WO2004105483A1 - Stockage de sang - Google Patents

Stockage de sang Download PDF

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Publication number
WO2004105483A1
WO2004105483A1 PCT/US2003/015063 US0315063W WO2004105483A1 WO 2004105483 A1 WO2004105483 A1 WO 2004105483A1 US 0315063 W US0315063 W US 0315063W WO 2004105483 A1 WO2004105483 A1 WO 2004105483A1
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WO
WIPO (PCT)
Prior art keywords
ribose
blood
cells
dpg
phosphate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2003/015063
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English (en)
Inventor
Clarence Johnson
Daniel G. Ericson
John A. St. Cyr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bioenergy Inc
Original Assignee
Bioenergy Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bioenergy Inc filed Critical Bioenergy Inc
Priority to PCT/US2003/015063 priority Critical patent/WO2004105483A1/fr
Priority to AU2003272198A priority patent/AU2003272198A1/en
Publication of WO2004105483A1 publication Critical patent/WO2004105483A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts
    • A01N1/12—Chemical aspects of preservation
    • A01N1/122—Preservation or perfusion media
    • A01N1/126—Physiologically active agents, e.g. antioxidants or nutrients
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/10—Preservation of living parts

Definitions

  • This invention pertains to the storage, preservation and rejuvenation of blood and blood products which include whole blood and red blood cells.
  • each donated unit of blood referred to as whole blood
  • the need for blood is great: on any given day, approximately 32,000 units of red blood cells are needed.
  • blood component therapy allows several patients to benefit from each unit of blood.
  • Whole blood is a living tissue that circulates through the heart, arteries, veins and capillaries, carrying nourishment, electrolytes, antibodies, heat and oxygen to the body tissues.
  • Whole blood is comprised of red blood cells, white blood cells and platelets suspended in a proteinaceous fluid termed blood plasma. If blood is treated to prevent clotting and permitted to stand in a container, red blood cells will settle to the bottom of the container, the plasma will remain on top and the white blood cells will form a layer on top of the red blood cells. A centrifuge is commonly used to hasten this separation. The platelet-rich plasma is then removed and placed into a sterile bag for further processing to separate, for example, platelets, clotting factors, albumin, immunoglobulins and the like.
  • red blood cells which contain hemoglobin, a complex iron-containing protein that carries oxygen throughout the body and gives blood its red color.
  • the percentage of blood volume that is composed of red blood cells is called the "hematocrit.”
  • the average hematocrit in the adult male is 47%.
  • red blood cells There are about one billion red blood cells in two or three drops of blood, and, for every 600 red blood cells, there are about 40 platelets and one white blood cell.
  • RBCs are enucleated, biconcave discs that are continuously being produced, broken down and destroyed.
  • the biconcave disc shape is crucial to the function of RBCs, presenting a maximal surface area for the capture of oxygen in the lungs and its release in the tissue.
  • the cells are flexible and able to bend in order to traverse the tiny tubules of the capillary beds. Since the cells are enucleated and lack mitochondria, they are unable to carry out cellular repair of damage or enzyme inactivation and must rely on anaerobic phosphorylation for energy. After an average 120 days in the circulatory system, the cells are senescent and are phagocytized by circulating monocytes or the fixed ' macrophages of the reticulo-endothelial system.
  • Red blood cells are prepared from whole blood by removing the plasma. When transfused into a patient, the hematocrit is raised while increase in blood volume is minimized, which is especially important to such patients as those with congestive heart failure.
  • the cells are typically suspended in about half the original volume; the preparation is referred to as packed red cells.
  • Patients benefitting most from transfusions of packed red cells include those with chronic anemia from disorders such as kidney failure, malignancies, gastrointestinal bleeding or acute blood loss as from trauma or surgery.
  • Standard solutions for the storage of whole blood comprise citrate-phosphate- dextrose solution (CPD) and citrate-phosphate-dextrose-adenine solution
  • CPDA Citrate or other anticoagulants such as heparin are necessary to prevent clotting. Because blood is a living tissue that maintains metabolic functions even at refrigerated temperatures, it has been considered necessary to provide an energy source such as glucose. Phosphate ion can be used to buffer the lactate produced from glucose utilization.
  • the need remains for a solution in which blood cells in whole blood or packed red cell suspensions can be stored for an increased time and survive functionally when transfused into a recipient.
  • the need also remains for a method to rejuvenate blood and RBCs which are suboptimally functional.
  • Figure 1 shows the decrease in 2,3 diphosphoglycerate in whole blood stored at room temperature.
  • Figure 2 shows the effect of 2,3 diphosphoglycerate levels on the oxygen- hemoglobin dissociation curve.
  • Figure 3 shows the rejuvenation of blood cells by ribose and phosphoenolpyruvate as measured by an increase in 2,3 diphosphoglycerate.
  • the present invention provides a composition in which whole blood and red blood cells can be stored for 42 to 120 days while remaining functional.
  • the solution comprises an anticoagulant, and a compound that is useable by blood cells to maintain structural and functional integrity.
  • the preferred anticoagulant is citrate at a concentration of from 2% to 6%.
  • the preferred compound is poorly utilized by contaminating bacteria.
  • the compound can be D-ribose, a ribose equivalent or a ribose-sparing monosaccharide, collectively referred to as "ribose-related compounds.”
  • Ribose equivalents include ribose-5-phosphate, ribulose-5-phosphate, ribulose, xylulose-5 -phosphate, xylulose, xylose and the related alcohol xylitol.
  • the preferred ribose-related compound is D-ribose.
  • the preferred ribose equivalent is xylose.
  • Ribose-related compounds are most preferably used at a concentration of from 3 mM to 20 mM.
  • the most preferred solution comprises 4% sodium citrate and 15mM D-ribose.
  • the preferred solution when hydrated, has a pH between 7.0 and 7.8.
  • the compositions of this invention do not contain dextrose.
  • An additional composition of this invention comprises an anticoagulant, a buffer and a compound that is useable by blood cells to maintain structural and functional integrity.
  • the preferred anticoagulant is sodium citrate at a concentration of from 2% to 6%.
  • the preferred buffer is sodium phosphate (NaH 2 PO 4 /Na 2 HPO 4 , to maintain a pH between 6.8 and 7.6) at a concentration of from 5 to 20 mM.
  • the preferred compound is poorly utilized by contaminating bacteria.
  • the compound is a ribose-related compound and can be D-Ribose, a ribose equivalent or a ribose-sparing monosaccharide.
  • Ribose equivalents include ribose-5-phosphate, ribulose-5-phosphate, ribulose, xylulose-5- phosphate, xylulose, xylose and the related alcohol xylitol.
  • the preferred ribose equivalent is xylose.
  • the ribose-related compound is most preferably at a concentration of from 5mM to 20 mM.
  • the most preferred solution comprises 10 mM sodium citrate, 10 mM sodium phosphate and 15mM D-ribose.
  • the preferred solution when hydrated, will have a pH between 7.0 and 7.8.
  • the compositions of this invention do not contain dextrose.
  • compositions of this invention are added to whole blood as it is collected.
  • the compositions are most conveniently placed in dry form or concentrated aqueous solution within the blood collection receptacle in amounts sufficient to provide the above concentrations.
  • RBCs that are packed are typically suspended in plasma or saline at about half the volume of the whole blood from which they were separated.
  • the compositions of this invention are added to the plasma or saline in amounts sufficient to provide the above compositions.
  • Suboptimal blood includes blood that has been left at room temperature for more than an hour or stored at 4°C for more than a week and blood that has been damaged by blood fractionation or leukofiltration procedures or pathogen inactivation treatment.
  • DPG 2,3 diphosphoglycerate
  • Suboptimal blood includes blood that has been left at room temperature for more than an hour or stored at 4°C for more than a week and blood that has been damaged by blood fractionation or leukofiltration procedures or pathogen inactivation treatment.
  • the blood is warmed to 20°C to 37°C, sufficient ribose-related compound to provide a concentration of from 5 to 20 mM is added and the blood bag gently shaken for 10 to 60 minutes, the rejuvenation period.
  • the ribose-related compound is most conveniently added as a concentrated solution through the side arm of the blood bag.
  • the most preferred ribose-related compound is 10 mM D-ribose, and the most preferred rejuvenation period is 30 minutes.
  • the blood is warmed to 37° C, sufficient ribose-related compound to provide a concentration of from 5 to 20 mM and sufficient sodium phosphate to provide a concentration of from 5 to 10 mM is added and the blood bag gently shaken for 10 to 60 minutes
  • Toxic substances formed during anoxia accumulate and are not carried away by the circulation as in vivo.
  • Intracellular glutathione which maintains the appropriate cellular redox level, decreases, leading to the accumulation of free radicals.
  • Lowered pH, the accumulation of free radicals and exhaustion of energy substrates are probably the main causes of storage lesion in stored RBC.
  • Mammalian RBCs contain high levels of the glycolytic intermediate 2,3 diphosphoglycerate (DPG) in concentrations roughly equimolar with hemoglobin.
  • DPG glycolytic intermediate 2,3 diphosphoglycerate
  • Binding decreases with increasing pH.
  • oxygen levels fall in vivo, hyperventilation occurs that reduces carbon dioxide and increases pH, thereby causing higher oxygen affinity and lower tissue delivery of oxygen. This reaction is accentuated by lower DPG levels; conversely, higher DPG levels maintain or lower the oxygen affinity for hemoglobin, thereby increasing tissue delivery.
  • RBC function is meant the ability of the RBC to bind oxygen at high oxygen tension (i.e., in the lungs in vivo) and release it at low oxygen tension (i.e., in the tissues in vivo). Therefore, DPG is both an enhancer of the lung-blood-tissue oxygen and tissue-blood-lungs carbon dioxide cycles and, because it correlates with function, a useful diagnostic parameter of RBC function.
  • OBC oxygen dissociation curve
  • Other parameters include ATP and glutathione levels, pH and hemoglobin oxygen affinity.
  • the FDA adds the additional criteria of greater than 75% RBC survival recovery with less than 1% hemolysis. Survival is determined experimentally by labeling the RBCs with radioactive chromium and determining the radioactivity circulating at 24 hours after transfusion. Lowered survival not only fails to deliver the increased oxygen capacity sought by transfusion, but also releases deleterious substances such as free hemoglobin.
  • the exemplar composition contains D-ribose. It has surprisingly been found by the inventors of this invention that the pentose monosaccharide D-ribose can be substituted for dextrose, the energy source for blood stored in CPD or CDPA.
  • ribose D-ribose or ribose equivalents which include but are not limited to ribose-5-phosphate, ribulose-5-phosphate, ribulose, xylulose-5-phosphate, xylulose, xylose and the related alcohol xylitol, all of which are collectively referred to as ribose-related compounds.
  • Ribose may be slowly converted in the cells to glucose, which enters the glycolytic pathway or may participate in other energy cycles. Thus one of the roles of ribose may be as an energy source for glycolysis.
  • Ribose has a further advantage over dextrose in that dextrose is a preferred substrate for contaminating bacteria, while ribose is a poor substrate for most bacteria.
  • Example 1 Composition for storage of whole blood and packed RBC.
  • Whole blood is collected into a bag containing dry powders or concentrated aqueous solution sufficient to provide a final concentration of 4% sodium citrate, 10 mM sodium phosphate at a pH of 7.4, and 15 mM D-ribose (CPR).
  • CPR D-ribose
  • Figure la shows that levels of DPG stored at 4° C levels of DPG remained high over 24 hours of storage, with the heparin stored RBC maintaining the initial levels somewhat better than those stored in CPDA. At room temperature, loss of DPG was accelerated, as shown in Figure lb. Those cells stored in CPDA lost 75% of the initial levels of DPG, while those stored in heparin were slightly better, losing only about 67% of the initial levels.
  • a unit of collected blood containing the composition of Example 1 will be stored at 4° C. At the time points 0 days, 15 days, 30 days, 45 days, 60 days, 90 days and 120 days, viability will be determined. The following tests will be performed: Trypan blue exclusion to determine % live versus dead RBC; free hemoglobin to determine lysed RBC; hematocrit to determine diminution of size and number of RBCs; pH; and 2,3-DPG.
  • Example 2 showed that storage at room temperature accelerated the decrease in DPG, the measure of RBC function. Whole blood stored at 4° C may also have decreased DPG levels. Additionally, many blood banks have a practice of holding blood or RBC at room temperature for eight to 12 hours in order to kill Yersinia sp., a psychrophilic bacterium that is a major contaminant of blood. As shown, it is expected that such blood will have low levels of DPG and hence be suboptimally functional on transfusion.
  • Example 5 Glycolytic intermediates enhancing the D-ribose effect.
  • Example 4 The rejuvenation experiment of Example 4 was repeated adding the high energy glycolysis intermediate phosphoenolpyruvate (PEP). Samples were held at for six days at room temperature until DPG levels were barely detectable. At that point, 15 mM D-Ribose, lOmM to lOOmM PEP or both were added and the blood incubated at 37° for 30 minutes. As seen in Figure 3, the DPG levels decreased from about 2 ⁇ mol/ml (baseline) to barely detectable levels at day 6. Adding PEP gave some benefit, raising the DPG levels to nearly 1 mmol/ml. Ribose also raised levels to about 1 ⁇ mol/ml. The effect of ribose plus PEP was additive: levels exceeded 1.5 ⁇ mol/ml, nearly the levels on day 0.
  • PEP high energy glycolysis intermediate phosphoenolpyruvate

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Selon cette invention, on ajoute D-Ribose, un tampon et un anticoagulant à du sang total ou à un culot globulaire de manière à étendre la fonction du stockage au-delà de 42 jours. Ladite invention a aussi trait à des méthodes qui permettent de rajeunir de manière suboptimale des globules rouges fonctionnelles. Ces méthodes comprennent l'incubation des cellules à 37 °C pendant 10 à 62 minutes en présence de D-Ribose.
PCT/US2003/015063 2003-05-14 2003-05-14 Stockage de sang Ceased WO2004105483A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2003/015063 WO2004105483A1 (fr) 2003-05-14 2003-05-14 Stockage de sang
AU2003272198A AU2003272198A1 (en) 2003-05-14 2003-05-14 Storage of blood

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2003/015063 WO2004105483A1 (fr) 2003-05-14 2003-05-14 Stockage de sang

Publications (1)

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WO2004105483A1 true WO2004105483A1 (fr) 2004-12-09

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WO (1) WO2004105483A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011103177A1 (fr) * 2010-02-16 2011-08-25 Viacell, Llc Compositions contenant un nucleoside et methode de traitement des erythrocytes
WO2011103179A1 (fr) * 2010-02-16 2011-08-25 Viacell, Llc Compositions contenant de l'arginine et procédés de traitement des globules rouges
US8871434B2 (en) 2008-03-21 2014-10-28 Fenwal, Inc. Red blood cell storage medium for extended storage
WO2014183134A1 (fr) * 2013-05-10 2014-11-13 President And Fellows Of Harvard College Solutions pour les globules rouges
US8968992B2 (en) 2008-03-21 2015-03-03 Fenwal, Inc. Red blood cell storage medium for extended storage
US9409128B2 (en) 2009-10-23 2016-08-09 Fenwal, Inc. Methods for storing red blood cell products
US10117428B2 (en) 2013-07-17 2018-11-06 Rythrx Therapeutics, Llc Compositions and methods for preserving donated blood
EP4319552A4 (fr) * 2021-04-07 2025-01-29 Hemerus Medical, LLC Système et solution pour stockage de sang total amélioré

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAWSON ET AL: "Blood preservation. XXVII. Fructose and mannose maintain ATP and 2,3-DPG", TRANSFUSION, vol. 18, no. 3, 1978, pages 347 - 352, XP002978141 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871434B2 (en) 2008-03-21 2014-10-28 Fenwal, Inc. Red blood cell storage medium for extended storage
US8968992B2 (en) 2008-03-21 2015-03-03 Fenwal, Inc. Red blood cell storage medium for extended storage
US9409128B2 (en) 2009-10-23 2016-08-09 Fenwal, Inc. Methods for storing red blood cell products
US9943077B2 (en) 2009-10-23 2018-04-17 Fenwal, Inc. Methods for storing red blood cell products
US11864553B2 (en) 2009-10-23 2024-01-09 Fenwal, Inc. Methods and systems for providing red blood cell products with reduced plasma
WO2011103179A1 (fr) * 2010-02-16 2011-08-25 Viacell, Llc Compositions contenant de l'arginine et procédés de traitement des globules rouges
CN102869364A (zh) * 2010-02-16 2013-01-09 维亚塞尔有限责任公司 含有精氨酸的组合物和用于处理红细胞的方法
US8980542B2 (en) 2010-02-16 2015-03-17 Viacell, Llc Arginine-containing compositions and methods for treating red blood cells
WO2011103177A1 (fr) * 2010-02-16 2011-08-25 Viacell, Llc Compositions contenant un nucleoside et methode de traitement des erythrocytes
US10537097B2 (en) * 2010-02-16 2020-01-21 Viacell, Llc Methods for treating red blood cells
US20110229871A1 (en) * 2010-02-16 2011-09-22 Ericson Daniel G Nucleoside-containing compositions and methods for treating red blood cells
WO2014183134A1 (fr) * 2013-05-10 2014-11-13 President And Fellows Of Harvard College Solutions pour les globules rouges
US10117428B2 (en) 2013-07-17 2018-11-06 Rythrx Therapeutics, Llc Compositions and methods for preserving donated blood
US10426160B2 (en) 2013-07-17 2019-10-01 Rythrx Therapeutics, Llc Compositions and methods for preserving red blood cells and platelets
US10779529B2 (en) 2013-07-17 2020-09-22 Rythrx Therapeutics, Llc Compositions and methods for preserving red blood cells and platelets
US11344026B2 (en) 2013-07-17 2022-05-31 Rythrx Therapeutics, Llc Compositions and methods for preserving red blood cells and platelets
US11779012B2 (en) 2013-07-17 2023-10-10 Rythrx Therapeutics, Llc Compositions and methods for preserving red blood cells and platelets
EP4319552A4 (fr) * 2021-04-07 2025-01-29 Hemerus Medical, LLC Système et solution pour stockage de sang total amélioré

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Publication number Publication date
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