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
  • A01N1/02—Preservation of living parts
  • A01N1/0205—Chemical aspects
  • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
  • A01N1/0221—Freeze-process protecting agents, i.e. substances protecting cells from effects of the physical process, e.g. cryoprotectants, osmolarity regulators like oncotic agents
• • 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
  • A01N1/02—Preservation of living parts
• • 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
  • A01N1/02—Preservation of living parts
  • A01N1/0205—Chemical aspects
  • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
  • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
• • 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
• • 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
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates generally to the separation of blood into its components such as red blood cells and plasma. More particularly, the present invention relates to the separation and collection of red blood cells whereby the red blood cells remain viable during extended storage.
• Blood may be separated into one or more of its components or fractions such as red cells, white cells, platelets and plasma, and one or more of the blood components or fractions may be collected.
• whole blood is withdrawn from a donor or patient, anticoagulant is added to the withdrawn whole blood and one or more desired components or fractions are separated from the anticoagulated whole blood.
• a separated component may be administered, immediately or soon thereafter, to a patient in need of the particular component. Alternatively, the collected component may be stored for a period of time until it is required for transfusion.
• Blood collection procedures and systems are often referred to as either “manual” or “automated.”
• “manual” blood collection procedures whole blood is withdrawn from a donor and collected in a container that typically includes an amount of anticoagulant. After the collection, the donor is free to leave and the collected unit of whole blood is then subjected to the separation procedure generally described above.
• Automated blood collection procedures the donor is directly connected to a blood collection device and whole blood is withdrawn from the donor. A desired component is separated and collected while the remaining components may be returned to the donor. Automated blood collection procedures have the advantage over manual blood collection procedures in that the initial collection of whole blood and the separation of the whole blood into the desired components or fractions can be achieved in a single procedure.
• Instruments used to perform automated blood collection procedures typically include a reusable hardware portion and a disposable tubing portion intended for one-time use only.
• the hardware portion may include pumps, such as peristaltic pumps for (1) withdrawing whole blood from a donor or patient, (2) introducing anticoagulant into the whole blood (3) introducing blood or blood components into a separation device for separating blood into its components and (4 ) withdrawing one or more blood components from the separation device for later use or for return to the donor or patient.
• Either the hardware portion or the disposable tubing portion may include the separation device which, for example, can be a rotating centrifuge as described in U.S. Patent No. 4,146,172 or a rotating membrane as described in U.S. Patent No.4,753,729.
• the disposable tubing portion typically includes, among other things, the venepuncture needle that is inserted into the donor and through which the whole blood is withdrawn, plastic tubing which transports the blood and/or blood components to and from the donor or patient and to and from the separation device. If a desired blood component is to be collected, the disposable tubing portion may also include plastic bags for collecting the desired blood component(s ) . Typically, the segments of the tubing are threaded over and engaged by the peristaltic pumps of the instrument.
• Peristaltic pumps include rotating members (rotors) driven by motors . Rotation of the pump rotors squeezes the tubing and consequently draws and pushes the blood or blood components through the tubing and through the system.
• a commercially available automated blood separation and collection system is the CS-3000® Plus, sold by Baxter Healthcare Corporation of Deerfield, Illinois.
• the CS-3000® Plus is an automated system for the separation and collection of blood components and/or fractions such as platelets, plasma, stem cells and the like.
• Another example of a commercially available automated blood separation and collection device is the Autopheresis-C®, also sold by Baxter Healthcare Corporation.
• the Autopheresis C® is an automated system for the collection of plasma.
• red cells can be stored for extended periods of time (e.g. beyond 24 hours) when combined with a suitable storage media.
• a suitable storage media e.g., water, methanol, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hem
• Factors that may affect the viability and function of stored red blood cells include ATP levels, 2,3 DPG levels, pH and the hemolysis of the red blood cells.
• ATP adenosine triphosphate
• ATP is produced when the red blood cells metabolize glucose.
• Reduced ATP levels result in increased fragility of the red blood cells and, consequently, reduced viability.
• 2,3 diphosphoglycerate (DPG) plays a role in the red blood cell's ability to release oxygen. When 2,3 DPG levels decrease, the efficiency of oxygen release is impaired.
• red blood cells must also be maintained. As the red cells break down glucose and form lactic acid, the pH of the red cells decreases and the red blood cells undesirably become more acidic. Finally, as red blood cells are stored, they undergo hemolysis. "Hemolysis” refers to the destruction of the red blood cell membrane.
• Storage solutions for storing components such as red blood cells often contain nutrients and other preservatives intended to preserve the viability of red blood cells by helping maintain acceptable ATP, 2,3-DPG and pH levels and suppressing the hemolysis of red blood cells. Although there have been several reported attempts at providing methods for preserving the viability of red blood cells during storage, further improvement in ATP levels and further reduction in hemolysis (as well as other storage parameters) is, nonetheless, still desirable.
• the present invention includes, but is not limited to, a method for collecting red blood cells which includes providing a quantity of whole blood and combining the whole blood with a quantity of an anticoagulant.
• the anticoagulant includes citric acid, trisodium citrate and dextrose.
• the anticoagulated whole blood is separated to provide a red blood cell concentrate.
• the red blood cell concentrate is combined with a quantity of a solution that includes dextrose, sodium chloride, adenine and mannitol.
• the present invention includes, but is not limited to, a red cell composition comprising between approximately 160-240 ml of red blood cells, 20-100 ml of plasma, 5-15 ml of an anticoagulant, which anticoagulant may include, among other things, citric acid, trisodium citrate and dextrose and 80-120 ml of a solution that may include, among other things, adenine, mannitol, dextrose and sodium chloride.
• the present invention includes, but is not limited to, a red cell composition comprising a quantity of red cells, a quantity of a solution comprising dextrose, sodium chloride, adenine and mannitol.
• the red cell concentrate is derived from whole blood that has been anticoagulated with an anticoagulant comprising citric acid, sodium citrate, dextrose and is free of phosphate.
• the present invention includes, but is not limited to, a method for suppressing the hemolysis of red blood cells providing a quantity of whole blood and combining the whole blood with a quantity of an anticoagulant.
• the anticoagulant may include citric acid, trisodium citrate and dextrose.
• the anticoagulated whole blood is separated to provide a red blood cell concentrate.
• the red blood cell concentrate is combined with a quantity of a solution that may include, among other things, dextrose, sodium chloride, adenine and mannitol.
• the combined red cell concentrate and solution are stored in a plastic container.
• FIG. 1 is a top plan view of a disposable tubing set that may be used to separate and collect blood components in accordance with the present invention
• Fig. 2 is a perspective view of a blood separation and collection device with the tubing set of Fig. 1 installed thereon.
• Fig. 3 is a perspective view of another disposable set that may be used to collect blood components in accordance with the present invention
• Fig. 3A is a perspective view of an integral closed disposable set that may be used to collect blood components in accordance with the present invention
• Fig. 4 is a graph comparing the pH levels of stored red blood cell compositions prepared in accordance with the present invention and red blood cell compositions prepared by a different method
• Fig. 5 is a graph comparing ATP levels of stored red blood cell compositions prepared in accordance with the present invention and red blood cell compositions prepared by a different method
• Fig. 6 is a graph comparing potassium levels of stored red blood cell compositions prepared in accordance with the present invention and red blood cell compositions prepared by a different method;
• Fig. 7 is a graph comparing glucose levels of stored red blood cell compositions prepared in accordance with the present invention and red blood cell compositions prepared by a different method;
• Fig. 8 is a graph showing the level of 2,3 DPG of stored red blood cell compositions prepared in accordance with the present invention
• Fig. 9 is a graph showing the level of lactate in stored red blood cell compositions prepared in accordance with the present invention.
• Fig. 10 is a graph comparing the levels of hemolysis in stored red blood cell compositions prepared in accordance with the present invention and red blood cell compositions prepared by a different method.
• FIG. 1 shows a disposable tubing set 10 for use in collecting red cells and/or plasma separated from whole blood.
• Tubing set 10 of Fig. 1 includes a venepuncture needle 12, attached to whole blood inlet tubing line 13, and an anticoagulant spike 14 attached to anticoagulant tubing line 16.
• Disposable tubing set 10 includes a saline spike 18, saline line 20 and a separation device 22.
• separation device 22 includes a whole blood inlet port 24, packed red blood cell port 26 in communication with packed cell line 27 and platelet-poor plasma port 28 in communication with platelet-poor plasma line 30.
• lines 27 and 30 are attached to containers 32 and 34 respectively for collecting red blood cells (32) and plasma (34).
• disposable tubing set 10 is installed on a blood separation and collection device 44.
• a tubing organizer 36 with tubing segments is placed over peristaltic pump rotors 40. Placement of the tubing set 10 onto the hemapheresis device 44 is described in greater detail in U.S. Patent No. 5,460,493 and U.S. Patent Application Serial No. 08/779,094 entitled "Disposable Tubing Set and Organizer Frame for Holding Flexible Tubing," filed January 6, 1997 in the name of J. Handler, M. Moubayed and M. Vandlik and assigned to the assignee of the present application.
• U.S. Patent No. 5,460,493 and U.S. Serial No. 08/779,094 are incorporated by reference herein.
• Fig. 3 shows an accessory disposable tubing set 50 which may be used in combination with the disposable set 10 of Fig. 1.
• Disposable tubing set 50 includes spike 52 and a tubing segment 54, and may include a container 55 of storage solution.
• Disposable tubing set 50 also may include a white cell removal filter 58 and a red blood cell collection container 60.
• Tubing set 50, including container 55, may be integral with tubing set 10 (as shown in Fig. 3A) to provide a unitary closed system or may be connected to tubing set 10 in a sterile manner.
• the collection of a red cell concentrate utilizing the above-described tubing sets 10 (and, if necessary, tubing set 50) will now be generally described.
• whole blood is withdrawn from a donor by inserting venipuncture needle 12 into the vein of a donor (not shown).
• Whole blood is withdrawn through needle 12 and flows through inlet line 13.
• Anticoagulant spike 14 is inserted into anticoagulant container 15 (Fig. 2) to introduce anticoagulant into tubing set 10 through line 16.
• Whole blood flowing from the donor through inlet line 13 is combined with anticoagulant from line 16 by any known conventional means such as "Y" connector 19.
• Anticoagulated whole blood is introduced into separation device 22 at whole blood inlet port 24.
• the separator which in Figs. 1 and 2 includes a rotating spinning membrane as generally described in U.S. Patent Nos. 4,753,729 and 5,194,145, and incorporated by reference herein, the anticoagulated whole blood is separated into packed red cells and plasma.
• the rotating spinning membrane may be rotated at a speed of between approximately 3600-3900 with a preferred speed of approximately 3800 rpm.
• the procedure which typically takes between 20-40 minutes, anywhere between 1000-2000 ml of whole blood may be processed.
• the volume of whole blood processed is between 1200-1400 ml.
• Separated plasma exits the separation device through port 28 and flows through line 30 to plasma container 34.
• Separated red cells exit the separation device through port 26 and, if they are to be collected, through line 27 to red cell collection container 32. It should be understood that it is not necessary that all of the separated red cells be collected in collection container 34. Some of the separated red cells may be returned to the donor.
• Red cells in container 32 may be combined with a storage medium that assists in preserving the viability of the red blood cells.
• red cells and the storage medium may be combined in red cell container 32.
• tubing set 50 shown in Fig. 3 may be used for transferring storage solution from container 55 of tubing set 50 to container 32 and, thereby, combining the red cell concentrate with the storage medium.
• spike 52 may be inserted into container 55 of storage media and a selected quantity of the storage solution can be transferred to container 32 via tubing 54 which may be connected in a sterile manner to container 32.
• red cell concentrate and storage solution in container 32 may be transferred through line 54 and filter 58 to container 60.
• Filters, for filtering blood components are well known and are commercially available. Two filters suitable for use in the above-described method are the Pall WBFl filter assembly available from the Pall Corporation of East Hills, New York and the Asahi RS2000 leukoreduction filter available from the Asahi Medical Co., Ltd. of Tokyo, Japan.
• tubing sets 10 and 50 may comprise one unitary closed system without the use of spikes and/or sterile connectors. Such a closed system may or may not include a filter as described above.
• ACD acid citrate dextrose
• ACD-A ACD, Solution A
• ACD-A One (1) liter of ACD-A includes 22.0 g of trisodium citrate, 7.3 g citric acid, 24.50 g of dextrose and 1 1 of water. Unlike CPD, ACD-A does not include phosphate.
• the amount of anticoagulant combined with blood must be sufficient to prevent the clumping of blood cells or coagulation of plasma of the blood cells during processing.
• too much anticoagulant may result in excess citrate being reinfused to the donor or infused to the recipient, resulting in a "citrate reaction," the symptoms of which may include anxiety, chills, and tingling sensations around the mouth and fingers.
• the ratio of whole blood to anticoagulant should be between approximately 8:1 and 14:1 with a preferred ratio of approximately 12:1 (i.e. 8% ACD/Whole Blood).
• the collected red cells which may include plasma and some residual anticoagulant, are combined with a quantity of a storage solution which allows for extended storage of the red cell concentrate.
• Storage solutions for red cells are known. Storage solutions which may be useful in the method of the present invention are described, for example, in U.S. Patent No. 5,248,506.
• One such storage solution which is preferred for storage of red cells collected in accordance with the present invention is a solution that includes adenine, mannitol, dextrose and sodium chloride.
• Adsol® Commercially available under the name Adsol® and sold by Baxter Healthcare Corporation of Deerfield, Illinois.
• Adsol® One liter of Adsol includes approximately 22.
• red cell composition having a total volume of approximately 250ml (which includes plasma and anticoagulant) is combined with approximately 100ml of Adsol.
• red blood cells collected in accordance with the above- described methods provides a viable red cell composition suitable for extended storage without compromising the viability of the red blood cells.
• the ATP, 2, 3-DPG, potassium and pH levels were comparable to the levels obtained in manually collected red cells using CPD as the anticoagulant for the whole blood and stored in 100 ml of Adsol solution.
• CPD the anticoagulant
• Adsol Adsol
• red blood cells Twenty one (21) units of red blood cells were collected from donors using the separation device generally described above. A total of approximately 1223 ml ( ⁇ 404 ml) was processed through a rotating membrane separation device of the type described above for approximately 25 minutes, ( ⁇ 8 min.) at a rotational speed of approximately 3800 rpm. The whole blood was anticoagulated with ACD-A solution in a ratio of approximately 12:1 whole blood to anticoagulant. Approximately 250ml of red blood cells having a hematocrit of approximately 70% were collected and combined with approximately 100ml of Adsol® solution added to the red blood cells immediately after collection.
• red cells were leukoreduced at room temperature using a Pall WBF 1 or Asahi RS2000 leukoreduction filter and stored for 49 days at 4°C ⁇ 2° C.
• the red cell compositions obtained in accordance with the above-described method wherein final hematocrit of the red cell composition is approximately 70% may include between 160-240 ml of red blood cells, 20-100 ml of plasma, 5-15 ml of anticoagulant and 80-120 ml of the storage solution. More specifically, the red cell composition may include approximately 175-185 ml of red blood cells, 60-70 ml of plasma, 6-10 ml of anticoagulant and 90-110 ml of storage solution.
• the red cell composition may include between about 40-79% red cell concentrate, between about 1-5% anticoagulant, 5- 30% of the plasma and 20-40% storage solution.
• these volumes and/or percentages will vary depending on the donor hematocrit and donor weight.

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• 1998
  • 1998-02-25 WO PCT/US1998/003712 patent/WO1998041087A1/en not_active Application Discontinuation
  • 1998-02-25 JP JP54051898A patent/JP4340927B2/ja not_active Expired - Lifetime
  • 1998-02-25 EP EP98908724A patent/EP0909128A1/de not_active Withdrawn
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