Blood plasma fractions for use in liver regeneration

Abstract

This invention describes methods and compositions for treating age-related diseases, as well as for liver regeneration, prevention of liver degeneration, and liver maintenance. The compositions used in these methods include plasma and plasma-derived plasma components that have therapeutic and / or preventative effects against diseases.

Description

Plasma components for liver regeneration This invention relates to the prevention and treatment of diseases, including age-related diseases. It also relates to the use of blood products (such as plasma and plasma components) to treat and / or prevent age-related conditions (related to liver growth, maintenance, and regeneration). The market for liver failure treatment is enormous, and currently, liver transplantation is the only treatment option. One in ten Americans (approximately 35 million people) suffers from some form of liver disease. This number continues to rise due to the prevalence of cirrhotic liver disease among a growing obese population. NAFLD (non-alcoholic fatty liver disease) is a major risk factor for cirrhosis, which can eventually lead to liver failure. Due to declining health in the general population, available organs for transplantation are scarce. Therefore, only about one-third of patients on the liver transplant list receive a transplant. Because the increased risks associated with organ transplantation are age-related, patients over 65 years of age are typically excluded from the list. The statistics are particularly alarming for cirrhotic patients awaiting a liver transplant. In the United States, there are 300,000 hospitalized patients with cirrhosis, and 36,000 people die from cirrhosis each year, with more than half of these patients being ineligible for transplantation. The availability of alternative treatments could have a devastating impact on the majority of liver disease patients who previously had no other treatment options. Liver failure can be acute or chronic. Acute liver failure is usually caused by viral infections (e.g., hepatitis B and C), overuse of drugs or toxins (e.g., acetaminophen), and metabolic or vascular diseases (such as autoimmune hepatitis and Wilson's disease). Chronic liver failure is usually classified as cirrhosis and can be caused by viral infections, alcoholism, NAFLD (caused by obesity, high cholesterol and triglycerides, and high blood pressure), autoimmune diseases, obstruction or damage to ducts (such as the bile ducts connecting the liver and intestines), exposure to toxins or certain drugs, parasites, and heart failure leading to blood pooling in the liver. Liver resection and transplantation can be performed for liver failure as described above, with transplantation being more common for chronic liver failure. These procedures can also be performed for primary and secondary malignancies (i.e., cancer). Improved prognosis for liver resection and transplantation is associated with attention to preoperative, perioperative, and postoperative care (Wrighton LJ et al., J Gastrointest Oncol., 3(1): 41-47, (2012)). These include improved surgical and anesthetic techniques, enhanced understanding of the physiological functions of the liver, nutritional support, glycemic control, and reduced postoperative infection. (Ibid.) Immunosuppressants are the most commonly used medications for liver transplantation. The attending physician responsible for managing liver transplant rejection and long-term complications (such as hypertension and obesity) has always played a crucial role in improving the corresponding prognosis (see Issa DH, Cleveland Clinic J of Med., 82(6):361-72 (2015)). There remains a severe lack of new therapies to improve outcomes for patients with liver failure and / or those who have undergone liver resection or transplantation. Furthermore, even when liver transplantation is performed, there are not enough donor livers available for all patients. (See, for example, Helwick C, ASCO Post, (September 25, 2017) stating, "The transplant problem is organ allocation.") One compound currently under investigation for treating cirrhosis is albumin. This is to compensate for the albumin loss caused by the reduced albumin production in the cirrhotic liver itself. The basic principle is that albumin helps increase osmotic pressure, bind to toxic substances, regulate homeostasis, and has an anti-inflammatory effect (Carvalho JR et al., Annals of Hepatology, 17(4): 547-60 (2018)). Therefore, the conventional thinking in the field is that the purer and higher the concentration of albumin, the stronger its efficacy. Therapeutic albumin is usually produced through plasma fractionation. Plasma fractionation produces an albumin solution, but it contains unwanted protein "contaminants" or "impurities". This invention provides novel therapies using plasma components to improve and accelerate the recovery of patients with liver disease, after hepatectomy, or after liver transplantation. Furthermore, since the liver is the only internal organ capable of regeneration, this invention provides methods to stimulate the proliferation and regeneration of existing liver tissue, which can promote postoperative recovery, for example, in certain liver-related indications. In addition, this invention utilizes so-called "contaminants" or "impurities" generated from plasma component separation to more effectively treat liver disease. [Cross-reference to related applications] Pursuant to Section 119(e) of Chapter 35 of the United States Code, this application claims priority over the filing dates of U.S. Provisional Patent Application No. 62 / 937,965, filed November 20, 2019, and U.S. Provisional Patent Application No. 62 / 975,637, filed February 12, 2020; the disclosures of these applications are incorporated herein by reference. [Incorporated] All publications and patents referenced in this specification are incorporated herein by reference, as each individual publication or patent is specifically and individually indicated to be incorporated by reference. A. Introduction This invention relates to the treatment of liver conditions or diseases. Plasma fractions (including plasma fraction isolates) have been shown to have significant activity in inducing liver recovery after hepatectomy. Furthermore, plasma fractions have been shown to activate cell proliferation in a quiescent, intact liver (before hepatectomy). Plasma fractions offer several advantages over whole plasma serum because the plasma fractionation process removes problematic clotting factors and eliminates the need for blood cross-matching. Additionally, in some analyses, plasma fractions have shown unexpectedly improved potency compared to plasma from younger individuals (see, for example, U.S. Patent Application No. 15 / 499,694 and U.S. Patent Application No. 16 / 432,114, the disclosures of which are incorporated herein by reference in their entirety). Therefore, predicting the potency of plasma fraction isolates using whole plasma serum is not reasonably predictable. Before describing the invention in detail, it should be understood that the invention is not limited to the specific methods and compositions described herein, as differences will certainly exist in actual implementation. It should also be understood that the terminology used herein is for describing specific embodiments only and is not intended to limit the inventive concept; the scope of the invention will be defined only by the claims of the supplementary applications. The publications discussed herein refer only to those disclosed prior to the filing date of this application. Nothing herein should be construed as an admission that prior inventions preclude this invention from preceding such publications. Furthermore, the publication dates provided may differ from actual publication dates and may require separate verification. Where a numerical range is provided, it should be understood that the present invention also specifically discloses intermediate values ​​between the upper and lower limits of the range, accurate to one-tenth of the lower limit unit unless the context clearly specifies otherwise. Smaller ranges between any specified value or intermediate value within the range and any other specified value or intermediate value within the range are included within the scope of the present invention. The upper and lower limits of these smaller ranges may be independently included in the range or excluded, and ranges in which neither or both of the upper and lower limits are included, are also included within the scope of the present invention, subject to the requirements of any specifically excluded limits within the range. Where the range includes one or two limits, ranges excluding either or both of the included limits are also included within the scope of the present invention. It should be noted that the claims can be drafted to exclude any optional elements. Therefore, this statement is intended as a precondition for the use of specialized terms such as "solely," "only," etc., relating to elements of the claims, or for the use of the limiting term "negative." Upon reading this invention, it will become apparent to those skilled in the art that each individual embodiment described and listed herein has layered components and features that can be quickly decomposed or combined with features of any embodiment in other embodiments without departing from the scope and spirit of the invention. Any stated method can be implemented in the order of events stated or in any other logically possible order. B. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials may be used in the practice or testing of this invention, some potentially preferred methods and materials are described below. All publications mentioned herein are incorporated by reference to disclose and describe methods and / or materials relating to the cited publications. It should be understood that, unless there is a conflict, the disclosure of this invention supersedes any disclosure in the incorporated publications. It should also be noted that the singular forms “a” and “the” used in this document and the claims of the appended applications also include their plural indicators, unless the context clearly indicates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells, and reference to “the peptide” includes reference to one or more peptides and their equivalents known to those skilled in the art, such as polypeptides, etc. In describing the methods of this invention, the terms "host," "subject," "individual," and "patient" are used interchangeably to refer to any mammal that needs to receive such administration according to the methods disclosed in this invention. These mammals include, for example, humans, sheep, cattle, horses, pigs, dogs, cats, non-human primates, mice, and rats. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is livestock. In other embodiments, the subject is a pet. In some embodiments, the subject is a mammal. In some cases, the subject is a human. Other subjects may include domestic pets (e.g., dogs and cats), livestock (e.g., cattle, pigs, goats, horses, etc.), rodents (e.g., mice, guinea pigs, and rats, animals that can be used in animal disease models), and non-human primates (e.g., chimpanzees and monkeys). Therefore, the subject of this invention includes, but is not limited to, mammals such as humans and other primates, such as chimpanzees, other apes, and monkeys, etc., and in some embodiments, the subject is a human. The term "subject" also includes any person or organism of any age, weight, or other physical characteristic, wherein the subject can be an adult, child, infant, or newborn. "Young person" or "young individual" refers to an individual whose chronological age is 40 years or younger, for example, 35 years or younger, including 30 years or younger, such as 25 years or younger or 22 years or younger. In some cases, the individual serving as the source of blood products containing plasma from a young person is an individual whose age is 10 years or younger, for example, 5 years or younger, including 1 year or younger. In some cases, the subject is a newborn and the source of the plasma product is the umbilical cord, where the plasma product is obtained from the newborn's umbilical cord. Therefore, "young person" and "young individual" can refer to a subject whose age is between 0 and 40 years, for example, 0, 1, 5, 10, 15, 20, 25, 30, 35, or 40 years. In other cases, "young person" and "young individual" can refer to physiological age (as opposed to chronological age), for example, an individual who does not exhibit plasma inflammatory cytokine levels seen in older individuals. Conversely, these "young people" and "young individuals" can refer to chronological age (as opposed to actual age), for example, individuals exhibiting higher levels of anti-inflammatory cytokines in their plasma compared to older individuals. For example (but not limitingly), the inflammatory cytokine is an eosinophil chemokine, and the fold change between young subjects or young individuals and older individuals is at least 1.5 times. Similarly, with respect to other inflammatory cytokines, the fold change between older and younger individuals can be used to refer to chronological age. See U.S. Patent Application No. 13 / 575,437, the contents of which are incorporated herein by reference. Typically, the individual is healthy, for example, the individual did not have a malignant blood disease or autoimmune disease at the time the relevant sample was collected. As used herein, the term "treatment" means either (i) prevention of a disease or condition, or (ii) relief or elimination of symptoms of a disease or condition. Treatment can be administered preventively (before the onset of liver disease or liver failure) and includes: (a) preventing the subject from developing the condition; (b) suppressing the condition, i.e., preventing its onset; or (c) alleviating the condition, i.e., causing the condition to subside. Treatment can elicit a variety of physical manifestations, such as regulation of gene expression, restoration of tissue or organ vitality, etc. Therapeutic agents can be administered before, during, or after the onset of symptoms. Targeted therapies can be administered during the symptomatic phase of the condition (and in some cases, after the symptomatic phase). Treatment can also be achieved through interventions such as plasma, plasma fractions, or blood products containing plasma fractions, administered before, during, and / or after liver resection or transplantation. "Improvement" related to liver function, regeneration, or recovery refers to any significant improvement in liver function as measured using standard methods well known in the art. For example (but not limitingly), this may include measurements of blood levels of certain proteins, such as alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), albumin and total protein, bilirubin, gamma-glutamyl transferase (GGT), L-lactate dehydrogenase (LD), and prothrombin time (PT). Examples of normal protein levels can be: ALT (7 to 55 U / L); AST (8 to 48 U / L); ALP (40 to 129 U / L); albumin (3.5 to 5.0 g / dL); total protein (6.3 to 7.9 g / dL); bilirubin (0.1 to 1.2 mg / dL); GGT (8 to 61 U / L); LD (122 to 222 U / L); and PT (9.4 to 12.5 seconds). Blood products containing plasma components. In carrying out the method of the present invention, blood products containing plasma components are administered to individuals in need, such as individuals exhibiting one or more of the following conditions: liver disease or liver failure. Therefore, the method according to embodiments of the present invention comprises administering blood products containing plasma components (derived from an individual (“donor individual” or “recipient”)) to an individual exhibiting one or more of the following conditions: liver disease or liver failure (“recipient individual” or “recipient”). “Blood products containing plasma components” refers to any product derived from blood that contains plasma (e.g., whole blood, plasma, or components thereof). In its conventional sense, the term “plasma” refers to the straw-colored / pale yellow liquid component of blood, which consists of approximately 92% water, 7% proteins (e.g., albumin, gamma globulin, antihemophilic factor, and other clotting factors), and 1% mineral salts, sugars, fats, hormones, and vitamins. Non-limiting examples of plasma-containing blood products applicable to the target method include whole blood treated with an anticoagulant (e.g., EDTA, citrate, oxalate, heparin, etc.), blood products obtained by filtering whole blood to remove leukocytes ("leukocyte removal"), blood products composed of plasma obtained by plasma removal or apheresis, fresh frozen plasma, blood products composed primarily of purified plasma, and blood products composed primarily of plasma components. In some cases, the plasma product used is a non-whole blood plasma product, meaning that the product is not whole blood and therefore lacks one or more components found in whole blood, such as red blood cells, white blood cells, etc., which are present in whole blood at least to some extent. In some cases, the plasma product is substantially (if not entirely) cell-free, wherein in this case, the cell content (by volume) may be 5% or less, for example 1% or less, including 0.5% or less; wherein in some cases, cell-free plasma components refer to compositions completely lacking cells, i.e., they do not contain cells. Collecting blood products containing plasma components. Embodiments of the methods described herein include administering blood products containing plasma components, which may be derived from a donor, including human volunteers. The term "human-derived" may refer to such products. Methods for collecting blood products containing plasma from a donor are well known in the art. (See, for example, the AABB Technical Manual (Mark A. Fung et al., eds., 18th edition, 2014), which is incorporated herein by reference.) In one embodiment, the donation is obtained via venipuncture. In another embodiment, the venipuncture is a single venipuncture. In yet another embodiment, saline volume replacement therapy is not used. In a preferred embodiment, the plasma removal process is used to obtain blood products containing plasma. The plasma removal process may include removing a weight-adjusted volume of plasma and returning cellular components to the donor. In a preferred embodiment, sodium citrate is used during the plasma removal process to prevent cell agglutination. After citrate administration, the volume of plasma collected from the donor is preferably between 690 and 880 mL, and preferably proportionate to the donor's body weight. C. Plasma components During World War II, a stable plasma expander was needed for use on the battlefield to address the significant blood loss of soldiers. Therefore, methods for preparing lyophilized plasma were developed. However, the use of lyophilized plasma in combat situations was difficult due to the need for sterile water for reconstitution. As an alternative, Dr. E.J. Cohn suggested using albumin and prepared a ready-to-use stable solution that could be immediately introduced to treat shock. (See Johan, Current Methods for Preparing Plasma Components (Blood Biotechnology) 165 (Jack Goldstein, ed., 1st ed., 1991)). Dr. Cohn utilized the denaturing effect of cold ethanol in the purification of plasma components and achieved separation through pH and temperature changes. One embodiment of the method described herein involves administering plasma components to a subject. Component separation is the process of separating certain protein subsets from plasma. Component separation techniques are known in the art and rely on procedures developed by Cohn et al. in the 1940s. (E. Cohn, Preparation and properties of serum and plasma proteins. IV. A system for separating protein and lipoprotein components from biological tissues and body fluids into individual components. 68, Journal of the American Chemical Society (J Am Chem Soc) 459 (1946), which is incorporated herein by reference). The process involves several steps, each involving a specific ethanol concentration and changes in pH, temperature, and osmotic pressure concentrations that cause selective precipitation of proteins. The precipitate is also separated by centrifugation or precipitation. The original "Cohn component separation process" involved separating proteins into five components by precipitation, designated as component I, component II+III, component IV-1, component IV-4, and component V. Albumin is the initially determined endpoint product (component V) in this process. According to embodiments of the invention, each component (or effluent from a previous separation step) contains or may contain a therapeutically useful protein component. (See Thierry Burnouf, Modern Plasma Component Separation, 21(2), Transfusion Medicine Review, 101 (2007); Adil Denizli, Plasma Component Separation: Conventional and Chromatographic Methods for the Purification of Albumin, 4, Journal of Biochemistry, 315 (2011); T. Brodniewicz-Proba, Human Plasma Component Separation and the Impact of New Technologies on the Use and Quality of Plasma-Derived Products, 5, Review of Hematology, 245 (1991); and U.S. Patents 3,869,431, 5,110,907, 5,219,995, 7,531,513, and 8,772,461, which are incorporated herein by reference). The above experimental parameters can be adjusted to obtain specific protein components. Recently, component separation has become more complex, therefore, other embodiments of the present invention are included. This recent increase in complexity is due to the introduction of chromatography to separate novel proteins from existing components (such as cryoprecipitates), non-frozen plasma, and Cohn fractions; improved IgG recovery by integrating chromatography and ethanol fraction separation processes; and virus reduction / inactivation / removal. (Ibid.) To capture proteins at physiological pH and ionic strength, anion exchange chromatography can be used. This preserves the functional activity of the protein and / or its components. Heparin and monoclonal antibodies are also used in affinity chromatography. Alternatively, components can be separated by gel filtration, salts, and polyethylene glycol. (Hosseini M, Iranian Biotechnology Journal (Iran J Biotech), 14(4):213-20 (2016), which is incorporated herein by reference). Those skilled in the art will recognize that the above parameters and techniques can be adapted to obtain plasma protein-containing components as particularly desired. Plasma component separation can also be performed using ammonium sulfate. For example, see Odunuga OO, Biochemical Compounds, 1:3 (2013); Wingfield PT, Curr Protoc Protein Sci, Appendix 3 (2001), which is incorporated herein by reference. In addition to obtaining specific blood components, a large amount of protein in the plasma was removed using an ammonium sulfate-based fractionation method. (Saha S) et al., Journal of Proteomics and Bioinformation, 5(8) (2012), which is incorporated herein by reference. In one embodiment of the invention, plasma is subjected to component separation in an industrial environment. Frozen plasma is thawed at 1°C to 4°C. The thawed plasma is subjected to continuous cryogenic centrifugation, and the cryoprecipitate is separated. The recovered cryoprecipitate is stored frozen at -30°C or lower. The non-cryoprecipitate (“non-frozen”) plasma is immediately processed to capture (e.g., by primary chromatography) unstable coagulation factors, such as factor IX complexes and their components, as well as protease inhibitors (e.g., antithrombin and C1 esterase inhibitors). Continuous centrifugation and precipitation separation can be performed in subsequent steps. Such techniques are known to those skilled in the art and are described in accordance with the following publications: for example, U.S. Patents Nos. 4,624,780, 5,219,995, and 5,288,853 and U.S. Patent Applications Nos. 201,403,432,55 and 201,503,430,255, the disclosures of which are incorporated herein by reference in their entirety. In one embodiment of the invention, the plasma component may comprise a plasma component containing a high amount of albumin. In another embodiment of the invention, the plasma component may comprise a plasma component containing a high amount of IgG or intravenous immunoglobulin (IGIV) (e.g., Gamunex-C®). In yet another embodiment of the invention, the plasma component may comprise an IGIV plasma component, such as Gamunex-C®, which substantially depletes immunoglobulin (IgG) through methods well known to those skilled in the art. For example, protein A-mediated depletion. (See Keshishian, H. et al., Multiplex, quantitative workflow for discovering sensitive biomarkers in plasma produces novel drug candidates suitable for early myocardial injury, Molecular & Cellular Proteomics, 14, 2375-93 (2015)). In another embodiment, the plasma component may be a plasma component in which substantially all clotting factors have been removed in order to preserve component potency and reduce the risk of thrombosis. For example, the plasma component may be the plasma component described in U.S. Patent No. 62 / 376,529, filed August 18, 2016, the disclosure of which is incorporated herein by reference in its entirety. D. Albumin products For those skilled in the art, albumin plasma products (“APP”) fall into two main categories: plasma protein fractions (“PPF”) and human albumin solutions (“HAS”). PPF is derived from a process that yields higher outputs but lower minimum albumin purity compared to HAS (>83% for PPF; >95% for HAS). (Producing Human Albumin Solutions: An Developing Colloid, P. Matejtschuk et al., British Journal of Anaesthesia, 85(6): 887-95, 888 (2000)). In some cases, PPF has an albumin purity of 83% to 95%, or 83% to 96%. This albumin purity can be determined by electrophoresis or other quantitative methods (e.g., by mass spectrometry). In addition, some have noted that PPF is defective due to the presence of protein “contaminants” (e.g., PKA). Ibid. Therefore, PPF preparations, as albumin plasma products, are no longer widely used and have even been removed from the pharmacopoeias of some countries. Ibid. In contrast to these problems, the present invention advantageously utilizes these "contaminants." In addition to α, β, and γ globulins and the aforementioned PKA, the method of the present invention also utilizes other proteins or factors in the "contaminants" that promote processes such as cell proliferation and tissue regeneration. Those skilled in the art will recognize that there are several existing or commercially available PPF formulations (“PPF commercial formulations”). These formulations include Plasma-Plex™ PPF (Armour Pharmaceutical Co., Tarryton, NY), Plasmanate™ PPF (Grifols, Clayton, North Carolina), Plasmatein™ (Alpha Therapeutics, Los Angeles, California), and Protectate™ PPF (Baxter Labs, Inc., Deerfield, Illinois). Those skilled in the art will also recognize that there are several existing or commercially available HAS formulations (“HAS commercial formulations”). These formulations include Albaminar™ (CSL Behring), AlbuRx™ (CSL Behring), Albutein™ (Grifols, Clayton, North Carolina), Buminate™ (Baxatla, Inc., Bannockburn, Illinois), Flexbumin™ (Baxatla, Inc., Bannockburn, Illinois), and Plasbumin™ (Grifols, Clayton, North Carolina). 1. Plasma protein components (human) (PPF) According to the U.S. Food and Drug Administration (“FDA”), “Plasma Protein Component (Human)” or PPF is the proprietary name for a product defined as “a sterile protein solution of albumin and globulin derived from human plasma” (CFR 21 CFR 640.90, which is incorporated herein by reference). The source material for PPF is plasma recovered from whole blood prepared in accordance with 21 CFR 640.1–640.5 (incorporated herein by reference) or source plasma prepared in accordance with 21 CFR 640.60–640.76 (incorporated herein by reference). PPF was tested in accordance with 21 CFR 640.92 (incorporated herein by reference) to determine its compliance with the following criteria: (a) The final product should be a protein solution of 5.0% + / - 0.30%; and (b) The total protein in the final product shall consist of at least 83% albumin and at most 17% globulin. Gamma globulin shall not exceed 1% of the total protein. The protein composition shall be determined by the Director of the Biological Products Evaluation and Research Center of the Food and Drug Administration, based on the approval methods for each manufacturer. As used in this article, “plasma protein fraction” or “PPF” refers to a sterile protein solution composed of albumin, globulin, and other plasma proteins derived from human plasma, wherein the albumin content is at least 83%, the globulin content is no more than 17% (including α1, α2, β, and γ globulins), and the γ globulin content is no more than 1% as determined by electrophoresis. (Hink, JH, Jr. et al., Preparation and properties of heat-treated human plasma protein fraction, VOX SANGUINIS, 2(174) (1957)). PPF can also refer to a solid form that has a similar composition when suspended in a solvent. Total globulin fraction can be determined by subtracting albumin from the total protein. (Busher, J., Serum albumin and globulin, Clinical methods: history, physics, and laboratory testing, Chapter 10, Walker HK, Hall WD, Hurst JD, eds (1990)). 2. Albumin (human) (HAS) According to FDA regulations, "albumin (human)" (also referred to herein as "HAS") is the proprietary name for a product defined as "a sterile solution of albumin derived from human plasma" (CFR 21 CFR 640.80, which is incorporated herein by reference). The source material used for albumin (human) is plasma recovered from whole blood prepared in accordance with 21 CFR 640.1–640.5 (incorporated herein by reference) or source plasma prepared in accordance with 21 CFR 640.60–640.76 (incorporated herein by reference). Further requirements for albumin (human) are found in 21 CFR 640.80–640.84 (incorporated herein by reference). Albumin (human) was tested according to 21 CFR 640.82 to determine whether it met the following criteria: (a) Protein concentration. The final product should meet one of the following concentration requirements: 4.0% + / - 0.25%; 5.0% + / - 0.30%; 20.0% + / - 1.2%; and 25.0% + / - 1.5% protein solution. (b) Protein composition. In the final product, albumin should account for at least 96% of the total protein, which can be determined by the method used by the Director of the Biological Products Evaluation and Research Center of the Food and Drug Administration for the approval of each manufacturer. As used in this article, "albumin (human)" or "HAS" refers to a sterile protein solution composed of albumin, globulins, and other plasma proteins derived from human plasma, wherein the albumin content is at least 95% and the globulin content is no more than 5% (including α1, α2, β, and γ globulins). HAS can also refer to a solid form, which has a similar composition when suspended in a solvent. The total globulin component can be determined by subtracting albumin from the total protein. Those skilled in the art will recognize that the PPF and HAS components can also be in lyophilized or other solid forms. For example, such formulations containing appropriate additives can be used to prepare tablets, powders, granules, or capsules. This solid form can be formulated into injectable formulations by dissolving, suspending, or emulsifying it in an aqueous or non-aqueous solvent, such as vegetable oils or other similar oils, synthetic fatty acid glycerides, higher fatty acid esters, or propylene glycol; and, if necessary, by adding conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives. E. Components with reduced clotting factors Another embodiment of the invention employs a plasma component in which all clotting factors have been substantially removed to preserve component potency and reduce the risk of thrombosis. For convenience, the blood product can be derived from a single young donor or a group of young donors and can be made free of any IgM to provide ABO-compatible young blood products. Currently, transfused plasma is ABO-matched because the presence of natural antibodies to A and B antigens can cause transfusion reactions. When patients receive ABO-incompatible plasma, IgM appears to be the cause of transfusion reactions. Removing IgM from the blood product or component helps eliminate transfusion reactions in subjects receiving the blood products and plasma components of the present invention. Therefore, in one embodiment, the present invention relates to a method of treating a subject suffering from adverse conditions associated with any of the following liver diseases or liver failure. The method comprises administering to the subject a blood product or blood component derived from whole blood of a single individual or a group of individuals, wherein the blood product or blood component is substantially free of (a) at least one clotting factor and / or (b) IgM. In some embodiments, the individual from which the blood product or blood component is derived is a young individual. In some embodiments, the blood product is substantially free of at least one clotting factor and IgM. In some embodiments, the blood product is substantially free of fibrinogen (factor I). In other embodiments, the blood product is substantially free of red blood cells and / or white blood cells. In a further embodiment, the blood product is substantially cell-free. In other embodiments, the blood product is derived from plasma. These embodiments of the invention are further supported by U.S. Patent Application No. 62 / 376,529, filed August 18, 2016, which is incorporated herein by reference in its entirety. F. Administration of protein-rich plasma protein products Other embodiments of the invention employ plasma fractions with a lower albumin concentration but an increased amount of globulins and other plasma proteins (sometimes referred to as "contaminants") compared to PPF. Like PPF, HAS, effluent I, and effluent II / III, these fractions are virtually free of any clotting factors. Such plasma fractions are hereinafter referred to as "protein-rich plasma protein products." For example, one embodiment of the invention may use a protein-rich plasma protein product consisting of 82% albumin and 18% α, β, and γ globulins and other plasma proteins. Another embodiment of the invention may use a protein-rich plasma protein product consisting of 81% albumin and 19% α, β, and γ globulins and / or other plasma proteins. Yet another embodiment of the invention may use a protein-rich plasma protein product consisting of 80% albumin and 20% α, β, and γ globulins and / or other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 70-79% albumin and a corresponding 21-30% α, β, and γ globulins and other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 60-69% albumin and a corresponding 31-40% α, β, and γ globulins and other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 50-59% albumin and a corresponding 41-50% α, β, and γ globulins and other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 40-49% albumin and a corresponding 51-60% α, β, and γ globulins and other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 30-39% albumin and a corresponding 61-70% α, β, and γ globulins and other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 20-29% albumin and a corresponding 71-80% α, β, and γ globulins and other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 10-19% albumin and a corresponding 81-90% α, β, and γ globulins and other plasma proteins. Other embodiments of the invention may use a protein-rich plasma protein product consisting of 1-9% albumin and a corresponding 91-99% α, β, and γ globulins and other plasma proteins. Further embodiments of the invention may use a protein-rich plasma protein product consisting of 0% albumin and 100% α, β, and γ globulins and other plasma proteins. The above embodiments of the present invention may also contain γ-globulin at a total concentration of 1-5%. The specific concentration of proteins in plasma components can be determined using techniques well known to those skilled in the art. Examples (but not limitations) of such techniques include electrophoresis, mass spectrometry, ELISA analysis, and Western blotting. G. Preparation of plasma components Methods for preparing PPF and other plasma components are well known to those skilled in the art. One embodiment of the invention allows blood for the preparation of human plasma protein components to be collected in a flask containing a citrate or citrate anticoagulant solution of dextran (or other anticoagulant) to inhibit coagulation, and further separated into components I, II+III, IV, and PPF according to the method disclosed by Hink et al. (See Hink, JH, Jr. et al., Preparation and properties of heat-treated human plasma protein components, VOX SANGUINIS, 2(174) (1957), which is incorporated herein by reference.) According to this method, the mixture can be collected and placed in an environment of 2–8°C. The plasma can then be separated by centrifugation at 7°C, removed, and stored at -20°C. The plasma can then be thawed at 37°C and the components separated, preferably within 8 hours of removal from the -20°C storage environment. Plasma can be separated from fraction I using 8% ethanol at pH 7.2 at a temperature of -2 to -2.5°C, where the protein concentration is 5.1% to 5.6%. While cooling the plasma to -2°C, 53.3% cold ethanol (176 mL / L plasma) and acetate buffer (200 mL 4M sodium acetate, 230 mL glacial acetic acid, and H2O to 1 L) can be added at a rate such as 450 mL / min using an effervescent device. Fraction I can be separated from the effluent (effluent I) and removed by ultracentrifugation. Fibrinogen can be obtained from fraction I using methods well known to those skilled in the art. At a pH of 6.8, a temperature of -6°C, and a protein concentration of 4.3%, components II+III can be separated from effluent I by adjusting the effluent to 21% ethanol. While cooling effluent I to -6°C, 95% cold ethanol (176 mL / L effluent I) and 10 M acetic acid for pH adjustment can be added using an effervescent device at a rate such as 500 mL / min. The resulting precipitate (components II+III) can be removed by centrifugation at -6°C. γ-globulin can be obtained from components II+III using methods well known to those skilled in the art. At pH 5.2, -6°C, and a protein concentration of 3%, fraction IV-1 can be separated from effluent II+III ("effluent II / III") by adjusting the effluent to 19% ethanol. H₂O and 10 M acetic acid can be added using an ejector to adjust the pH while effluent II / III is incubated at -6°C for 6 hours. Precipitated fraction IV-1 can precipitate at -6°C for 6 hours and then be separated from the effluent by centrifugation at the same temperature. At pH 4.65, -7°C, and a protein concentration of 2.5%, stable plasma protein components can be recovered from effluent IV-1 by adjusting the ethanol concentration to 30%. This can be achieved by adjusting the pH of effluent IV-1 with cold acid-ethanol (two parts 2 M acetic acid and one part 95% ethanol). While maintaining a temperature of -7°C, 170 mL of cold ethanol (95%) was added to each liter of conditioned effluent IV-1. This allowed the precipitated proteins to settle for 36 hours, followed by removal by centrifugation at -7°C. The IV-4 paste could also be obtained via the Cohn fraction separation process. In fact, the IV-4 fraction and its production process are as described previously (Schopfer LM et al.). PLoS ONE, 14(1):e0209795 (2018), which is incorporated herein by reference in its entirety (Schopfer LM et al., PLoS ONE, 14(1):e0209795 (2018); and Bertolini J, Goss N, Curlin J (eds.), Production of plasma proteins for therapeutic purposes, 16.4: 231:232 (2013), which are incorporated herein by reference in their entirety. The recovered protein (a stable plasma protein component) can be dried (e.g., by freeze-drying) to remove ethanol and H2O. The resulting dried powder can be dissolved in sterile distilled water, for example, using 15 L water / kg powder, and the pH of the solution adjusted to 7.0 with 1 M NaOH. By adding sterile distilled water containing sodium acetyltryptophan, sodium octate, and NaCl, the final concentrations of acetyltryptophan, octate, and sodium can be adjusted to 0.004 M, 0.004 M, and 0.112 M, respectively, to achieve a final protein concentration of 5%. Finally, the solution can be filtered at 10°C to obtain a clear solution, followed by heat treatment to inactivate the pathogen at 60°C for at least 10 hours. Those skilled in the art will recognize that each of the different components, effluents, or pastes thereof described above can be combined with the method of the present invention for the treatment of conditions such as liver disease or liver failure. For example (but not limitingly), effluent I or effluents II / III can be used to treat conditions such as liver disease or liver failure, and are embodiments of the present invention. Another example is that Component I paste, Component II + III paste, Component IV-1 paste, Component IV-4 paste, and / or Component V paste, or a suspension thereof, can be used to treat conditions such as liver disease or liver failure, and are embodiments of the present invention. The foregoing methods for preparing plasma fractions and plasma protein fractions (PPFs) are merely exemplary methods and relate only to embodiments of the invention. Those skilled in the art will recognize that these methods can be varied. For example, in different embodiments and methods of the invention, among other things, pH, temperature, and ethanol concentration can be adjusted to cause different variations in the plasma fractions and plasma protein fractions. In another example, other embodiments of the invention contemplate the use of nanofiltration to remove or inactivate pathogens from the plasma fractions and plasma protein fractions. Other embodiments of the invention contemplate methods and compositions using and / or containing other plasma components. For example, among other things, the invention considers that specific concentrations of albumin are not important for the treatment of symptoms associated with liver disease or liver failure. Therefore, the invention contemplates components with reduced albumin concentrations, such as those with albumin concentrations below 83%. H. Treatment The methods of the present invention described herein include treating a subject with a blood product containing plasma (e.g., plasma components as described above). One embodiment includes treating a human subject with a blood product containing plasma. Those skilled in the art will recognize that methods of treating a subject with a blood product containing plasma are well known in the art. For example (and not limitingly), one embodiment of the methods of the present invention described herein includes administering a plasma component or fresh frozen plasma to a subject to treat liver-related conditions such as acute or chronic liver failure. Other embodiments of the invention include cases where the acute liver failure is associated with infectious diseases (such as hepatitis B or C), overuse of drugs or toxins (e.g., acetaminophen, isoniazid), and metabolic or vascular diseases (such as autoimmune hepatitis and Wilson's disease). Other embodiments of the invention include cases where the chronic liver failure is associated with viral infections, alcoholism, NAFLD (caused by obesity, high cholesterol and triglycerides, and high blood pressure), autoimmune diseases, obstruction or damage to ducts (such as bile ducts connecting the liver and intestines), exposure to toxins or certain drugs, parasites, or heart failure leading to intrahepatic blood pooling. Other embodiments of the invention include liver diseases or liver failure associated with hereditary disorders, such as (but not limited to): α-1 antitrypsin deficiency; bile acid synthesis disorders (Wilson's disease, progressive familial intrahepatic cholestasis of life type 3); carbohydrate metabolism disorders (hereditary fructose intolerance, glycogen storage disease type IV); amino acid metabolism disorders (tyrosinemia type I); urea cycle disorders (argininosuccinate lyase deficiency, citric acid deficiency—CTLN2, NICCD); lipid metabolism disorders (cholesterol ester deposition disease); cystic fibrosis; hemochromatosis; Alstrom's syndrome and congenital liver fibrosis. (Scorza M et al., International Journal of Hepatology (Int 'l J Hepatology), 2014, paper ID 713754 (2014)). Other embodiments of the invention include liver diseases or liver failure associated with pathogens, such as (but not limited to): viruses (Epstein-Barr virus, cytomegalovirus, herpes simplex virus and other herpesviruses, yellow fever, dengue fever, hepatitis B and C); bacteria (typhoid fever, Mycobacterium tuberculosis, brucellosis, Q fever, leptospirosis, spirochetal-syphilis, borborygmus); parasites (schistosomiasis, malaria); fungi (Candida). (Talwani R et al., Clinical Liver Dis., 15(1):111-30 (2011)). Other embodiments of the invention include liver disease or liver failure associated with drugs or toxic substances, such as (but not limited to): acetaminophen, isoniazid, and drugs metabolized by the liver. Other embodiments of the invention include liver diseases in which the liver is partially or completely removed. Other embodiments include liver diseases in which a donor liver is transplanted into a subject with a liver disease. Other embodiments include administering therapeutic agents, such as blood products or plasma components, to the subject before, during, and / or after surgery. In one embodiment, the blood product containing plasma can be administered immediately (e.g., within approximately 12-48 hours after collection from a donor) to an individual exhibiting symptoms associated with liver disease or liver failure. In this case, the product can be stored under refrigeration conditions such as 0-10°C. In another embodiment, the fresh frozen plasma is plasma that has been frozen and stored (cryopreserved) at -18°C or lower. The fresh frozen plasma is thawed before administration, and once thawed, it is administered to the subject 60-75 minutes after the start of the thawing process. Each subject preferably receives a single unit of fresh frozen plasma (200-250 mL), which is preferably derived from a donor within a predetermined age range. In one embodiment of the invention, the fresh frozen plasma is donated by a young individual. In another embodiment of the invention, the fresh frozen plasma is donated by a donor of the same sex. In yet another embodiment of the invention, the fresh frozen plasma is donated by a donor aged between 18 and 22 years. In one embodiment of the invention, blood products containing plasma are screened according to blood type after donation. In another embodiment of the invention, blood products containing plasma suitable for treatment of infectious diseases (e.g., HIV I and II, HBV, HCV, HTLV I and II, anti-HBc) are screened in accordance with the requirements of 21 CFR 640.33 and the recommendations contained in the FDA guidance document. In another embodiment of the invention, a plasma component is used to treat a subject. In one embodiment of the invention, the plasma component is PPF, HAS, component IV-1 or component IV-1 paste, component IV-4 or component IV-4 paste. In a further embodiment of the invention, the plasma component is one of a commercially available HAS formulation or a commercially available PPF formulation. In another embodiment of the invention, the plasma component is a PPF, HAS, component IV-4 or component IV-4 paste derived from a specific age range of individuals (e.g., young individuals), or a modified PPF, HAS, component IV-4 or component IV-4 paste component that has undergone additional component separation or processing (e.g., a PPF, HAS, component IV-1, component IV-1 paste, component IV-4 or component IV-4 paste with one or more specific proteins partially or substantially removed). In another embodiment of the invention, the plasma component is an IGIV plasma component with substantially depleted immunoglobulin (IgG). A blood component that is “substantially depleted” or for which a particular protein (e.g., IgG) has been “substantially removed” refers to a blood component present in less than about 50% of the amount present in the reference product or whole plasma, such as less than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.1%, undetectable levels, or any integer between these values, the content of which is determined using standard assays well known in the art. I. Application The methods of the present invention described herein include treating a subject with a blood product containing plasma (e.g., plasma or plasma components as described above). One embodiment includes treating a human subject with a blood product containing plasma. Those skilled in the art will recognize that methods of treating a subject with a blood product containing plasma are well known in the art. For example (but not limitingly), one embodiment of the methods of the present invention described herein includes administering fresh frozen plasma to a subject to treat conditions such as liver disease or liver failure. In one embodiment, the blood product containing plasma may be administered immediately (e.g., within approximately 12-48 hours after collection from a donor) to an individual exhibiting adverse symptoms associated with liver disease or liver failure. In this case, the product may be stored under refrigeration conditions such as 0-10°C. In another embodiment, the fresh frozen plasma is plasma that has been frozen and stored (cryopreserved) at -18°C or colder. The fresh frozen plasma is thawed before administration, and once thawed, it is administered to the subject 60-75 minutes after the start of the thawing process. Each subject preferably receives a single unit of fresh frozen plasma (200-250 mL), which is preferably derived from a donor within a predetermined age range. In one embodiment of the invention, the fresh frozen plasma is donated by a young individual. In another embodiment of the invention, the fresh frozen plasma is donated by a donor of the same sex. In yet another embodiment of the invention, the fresh frozen plasma is donated by a donor aged between 18 and 22 years. In one embodiment of the invention, blood products containing plasma are screened according to blood type after donation. In another embodiment of the invention, blood products containing plasma suitable for treatment of infectious diseases (e.g., HIV I and II, HBV, HCV, HTLV I and II, anti-HBc) are screened in accordance with the requirements of 21 CFR 640.33 and the recommendations contained in the FDA guidance document. In another embodiment of the invention, a plasma component is used to treat a subject. In one embodiment of the invention, the plasma component is a PPF or HAS. In a further embodiment of the invention, the plasma component is one of a commercially available HAS formulation or a commercially available PPF formulation. In another embodiment of the invention, the plasma component is a PPF or HAS derived from a specific age range of individuals (e.g., young individuals), or a modified PPF or HAS that has undergone additional component separation or processing (e.g., a PPF or HAS with one or more specific proteins partially or substantially removed). In another embodiment of the invention, the plasma component is an IGIV plasma component with substantially depleted immunoglobulin (IgG). A blood component that is “substantially depleted” or for which a particular protein (e.g., IgG) has been “substantially removed” refers to a blood component present in less than about 50% of the amount present in the reference product or whole plasma, such as less than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.1%, undetectable levels, or any integer between these values, the content of which is determined using standard assays well known in the art. One embodiment of the invention includes treating a subject with symptoms such as liver disease or liver failure by administering an effective amount of plasma or plasma fraction to the subject. Another embodiment of the invention includes administering an effective amount of plasma or plasma fraction, followed by monitoring for improvement in liver function, liver regeneration, marker presence, pain reduction, or inflammation reduction in the subject. Another embodiment of the invention includes treating a subject with symptoms such as liver disease or liver failure by administering an effective amount of plasma or plasma fraction to the subject, wherein the plasma or plasma fraction is administered in a manner that improves liver function, promotes liver regeneration, detects the presence of markers, reduces pain, or reduces inflammation after the mean or median half-life of the plasma protein or plasma fraction protein relative to the most recently administered dose (referred to herein as "pulse administration") has been reached (see U.S. Patent Applications Nos. 15 / 499,697 and 62 / 701,411, which are incorporated herein by reference in their entirety). Another embodiment of the invention includes administering plasma or plasma fraction according to a dosing regimen of at least two consecutive days, and monitoring for improvement in liver function or HSC marker levels in the subject for at least three days after the last administration date. Further embodiments of the invention include administering plasma or plasma fractions according to a dosing regimen of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days, and monitoring the subject for improvement in liver function, liver regeneration, marker presence, pain reduction, or inflammation reduction for at least 3 days after the last administration date. Another embodiment of the invention includes administering plasma or plasma fractions according to a dosing regimen of at least 2 consecutive days, and monitoring the subject for improvement in liver function, marker presence, pain reduction, or inflammation reduction when the mean half-life of the protein in the plasma or plasma fraction is reached after the last administration date. Yet another embodiment of the invention includes administering plasma or plasma fractions according to a discontinuous dosing regimen of 2 to 14 days, wherein each interval between doses may be 0-3 days. In some cases, pulse dosing according to the invention includes administration of a first group of agents (e.g., as described above), followed by a withdrawal period, such as a "withdrawal period," after which administration of another agent or another group of agents is performed. The duration of this "withdrawal" period can vary, but in some embodiments, it is 7 days or longer, such as 10 days or longer, including 14 days or longer. In some cases, the withdrawal period is 15 to 365 days, such as 30 to 90 days, including 30 to 60 days. Therefore, embodiments of the method include non-long-term (i.e., non-continuous) dosing, such as non-long-term administration of blood products. In some embodiments, the pattern of pulse dosing followed by a withdrawal period is repeated as needed, and in some cases, this pattern lasts for 1 year or longer, such as 2 years or longer, until and including the end of the subject's life. Another embodiment of the invention includes administration of plasma or plasma components according to a dosing regimen of 5 consecutive days of administration, followed by a 2-3 day withdrawal period, and then 2-14 consecutive days of administration. Other embodiments of the invention include liver diseases in which the liver is partially or completely removed. Other embodiments include liver diseases in which a donor liver is transplanted into a subject with a liver disease. Other embodiments include administering therapeutic agents, such as blood products or plasma components, to the subject preoperatively, perioperatively, and / or postoperatively. Methods of liver resection and transplantation are well known in the art. In biochemistry, the "effective amount" or "effective dose" of an active agent refers to the amount of an active agent that inhibits, antagonizes, reduces, diminishes, or represses by about 20% or more, such as 30% or more, 40% or more, or 50% or more, in some cases 60% or more, 70% or more, 80% or more, or 90% or more, and in some cases about 100%, a negligible amount, and in some cases, can reverse adverse conditions such as liver disease or liver failure. J. Plasma protein components In carrying out the method of the present invention, a plasma component is administered to the subject. In one embodiment, the plasma component is a plasma protein component (PPF). In other embodiments, the PPF is selected from commercially available PPF formulations. In another embodiment, the PPF consists of 88% normal human albumin, 12% α and β globulins, and no more than 1% γ globulin (as determined by electrophoresis). Further embodiments of this embodiment for carrying out the method of the invention include, for example, an embodiment of a 5% PPF solution buffered with sodium carbonate and stabilized with 0.004 M sodium octanoate and 0.004 M acetyltryptophan. Other formulations (including formulations that vary the percentage of PPF in the solution (e.g., from about 1% to about 10%, from about 10% to about 20%, from about 20% to 25%, from about 25% to 30%) and solvent concentrations) and stabilizers may be used to carry out the method of the invention. K. Plasma components from donors of specific ages Other embodiments of the invention include administering plasma protein components derived from plasma from individuals within certain age ranges. One embodiment includes administering a PPF or HAS derived from plasma from a young individual. In another embodiment of the invention, the young individual has a single specific age or a specific age range. In yet another embodiment, the donor's average age is less than the subject's average age or less than the average age of the subject receiving treatment. Some embodiments of the invention involve collecting blood or plasma from individuals within a specific age range and performing component separation of the plasma as described above to obtain plasma protein component products, such as PPF or HAS. In alternative embodiments of the invention, the plasma protein component or a specific plasma protein component is obtained from specific individuals falling within a specific age range. L. Indications One embodiment of the invention involves administering plasma components or plasma fractions to a subject diagnosed with liver disease or liver failure that may benefit from improvements in hepatocyte proliferation or liver regeneration. Another embodiment of the invention includes cases where the disease is associated with acute liver failure, chronic liver failure, or acute-on-chronic liver failure. Acute-on-chronic liver failure occurs in patients with relatively stable chronic liver disease who suddenly develop acute liver failure. This often results in a high mortality rate. Another embodiment of the invention involves acute failure associated with infectious diseases (such as hepatitis B or C), overuse of drugs or toxins (e.g., acetaminophen, isoniazid), and metabolic or vascular diseases (such as autoimmune hepatitis and Wilson's disease). Other embodiments of the invention include chronic liver failure associated with viral infections, alcoholism, NAFLD (caused by obesity, high cholesterol and triglycerides, and high blood pressure), autoimmune diseases, obstruction or damage to ducts (such as the bile ducts connecting the liver and intestines), exposure to toxins or certain drugs, parasites, or heart failure leading to intrahepatic blood pooling. Other embodiments of the invention include liver diseases or liver failure associated with hereditary disorders, such as (but not limited to): α-1 antitrypsin deficiency; bile acid synthesis disorders (Wilson's disease, progressive familial intrahepatic cholestasis of life type 3); carbohydrate metabolism disorders (hereditary fructose intolerance, glycogen storage disease type IV); amino acid metabolism disorders (tyrosinemia type I); urea cycle disorders (argininosuccinate lyase deficiency, citric acid deficiency—CTLN2, NICCD); lipid metabolism disorders (cholesterol ester deposition disease); cystic fibrosis; hemochromatosis; Alstrom's syndrome and congenital liver fibrosis. (Scorza M et al., International Journal of Hepatology (Int 'l J Hepatology), 2014, paper ID 713754 (2014)). Other embodiments of the invention include liver diseases or liver failure associated with pathogens, such as (but not limited to): viruses (Epstein-Barr virus, cytomegalovirus, herpes simplex virus and other herpesviruses, yellow fever, dengue fever, hepatitis B and C); bacteria (typhoid fever, Mycobacterium tuberculosis, brucellosis, Q fever, leptospirosis, spirochetal-syphilis, borborygmus); parasites (schistosomiasis, malaria); fungi (Candida). (Talwani R et al., Clinical liver disease (Clin Liver Dis.), 15(1):111-30 (2011)). Other embodiments of the invention include liver disease or liver failure associated with drugs or toxic substances, such as (but not limited to): acetaminophen, isoniazid, and drugs metabolized by the liver. Other embodiments of the invention include liver diseases in which a portion of the liver has been removed. Other embodiments include liver diseases in which a donor liver is transplanted into a subject with a liver disease. Other embodiments include administering therapeutic agents, such as blood products or plasma components, to the subject preoperatively, perioperatively, and / or postoperatively. M. Reagents, equipment and kits The present invention also provides reagents, apparatus, and kits thereof for carrying out one or more of the above methods. The target reagents, apparatus, and kits thereof can vary considerably. The reagents and equipment of interest include those mentioned above concerning methods for preparing blood products containing plasma for transfusion into subjects in need, such as anticoagulants, cryopreservatives, buffer solutions, isotonic solutions, etc. The kit may also include blood collection bags, tubes, needles, centrifuge tubes, etc. In other embodiments, the kit described herein includes two or more containers of plasma products (e.g., plasma protein components), for example, three or more, four or more, five or more, including six or more plasma product containers. In some cases, the number of plasma product containers in the kit may vary, and may be nine or more, 12 or more, 15 or more, 18 or more, 21 or more, 24 or more, 30 or more, including 36 or more, such as 48 or more. Each container may have associated identification information, including various information about the plasma product contained therein, which may include one or more of the following: the age of the plasma product donor, details of the processing of the plasma product, such as whether the plasma product was processed to remove proteins above average molecular weight (as described above), blood type details, etc. In some cases, each container in the kit includes identification information about the plasma it contains, including information about the age of the plasma donor. For example, this identification information may confirm the donor's age (where such identification information could be the donor's age at the time of collection). In some cases, each container in the kit contains plasma from donors of substantially the same age; that is, all containers contain plasma from donors whose ages differ but are substantially the same. "Substantially the same age" means that the ages of the donors from whom the plasma products shown in the kit are obtained differ by 5 years or less in some cases, such as 4 years or less, for example, 3 years or less, including 2 years or less, such as 1 year or less, for example, 9 years or less, 6 months or less, 3 months or less, including 1 month or less. Identification information can be present on any suitable part of the container, such as a tag, RFID chip, etc. This identification information can be human-readable, computer-readable, etc., as needed. The container can have any suitable configuration. While the volume of the container can vary, in some cases it ranges from 10 ml to 5000 mL, for example, 25 mL to 2500 mL, 50 ml to 1000 mL, including 100 mL to 500 mL. The container can be rigid or flexible and can be made of any suitable material, such as polymeric materials, including medical-grade plastics. In some cases, the container has a pouch or sachet configuration. In addition to the container, such kits may further include a drug delivery device such as those described above. The components of such kits can be housed in any suitable packaging, such as a box or similar structure, configured to contain the container and other kit components. In addition to the components described above, the kit may also include instructions for use. These instructions may be presented in various forms within the kit. One form of these instructions may be information printed on a suitable medium or substrate, such as one or more sheets of paper with the information printed in the kit packaging or packaging inserts. Another form is the information recorded on a computer-readable medium, such as a memory disk, CD, or portable flash memory drive. Yet another form is a website address that can be used via the Internet to access information from a removed site. The kit may use simplified descriptions. N. Experimental Examples 1. Example 1 a) PPF1 Induced 70% After partial hepatectomy 20 Age in months C57BL / 6 Recovery of liver function in mice Twenty-month-old male C57BL / 6J mice (The Jackson Laboratory, Sacramento, California) were used. All mice were housed individually under specific pathogen-free conditions, receiving a 12-hour light-12-hour dark cycle, and all animal handling and use complied with the standard guidelines approved by the Institutional Animal Care and Use Committee. Animals were fed a 60% high-fat diet (Bio-Serv F3282) for 7–8 weeks and were randomly assigned to solvent-based or PPF1-based administration groups based on their post-diet weight and ALT levels to ensure identical mean body weight and serum ALT levels across groups. Minor modifications to the surgical procedure were made as previously described (Nevzorova, Y. et al.). Laboratory animals (Lab. Anim.) 49, 81–88 (2015). The resected liver (left and inner lobes) served as a preoperative control, and the residual liver (caudate and right lobes) was harvested 48 hours postoperatively. At 24 hours postoperatively, EdU (2.5 mg / mL stock solution in physiological saline) was administered intraperitoneally at a dose of 30 mg / kg body weight. At 46 hours postoperatively, BrdU (10 mg / mL stock solution in physiological saline) was administered intraperitoneally at a dose of 30 mg / kg body weight. At 48 hours postoperatively, all animals were weighed, and the residual liver (inner and caudate lobes) and serum were collected for ALT analysis. Commercially available PPF (“PPF1”) (as described above, a commercially available PPF formulation dissolved in a 5% solution) was stored at 4°C. PPF1 is a PPF containing approximately 88% normal human albumin (relative to total protein), 12% α and β globulins, and no more than 1% γ globulin (as determined by electrophoresis). Unless otherwise stated, in the examples herein, PPF1 is administered via a 5% solution (w / v, 50 g / L). For qPCR analysis, RNA was extracted from the resected liver or residual liver tissue and then pulverized using liquid nitrogen and a mortar / pestle. Extraction was then performed using Trizol (Ambion / Fisher 15-596-018) and the RNeasy Mini Kit (Qiagen 74106). cDNA was then amplified using the iScript Reverse Transcription Super Mixture (Bio-Rad 1030). qPCR was amplified using the SsoAdvanced Universal SYBR Green Master Mixture (Bio-Rad 1725272) and performed on a Quant Studio 6 Flex (Applied Biosystem). Gene expression was normalized based on RPS18 (ribosomal protein s18). For immunostaining, 12-micron thick frozen liver sections embedded in an OCT compound (Sakura 4583) were used for immunofluorescence staining. Antigen retrieval was performed for 30 minutes at 95°C using citrate buffer (Sigma C9999). EdU labeling was performed using Click-IT Plus EdU Alexa Fluor 555 (Fisher C10638). Cell nuclei were labeled with Hoechst 33342 at a concentration of 1 / 100,000 in ddH2O for 3 minutes (Fisher H3570). Oil Red O staining was performed to observe triglyceride accumulation in the liver. Briefly, frozen liver sections were immersed in 0.375% Oil Red O dissolved in isopropanol for 5 minutes. The sections were rinsed under running tap water for 30 minutes and fixed with Prolong Gold anti-fading reagent (Invitrogen P36934). Figure 1 shows the weight changes of 20-month-old C57BL / 6 mice fed a high-fat diet ("HFD"). After 8.5 weeks of HFD, the mice showed a significant increase in body weight. Mean ± SEM, p < 0.0001. One-way ANOVA. Figure 2 is picture Image of mouse liver stained with Oil Red O shown in 1. Mice subjected to HFD developed fatty liver compared to mice receiving a normal diet ("normal feeding"). Figure 3 shows the experimental design for evaluating the effect of PPF1 on 20-month-old C57BL / 6 mice fed the high-fat diet described above. Figure 4 shows picture The mice shown in Figure 3 that received the drug underwent 70% hepatectomy, including the removed and remaining leaves. Figure 5 shows picture The results shown in Figure 3 are the determination of the liver weight to body weight ratio of the livers removed by hepatectomy from mice that received the drug, treated with the solvent and PPF1. Figure 6 shows picture The liver weight shown in Figure 3 is from the excised liver of a mouse that received the drug, and was treated with solvent and PPF1. Figure 7 illustrates the normal and unaffected serum ALT levels in mice that underwent hepatectomy prior to HFD and PPF1 administration. ALT levels below 50-60 units / L are considered within the normal range. See, for example, Mazzaccara C et al. PLoS ONE , 3(11):e3772 (2008)). Figure 8 shows picture Figure 3 shows the liver weight to body weight ratio in mice with residual liver that received both solvent and PPF1 at 48 hours post-hepatectomy. Animals receiving PPF1 showed a significant increase in liver weight at 48 hours post-hepatectomy compared to those receiving solvent. Mean ± SEM, **p < 0.001, unpaired t-test, Whitney correction. Figure 9 shows picture Liver weight of mice with residual liver at 48 hours post-hepatectomy, as shown in Figure 3, after receiving both solvent and PPF1. Animals receiving PPF1 showed a significant increase in liver weight at 48 hours post-hepatectomy compared to those receiving solvent. Mean ± SEM, *p < 0.05, unpaired t-test, Whitney correction. Figure 10 shows picture Figure 3 shows the serum ALT levels in mice with residual liver that received both solvent and PPF1 at 48 hours post-hepatectomy. Compared to animals receiving solvent, animals receiving PPF1 showed significantly lower serum ALT levels at 48 hours post-hepatectomy, indicating a significantly reduced degree of liver injury. Mean ± SEM, **p < 0.001, unpaired t-test, Whitney correction. Conversely, the differences in resected liver weight, liver weight / body weight ratio, and ALT levels between animals receiving solvent administration and those receiving PPF1 administration were not statistically significant. Figure 11 reports the cell proliferation rate after hepatectomy. EdU was delivered 24 hours after hepatectomy, and the proliferation rate was tracked by labeling EdU-positive cells with Click-it. For the residual liver, PPF1 significantly increased the number of EdU-positive cells per field of view compared with animals receiving solvent-based administration. Figure 12 reports cell proliferation at 48 hours post-hepatectomy, measured by the number of Ki67-positive cells in each field of view. For the residual liver, PPF1 significantly increased the number of Ki67-positive cells in each field of view compared to animals receiving solvent-based administration. Figure 13 reports cell proliferation rates measured by qPCR gene expression in residual liver tissue, showing the relative expression of the cell cycle marker Cycle B1. Cyclin B1 expression was significantly upregulated in residual liver sections compared to mice treated with solvent. Mean ± SEM, *p < 0.05, unpaired T test, Whitney correction. Figure 14A to picture 14D reported the qPCR expression of multiple markers in resected liver, showcasing the cell cycle marker Cycle B1 (… picture 14A), Cyclin A2 ( picture 14B) and Ki67 picture The relative expression of 14C. For all three cell cycle markers, surprisingly, cell proliferation was significantly increased in the PPF1 group compared to the solvent control in resected liver sections (retrieved as a preoperative control during hepatectomy). picture 14D reported the relative expression levels of TNFα in resected liver sections. TNFα is known to contribute to the recovery of functional liver tissue by promoting hepatocyte proliferation and liver regeneration. In summary, PPF1 administration facilitated the activation of cell proliferation in resting, intact liver (pre-hepatectomy) compared to the solvent control. Mean ± SEM, *p < 0.05, unpaired T test, Whitney correction. Figure 15 shows the situation in picture The Ki67 immunostaining in the resected liver reported in 14C confirmed that the number of Ki67-positive cells in the resected liver treated with PPF1 was significantly higher than that in the solvent control. Figure 16 reports picture The quantitative results of immunostaining shown in Figure 15 indicate an increased number of Ki67-positive cells in resected liver tissue treated with PPF1. Mean ± SEM, *p < 0.05, unpaired T test, Whitney correction. Figure 17 is a graph showing the total number of animals that underwent hepatectomy and the survival rate of animals receiving each treatment. Animals receiving PPF1 showed an increasing trend in survival compared to animals receiving solvent-based administration. Figure 18 shows two confocal microscopic views of the EdU-doped residual liver 24 hours after hepatectomy (see Figure 18). picture 3) Tissue sections were stained with GFAP antibody (astrocytocyte marker), and the level of colocalization between EdU and GFAP was observed. The lack of colocalization between EdU and GFAP confirmed that no PPF1-related cell proliferation occurred in the stellate cells. Figure 19 shows two confocal microscopic views of the EdU-doped residual liver 24 hours after hepatectomy (see Figure 19). picture 3) Tissue sections were stained with CD68 antibody (Kouffer cell marker), and the level of colocalization between EdU and CD68 was observed. Based on the lack of colocalization between EdU and CD68, it was determined that no cell proliferation associated with PPF1 administration occurred in Koupffer cells. Figure 20 shows the confocal microscopic view of the EdU-doped residual liver 24 hours after hepatectomy (see Figure 20). picture 3) Tissue sections were stained with HNF4a antibody (hepatocyte marker), and the level of colocalization between EdU and HNF4a was observed. Based on the lack of colocalization between EdU and HNF4a, it was determined that no cell proliferation associated with PPF1 administration occurred in hepatocytes. Figure 21 shows the confocal microscopic view of the EdU-doped residual liver 24 hours after hepatectomy (see Figure 21). picture 3) Tissue sections were stained with CD3 antibody (T cell marker), and the level of colocalization between EdU and CD3 was observed. Based on the lack of colocalization between EdU and CD3, it was determined that no cell proliferation associated with PPF1 administration occurred in T cells. Figure 22 shows two confocal microscopic views of the EdU-doped residual liver 24 hours after hepatectomy (see Figure 22). picture 3) Tissue sections were stained with CD31 antibody (a marker for sinusoidal endothelial cells), and the level of colocalization between EdU and CD31 was observed. Based on the positive colocalization between EdU and CD31, it was determined that cell proliferation induced by PPF1 administration was related to hepatic sinusoidal endothelial cells (LSECs). These results indicate that PPF1 increases the proliferation of capillary cells in the liver, thereby increasing blood delivery to the site of injury, demonstrating the mechanism by which tissue repair and regeneration are achieved after PPF1 administration. (Arrows indicate LSECs containing EdU-positive cells). 2. Example 2 a) Effects of PPF1, recombinant human albumin, and HAS1 on the liver of 20-month-old C57BL / 6 mice after 70% partial hepatectomy. Recombinant human albumin Male C57BL / 6J cells were treated as described previously in Example 1 above, but another cohort was treated with recombinant human albumin (“rhAlbumin”). Comparisons were made between the PPF1-treated group, the rhAlbumin-treated group, and the solvent-treated group. Figure 23 illustrates the experimental design for evaluating the effects of PPF1 (a plasma component of type "PF") and recombinant human albumin (rhAlbumin) on 20-month-old C57BL / 6 mice on a high-fat diet. Mice were initially fed a 60% high-fat diet for 8 weeks, followed by 7 consecutive days of treatment with PPF1, rhAlbumin, or a solvent. Surgery (70% hepatectomy) was performed the day after the last dose of PPF1, rhAlbumin, or solvent, and the anterior middle and left lobes (resected portions) were removed during the hepatectomy. The right and caudate lobes (residual portions) were harvested 48 hours post-hepatectomy. Figure 24 reports cell proliferation in the resected liver 48 hours after hepatectomy, measured by the number of Ki67-positive cells in each field of view. PPF1 significantly increased the number of Ki67-positive cells per field of view compared to animals receiving the solvent-based drug. Conversely, there was no significant difference between animals receiving rhAlbumin and those receiving the solvent-based drug. Mean ± SEM, ***p < 0.0001, unpaired T test, Whitney correction, ns = not significant. Figure 25 reports the cell proliferation rate in the resected liver after hepatectomy. EdU was delivered 24 hours post-hepatectomy, and proliferation rate was tracked by click chemistry. PPF1 significantly increased the number of EdU-positive cells per field of view compared to animals receiving solvent-based administration. Conversely, animals receiving rhAlbumin did not show a significant increase in proliferation compared to animals receiving solvent-based administration. These results suggest that albumin (the most abundant component in PPF1) may not be the primary component responsible for PPF1's proliferative, tissue repair, and regeneration activities. Instead, it indicates that other components of PPF1 (often considered impurities left after plasma fractionation) surprisingly drive these activities. Human albumin solution (HAS) Male C57BL / 6J were treated in the same manner as previously described in Example 1 above, but another cohort was treated with human albumin solution (“HAS1”). Comparisons were made between the PPF1-treated group, the HAS1-treated group, and the solvent-treated group. Figure 26 illustrates the experimental design for evaluating the effects of PPF1 and HAS1 on 20-month-old C57BL / 6 mice on a high-fat diet. Mice were initially fed a 60% high-fat diet for 8 weeks, followed by 7 consecutive days of treatment with PPF1, rhAlbumin, or a solvent. Surgery (70% hepatectomy) was performed the day after the last dose of PPF1, HAS1, or solvent, and the anterior middle and left lobes (resected portions) were removed during the hepatectomy. The right and caudate lobes (residual portions) were harvested 48 hours post-hepatectomy. Figure 27 reports the cell proliferation rate 24 hours after hepatectomy. EdU was delivered 24 hours after hepatectomy. Compared with the solvent group, the number of EdU-positive cells in the residual liver of both the PPF1 and HAS1 groups was significantly increased. *p<0.05, Welch t test. Error bar = SEM. HAS1 is a commercially available HAS, such as the commercially available HAS formulation described above stored in a 5% solution at 4°C. Figure 28 shows the cell proliferation rate 48 hours after hepatectomy. Ki67 immunostaining was performed on the residual liver removed 48 hours after hepatectomy. Although cell proliferation was significantly increased in both the PPF1 and HAS groups compared to the control group, PPF1-induced proliferation was significantly higher than that in animals receiving HAS1. *p<0.05, **p<0.005, ***p<0.0005, Welch t test. Error bar = SEM. These results indicate that plasma fraction-induced hepatocyte proliferation was observed in steatotic livers treated with both HAS1 and PPF1. However, although both plasma fractions (HAS1 and PPF1) significantly induced proliferation at 24 hours compared to the solvent group, the effect of PPF1 was more significant at 48 hours compared to HAS1, and even more significant than that of the solvent group. This again demonstrates, surprisingly, that albumin (which is present in higher purity and concentration in HAS1 compared to PPF1) is not the primary component responsible for the effects of plasma fractions on proliferation, tissue repair, and regeneration. Instead, it suggests that other components in the plasma fractions, or "impurities" left after plasma fraction separation, can unexpectedly drive these activities. 3. Example 3 a) Two hours after the last dose, PPF1 20 Age C57BL / 6 months Effects on mouse liver Twenty-month-old male C57BL / 6 mice were randomly assigned to either a solvent-based administration group or a PPF1-based administration group to ensure identical mean body weight between groups. Mice were fed a normal diet, not a high-fat diet. Animals were administered 150 µL of solvent or PPF1 intravenously daily for 7 consecutive days. On day 7, the liver was harvested 2 hours after administration. For gene expression analysis, RNA was extracted and reverse transcribed, and TNFα was analyzed using SYBR qPCR. Gene expression was normalized using RPS18. For immunostaining, proliferating cells in the harvested liver were labeled with Ki67 antibody. Figure 29 shows the experimental design for evaluating the effect of PPF1 on 20-month-old C57BL / 6 mice 2 hours after the last dose. Figure 30 shows the above text picture The results of TNFα gene expression analysis in mice that received the drug are shown in Figure 29. TNFα gene expression was significantly increased in mice receiving PPF1, as measured by qPCR, compared to animals receiving solvent-based administration. **p < 0.005. Welch t-test, error bar = SEM. Figure 31 shows the above text picture The results of Ki67 immunostaining analysis performed on mice that received the drug are shown in Figure 29. Compared with animals that received solvent-based administration, animals that received PPF1 showed a significant increase in Ki67-positive cells 2 hours after the last dose, indicating that PPF1 can increase hepatocyte proliferation. *p<0.05. Welch t-test, error bar = SEM. These results demonstrate that even in healthy, non-steatodegenerative aged livers, plasma components such as PPF1 can effectively induce proliferation and regeneration. 4. Example 4 a) Component IV-1 Paste to 70% 20 days after partial hepatectomy Age C57BL / 6 months Effects on mouse liver Twenty-month-old male C57BL / 6J mice (The Jackson Laboratory, Sacramento, California) were used. All mice were housed individually under specific pathogen-free conditions, receiving a 12-hour light-12-hour dark cycle, and all animal handling and use complied with the standard guidelines approved by the Institutional Animal Care and Use Committee. Animals were fed a 60% high-fat diet (Bio-Serv F3282) for 7–8 weeks and were randomly assigned to either the solvent-based administration group or the component IV-1 paste suspension group based on their post-diet weight and ALT levels to ensure identical mean body weight and serum ALT levels across groups. The surgical procedure was slightly modified as previously described (Nevzorova, Y). people? laboratory animals (Lab. Anim.) , 49, 81–88 (2015). Resected liver lobes (left and medial lobes) were used as preoperative controls, and residual liver lobes (caudate and right lobes) were harvested 48 hours postoperatively. EdU (2.5 mg / mL stock solution in physiological saline) was administered intraperitoneally at 30 mg / kg body weight at 24 hours postoperatively. BrdU (10 mg / mL stock solution in physiological saline) was administered intraperitoneally at 30 mg / kg body weight at 46 hours postoperatively. All animals were weighed at 48 hours postoperatively, and residual liver (medial and caudate lobes) and serum were collected for ALT analysis. The effects of Component IV-1 paste suspension and solvent on these experimental reads were compared. Additionally, the effects of Component IV-1 paste suspension on these experimental reads were compared with those of other plasma components. [Figure 1] [Image showing weight changes in 20-month-old C57BL / 6 mice fed a high-fat diet ("HFD"). After 8.5 weeks of HFD, the mice showed a significant increase in body weight.] [Figure 2] 〕 yes picture Image of mouse liver stained with Oil Red O shown in 1. Mice subjected to HFD developed fatty liver compared to mice receiving a normal diet ("normal feeding"). [Figure 3] This study presents an experimental design to evaluate the effects of PPF1 on 20-month-old C57BL / 6 mice with fatty liver. Mice were initially fed a 60% high-fat diet for 7 weeks, followed by 7 consecutive days of treatment with either PPF1 or a solvent. Surgery (70% hepatectomy) was performed the day after the last dose of PPF1 or solvent, and the anterior middle and left lobes (resected portions) were removed during the hepatectomy. The right and caudate lobes (residual portions) were harvested 48 hours post-hepatectomy. [Figure 4] 〕 marked picture The mice shown in Figure 3 that received the drug underwent 70% hepatectomy, including the removed and remaining leaves. [Figure 5] [Shown] picture The results shown in Figure 3 are the determination of the ratio of the weight of the liver resection portion to the body weight in mice that received solvent administration and mice that received PPF1 administration and underwent hepatectomy. [Figure 6] [Shown] picture The weight of the liver resection portion in mice that received solvent administration and those that received PPF1 administration is shown in Figure 3. [Figure 7] [Image showing mice that received HFD and PPF1 before hepatectomy had normal and unaffected serum ALT levels.] [Figure 8] [Shown] picture The results of the liver weight to body weight ratio of mice with residual liver that were administered solvent and PPF1 48 hours after hepatectomy are shown in Figure 3. [Figure 9] [Shown] picture The liver weight of mice with residual liver that were administered solvent and PPF1 48 hours after hepatectomy, as shown in Figure 3. [Figure 10] [Shown] picture The results of serum ALT levels in mice that received solvent and PPF1 48 hours after hepatectomy are shown in Figure 3. [Figure 11] Cell proliferation rates following hepatectomy were reported. EdU was delivered 24 hours post-hepatectomy, and proliferation rates were tracked by labeling EdU-positive cells with Click-it. Compared to animals receiving solvent-based administration, PPF1 significantly increased the number of EdU-positive cells per field of view. [Figure 12] Cell proliferation at 48 hours post-hepatectomy was reported, measured by the number of Ki67-positive cells per field of view. PPF1 significantly increased the number of Ki67-positive cells per field of view compared to animals receiving solvent-based administration. [Figure 13] This report presents cell proliferation rates measured in residual liver tissue via qPCR gene expression, demonstrating the relative expression of the cell cycle marker Cycle B1. Cyclin B1 expression was significantly upregulated in residual liver sections compared to mice treated with solvent-based drugs, in mice treated with PPF1. [Figure 14A] 〕 to 〔picture 14 D This report presents the qPCR expression of multiple markers in resected liver, showcasing the cell cycle marker Cycle B1 (…). picture 14A), Cyclin A2 ( picture 14B) and Ki67 picture The relative expression of 14C. For all three cell cycle markers, surprisingly, cell proliferation was significantly increased in the PPF1 group compared to the solvent control in resected liver sections (retrieved as a preoperative control during hepatectomy). Figure 14D reports the relative expression levels of TNFα in resected liver sections. TNFα is known to contribute to the recovery of functional liver tissue by promoting hepatocyte proliferation during liver regeneration. [Figure 1] 5 [This shows] picture Representative images of Ki67 immunostaining in resected liver reported in 14C confirm that the number of Ki67-positive cells in resected liver treated with PPF1 was significantly greater than that in solvent controls. [Figure 16] The report was submitted. picture The quantification of immunostaining shown in 15 indicates an increase in the number of Ki67-positive cells in the resected liver treated with PPF1. [Figure 17] [This is a chart listing the total number of animals that underwent liver resection and the survival rate for each treatment.] [Figure 18] This image shows two representative confocal microscopic views of the EdU-doped residual liver 24 hours after hepatectomy (see...). picture 3) Tissue sections were stained with GFAP antibody (astrocytocyte marker), and the level of colocalization between EdU and GFAP was observed. The lack of colocalization between EdU and GFAP confirmed that no PPF1-related cell proliferation occurred in the stellate cells. [Figure 19] This image shows two representative confocal microscopic views of the EdU-doped residual liver 24 hours after hepatectomy (see...). picture 3) Tissue sections were stained with CD68 antibody (Kouffer cell marker), and the level of colocalization between EdU and CD68 was observed. Based on the lack of colocalization between EdU and CD68, it was determined that no cell proliferation associated with PPF1 administration occurred in Koupffer cells. [Figure 20] This image shows a representative confocal microscopic view of the EdU-doped residual liver 24 hours after hepatectomy (see [link]). picture 3) Tissue sections were stained with HNF4a antibody (hepatocyte marker), and the level of colocalization between EdU and HNF4a was observed. Based on the lack of colocalization between EdU and HNF4a, it was determined that no cell proliferation associated with PPF1 administration occurred in hepatocytes. [Figure 21] This image shows a representative confocal microscopic view of the EdU-doped residual liver 24 hours after hepatectomy (see [link]). picture 3) Tissue sections were stained with CD3 antibody (T cell marker), and the level of colocalization between EdU and CD3 was observed. Based on the lack of colocalization between EdU and CD3, it was determined that no cell proliferation associated with PPF1 administration occurred in T cells. [Figure 22] This image shows two representative confocal microscopic views of the EdU-doped residual liver 24 hours after hepatectomy (see...). picture 3). Tissue sections were stained with CD31 antibody (a marker for sinusoidal endothelial cells), and the level of colocalization between EdU and CD31 was observed. Based on the positive colocalization between EdU and CD31, it was determined that cell proliferation induced by PPF1 administration was related to hepatic sinusoidal endothelial cells (LSECs). Arrows indicate LSECs containing EdU-positive cells. [Figure 23] This study presents an experimental design to evaluate the effects of PPF1 (plasma component "PF") and recombinant human albumin (rhAlbumin) on 20-month-old C57BL / 6 mice. Mice were initially fed a 60% high-fat diet for 8 weeks, followed by 7 consecutive days of treatment with PPF1, rhAlbumin, or a solvent. Surgery (70% hepatectomy) was performed the day after the last dose of PPF1, rhAlbumin, or solvent, and the anterior middle and left lobes (resected portions) were removed during the hepatectomy. The right and caudate lobes (residual portions) were harvested 48 hours post-hepatectomy. [Figure 24] This study reported cell proliferation in the resected liver 48 hours after hepatectomy, measured by the number of Ki67-positive cells per field of view. PPF1 significantly increased the number of Ki67-positive cells per field of view compared to animals receiving solvent-based administration. Conversely, there was no significant difference between animals receiving rhAlbumin and those receiving solvent-based administration. [Figure 25] This study reports cell proliferation rates in the resected liver following hepatectomy. EdU was delivered 24 hours post-hepatectomy, and proliferation rates were tracked using click chemistry. Compared to animals receiving solvent-based administration, PPF1 significantly increased the number of EdU-positive cells per field of view. Conversely, animals receiving rhAlbumin showed no significant proliferation trend compared to those receiving solvent-based administration. [Figure 26] This study presents an experimental design to evaluate the effects of PPF1 and HAS1 on 20-month-old C57BL / 6 mice. Mice were initially fed a 60% high-fat diet for 8 weeks, followed by 7 consecutive days of treatment with different plasma fractions (PFs) of PPF1 and HAS1 or a solvent. Surgery (70% hepatectomy) was performed the day after the last dose of PPF1, HAS1, or solvent, and the anterior middle and left lobes (resected portions) were removed during the hepatectomy. The right and caudate lobes (residual portions) were harvested 48 hours post-hepatectomy. [Figure 27] The cell proliferation rate at 24 hours post-hepatectomy was reported. EdU was delivered 24 hours post-hepatectomy. Compared with the solvent group, the number of EdU-positive cells in the residual liver of both the PPF1 and HAS1 groups was significantly increased. [Figure 28] The cell proliferation rate is shown at 48 hours post-hepatectomy. Ki67 immunostaining was performed on the residual liver removed 48 hours post-hepatectomy. Although cell proliferation was significantly increased in both the PPF1 and HAS groups compared to the control group, PPF1-induced proliferation was significantly higher than that induced by HAS1. [Figure 29] This study demonstrates an experimental design to evaluate the effect of PPF1 on 20-month-old C57BL / 6 mice 2 hours after the last dose. [Figure 30] [This shows the above text] picture The results of TNFα gene expression analysis performed on mice that received the drug are shown in Figure 29. Compared with animals that received solvent-based administration, animals that received PPF1 showed significantly increased TNFα gene expression as determined by qPCR. [Figure 31] [This shows the above text] picture The results of Ki67 immunostaining analysis performed on mice that received the drug are shown in Figure 29. Compared with animals that received the solvent-based drug, animals that received PPF1 showed a significant increase in Ki67-positive cells 2 hours after the last dose, indicating that PPF1 can increase hepatocyte proliferation.

Claims

1. The use of a plasma protein fraction (PPF) in the preparation of a medicament for improving liver regeneration in an individual diagnosed with liver disease, wherein the PPF comprises 83% to 95% albumin relative to total protein, wherein the PPF comprises not more than 17% globulins and other plasma proteins, and wherein the PPF comprises not more than 1% gamma globulin.

2. As per the purpose of claim 1, wherein the drug is administered according to a pulsed dosing regimen.

3. As per the purpose of request item 1, the liver disease is acute liver failure.

4. As per the purpose of request item 1, the liver disease is chronic liver failure.

5. As per the purpose of request item 1, the liver disease is acute-on-chronic liver failure.

6. The use of a plasma protein fraction (PPF) in the preparation of a medicament for stimulating existing liver proliferation and regeneration in individuals who have undergone liver resection, wherein the PPF comprises 83% to 95% albumin relative to total protein, wherein the PPF comprises not more than 17% globulins and other plasma proteins, and wherein the PPF comprises not more than 1% gamma globulin.

7. As per claim 6, the drug is to be administered postoperatively.

8. The use of a plasma protein fraction (PPF) in the preparation of a medicament for stimulating the proliferation and regeneration of a transplanted liver in an individual undergoing a liver transplant, wherein the PPF comprises 83% to 95% albumin relative to total protein, wherein the PPF comprises not more than 17% globulins and other plasma proteins, and wherein the PPF comprises not more than 1% gamma globulin.

9. As per claim 8, the drug is to be administered postoperatively.

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