Whole blood collection and storage system

Abstract

In some embodiments, the invention provides a system for collecting whole blood. In some embodiments, the system comprises two bags containing solutions which are mixed prior to, at the same time as, or shortly after the addition of donated whole blood to one of the bags. In some embodiments, the blood bags of the system are substantially free of the plasticizer di(2- ethylhexyl) phthalate. In some embodiments, all components of the system are substantially free of the plasticizer di(2-ethylhexyl) phthalate.

Description

WHOLE BLOOD COLLECTION AND STORAGE SYSTEMCross-Reference to Related Applications

[0001] The present application claims priority to U.S. provisional patent application Serial No. 63 / 708,628 filed October 17, 2024, the entire contents of which is hereby incorporated by reference.Statement regarding Federally Sponsored Research or Development

[0002] This invention was made with U.S. government support under Award No. W81XWH-22- 2-0009 awarded by the Defense Health Agency, Medical Research and Development Branch (DHA / MRDB). The government has certain rights in the invention.Background

[0003] The present invention relates to the field of blood collection and storage. In particular, the invention relates to systems and methods for collecting and storing whole blood.

[0004] Hemorrhage is the leading cause of preventable death in both military and civilian traumatic injury. Recently, the military and civilian medical practitioners have adopted the practice of whole blood (WB) transfusion in certain situations (e.g., hemorrhage, combat casualties with severe blood loss) instead of transfusion of blood components (i.e., individual blood component therapy - "CT") such as transfusion of plasma, platelets, and / or red blood cells (RBCs). Whole blood has multiple advantages compared to individual blood component therapy (CT). As an example, transfusion of ABO-compatible RBCs carries an approximately 1 :80,000 risk of fatal hemolytic reaction due to transfusion of ABO-incompatible RBCs, largely due to human error in matching donor and recipient appropriately. In contrast, Low Titer Group O Whole Blood ("LTOWB") unseparated blood that is collected from a group O human donors with "low" IgM and / or IgG anti-A and anti-B - antibodies can be used without waiting for crossmatch results, thereby reducing the time to transfusion, and potentially improving survival. Studies have shown that time is of the essence and minutes matter when it comes to transfusing blood to prevent hemorrhaging combat casualties. LTOWB and other whole blood(e.g., blood taken from human donors with blood types other than group 0) also has the advantage of requiring only refrigeration for storage.

[0005] Human whole blood from donors with other group types (e.g., A, B, and AB) in addition to whole blood from group O donors is also useful for transfusion to recipients in need.Improved methods and systems for the collection and storage of whole blood is, therefore, useful.Summary of the Invention

[0006] In a first aspect, the invention provides a whole blood collection system comprising: a first bag containing a first solution comprising dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and a second bag containing a second solution comprising D-mannitol, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, adenine, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

[0007] In another aspect, the invention provides a whole blood collection system comprising: a first bag containing a first solution comprising dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and a second bag containing a second solution comprising D-mannitol, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

[0008] In another aspect, the invention provides a whole blood collection system comprising: a first bag containing a first solution comprising dextrose, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and a second bag containing a second solution comprising D-mannitol, sodium citrate, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, adenine, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

[0009] In a further aspect, the invention provides a whole blood collection system comprising: a first bag containing a first solution comprising dextrose, sodium acetate, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and a second bag containing a second solution comprising D-mannitol, sodium phosphate, sodium bicarbonate, adenine, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

[0010] In still a further aspect, the invention provides a whole blood collection system comprising: a first bag containing a first solution comprising dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and a second bag containing a second solution comprising D-mannitol, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

[0011] In another aspect, the invention provides a whole blood collection system comprising: a first bag containing a first solution comprising D-mannitol, dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and a second bag containing a second solution comprising dibasic sodium phosphate, sodium bicarbonate, sodium acetate, adenine, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

[0012] In various embodiments, the systems described herein comprise at least one additional bag containing at least one additive solution, wherein the first solution, the second solution, and the at least one additive solution are mixed to form the complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, the at least one additive solution, or the complete solution.

[0013] In various embodiments, the first bag and the second bag are substantially free of the plasticizer di(2-ethylhexyl) phthalate.

[0014] In various embodiments, the donor whole blood is from a human.

[0015] In some embodiments, the donor whole blood is from a human with type O blood.

[0016] In some embodiments, the donor whole blood is from a human with Rh negative blood.

[0017] In some embodiments, the donor whole blood added to the first solution, the second solution, or the complete solution of the systems described herein maintains a majority of its hemostatic function after being stored in the complete solution in the first bag and / or second bag for 3 days, or for 7 days, or for 14 days, or for 21 days, or for 28 days, or for 35 days, or for 42 days, or for 49 days, or for 56 days as compared to whole blood freshly donated by a donor.Brief Description of the Drawings

[0018] Figure 1 is a schematic drawing of a non-limiting blood bag in a non-limiting blood collection and storage system of the invention.

[0019] Figure 2A is a schematic drawing of a non-limiting blood collection and storage system of the invention.

[0020] Figure 2B is a schematic drawing of a non-limiting blood collection and storage system of the invention that incorporates the system shown in Figure 2A and additionally includes a diversion bag and a blood sampling port.

[0021] Figure 3 is a schematic drawing of a non-limiting blood collection and storage system of the invention, in which solution "A" and solution "B" are mixed to form a complete solution prior to the addition of whole blood to the complete solution.

[0022] Figure 4 is a schematic drawing of a non-limiting blood collection and storage system of the invention, where donor whole blood has been added to the complete solution of Figure 3.

[0023] Figure 5 is a non-limiting blood bag in a non-limiting blood collection and storage system of the invention, where donor whole blood has been added to solution "A".

[0024] Figure 6 is a schematic drawing of a non-limiting blood collection and storage system of the invention, where solution "B" has been added to the mixture of solution "A" plus whole blood from Figure 5.

[0025] Figure 7 is a schematic drawing of a non-limiting blood collection and storage system of the invention, where the system also includes additional components including a filter betweenthe whole blood collection bag and the secondary bag containing solution B, a diversion bag, a blood sampling port, and AS-7 (SOLX) red blood cell storage solution bags.

[0026] Figure 8 is a schematic drawing of a non-limiting blood collection and storage system of the invention, where a filter separates the whole blood collection bag containing solution "A" from the bag containing solution "B", and the system further includes a breakaway canula between the filter and the secondary bag containing solution B.

[0027] Figure 9 shows the system of Figure 8, where whole blood from a donor is collected into the bag for whole blood collection.

[0028] Figure 10 shows the system of Figure 9 with the needle assembly sealed, separated and discarded and where solution B has been transferred from the secondary bag through the filter and into the whole blood collection bag that already contained the collected whole blood in solution A.

[0029] Figure 11 shows the system of Figure 10, where the contents of the whole blood collection bag are transferred through the filter into the secondary bag.

[0030] Figure 12 shows the secondary bag of Figure 11 containing the filtered collected whole blood in the complete solution (i.e., in both solutions A and B) after the secondary bag has been sealed and separated from the rest of the system of Figure 11 via the breakaway cannula.Detailed Description of the Preferred Embodiments

[0031] The published patents, patent applications, websites, company names, and scientific literature referred to herein establish the knowledge that is available to those with skill in the art and are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specification shall be resolved in favor of the latter.

[0032] Terms defined or used in the description and the claims shall have the meanings indicated, unless context otherwise requires. Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Any conflict between an art-understood definition of a wordor phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter. As used herein, the following terms have the meanings indicated. As used in this specification, the singular forms "a," "an" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise. The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 30%.

[0033] As used herein, by "whole blood" is meant the fluid that circulates throughout an organism, such as a human, in veins and arteries, and through the heart. Whole blood includes components including cells (e.g., red blood cells, white blood cells, platelets), as well as noncellular components such as proteins (e.g., insulin, immunoglobulins, albumin), fatty acids and carbohydrates (e.g., cholesterol and glucose). Humans have different blood group types including group A, group B, group AB, and group 0, that results from the presence or absence of antigens on the surface of red blood cells. When only the A antigen is present, the individual has group A blood type. When only the B antigen is present, the individual has the blood type of group B. When both the A antigen and the B antigen are present, the individual has blood type AB. When neither the A antigen nor the B antigen are present on the red blood cell, that individual has the group 0 blood type.

[0034] As red blood cells from group O individuals do not have either A antigen or B antigen on their red blood cells, blood donated by a group O individual can be given to a recipient having group O type blood, group A type blood, group B type blood, or group AB blood. However, if a recipient with group O blood receives blood donated from an individual who is not group O, the immune system of the group O recipient will view the presence of the A antigen and / or the B antigen as foreign. Thus, if a group O individual is exposed to red blood cells from a group A or a group B (or a group AB) individual, the group O individual may generate antibodies that are anti-A antigen or anti-B antigen.

[0035] Thus, in some embodiments, donated whole blood is low titer Group 0 Whole Blood ("LTOWB"). LTOWB is unseparated whole blood that is collected from a group 0 human donor with "low" IgM and / or IgG anti-A antigen and anti-B antigen antibodies. In some embodiments, a donor of LTOWB has not received a blood transfusion from a donor who is not of the group 0 blood type. In some embodiments, a donor of LTOWB has not received a blood transfusion (e.g., from a blood donor of any blood type). In some embodiments, the recipient of whole blood collected and stored in the system described herein has blood type A. In some embodiments, the recipient of whole blood collected and stored in the system described herein has blood type AB. In some embodiments, the recipient of whole blood collected and stored in the system described herein has blood type B. In some embodiments, the recipient of whole blood collected and stored in the system described herein has blood type 0.

[0036] Another antigen on the surface of some human red blood cells is called the Rhesus factor (also known as Rh factor). A majority of people are Rh-positive, meaning their red blood cells have Rh factor on their surface. Some people (a minority of the population) are Rh- negative, meaning that their red blood cells do not have Rh factor on their surface. In some embodiments, the donor whose whole blood is being collected and / or stored in the systems described herein is Rh-negative.

[0037] Solutions for blood collection and storage containing anticoagulants and preservatives are well known and include Anticoagulant Citrate Phosphate Dextrose Solution (according to the standards of the United States Pharmacopeial Convention (USP)), Anticoagulant Citrate Phosphate Dextrose Adenine Solution (USP), Anticoagulant Citrate Dextrose Solution A (USP), Anticoagulant Citrate Dextrose Solution B (USP), Anticoagulant Sodium Citrate Solution (USP), Anticoagulant Heparin Solution (USP), Anticoagulant sodium citrate (USP), and Ethylenediaminetetraacetic acid Solution (EDTA). Table 1 provides a non-comprehensive list of typical anticoagulants used in the United States and Europe for blood banking. Currently used liquid anticoagulant and preservative solutions are acidic to prevent caramelization of sugars during steam sterilization and long-term storage of blood bag sets.

[0038] Table 1: Common Anticoagulant and Preservative Solutions

[0039] As can be seen from Table 1, the anticoagulants in use in the United States and other countries (e.g., European and Asian countries) are in liquid form in a blood bag into which collected donor blood is added. Figure 1 shows a standard whole blood collection and storage bag containing liquid anticoagulant. Donated blood entering the bag will mix, actively or passively, with the liquid anticoagulant using standard blood collection procedures. After the desired volume of donated whole blood (e.g., 450 ml + / - 10%, 500 ml + / - 10%) is added to the bag while actively or passively mixing, the tubing can be closed off and the bag inverted at least once or repeatedly to thoroughly mix the donor blood with the liquid anticoagulant. The typical ratio of anticoagulant to nominal whole blood collection volume is about 0.14.

[0040] Additional anticoagulant solutions for whole blood have been described. For example, Hess et al., PCT Publication No. WO2022 / 216937 describes a whole blood storage system and Cancelas et al., PCT Publication No. WO2022 / 216955 describes a whole blood anticoagulant composition and system. PCT Publication Nos. WO2022 / 216937 and WO2022 / 216955 are hereby incorporated by reference herein in their entireties.

[0041] Blood collection systems must, of course, be sterilized prior to use. As the blood collection systems described herein contain liquid, in some embodiments, steam sterilization is one standard method for sterilizing blood bags containing liquid solutions.

[0042] In some embodiments, to facilitate steam sterilization of blood bags, the solution may be steam sterilized in two separate solutions that are then mixed when the whole blood is added. For example, an anticoagulant solution may have an "A" component in a first (primary) blood bag and a "B" component in a second (secondary) blood bag (see Figure 2A and 2B). The blood bags, in some embodiments, are steam sterilized according to standard methods. Onenon-limiting method for steam sterilization is to place the blood bags and / or entire system (e.g., the bags or systems depicted in Figures 2A and 2B) into an air-over steam autoclave and follow the autoclave manufacturer's instructions (e.g., run the autoclave for at least 30 minutes at a temperature of about 250°F with a balance mixture of steam and compressed air at approximately 15 psig for at least 30 minutes, ensuring the chamber pressure is controlled throughout the cycle to prevent bag deformation or rupture). In some embodiments, the solutions in the whole blood collection and storage systems described herein do not caramelize during steam sterilization. In some embodiments, ingredients in the solutions in the whole blood collection and storage systems described herein do not precipitate out of the solution during steam sterilization. Thus, in some embodiments, the complete solution is separated into two or more solutions that are mixed prior to, at the same time as, or shortly after (e.g., within an hour, or within thirty minutes, or within ten minutes, or within five minutes, or within one minute) the addition of donor whole blood.

[0043] In some embodiments, prior to adding whole blood, the "B" component is mixed with the "A" component (see Figure 3), and then the whole blood is added to the blood bag containing the mixture of "A" and "B" (see Figure 4). In some embodiments, the whole blood could be added to the bag containing the "B" component and, after the whole blood is mixed with the "B" component, the "A" component may be added to the mixture of the "B" component and the whole blood. In some embodiments, donor whole blood is added directly to the solution that includes an anticoagulant such as citric acid and or sodium citrate (e.g., solution A, see "Part A" in Table 2). Thus, in some embodiments, the whole blood is added to the bag containing the "A" component (see Fig. 5) and, after the whole blood is mixed with the "A" component, the "B" component is added to the mixture of the "A" component and the whole blood (see Fig. 6).

[0044] It will, of course, be understood that a complete anticoagulant solution may be in three parts (e.g., an "A" component, a "B" component, and a "C" component) or even more than three components, so long as the complete anticoagulant solution is created prior to (e.g., Figs. 2A and 3), at the same time as, or shortly after (e.g., within an hour, or within thirty minutes, or within ten minutes, or within five minutes, or within one minute) one of the components ismixed with whole blood. For example, whole blood may be added to the blood bag with the "A" component and the "B" component immediately added to the bag containing the "A" component and the whole blood. See Figure 5 and 6.

[0045] In some embodiments, when the "A" and "B" solutions are mixed before the whole blood is added to the complete solution, one of the solutions (i.e., either the "A" solution or the "B" solution) can be pushed through a filter such as a platelet sparing leukoreduction filter (e.g., commercially available from Terumo). For example, the solution can be pushed through the filter backwards. One non-limiting reason to do this is to remove any air trapped in either the line or the filter itself. In one non-limiting configuration, Figure 7 shows a platelet sparing leukoreduction filter (labelled "WBF" in Figure 7, which allows platelets through but does not allow larger white blood cells through) between the solution "B" and solution "A". In this configuration, whole blood is collected and mixed with "A" solution, thereafter "B" solution is pushed into the bag labeled "Apex Additive Solution A" which contains whole blood mixed with "A" solution. This whole blood plus complete solution is then allowed to flow through the filter into the storage bag (labeled "WB / RBC storage bag" in Figure 7). Note that in Figure 7, additional bags holding red blood cell additive solution (namely the SOLX (AS-7) additive solution) are shown, but it should be understood that the additional SOLX bags are not required in the whole blood collection and storage systems described herein.

[0046] It will be understood that in Figures 4 and 6, after the whole blood collected is mixed with both solutions A and B, the whole blood can be stored in either the Whole Blood Collection bag or the Secondary Bag.

[0047] In another embodiment, a filter, such as a platelet-sparing leukocyte reduction filter, separates the whole blood collection bag containing solution "A" and the secondary bag containing solution B. Such a non-limiting system is depicted in Figure 8. In one embodiment, the whole blood from a donor is collected only into solution "A" in the whole blood collection bag (see Figure 9). The donor line is sealed separated from the whole blood blood collection system. Next, solution B in the secondary bag is passed through the filter backwards so that it combines with solution A and the collected whole blood in the whole blood collection bag (see Figure 10). The collected whole blood in the mixture of solutions A and B (i.e., in the completesolution) is then passed from the whole blood collection bag through the filter into the secondary bag (see Figure 11). The whole blood can then be stored in the secondary bag which, in some embodiments, can be detached from the rest of the system resulting in a stand-alone bag containing the collected whole blood stored in the complete solution (see Figure 12).

[0048] In another embodiment of the system depicted in Figure 8, the whole blood collected and mixed with both solutions A and B (i.e., the complete solution) is passed through the filter and stored in the secondary bag. In other words, prior to adding the donated whole blood, solution B in the secondary bag is passed through the filter backwards so that it combines with solution A in the whole blood collection bag to create a complete solution into which the donated whole blood is added. The collected whole blood in the complete solution is then passed from the whole blood collection bag of Figure 8 through the filter into the secondary bag where it is stored.

[0049] In another embodiment of the system depicted in Figure 8, the whole blood from a donor is collected only into solution A in the whole blood collection bag (see Figure 9), and then the collected whole blood combined with solution A is passed through the filter into the secondary bag where it is mixed with solution B and stored in the secondary bag which, in some embodiments, can be sealed and detached from the rest of the system (see Fig. 12).

[0050] It should be noted that the filter in the systems described herein can be any type of filter used in the blood banking industry. For example, the filter may be a platelet-sparing leukocyte reduction filter. The filter may also be a leukocyte reduction filter that is not platelet-sparing. The filter may also be a filter that incorporates synthetic and or natural antigens that anti-B antibodies will bind to, so that whole blood passing through it will be further depleted of anti-B antibodies. The filter may also be a filter that incorporates synthetic and or natural antigens that anti-A antibodies will bind to, so that whole blood passing through it will be further depleted of anti-A antibodies. The filter may also be a filter that incorporates synthetic and / or natural antigens that anti-Rh factor antibodies will bind to, so that whole blood passing through it will be depleted of anti-Rh factor antibodies. In some embodiments, filter may be a plateletsparing leukocyte reduction filter that also depletes at least one of anti-A antibodies, anti-B antibodies, or anti-Rh factor antibodies.

[0051] In some embodiments, the anticoagulant described herein is separated into two components, namely component A and component B. In some embodiments, when compared to anticoagulants CPD and CPDA-1, the solutions described herein, for example, the "A" component, the "B" component, and the Complete Solution may have the ingredients in the amounts shown below in Tables 2, 3, 4, and 5 for the addition of 500 mL of whole blood. Additional Complete Solutions are not listed. It will be understood that if only 450 mL whole blood is collected, the amounts of ingredients in the solutions will decrease by about 10%.

[0052] Table 2

[0053] Table 3

[0054] Table 4

[0055] Table s

[0056] Table 6 Ranges for Complete Solution for addition to 500 mL Whole Blood

[0057] For addition to 500 mL of whole blood, components of "A" solution may be as follows in Table 7. It will be understood that if only 450 mL whole blood is collected, the amounts of ingredients in the solutions will decrease by about 10%.

[0058] It will be understood that the names of components in the solutions described herein may vary. For example, D-glucose (or D(+)-glucose is commonly referred to as dextrose.Similarly, sodium dihydrogen phosphate monohydrate (NaH2PO4.H2O) is commonly referred to as monosodium phosphate monohydrate and di-sodium hydrogen phosphate anhydrous (Na2HPO4) is commonly referred to as dibasic sodium phosphate. Table 6.1 lists chemical names that are included in a non-limiting complete solution as described herein.

[0059] Table 6.1 Chemical names, molecular formula, and molecular weights for components in a complete solution

[0060] Table 7: Each 70 mL of Solution "A" may contain in sterile water

[0061] For addition to 500 mL of whole blood, components of "B" solution may be as follows in Table 8. It will be understood that if only 450 mL whole blood is collected, the amounts of ingredients in the solutions will decrease by about 10%.

[0062] Table 8: Each 50 mL of Solution "B" may contain in sterile water

[0063] It will be understood that the above tables are just exemplary and not limiting in any way. Further, any particular ingredient (e.g., adenine) can be moved in whole or in part from one bag or Part to the other as long as the overall content of the Complete Solution is as stated (see, e.g., Table 6).

[0064] After the donated whole blood is collected and mixed with the liquid anticoagulant, whole blood may be stored for future use and / or separated into desired blood components in an in-line system or dockable system whereby all the contents of the system remain sterile.

[0065] In some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) the majority of the hemostatic function (e.g., at least 35%, at least 40%, or at least 45%, or at least 50%, or at least 51%, or at least 55%, or at least 60%, or at least 75%, or at least 80%, or at least 90%) of the stored whole blood for three days, or for seven days, or for fourteen days, or for 21 days, or for 28 days, or for 35 days, or for 42 days, or for 49 days, or for 56 days as compared to freshly donated whole blood. By "freshly donated" is meant whole blood that was donated within 24 hours of being tested for hemostatic function. In some embodiments, the freshly donated whole blood is added to an anticoagulant (e.g., citrate) prior to being tested for hemostatic function. Hemostatic function of freshly donated or stored blood can be measured according to standard methods (e.g., clotting time, platelet count, thrombin time (TT), viscoelastic tests (including thromboelastography (TEG) and rotational thromboelastometry (ROTEM)), fibrinogen assays, prothrombin time (PT), activated partial thromboplastin time (aPTT), etc.). Tests for each of the three phases of hemostasis: coagulation (fibrin clot formation), platelet plug formation, and fibrinolysis, are known and available.

[0066] As a non-limiting example, in some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) at least 60% of the hemostatic function of the stored whole blood for 28 days as compared to freshly donated whole blood. In another non-limiting example, in some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) at least 45% of the hemostatic function of the stored whole blood for 42 days as compared to freshly donated whole blood. In another non-limiting example, in some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) at least 45% of the hemostatic function of the stored whole blood for 56 days as compared to freshly donated whole blood. In some embodiments, the same individual who donated the stored whole blood also the individual who donated the freshly donated whole blood. In some embodiment, the individual who donatedthe stored whole blood is different than the individual who donated the freshly donated whole blood.

[0067] In some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) the majority of the hemostatic function contributed by the cellular component (e.g., at least 35%, at least 40%, or at least 45%, or at least 50%, or at least 51%, or at least 55%, or at least 60%, or at least 75%, or at least 80%, or at least 90%) of the stored whole blood for three days, or for seven days, or for fourteen days, or for 21 days, or for 28 days, or for 35 days, or for 42 days, or for 49 days, or for 56 days as compared to freshly donated whole blood. In some embodiments, the freshly donated whole blood is added to an anticoagulant (e.g., citrate) prior to being tested for hemostatic function contributed by the cellular component. Hemostatic function contributed by the cellular component freshly donated or stored blood can be measured according to standard methods (e.g., clotting time, platelet count, thrombin time (TT), viscoelastic tests (including thromboelastography (TEG) and rotational thromboelastometry (ROTEM)), fibrinogen assays, prothrombin time (PT), activated partial thromboplastin time (aPTT), etc.). Tests for each of the three phases of hemostasis: coagulation (fibrin clot formation), platelet plug formation, and fibrinolysis, are known and available. See, for example, Reddoch-Cardenas et al., Transfusion 65: S184-S192, 2025. Mean differences in TEG MA values between whole blood and platelet-poor plasma can be used to estimate the effect of cellular components in clot generation.

[0068] As a non-limiting example, in some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) at least 60% of the hemostatic function of the stored whole blood for 28 days as compared to freshly donated whole blood. In another non-limiting example, in some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) at least 45% of the hemostatic function of the stored whole blood for 42 days as compared to freshly donated whole blood. In another non-limiting example, in some embodiments, the whole blood system (including the anticoagulant solution therein) preserves (or maintains) at least 45% of the hemostatic function of the stored whole blood for 56 days as compared to freshly donated whole blood. In some embodiments, the same individual who donated the stored whole blood also the individual whodonated the freshly donated whole blood. In some embodiment, the individual who donated the stored whole blood is different than the individual who donated the freshly donated whole blood.

[0069] In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system of the invention comprises plasticized polyvinyl chloride (PVC). In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein comprise a non- polyvinyl chloride (PVC) including, without limitation, polyolefins, ethylene vinyl acetate (EVA), polyethylene terephthalate (PET), polyurethane (PU), Thermoplastic elastomers (TPEs), Polybutadiene or combinations of one or two of these and / or other plastics). In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein comprise ethylene-tetrafluoroethylene (ETFE). In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein comprise polyethylene (PE), such as high-density polyethylene. In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein comprise polyvinylidene fluoride (PVDF). In some embodiments, the blood bag comprises Ethylene-vinyl acetate (EVA). In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein comprise polyolefin.

[0070] Polyvinyl chloride (PVC) is a commonly used material in blood storage bags. However, as PVC is stiff and generally heat-sensitive, a plasticizer is typically added to the PVC material to give the flexibility and thermal properties needed for blood bag manufacture. A plasticizer is a substance or material incorporated in a material (e.g., PVC) to increase that material's flexibility, workability, or distensibility. Plasticizer molecules do not form chemical bonds with the polymer; rather, they are embedded in the PVC matrix, which means that plasticizer molecules can freely migrate and are often found to leach out of the bag material. The rate of leaching is different for each plasticizer and is also influenced by the handling of the bag.

[0071] Di (2-ethylhexyl) phthalate (DEHP) is a common plasticizer used in PVC bags. Typically, a PVC-DEHP bag contains 20-50% plasticizer by weight.

[0072] In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein include PVC comprising the DEHP plasticizer.

[0073] Note that di (2-ethylhexyl) phthalate (DEHP) is an ortho-phthalate. The leaching of ortho-phthalates into donor blood contained within PVC bags comprising an ortho-phthalate plasticizer may result in detrimental health effects to patients receiving donor blood stored in such bags.

[0074] Accordingly, in some embodiments, the blood bags of the whole blood collection and storage systems described herein described herein are free of or are substantially free orthophthalates. For example, a blood bag (or other component of the systems described herein) that is substantially free of an ortho-phthalate is 95% free, or 98% free, or 99% free, or 99.9% free, by weight, of an ortho-phthalate plasticizer such as DEHP.

[0075] In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein include PVC comprising a plasticizer that is not an ortho-phthalate plasticizer.

[0076] In some embodiments, the blood bags, tubing, and other components of the whole blood collection and storage system described herein are substantially free of ortho-phthalate, such as DEHP.

[0077] In some embodiments, the blood bags of the whole blood collection and storage systems described herein comprises a non-ortho-phthalate plasticizer. In some embodiments, the non-ortho-phthalate plasticizer is n-butyryl tri-n-hexyl-citrate (BTHC). In some embodiments, the non-ortho-phthalate plasticizer is trioctyl trimellitate (TOTM). In some embodiments, the non-ortho-phthalate plasticizer is acetyl tributyl citrate (ATBC). In some embodiments, the non-ortho-phthalate plasticizer is di- (2-ethylhexyl) terephthalate (DEHT), which may also be referred to as Di(ethylhexyl) terephthalate (DOTP). In some embodiments, the non-ortho-phthalate plasticizer is di(isononyl) cyclohexane-l,2-dicarboxylate, which is also called 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH).

[0078] The embodiments of the invention described above are intended to be merely exemplary; numerous variations and modifications will be apparent to those skilled in the art.All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.What is claimed is:

Claims

Claims1. A whole blood collection system comprising: a) at least a first bag containing a first solution comprising dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and b) at least a second bag containing a second solution comprising D-mannitol, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, adenine, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

2. A whole blood collection system comprising: a) at least a first bag containing a first solution comprising dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and b) at least a second bag containing a second solution comprising D-mannitol, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

3. A whole blood collection system comprising: a) at least a first bag containing a first solution comprising dextrose, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and b) at least a second bag containing a second solution comprising D-mannitol, sodium citrate, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, adenine, and water,wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

4. A whole blood collection system comprising: a) at least a first bag containing a first solution comprising dextrose, sodium acetate, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and b) at least a second bag containing a second solution comprising D-mannitol, sodium phosphate, sodium bicarbonate, adenine, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

5. A whole blood collection system comprising: a) at least a first bag containing a first solution comprising dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; and b) at least a second bag containing a second solution comprising D-mannitol, dibasic sodium phosphate, sodium bicarbonate, sodium acetate, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

6. A whole blood collection system comprising: a) at least a first bag containing a first solution comprising D-mannitol, dextrose, sodium citrate, citric acid, monobasic sodium phosphate, magnesium citrate, adenine, and water; andb) at least a second bag containing a second solution comprising dibasic sodium phosphate, sodium bicarbonate, sodium acetate, adenine, and water, wherein the first solution and the second solution are mixed to form a complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, or the complete solution.

7. The whole blood collection systems of claim 1, 2, 3, 4, 5, or 6, wherein the system comprises at least one additional bag containing at least one additive solution, wherein the first solution, the second solution, and the at least one additive solution are mixed to form the complete solution prior to, at the same time as, or shortly after the addition of donor whole blood to the first solution, the second solution, the at least one additive solution, or the complete solution.

8. The whole blood collection systems of claim 1, 2, 3, 4, 5, or 6, wherein the first bag and / or the second bag does not include the plasticizer d i(2-ethyl hexyl) phthalate.

9. The whole blood collection systems of claim 1, 2, 3, 4, 5, or 6, wherein the first bag and / or the second bag substantially lacks ortho-phthalates.

10. The whole blood collection systems of claim 1, 2, 3, 4, 5, or 6, wherein the first bag and / or the second bag includees a non-ortho-phthalate plasticizer.

11. The whole blood collection systems of claim 1, 2, 3, 4, 5, 6, or 7, wherein the whole blood is human.

12. The whole blood collection systems of claim 1, 2, 3, 4, 5, 6, or 7, wherein the whole blood is human type 0 blood.

13. The whole blood collection systems of claim 1, 2, 3, 4, 5, 6, or 7, wherein the whole blood is human Rh negative blood.

14. The whole blood collection systems of claim 1, 2, 3, 4, 5, or 6, wherein the donor whole blood added to the first solution, the second solution, or the complete solution maintains a majority of its hemostatic function after being stored in the complete solution in the first bag and / or second bag for 3 days, or for 7 days, or for 14 days, or for 21 days, or for 28 days, or for 35 days, or for 42 days, or for 49 days, or for 55 days as compared to whole blood freshly donated by a donor.

15. The whole blood collection systems of claim 1, 2, 3, 4, 5, or 5, further comprising a filter separating the first bag from the second bag.

16. The system of claim 15, wherein the filter is a platelet-sparing leukoreduction filter.

17. The whole blood collection systems of claim 7, wherein the donor whole blood added to the first solution, the second solution, the at least one additive solution, or the complete solution maintains a majority of its hemostatic function after being stored in the complete solution in the first bag and / or second bag for 3 days, or for 7 days, or for 14 days, or for 21 days, or for 28 days, or for 35 days, or for 42 days, or for 49 days, or for 56 days as compared to whole blood freshly donated by a donor.

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