, leading to dysregulation of intracellular regulatory pathways that maintain vascular homeostasis. See Baynes et al., “Role of oxidative stress in diabetic complications: a new perspective on an old paradigm,” Diabetes. 48(1): 1-9 (1991) (hereby incorporated by reference in its entirety).
  • Providing oxygen reduced stored blood cells provides superior anti-oxidative protection, as evidenced, for example, by increased NADPH reservoirs (see e.g., FIG. 5 , FIG. 6 , and FIG. 7 ), elevated levels of cysteine (see e.g., FIG. 13 ), elevated ratios of GSH to GSSG (see e.g., FIG.
  • red cells will avoid introducing or aggravating oxidative injury in a patient with diabetes, and thereby reduce the risk of aggravating diabetic co-morbidities post-transfusion.
  • the present disclosure provides for, and includes, a method for reducing oxidative stress in a human patient in need of a blood transfusion comprising providing oxygen reduced stored blood for transfusion into a human patient in need of a blood transfusion having an increased risk for transfusion mediated oxidative stress, wherein said oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has an increased risk of oxidative stress.
  • oxygen reduced stored blood results in higher cysteine, GSH, NADH, NADPH and higher ratios of GSH/GSSG, NADPH/NADP, and NADH/NAD (See Table 1). These results show that oxygen reduced stored blood has a lower oxidation/reduction potential and thus provide a higher antioxidant capacity after transfusion.
  • oxygen reduced stored blood of the present disclosure provides superior defensive capability against oxidative damage.
  • the chronically transfused sickle cell disease or thalassemia patient replacing conventionally stored blood with oxygen reduced stored blood will avoid additional oxidative stress from the conventionally stored red blood cells and provide additional defense against oxidative damage.
  • the present disclosure provides for methods to reduce oxidative stress by providing a transfusion of oxygen reduced stored blood to a patient that further comprises reduced levels of inflammatory factors.
  • Methods of the present disclosure provide for, and include, identifying a patient at risk that will benefit from reducing oxidative stress when the patient requires a blood transfusion and providing the identified patient oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period.
  • providing oxygen reduced stored blood includes whole blood as provided in paragraph [00128], and red blood cells as provided at paragraphs [00129] and [00130].
  • Oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period can be prepared with improved resistance to oxidative stress (see e.g., Table 1 and examples). As provided by the present disclosure, certain improvements are evident beginning at an initial saturation level of 20%. As used herein, improvements and benefits to the selected patients provided in the present disclosure are relative to (e.g., compared to) non-oxygen reduced stored blood stored for an identical storage period. Importantly, these differences become more pronounced as the storage period increases and as the initial oxygen saturation prior to storage is reduced.
  • oxygen reduced stored blood suitable for reducing risks of oxidative stress includes oxygen reduced stored blood having one or more of reduced methemoglobin, reduced oxidation of beta-hemoglobin at residue H93, increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH), increased GSH, increased ATP, increased DPG, increased NADPH reservoir, reduced PIP to PIP3 ratio, increased methylene THF, increased glutamate, increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio), increased urate, or increased cysteine.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • GSH nicotinamide adenine dinucleotide phosphate
  • ATP increased ATP
  • DPG increased NADPH reservoir
  • reduced PIP to PIP3 ratio increased methylene THF
  • glutamate increased ratio of GSH to glutathione disulfide (GSSG)
  • oxygen reduced stored blood having an initial oxygen saturation of 20% or less as identified in paragraphs [0015] and [0081], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93. See Wither 2016; and Reisz 2016, (hereby incorporated by reference in their entireties).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased of GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased of methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • oxygen reduced stored blood having an initial oxygen saturation of 20% or less as identified in paragraphs [0015] and [0081], and stored for at least 2 days has reduced methemoglobin, reduced oxidation of beta-hemoglobin at residue H93, increased reservoir of reduced nicotinamide adenine dinucleotide phosphate+hydrogen (NADPH), increased GSH, increased ATP, increased DPG, increased NADPH reservoir, reduced PIP to PIP3 ratio, increased methylene THF, increased glutamate, increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio), increased urate, and increased cysteine.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate+hydrogen
  • oxygen reduced stored blood having an initial oxygen saturation of 10% or less as identified in paragraphs [0015] and [0081], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate+hydrogen (NADPH).
  • NADPH nicotinamide adenine dinucleotide phosphate+hydrogen
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio). In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • GSSG GSH to glutathione disulfide
  • oxygen reduced stored blood having an initial oxygen saturation of 5% or less as identified in paragraphs [0015] and [0081], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced dioxidation of Cys152 in Glyceraldehyde-3-Phosphate Dehydrogenase.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate+hydrogen (NADPH).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • oxygen reduced stored blood having an initial oxygen saturation of 3% or less as identified in paragraphs [0015] and [0081], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced dioxidation of Cys152 in Glyceraldehyde-3-Phosphate Dehydrogenase.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • Methods of the present disclosure provide for, and include, identifying a patient at risk that will benefit from reducing oxidative stress when the patient requires a blood transfusion and providing the identified patient oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period. Methods also provide for providing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period for transfusion to a patient at risk of oxidative stress when the patient requires a blood transfusion. Also included are methods comprising transfusing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period to a patient at risk of oxidative stress.
  • methods providing oxygen reduced stored blood having an initial oxygen saturation of 20% or less include providing oxygen reduced stored blood having an initial oxygen saturation of 10% or less.
  • Methods of providing oxygen reduced stored blood having an initial oxygen saturation of 20% or less further include providing oxygen reduced stored blood having an initial oxygen saturation of 5% or less.
  • Methods of providing oxygen reduced stored blood having an initial oxygen saturation of 20% or less further include providing oxygen reduced stored blood having an initial oxygen saturation of 3% or less.
  • a patient in need of a blood transfusion having an increased risk of oxidative stress includes a trauma patient requiring four or more units of blood, a trauma patient requiring ten or more units of blood, a patient having sickle cell disease, a patient having thalassemia, and combinations thereof.
  • the methods provide for providing oxygen reduced stored blood for transfusion into a human patient in need of a blood transfusion having an increased risk for transfusion mediated oxidative stress, wherein said oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has sickle cell anemia.
  • the methods provide for providing oxygen reduced stored blood for transfusion into a human patient in need of a blood transfusion having an increased risk for transfusion mediated oxidative stress, wherein said oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has thalassemia.
  • the thalassemia is ⁇ -thalassemia.
  • the thalassemia is ⁇ -thalassemia.
  • the disclosure further provides for a method of reducing the risk of oxidative stress to a trauma patient requiring four or more units of blood.
  • the patient in need of reduced risk of oxidative stress is a trauma patient requiring ten or more units of blood.
  • a sickle cell patient is provided a unit of oxygen reduced stored blood having an initial oxygen saturation of 20% or less prior to storage and an additional unit of oxygen reduced stored blood when the hemoglobin concentration below 5 g/dL.
  • a sickle cell patient is provided with an additional unit of oxygen reduced stored blood when the peak, centerline flow velocity of the middle cerebral artery is greater than 200 cm/sec as determined by transcranial Doppler ultrasound (TCD).
  • TCD transcranial Doppler ultrasound
  • an additional unit of blood is provided to a sickle cell patient when sickle hemoglobin levels rise above 30%.
  • the sickle cell patient receives periodic transfusions of oxygen reduced stored blood to maintain the level of sickle hemoglobin below 30% of total hemoglobin.
  • a sickle cell patient in need of reduce oxygen stress receives a transfusion about every thirty days. As use herein, about every thirty days means between 25 and 35 days.
  • the present disclosure provides for, and includes, providing oxygen reduced stored blood to a sickle cell patient having an acute attack to reduce the symptoms and provides for reduced oxidative stress.
  • the sickle cell patient is experiencing a vaso-occlusive crisis.
  • the present disclosure provides for, and includes, providing oxygen reduced stored blood to a sickle cell patient in need of surgery.
  • the sickle cell patient receives one or more pre-operative transfusions to reduce perioperative hypoxia, hypoperfusion or acidosis.
  • the sickle cell patient receives two or more pre-operative transfusions.
  • the sickle cell patient receives three or more pre-operative transfusions.
  • the sickle cell patient receives four or more pre-operative transfusions.
  • the present disclosure provides for, and includes, a method for reducing the risk of an adverse event in a hemoglobinopathy patient in need of a blood transfusion comprising providing oxygen reduced stored blood for transfusion into a hemoglobinopathy patient in need of a blood transfusion, wherein oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has an increased risk of an adverse event.
  • the methods of the present disclosure provide for a reduction in delayed hemolytic transfusion reactions following transfusion to treat sickle cell disease or thalassemia by providing blood having a higher phosphatidylinositol 4-phosphate to phosphatidylinositol (3,4,5)-triphosphate ratio.
  • the methods of the present disclosure provide for an improved red blood cell membrane wherein the membrane after storage is more physiological membrane.
  • the hemoglobinopathy patient in need of blood transfusion is a sickle cell patient.
  • methods of the present disclosure provide for reducing delayed hemolytic transfusion reactions following transfusion to treat sickle cell disease or thalassemia by providing blood having a higher phosphatidylinositol 4-phosphate to phosphatidylinositol (3,4,5)-triphosphate ratio.
  • the present disclosure provides for, and includes, a method for reducing delayed hemolytic transfusion reactions following transfusion to treat sickle cell disease or thalassemia by providing blood which maintains a more physiologic membrane over the course of cold storage.
  • a more physiological membrane refers to a membrane having one or more of the following characteristics:
  • Oxygen reduced stored blood provides for a more physiological membrane through a variety of mechanisms. For example, decreased activity of Ca2+ ion channels is indicated by the high PIP:PIP3 ratio, and lower intracellular Ca2+ can be measured directly with fluorescent probe such as Fura-2 (Thermo-Fisher Scientific) using flow cytometer. See Mahmud et al., “Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure-associated anaemia,” Cardiovasc Res 98(1):37-46 (2013) (hereby incorporated by reference in its entirety). As provided in the present disclosure, oxygen reduced stored blood can provide low oxidative stress as evidenced by high NADPH, NADP, and GSH ratios resulting in reduced membrane hyperpolarization.
  • Oxygen reduced stored blood further provides reduced dehydration and retained deformability by providing reduced calcium ion flux, where oxidation results in activation of calcium ion channels.
  • Cell membrane scrambling is promoted by activation of JAK3 kinase, which is phosphorylated as the result of energy depletion (ATP loss) within the cell.
  • Oxygen reduced stored blood retains high ATP production as evidenced by stimulation of the PPP and EMP pathways.
  • Membrane scrambling can be characterized by phosphatidylserine expression that can be measured through labeling cell membrane with fluorescent annexin-V and quantifying with flow cytometry or microscopy. See Yoshida et al., 2008, supra.
  • JAK3 kinase activity can be measured through Western Blot analysis, Luminex technology, and other methods well known in the art. See Chang et al., “Mammalian MAP kinase signaling cascades,” Nature 410(6824):37-40 (2001) (hereby incorporated by reference in its entirety).
  • Methods of the present disclosure provide for, and include, a method for reducing delayed hemolytic transfusion reactions following transfusion to treat sickle cell disease or thalassemia wherein the oxygen reduced stored blood comprises fewer pre-eryptotic biomarkers.
  • pre-eryptotic biomarkers refers the following characteristics:
  • Transfusion of red blood cells is one of the primary treatments people with sickle cell disease and thalassemia.
  • high oxidative environment characteristic to these hematological diseases triggers rapid influx of calcium ions into the RBC, resulting in alterations to the cell membrane, leading to redistribution of cytosolic biomarkers to the extracellular leaflet of plasma membrane.
  • the calcium dependent reorganization of the cell membrane leads to rapid clearance of the circulating red blood cell through eryptosis. See Lang et al., “Triggers, Inhibitors, Mechanisms, and Significance of Eryptosis: The Suicidal Erythrocyte Death,” BioMed Research International, vol.
  • DHTR can be triggered due to induction of eryptosis in the donated cells as a result of a loss of intracellular energy (ATP) inducing kinase signaling pathways (JAK3 activation, AMPK ⁇ 1 and cGKI inhibition).
  • ATP intracellular energy
  • J Biochem Cell Biol 44(8): 1236-43 (2012) hereby incorporated by reference in its entirety.
  • oxygen reduced stored blood in transfusion therapy for sickle cell disease would preserve the native configuration of the red blood cell membrane, thereby preventing the extracellular expression of pro-eryptotic biomarkers, and thus allowing transfused RBCs to survive the sickle cell circulatory environment. Ultimately, this can lead to the ability for clinicians to reduce the therapeutic dose per transfusion and/or decrease the frequency at which the patient requires medical intervention.
  • Storage of oxygen reduced red blood cells has been shown to establish a higher energetic state of the red blood cell during storage. Reduction of oxygen, and subsequent maintenance of low oxygen during storage, promotes higher EMP flux, larger de novo synthesis of ATP via the pentose phosphate pathway, and preservation of GAPDH enzymes thereby maintaining homeostatic metabolism regulation.
  • generation and use of oxygen reduced stored blood for therapeutic transfusions in sickle cell disease and thalassemia mitigates the development of DHTR, allowing for a safer, more effective treatment.
  • Sickle cell disease is a genetic mutation that primarily afflicts people of Sub-Saharan African, Middle Eastern, and South-East Asian descent. Transfusion of red blood cells is one of the primary treatments for both acute and chronic vaso-occlusive symptoms in people with sickle cell disease (SCD).
  • SCD sickle cell disease
  • recipients of therapeutic blood transfusions often develop alloimmunization against the donated blood cells leading to reduction in efficacy of the treatment or severe, systemic complications.
  • SCD sickle cell disease
  • G6PD glucose-6-phosphate hydrogenase
  • G6PD activity is essential for maintaining the energetic molecules, such as NADPH, that fuel the native anti-oxidative pathways (i.e. glutathione mediated reduction of hydrogen peroxide) essential for maintaining bioactivity of the hemoglobin molecules in the red blood cell; loss or reduction of activity in this enzyme leads to premature hemolysis in storage and poor retention of the cells post-transfusion.
  • oxygen reduced stored blood has results in an intracellular reservoir of NADPH, as well as increased concentrations of the reduced form of glutathione (GSH).
  • GSH reduced form of glutathione
  • oxygen reduced stored blood has increased methylenetetrahydrofolate, which can promote overall NADPH production.
  • Low oxygen storage of blood can allow for better survivability, and therefore usability, of blood from G6PD-deficient donors. This will increase the blood supply available for people with sickle cell disease receiving therapeutic transfusions, especially in rural areas where the blood supplies are more limited.
  • oxygen reduced stored blood suitable for reducing risks of hemoglobinopathy includes oxygen reduced stored blood having reduced methemoglobin, reduced oxidation of beta-hemoglobin at residue H93, increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH), increased GSH, increased ATP, increased DPG, increased NADPH reservoir, reduced PIP to PIP3 ratio, increased methylene THF, increased glutamate, increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio), increased urate, and increased cysteine.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • DHTR delayed hemolytic transfusion reaction
  • Oxygen reduced stored blood has superior anti-oxidative protection, as evidenced by increased NADPH reservoirs (see e.g., FIG. 5 , FIG. 6 , and FIG. 7 ), elevated levels of cysteine (see e.g., FIG. 13 ), elevated ratios of GSH to GSSG (see e.g., FIG. 12 ).
  • eryptosis is also promoted when red cells no longer have sufficient levels of ATP, which also occurs during conventional storage.
  • GUrer et al. “Arachidonic acid metabolites and colchicine in Behcet's disease (BD)” Prostaglandins, leukotrienes, and essential fatty acids 43(4):257-9 (1999) (hereby incorporated by reference in its entirety).
  • oxygen reduced blood has improved overall ATP levels (see e.g., FIG. 16 ), and improved metabolic activity by sustaining glycolysis through the pentose phosphate pathway (see e.g., FIG. 15 ).
  • oxygen reduced stored blood having an initial oxygen saturation of 20% or less as identified in paragraph [0017], [0093], [0099], and [00106], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased of GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased of methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio). In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • GSSG GSH to glutathione disulfide
  • oxygen reduced stored blood having an initial oxygen saturation of 20% or less as identified in paragraphs [0017], [0093], [0099], and [00106], and stored for at least 2 days has reduced methemoglobin, reduced oxidation of beta-hemoglobin at residue H93, increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH), increased GSH, increased ATP, increased DPG, increased NADPH reservoir, reduced PIP to PIP3 ratio, increased methylene THF, increased glutamate, increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio), increased urate, and increased cysteine.
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • oxygen reduced stored blood having an initial oxygen saturation of 10% or less as identified in paragraphs [0017], [0093], [0099], and [00106], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio). In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • GSSG GSH to glutathione disulfide
  • oxygen reduced stored blood having an initial oxygen saturation of 5% or less as identified in paragraph [0017], [0093], [0099], and [00106], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced dioxidation of Cys152 in Glyceraldehyde-3-Phosphate Dehydrogenase.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • oxygen reduced stored blood having an initial oxygen saturation of 3% or less as identified in paragraph [0017], [0093], [0099], and [00106], and stored for at least 2 days has reduced methemoglobin.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced dioxidation of Cys152 in Glyceraldehyde-3-Phosphate Dehydrogenase.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced oxidation of beta-hemoglobin at residue H93.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased reservoir of reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased GSH. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ATP and DPG. In a further aspect, oxygen reduced stored blood of the present disclosure further includes increased NADPH reservoir, and increased GSH, ATP, and DPG. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having reduced PIP to PIP3 ratio. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased methylene THF. In an aspect, the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased glutamate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased ratio of GSH to glutathione disulfide (GSSG) (GSH/GSSG ratio).
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased urate.
  • the oxygen reduced stored blood of the present disclosure is oxygen reduced stored blood having increased cysteine.
  • Ischemia reperfusion injury occurs when the blood supply is interrupted then re-established and is a significant cause of mortality and morbidity.
  • Surgeries involving interruption of the blood supply for example cardiac surgery, kidney transplant, liver resection or colectomy all put the patient at risk of ischemia reperfusion injury.
  • Improved methods for providing blood for transfusion during bypass or p surgery is desirable.
  • the oxidative damage results in cellular death and organ dysfunction as a direct result of re-establishment of oxygenated blood flow. It is further thought that in addition to oxidative damage, reperfusion initiates an inflammatory response that, among other effects, can result in hypercoagulability and further cell damage.
  • a patient experiencing ischemia/reperfusion injury can present the following clinical manifestations and combinations thereof
  • oxygen reduced stored blood has reduced levels of BRMs RANTES, Eotaxin 1, cell free hemoglobin, and isoprostane.
  • Oxygen reduced stored blood has generally reduced levels of inflammatory factors when compared to conventionally stored blood. Accordingly, conventionally stored blood containing pro-inflammatory compounds can be a significant risk for mortality and adverse events.
  • a human patient in need of a blood transfusion is a patient in need of a massive transfusion, recurrent transfusions or chronic transfusions.
  • a human patient in need of a blood transfusion has sickle cell disease with a hemoglobin concentration below 5 g/dL.
  • a human patient in need of a blood transfusion has sickle cell disease and the peak, centerline flow velocity of the middle cerebral artery is greater than 200 cm/sec as determined by transcranial Doppler ultrasound (TCD).
  • TCD transcranial Doppler ultrasound
  • a human patient in need of a blood transfusion has sickle cell disease and receives transfusions to reduce sickle hemoglobin levels to below 30% of total hemoglobin in the body.
  • a human patient in need of a blood transfusion has sickle cell disease and is experiencing acute chest syndrome.
  • a human patient in need of a blood transfusion has sickle cell disease and is experiencing a vaso-occlusive crisis.
  • a human patient in need of a blood transfusion has sickle cell disease and is in need of surgery, wherein said patient receives one or more pre-operative transfusions to reduce perioperative hypoxia, hypoperfusion, and acidosis.
  • a human patient in need of a blood transfusion has thalassemia with a hemoglobin concentration below 5 g/dL.
  • a human patient in need of a blood transfusion is a surgery patient.
  • a human patient in need of a blood transfusion has systemic inflammatory response syndrome (SIRS).
  • SIRS systemic inflammatory response syndrome
  • a human patient in need of a blood transfusion has chronic vascular inflammation.
  • a human patient in need of a blood transfusion has diabetes.
  • a human patient in need of a blood transfusion having chronic vascular inflammation has diabetes.
  • a human patient in need of a blood transfusion has inflammation, endotheliopathy, adhesion to endothelial cell wall, hypercoagulability, vasoconstriction, complement system activation, impaired perfusion, infection, or immunomodulation.
  • blood refers to whole blood, leukoreduced RBCs, platelet reduced RBCs, and leukocyte and platelet reduced RBCs.
  • the term blood further includes packed red blood cells, platelet reduced packed red blood cells, leukocyte reduced packed red blood cells, and leukocyte and platelet reduced packed red blood cells.
  • the temperature of blood can vary depending on the stage of the collection process, starting at the normal body temperature of 37° C. at the time and point of collection, but decreasing rapidly to about 30° C. as soon as the blood leaves the patient's body and further thereafter to room temperature in about 6 hours when untreated, and ultimately being refrigerated at between about 4° C. and 6° C.
  • blood product includes separated platelets, plasma, or white blood cells.
  • whole blood includes white blood cells (WBCs), platelets suspended in plasma, and includes electrolytes, hormones, vitamins, antibodies, etc.
  • WBCs white blood cells
  • white blood cells are normally present in the range of between 4.5 and 11.0 ⁇ 10 9 cells/L, and the normal RBC range at sea level is 4.6-6.2 ⁇ 10 12 /L for men and 4.2-5.4 ⁇ 10 12 /L for women.
  • the normal hematocrit, or percent packed cell volume is about 40-54% for men and about 38-47% for women.
  • the platelet count is normally 150-450 ⁇ 10 9 /L for both men and women.
  • Whole blood is collected from a blood donor, and is usually combined with an anticoagulant. Whole blood, when collected is initially at about 37° C.
  • Whole blood can be processed according to methods of the present disclosure at collection, beginning at 30-37° C., or at room temperature (typically about 25° C.).
  • red blood cells include RBCs present in whole blood, leukoreduced RBCs, platelet reduced RBCs, leukocyte and platelet reduced RBCs, and packed red blood cells (pRBCs).
  • RBCs red blood cells
  • pRBCs packed red blood cells
  • Human red blood cells in vivo are in a dynamic state.
  • the red blood cells contain hemoglobin, the iron-containing protein that carries oxygen throughout the body and gives red blood its color.
  • the percentage of blood volume composed of red blood cells is called the hematocrit.
  • RBCs also includes packed red blood cells (pRBCs).
  • oxygen reduced stored RBCs can include oxygen and carbon dioxide reduced stored RBCs.
  • stored blood includes oxygen reduced or oxygen and carbon dioxide reduced blood stored from 1 to 6° C.
  • stored blood includes stored red blood cells.
  • stored red blood cells includes oxygen reduced or oxygen and carbon dioxide reduced red blood cells stored from 1 to 6° C.
  • stored red blood cells include red blood cells (RBC) present in whole blood.
  • stored red blood cells include RBC present in leukoreduced whole blood.
  • stored red blood cells include red blood cells (RBC) present in leukoreduced RBC.
  • stored red blood cells include red blood cells (RBC) present in platelet reduced RBC.
  • stored red blood cells include red blood cells (RBC) present in leukoreduced and platelet reduced RBC.
  • oxygen reduced stored red blood cells can be stored for a period of at least 2 days. In another aspect, oxygen reduced stored red blood cells can be stored for a period of at least 7 days. In another aspect, oxygen reduced stored red blood cells can be stored for a period of at least 14 days. In another aspect, oxygen reduced stored red blood cells can be stored for a period of at least 21 days. In another aspect, oxygen reduced stored red blood cells can be stored for a period of at least 28 days. In another aspect, oxygen reduced stored red blood cells can be stored for a period of up to 42 days.
  • a “unit” of blood is about 450-500 ml including anticoagulant.
  • Suitable anticoagulants include CPD, CPDA1, ACD, and ACD-A.
  • Suitable blood for use in this method comprises oxygen reduced stored blood having an anticoagulant.
  • oxygen reduced red blood cells is stored for up to 6 weeks to produce oxygen reduced stored blood.
  • oxygen reduced stored blood usually further comprise an additive solution.
  • Suitable additive solutions according to the present disclosure include AS-1, AS-3 (Nutricel®), AS-5, SAGM, PAGG-SM, PAGG-GM, MAP, AS-7, ESOL-5, EAS61, OFAS1, OFAS3, and combinations thereof.
  • the additive solution is added at the time of component separation.
  • the additive solution is AS-1.
  • the additive solution is AS-3.
  • the additive solution is SAGM.
  • oxygen reduced stored blood and oxygen and carbon dioxide reduced stored blood have an initial oxygen saturation of 40% or less. In another aspect, oxygen reduced stored blood have an initial oxygen saturation of 20% or less. In another aspect, oxygen reduced stored blood have an initial oxygen saturation of 10% or less. In another aspect, oxygen reduced stored blood have an initial oxygen saturation of 5% or less. In another aspect, oxygen reduced stored blood have an initial oxygen saturation of 3% or less.
  • oxygen reduced stored blood has an initial oxygen saturation of 40% or less and is stored for at least 2 days. In an aspect, oxygen reduced stored blood has an initial oxygen saturation of 40% or less is stored for at least 4 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 7 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 40% or less is stored for at least 14 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 40% or less is stored for at least 21 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 40% or less is stored for at least 28 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 40% or less is stored for at least 35 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 40% or less is stored for 42 days.
  • oxygen reduced stored blood has an initial oxygen saturation of 20% or less and is stored for at least 2 days. In an aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 4 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 7 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 14 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 21 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 28 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 35 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for 42 days.
  • oxygen reduced stored blood has an initial oxygen saturation of 10% or less is stored for at least 2 days. In an aspect, oxygen reduced stored blood has an initial oxygen saturation of 10% or less is stored for at least 4 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 10% or less is stored for at least 7 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 10% or less is stored for at least 14 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 10% or less is stored for at least 21 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 10% or less is stored for at least 28 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 10% or less is stored for at least 35 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for 42 days.
  • oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for at least 2 days. In an aspect, oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for at least 4 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for at least 7 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for at least 14 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for at least 21 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for at least 28 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for at least 35 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 5% or less is stored for 42 days.
  • oxygen reduced stored blood has an initial oxygen saturation of 3% or less is stored for at least 2 days. In an aspect, oxygen reduced stored blood has an initial oxygen saturation of 20% or less is stored for at least 4 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 3% or less is stored for at least 7 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 3% or less is stored for at least 14 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 3% or less is stored for at least 21 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 3% or less is stored for at least 28 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 3% or less is stored for at least 35 days. In another aspect, oxygen reduced stored blood has an initial oxygen saturation of 3% or less is stored for at least 42 days.
  • the present disclosure provides for, and includes, a method for improving energy metabolism in a human patient in need of a blood transfusion comprising providing oxygen reduced stored blood for transfusion into a human patient in need of a blood transfusion having an increased risk for transfusion mediated oxidative stress, wherein said oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has an increased risk of oxidative stress.
  • oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period, provided to a patient in need of a blood transfusion reduces the total number of units to be transfused.
  • the total number of units to be transfused is reduced by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, and at least 10.
  • the total number of units to be transfused is reduced by between 1 and 2, between 2 and 4, between 4 and 6. Between 6 and 8, and between 8 and 10.
  • the present disclosure provides for, and includes, a method of reducing the risk of adverse transfusion events, including but not limiting to, inflammatory responses in a patient and in need of a blood transfusion comprising providing oxygen reduced stored blood having reduced levels of at least one inflammatory factor when compared to non-oxygen reduced stored blood stored for an identical storage period wherein said patient has an increased risk of an inflammatory response.
  • the present disclosure provides for, and includes, a method of a method of decreasing the risk of septic complications in critically ill patients, owing to the improved osmotic and mechanical resistance of oxygen controlled RBCs, which in turn decreases the likelihood of in vivo post-transfusion hemolysis and subsequently provides benefits in terms of iron overload and non-transferrin-bound iron (NTBI) burden in septic recipients.
  • NTBI non-transferrin-bound iron
  • the term “greater” or “increased” means that the measured values of oxygen reduced and anaerobically stored blood, when compared to the measured values of otherwise equivalently treated normoxic or hyperoxic conventionally stored blood, are at least 1 standard deviation greater, with a sample size of at least 5 for each compared measured condition.
  • the term “decreased” or “less” means that the measured values of oxygen reduced and anaerobically stored blood when compared to the measured values of otherwise equivalently treated normoxic or hyperoxic conventionally stored blood RBCs, are at least 1 standard deviation lower, with a sample size of at least 5 for each compared measured condition.
  • the term “less than” refers to a smaller amount and an amount greater than zero.
  • compositions, method or structure can include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” can include a plurality of compounds, including mixtures thereof.
  • a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
  • the phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
  • the term “method” refers to manners, means, techniques, and procedures for accomplishing a given task including, but not limited to, providing a human patient in need of a blood transfusion with oxygen reduced stored blood having an initial oxygen saturation of 20% or less and stored for at least 2 days as provided in paragraphs [0048]-[0051], [0086]-[0091], and [00111]-[00115].
  • the term “equivalent” means that the measured values of oxygen reduced stored blood with 20, 10, 5, and ⁇ 3% SO 2 when compared to the measured values of otherwise equivalently treated normoxic or hyperoxic conventionally stored blood, are within 1 standard deviation of each other with a sample size of at least 4 for each compared measured condition.
  • the present disclosure provides for the following embodiments:
  • a method of reducing the risk of an inflammatory response in a human patient and in need of a blood transfusion comprising
  • said human patient and in need of a blood transfusion is selected from the group consisting of a surgery patient requiring a tissue perfusion bypass, a patient having chronic vascular inflammation, a patient having chronic inflammatory bowel disease, a patient having chronic obstructive pulmonary disease (COPD), a patient having sickle cell disease, a patient having thalassemia, a patient having organ failure, a patient having systemic inflammatory response syndrome (SIRS), a patient having diabetes mellitus, a patient having Bechet's disease, a patient having rheumatoid arthritis, a patient having smoke inhalation, and a patient having a combination thereof.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • SIRS systemic inflammatory response syndrome
  • invention 5 further comprising an inflammatory cytokine selected from RANTES, eotaxin 1, or soluble CD40-ligand (SCD40L).
  • an inflammatory cytokine selected from RANTES, eotaxin 1, or soluble CD40-ligand (SCD40L).
  • a method for reducing oxidative stress in a human patient in need of a blood transfusion comprising
  • said human patient in need of a blood transfusion having an increased risk of oxidative stress is selected from the group consisting of a trauma patient requiring four or more units of blood, a trauma patient requiring ten or more units of blood, a patient having sickle cell disease, a patient having thalassemia, and combinations thereof.
  • said storage period is at least 42 days and said oxygen reduced stored blood further comprises a reduced level of oxidation of beta-hemoglobin at residue H93 wherein said reduction in said oxygen reduced stored blood is relative to non-oxygen reduced stored blood stored for an identical storage period.
  • a method for reducing the risk of an adverse event in a hemoglobinopathy patient in need of a blood transfusion comprising providing oxygen reduced stored blood for transfusion into a hemoglobinopathy patient in need of a blood transfusion, wherein said oxygen reduced stored blood has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has an increased risk of an adverse event.
  • hemoglobinopathy patient in need of a blood transfusion is a sickle cell patient.
  • hemoglobinopathy patient in need of a blood transfusion is a sickle cell patient having a hemoglobin concentration below 5 g/dL.
  • said providing oxygen reduced stored blood for transfusion comprises providing chronic transfusion therapy wherein said transfusion is provided every three weeks or when hemoglobin concentrations decline below 5 g/dL.
  • hemoglobinopathy patient in need of a blood transfusion is a thalassemia patient in need of a blood transfusion.
  • thalassemia patient in need of a blood transfusion is a thalassemia patient having a hemoglobin concentration below 7 g/dL.
  • said providing oxygen reduced stored blood for transfusion comprises providing chronic transfusion therapy wherein said transfusion is provided every two weeks or when hemoglobin concentrations decline below 7 g/dL.
  • said storage period is at least 42 days and said oxygen reduced stored blood further comprises a reduced level of oxidation of beta-hemoglobin at residue H93 wherein said reduction in said oxygen reduced stored blood is relative to non-oxygen reduced stored blood stored for an identical storage period.
  • hemoglobinopathy patient in need of a blood transfusion is a patient in need of a massive transfusion or chronic transfusions.
  • a method for reducing cardiac, renal and gastrointestinal ischemia reperfusion injury in a patient in need of a blood transfusion comprising
  • said patient in need of a blood transfusion is a patient selected from the group consisting of a cardiac surgery patient, kidney transplant patient, liver resection patient, or colectomy patient.
  • said storage period is at least 42 days and said oxygen reduced stored blood further comprises a reduced level of oxidation of beta-hemoglobin at residue H93 wherein said increase or said reduction in said oxygen reduced stored blood is relative to non-oxygen reduced stored blood stored for an identical storage period.
  • a method for reducing delayed hemolytic transfusion reaction in a patient in need of a blood transfusion comprising providing oxygen reduced stored blood that has an initial oxygen saturation of 20% or less prior to being stored for a storage period wherein said patient has an increased risk of a delayed hemolytic transfusion reaction.
  • said patient in need of a blood transfusion is a patient selected from the group consisting of a sickle cell patient or a thalassemia patient, a trauma patient receiving massive transfusion, and a patient receiving chronic transfusions.
  • a total of up to 6 double red blood cell (2RBC) units are collected from healthy donors by apheresis, leukoreduced, and stored in CPD2/AS-3. 2RBC units are pooled and split into six samples of hyperoxic, normoxic, or various levels of hypoxia 2RBCs, as described in Table 3.
  • Each 2RBC unit (samples 3 to 6) to be reduced is processed by connecting the collection bag to a Sorin D100 membrane oxygenator (Sorin Group, Arvada, Colo.) and pumped at a flow rate of 700 ml/minute with a mixture of 95% N 2 and 5% CO 2 gas to achieve pre-storage % SO 2 , while maintaining pCO2 ⁇ 30 mmHg (37° C.).
  • Oxygen-reduced units are stored anaerobically in a canister, and sampling, as well as separation of RBC and supernatant are carried out in N2-filled anaerobic glove box.
  • For hyperoxic units (Sample 2), calculated volume of O 2 gas is added sterilely to achieve 90-98% SO 2 .
  • Hyperoxic (Sample 2) and control (Sample 1) units are stored in ambient air. All units are stored for 6 weeks at 4° C. and sampled at days 0, 2, 7, 14, 21, 28, 35 and 42. As shown in FIG. 1 , % SO 2 in hypoxic units continue to decrease and hyperoxic units remain unchanged over the 42 days of storage.
  • CVs Technical reproducibility
  • Leukotriene B4 is an effective polymorphonuclear neutrophil chemoattractant. As shown in FIG. 2 , leukotriene B4 accumulates in conventionally stored normoxic (control; solid line) and hyperoxic RBCs over 42 days of storage, however, leukotriene B4 remains undetectable in hypoxic RBCs.
  • Thromboxane A2 is an unstable, potent vasoconstrictor which stimulates vessel contraction through vascular smooth muscle thromboxane A2 receptors.
  • Thromboxane B2 a more stable form of thromboxane A2, accumulates less in hypoxic RBCs over 42 days of storage when SO 2 is ⁇ 3%, compared to control (solid line) RBCs ( FIG. 3 ).
  • oxidized lipid products like HETEs, accumulate less in hypoxic stored blood compared to normoxic and hyperoxic stored blood in supernatant. This decrease in HETE accumulation in hypoxic RBCs compared to normoxic (solid line) blood is also displayed in the cells.
  • Relative flux of glucose through glycolysis (EMP) and pentose pathway (PPP) can be determined by including 13 C 1,2,3 -glucose ( 13 C-glucose) in the additive solution.
  • 13 C-lactate produced by oxidative PPP does not include 13 C at all, or two ( 13 C 2,3 -lactate), while lactate produced directly from glucose via EMP has either all three carbons with 13C or none at all.
  • oxygen reduced stored blood has a higher rate of NADPH and NADPH/NADP+ synthesis compared to control blood (solid line). Thereby the oxygen reduced stored blood that is stored up to 42 days have lower levels of oxidative stress.
  • Oxygen reduced stored blood further shows a higher rate of NADH+ NAD pool synthesis compared to control and hyperoxic blood ( FIG. 8 ).
  • the beneficial effects of oxygen reduced stored blood is seen between 21 to 42 days of storage.
  • Oxygen reduced stored blood also has increased methylenetetrahydrofolate (methylene THF) levels compared to control (solid line). Methylenetetrahydrofolate promotes the production of NADPH. Specifically, oxygen reduced stored blood shows a 1.4- and 2-fold increase of methylenetetrahydrofolate compared to control blood, at 14 and 42 days, respectively ( FIG. 9 ).
  • methylene THF methylenetetrahydrofolate
  • Glutamate a precursor for glutathione synthesis, is also increased in oxygen reduced stored blood compared to control (solid line) beginning at day 14 ( FIG. 10 ).
  • glutamate is increased by approximately 2-fold in oxygen reduced stored blood at day 42 of storage compared to control (solid line).
  • glutathione (GSH) levels are increased in oxygen reduced stored blood in a dose-dependent manner over the 42 day storage period compared to control (solid line).
  • oxygen reduced stored blood show a 2-fold increase in glutathione over control at days 7 and 42 ( FIG. 11 ).
  • the high glutamate and reduced glutathione and GSH/GSSG ratios ( FIG. 12 ) are suggestive of decreased oxidative stress in oxygen reduced stored blood.
  • Cysteine is a rate limiting substrate of GSH synthesis and the cysteine levels are evaluated in control, hyperoxic, and oxygen reduced stored blood. Cysteine synthesis through methionine catabolism via cytosolic one-carbon metabolism reactions is the highest in oxygen reduced stored blood. The increase in cysteine synthesis over control blood is evident after 28 days of storage ( FIG. 13 ).
  • Another indicator of reduced oxidative stress is the accumulation of the antioxidant urate. As shown in FIG. 14 , oxygen reduced stored blood displays increased levels of urate compared to control blood after 28 to 42 days of storage.
  • oxygen reduced stored blood exhibits increased flux through EMP and thereby generate higher levels of ATP and 2, 3-DPG. oxygen reduced stored blood also exhibits increased de novo ATP via the Pentose Phosphate Pathway between 7 to 35 days of storage ( FIG. 16 ).
  • redox-sensitive residue Cys152 is observed to be oxidatively modified in oxygen reduced stored blood (grey bars) compared to control (black bars; FIG. 17 ). This loss in catalytic activity of results in GAPDH migration to the membrane and removal through vesiculation.
  • Eryptosis can also be responsible for increased inflammation in transfusion recipients. Eryptosis is the suicidal death of RBC which is characterized by reduced phosphatidylserine exposure, cell shrinkage, and membrane blebbing. Reduced phosphatidylserine asymmetry combined with cell surface glycoproteins, mediated by membrane vesiculation, play a role in RBC clearance.
  • PIP phosphorylation to PIP3 is measured in the 6 normoxic, hyperoxic, and hypoxic stored blood samples. As shown in FIG. 18A and FIG. 18B , phosphorylation of PIP to the calcium channel agonist PIP3 is reduced under anaerobic conditions. Phosphorylation of PIP to PIP3 is reduced in a dose-dependent manner in oxygen reduced stored blood compared to control (solid line), over 42 days of storage.
  • Oxygen reduced stored blood result in a reduction in microparticle formation as consequences of oxidation of beta-hemoglobin at residue H93 compared to control after 42 days of storage ( FIG. 19 ).
  • Methemoglobin is unstable and denatures into hydrophobic and reactive globin and hemin, which can disrupt RBC membrane, induce vesiculation, induce morphology change and catalyze hydroxyl radical generation. As shown in FIG. 20 , oxygen reduced stored blood has reduced Methemoglobin levels at every time point analyzed compared to control (solid line) and hyperoxic stored blood.
  • Methemoglobin reductase the enzyme responsible for the reduction of oxidized iron in the prosthetic group of hemoglobin, requires NAD(P)H to function.
  • Increases in NADH/NAD+ ratios are observed in hypoxically or anaerobically stored RBCs, owing to increased glycolytic fluxes (higher lactate/pyruvate ratios) and resulting from alterations of the cytosolic reducing environment owing to the removal of oxygen (consistent with the Nemst equation).

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