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Blood fractionation
Blood fractionation
Blood fractionation
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Blood components after centrifugation.
When blood is collected into a serum-separating tube (SST) and centrifuged, the serum becomes isolated from the red blood cells by a gel acting as a physical barrier to prevent inadvertent remixing of the components.

Blood fractionation is the process of fractionating whole blood, or separating it into its component parts. This is typically done by centrifuging the blood.

The resulting components are:

Serum separation tubes (SSTs) are tubes used in phlebotomy containing a silicone gel; when centrifuged the silicone gel forms a layer on top of the buffy coat, allowing the blood serum to be removed more effectively for testing and related purposes.

As an alternative to energy-consuming centrifugation, more energy-efficient technologies have been studied, such as ultrasonic fractionation.[1]

Plasma protein fractionation

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See also: Cohn process

Plasma proteins are separated by using the inherent differences of each protein. Fractionation involves changing the conditions of the pooled plasma (e.g., the temperature or the acidity) so that proteins that are normally dissolved in the plasma fluid become insoluble, forming large clumps, called precipitate. The insoluble protein can be collected by centrifugation. One of the very effective ways for carrying out this process is the addition of alcohol to the plasma membrane pool while simultaneously cooling the pool. This process is sometimes called cold alcohol fractionation or ethanol fractionation. It was described by and bears the eponym of Dr Edwin J. Cohn. This procedure is carried out in a series of steps so that a single pool of plasma yields several different protein products, such as albumin and immune globulin.[2][3] Human serum albumin prepared by this process is used in some vaccines, for treating burn victims, and other medical applications.

See also

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References

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Blood fractionation

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Blood fractionation is the process of separating into its primary components—such as , platelets, and plasma—primarily through based on differences in specific gravity, size, and rates. This separation enables targeted transfusion therapies, maximizing the utility of a single donation to treat multiple patients with specific needs, such as , clotting disorders, or immune deficiencies. The plasma fraction, comprising about 55% of , can undergo further fractionation to isolate therapeutic proteins essential for treating conditions like hemophilia and primary immunodeficiencies. The practice of blood fractionation originated in the mid-20th century, with initial advancements in plasma protein separation during the using cold methods developed by Edwin J. Cohn and colleagues to produce albumin for military use during . By the 1960s, refrigerated techniques allowed for the routine separation of components from single units, marking the shift toward component therapy over transfusions. Subsequent innovations, including in the and chromatographic purification in the , improved yield, purity, and safety, particularly after addressing and transmission risks through viral inactivation processes. In fractionation, collected blood (typically 350–450 mL in anticoagulant solutions like CPDA-1) is processed within 5–8 hours using refrigerated . Common methods include single-step heavy-spin (around 5,000 g for 10–15 minutes) to yield and , or two-step processes involving a light spin (1,500 g) followed by a heavy spin to also isolate platelet concentrates. , an automated or technique, allows for the selective collection of components like platelets or plasma while returning the rest to the donor, enhancing efficiency for high-demand products. Plasma fractionation builds on this by employing biochemical separation techniques to extract over 25 distinct proteins from pooled plasma donations, often sourced via . The foundational Cohn process uses sequential at controlled temperatures (-3°C to -6°C), levels (4.5–7.4), and concentrations (10%–40%) to fractionate proteins into groups, such as albumin-rich Fraction V and immunoglobulin-rich Fraction II. Modern refinements incorporate cryoprecipitation (thawing at 1–4°C to precipitate fibrinogen and ), for further purification, and multiple viral inactivation steps like solvent-detergent treatment, , and nanofiltration to ensure safety. Globally, over 55 million liters of plasma are fractionated annually across more than 80 facilities, as of 2024, producing therapies that treat rare bleeding disorders, immune conditions, and burns. Key products from blood fractionation include for oxygen transport in surgeries and anemias; platelet concentrates for preventing bleeding in patients; for clotting factor replacement; and plasma-derived therapeutics like human albumin (yielding 24–26 g/L at 96–99% purity) for volume expansion, intravenous immunoglobulins (3.5–4.5 g/L recovery) for antibody deficiencies, and coagulation factors (e.g., at 100–200 IU/L) for hemophilia. These components have transformed , reducing risks associated with use and enabling precise, patient-specific treatments while adhering to strict regulatory standards from bodies like the FDA and WHO.

Overview

Definition and Principles

Blood fractionation is the process of separating or its plasma component into individual constituents, such as red blood cells, platelets, , and various plasma proteins, to enable their use in medical therapies and research. This separation leverages differences in physical and chemical properties to isolate components like , which contains concentrated clotting factors, from the complex mixture of blood. The fundamental principles of blood fractionation rely on disparities in molecular weight, solubility, charge, and density among blood components. For cellular elements, centrifugation exploits density differences; an initial light spin sediments red blood cells, allowing to be decanted, while a subsequent heavy spin pellets platelets from the plasma. In plasma fractionation, techniques capitalize on variations, often induced by changes in , , or solvent addition, to selectively isolate proteins such as albumins and immunoglobulins. These methods ensure the purification of therapeutic fractions without compromising their . Whole blood can be fractionated directly, yielding cellular components alongside plasma, whereas plasma fractionation focuses primarily on the liquid portion, which constitutes about 55% of and contains approximately 7% proteins by (60-80 mg/mL). Plasma serves as the main substrate for protein isolation due to its rich content of therapeutically valuable molecules, including factors and antibodies. The basic workflow begins with blood collection from donors, followed by anticoagulation using agents like citrate to prevent clotting. Initial separation via isolates plasma from cellular components, after which plasma undergoes further steps, such as cold precipitation to form or solvent-based isolation of proteins. This sequential process maximizes yield and safety for downstream applications.

Historical Development

The discovery of human blood groups by in 1901 provided the foundational understanding of blood compatibility, enabling safer transfusions and setting the stage for later advancements in plasma processing and fractionation techniques. Blood fractionation emerged prominently during , driven by the urgent need for stable plasma-derived products to treat wounded soldiers. In 1940, Edwin J. Cohn, a biochemist at , was commissioned by the U.S. military to develop methods for separating plasma proteins; by late 1940, his team established the cold ethanol fractionation process, which allowed for the large-scale production of as a for . This marked the first systematic, industrial-scale fractionation of human plasma, relying on principles of protein solubility in ethanol-water mixtures at low temperatures to isolate key components without denaturing them. Following the , the and saw the commercialization and expansion of plasma fractionation, transforming it from a wartime expedient into a routine medical practice. Firms like , which had begun commercial production in 1942, scaled up operations to meet growing demand for plasma derivatives, including immunoglobulins and coagulation factors. By the late , purification methods enabled the isolation of from pooled plasma, providing the first concentrated treatments for hemophilia patients and significantly improving their . The 1970s and 1980s brought profound challenges with the epidemic, which exposed vulnerabilities in plasma-derived products and infected thousands of hemophilia patients worldwide through contaminated clotting factors. In response, the industry rapidly adopted viral inactivation techniques, such as dry heat treatment, to eliminate and other pathogens from products like concentrates by the mid-1980s. This crisis also accelerated the shift toward recombinant DNA technology; the cloning of the gene in the early 1980s led to the approval of the first recombinant versions in the early 1990s, offering virus-free alternatives and reducing reliance on human plasma. From the 1990s onward, blood fractionation evolved through technological integration and globalization, enhancing efficiency and amid rising demand. Chromatographic methods, initially explored in the 1970s, became standard in the 1990s for higher-purity separations, complementing traditional . in processing facilities improved yield and consistency, while global supply chains expanded, with the plasma market growing from niche production to a multibillion-dollar industry primarily sourcing from the and select European countries by the 2020s. In the 2020s, advancements in pathogen reduction technologies, such as the INTERCEPT Blood System—first approved in in 2002 and in the U.S. in 2014—further minimized transfusion-transmitted risks by inactivating a broad spectrum of pathogens in platelets and plasma using amotosalen and UVA light. In the mid-2020s, plasma fractionation has further evolved with greater integration of for improved and ongoing efforts to extend pathogen reduction technologies like INTERCEPT to red blood cells, enhancing overall and yield as of 2025.

Separation Methods

Physical Techniques

Physical techniques in blood fractionation primarily rely on mechanical forces and physical properties such as , , and in response to temperature changes to separate blood components without the use of chemical agents. These methods form the foundational steps for isolating plasma from cellular elements and further subdividing plasma into concentrates like , enabling scalable processing for therapeutic products. , , and controlled freezing-thawing are the core approaches, often integrated with specialized equipment to handle large volumes efficiently while maintaining component integrity. Centrifugation exploits differences in rates under to separate components based on their relative densities. In the (PRP) method, a low-speed at 100-250g for 10-15 minutes pellets red cells, yielding PRP as the supernatant containing platelets and plasma. Platelets are then isolated by centrifuging the PRP at higher speeds of 3000-5000g for 5-10 minutes, producing a platelet pellet and supernatant. Alternatively, a single-step high-speed at 3000-5000g for 5-10 minutes directly yields and . This process is widely used in banks and industrial settings to fractionate into red cell concentrates, , and plasma fractions. extends this technique by selectively collecting specific components, such as plasma or platelets, through continuous flow in automated devices; is withdrawn, separated via spinning in a bowl, and unwanted elements returned to the donor, minimizing volume loss and enabling high-yield collection for . Filtration methods, particularly and tangential flow filtration (TFF), provide gentle, non-shear alternatives or complements to for cell removal and plasma concentration. uses semi-permeable s with pore sizes of 0.1-0.2 μm to retain cells and while passing plasma, often applied post- to clarify and concentrate the fluid phase. TFF enhances this by directing feed flow parallel to the membrane surface, reducing and enabling continuous processing at rates up to several hundred liters per hour, which is crucial for industrial-scale isolation from animal or human sources. These techniques minimize protein denaturation and are scalable for production. Freezing and thawing, as in cryoprecipitation, leverage temperature-dependent solubility to precipitate high-molecular-weight proteins from plasma. Fresh plasma is rapidly frozen to -20°C or below and stored frozen. To prepare , the frozen plasma is slowly thawed at 1-6°C over 10-24 hours to form a precipitate containing fibrinogen, , , and , while soluble proteins remain in the supernatant (cryo-poor plasma). The insoluble fraction is recovered by low-speed , yielding a paste-like precipitate that is refrozen for storage. This physical process isolates these clotting factors efficiently from single units or pools, supporting hemostatic therapies. Industrial scalability of these techniques depends on advanced equipment, such as continuous flow centrifuges, which process uninterrupted streams of or plasma at throughputs exceeding 100 liters per hour without batch interruptions. These systems, often refrigerated for cryoprecipitate recovery, feature rotating bowls or discs that separate components via gradients, reducing labor and risks while accommodating high-volume demands in plasma fractionation facilities. Integration of such centrifuges with TFF modules further optimizes yield and purity in large-scale operations.

Chemical Fractionation Processes

Chemical fractionation processes in separation primarily involve manipulating protein solubility through the addition of precipitants, adjustments to , , and , enabling the isolation of specific protein fractions without relying on mechanical separations alone. These methods exploit differences in protein hydrophobicity, charge, and size, typically performed at low temperatures to prevent denaturation and maintain . The most established technique is ethanol-based , which has been refined over decades for industrial-scale production of therapeutic proteins. The Cohn process, developed in the 1940s, represents the foundational chemical fractionation method, utilizing sequential ethanol additions to plasma at controlled conditions to yield five main fractions (I through V). This multi-step procedure begins with plasma cooled to around 0–5°C, followed by progressive increases in ethanol concentration from 8% to 40% (v/v), pH adjustments between 4.8 and 7.2, and temperatures lowered to -5°C, promoting selective precipitation based on protein isoelectric points and solubility curves. Fraction I, precipitated at 8% ethanol, pH ~7.2, and -2°C, primarily contains fibrinogen. Fraction II+III, obtained at 20–25% ethanol, pH ~6.8, and -5°C, is enriched in gamma globulins such as immunoglobulins (IgG, IgA, IgM) and clotting factors like factor VIII. Fraction IV, subdivided into IV-1 (18–25% ethanol, pH ~5.2, -5°C) and IV-4 (25–30% ethanol, pH ~5.2, -5°C), yields alpha and beta globulins including α1-antitrypsin, antithrombin III, and transferrin. Finally, Fraction V at 40% ethanol, pH ~4.8, and -5°C, isolates albumin as the predominant component (50–60% of the fraction's protein content). Variants of the Cohn process, such as the Kistler-Nitschmann method introduced in the 1950s, optimize efficiency by using lower volumes (approximately 1200 L per L of plasma compared to 2000 L in Cohn) and simplified steps while achieving higher purity. In this approach, IgG is precipitated at 19% and pH 5.85 for 99% purity, and is isolated at 94% purity without intermediate Fraction IV removal, enhancing overall recovery for large-scale operations. Modern adaptations integrate these precipitations with ion-exchange chromatography to further refine fractions, removing impurities like lipoproteins and boosting purity to over 99% for clinical-grade products. Alternative precipitants beyond include and (PEG), which enable selective isolation by or altering protein hydration shells, often combined with and temperature controls to target isoelectric points. , typically at 20–80% saturation, depletes abundant proteins like from plasma supernatants, facilitating downstream purification of less common globulins. PEG, used at concentrations of 4–12%, promotes precipitation of immunoglobulins and viruses through exclusion effects, offering a non-toxic alternative for scalable processes with reduced organic solvent needs. These chemical methods demonstrate high efficiency in industrial settings, with albumin yields typically reaching 24–26 g per liter of starting plasma at 90–95% purity, supporting batches exceeding 10,000 liters for global supply demands. Such outcomes underscore the processes' scalability and economic viability, though ongoing refinements focus on minimizing solvent use and maximizing byproduct recovery.

Key Components and Products

Plasma Proteins

Plasma proteins constitute a significant portion of the soluble components isolated during blood fractionation, primarily through cold ethanol precipitation methods such as the Cohn process. These proteins, including , immunoglobulins, and factors, are separated into distinct fractions based on their properties under controlled conditions of , , and ethanol concentration. The resulting fractions undergo further purification to yield therapeutic-grade products, with stability ensured through processes like and lyophilization. Albumin, the most abundant plasma protein, accounts for 50-60% of total plasma proteins and is present at concentrations of 35-50 g/L in human plasma. This monomeric protein has a molecular weight of approximately 66.5 and consists of a single chain of 585 , lacking . It maintains and serves as a carrier for hormones, fatty acids, and drugs due to its binding sites. In fractionation, is primarily recovered from Fraction V, the final precipitate after sequential extractions, where it constitutes the major component. To ensure stability and inactivate potential pathogens, the purified solution is pasteurized at 60°C for 10 hours, yielding a product with over 95% purity. Immunoglobulins, particularly IgG and IgM, are key humoral components isolated from plasma fractions. IgG, the predominant subclass, comprises four subtypes (IgG1, IgG2, IgG3, IgG4) with molecular weights around 150 , while IgM exists as a pentamer with a molecular weight of approximately 900 . These proteins are mainly obtained from Cohn Fractions II and III (or II+III), which precipitate at 8-18% concentrations and contain up to 90% of plasma IgG. Further purification employs to remove impurities like IgA and aggregates, followed by steps such as immune-affinity capture to deplete isoagglutinins, achieving >99% IgG purity while preserving subclass distribution. Stability requires storage at low temperatures (-20°C or below) to prevent dimerization and loss of functionality. Coagulation factors represent critical hemostatic proteins derived from specific plasma fractions. Fibrinogen, a 340 kDa hexameric protein with plasma concentrations of 2-4 g/L, is isolated from Fraction I, the initial cold precipitate containing prothrombin and other clotting elements. (molecular weight ~330 kDa) and (vWF, multimeric with subunits of 270 kDa) are concentrated in , obtained by thawing frozen plasma at 1-6°C, which yields a fibrinogen-rich precipitate comprising 10-20% of plasma volume. These factors exhibit temperature sensitivity, necessitating rapid freezing of source plasma and maintenance at -18°C or lower to preserve activity levels above 80 IU/dL for . Other notable plasma proteins include (AAT), a inhibitor with a molecular weight of 52 kDa and plasma concentration of about 1.5 g/L. AAT is recovered from IV-1 during Cohn and purified via to remove contaminants, with stability enhanced by stabilization with human . Complement proteins, a group of over 30 circulating factors (e.g., C3 at 1.2 g/L, molecular weight 185 kDa), are distributed across multiple fractions, including II+III and IV, and can be further isolated using for research purposes. These proteins require cold processing to maintain their labile enzymatic activities.

Cellular Components

Blood fractionation separates the cellular elements of —primarily red blood cells, platelets, and —through , yielding products essential for transfusion and therapy. These components are isolated after an initial low-speed step that partitions plasma from the cellular , followed by further processing to concentrate specific cell types. Red blood cells, comprising the majority of cellular volume, are processed into packed red blood cell (PRBC) units by removing most plasma after , resulting in a of approximately 55-65%. PRBCs are resuspended in additive solutions such as AS-1 (Adsol), which includes , glucose, , and to preserve ATP levels and reduce during storage. These units are refrigerated at 1-6°C, achieving a of up to 42 days while maintaining post-transfusion recovery above 75%. From a typical 450 mL donation, PRBC yields average around 260 mL in volume. Platelet concentrates are derived either by , directly collecting platelets from circulating blood, or from the intermediate layer obtained via . methods pool multiple donations to form therapeutic units containing at least 5.5 × 10¹⁰ platelets. Storage occurs at 20-24°C with horizontal agitation to prevent aggregation and maintain discoid shape, limiting to 5-7 days due to metabolic changes and bacterial risk. These concentrates address platelet deficiencies, such as in . White blood cells, particularly granulocytes, are collected via , an automated process that selectively harvests neutrophils for short-term use in severe infections. This method yields concentrates with high granulocyte counts while minimizing red cell contamination. Hematopoietic stem cells, mobilized into peripheral blood using growth factors like G-CSF, are similarly isolated by for allogeneic or autologous transplantation in hematologic disorders. These products require prompt use due to limited storage viability. Cryopreservation extends availability for rare or autologous needs. Red blood cells of uncommon phenotypes are frozen with 40% w/v as a permeating cryoprotectant, stored at -80°C or in vapor phase (-150°C), and deglycerolized post-thaw via washing. This preserves cell integrity for up to 10 years, supporting inventory for rare blood types. For platelets, cryopreservation typically employs 5-6% (DMSO) at -80°C, though recovery rates are lower than fresh units, limiting routine use. fractionation from 450 mL also yields 200-300 mL of plasma as a .

Applications and Uses

Therapeutic Applications

Blood fractionation enables the isolation of specific components from , which are then used in various therapeutic contexts to address clinical deficiencies and support patient care. These products, including plasma-derived proteins and cellular elements, play a critical role in managing conditions such as , immune disorders, coagulopathies, and anemias, often improving outcomes through targeted replacement therapy. Albumin, a major plasma protein fraction, is administered intravenously to treat in shock states, where it helps restore intravascular volume due to its that maintains within the vascular compartment. It is also indicated for burn patients to prevent and support hemodynamic stability during . In , albumin infusions address and associated complications like and , with solutions typically available at 5% or 25% concentrations for tailored dosing based on severity. Intravenous immunoglobulin (IVIG), derived from pooled plasma, serves as replacement for primary immunodeficiencies, where it provides essential antibodies to prevent recurrent infections, administered at doses of approximately 0.4 g/kg monthly. For autoimmune diseases, including Guillain-Barré syndrome, IVIG exerts immunomodulatory effects to reduce inflammation and accelerate recovery, with typical dosing ranging from 0.4 to 1 g/kg over several days. Coagulation factors obtained through fractionation, such as those in , are used to treat hemophilia A by supplying to control bleeding episodes. is also essential for fibrinogen deficiencies, providing concentrated fibrinogen to achieve in cases of acquired hypofibrinogenemia from massive hemorrhage or . The advent of recombinant factors has decreased reliance on plasma-derived fractions for hemophilia management, offering safer, virus-inactivated alternatives that improve long-term prophylaxis and reduce transfusion-related risks. Cellular components from fractionation support therapies for hematologic disorders; (RBC) transfusions are indicated for symptomatic , increasing oxygen-carrying capacity in patients with levels below 7-8 g/dL or acute blood loss. Platelet transfusions address bleeding in thrombocytopenic patients or those with platelet function disorders, preventing or treating hemorrhage when counts fall below 10,000/μL in stable cases or higher in active bleeding. transfusions aid neutropenic patients with severe infections unresponsive to antibiotics, temporarily boosting counts to combat bacterial or fungal threats during chemotherapy-induced marrow suppression, though their efficacy remains under evaluation in ongoing research. In the United States, approximately 10.3 million units of RBCs were transfused annually as of 2023, alongside about 1.9 million units of plasma products, underscoring the scale of these interventions in routine medical practice. These figures highlight the essential role of fractionated blood in sustaining healthcare systems, though shortages during the disrupted supplies due to reduced donations and increased demand from overwhelmed hospitals; supplies have since stabilized.

Research and Industrial Uses

Blood fractionation plays a pivotal role in by providing isolated plasma proteins that serve as models for studying and chaperone interactions. For instance, human plasma proteins have been identified as major clients for , a chaperone involved in and deposition prevention, through analysis of clusterin-client complexes formed under stress conditions. Similarly, the diverse plasma proteome, comprising over 300 proteins, enables quantitative studies of variability in protein levels and their implications for folding stability and . Cellular components obtained via fractionation, such as dendritic cells from peripheral blood mononuclear cells, are crucial for development, where they are loaded with antigens to stimulate immune responses against tumors or pathogens. Blood-derived dendritic cell subsets have demonstrated feasibility in inducing functional antigen-specific T cells in clinical trials, highlighting their utility in personalized . In diagnostics, fractionated blood components like albumin and clotting factors are essential for laboratory assays evaluating organ function. Albumin levels in serum, measured via blood tests, indicate liver synthetic capacity and kidney filtration efficiency, with low concentrations signaling potential disorders in these organs. Clotting factors, assessed through prothrombin time (PT) or international normalized ratio (INR) tests, provide insights into liver function due to the organ's role in their production, offering a sensitive marker for both acute and chronic hepatic impairment. Fractionated red blood cell antigens are incorporated into serological kits for blood typing, enabling accurate determination of ABO and Rh groups through agglutination reactions with specific antibodies. Industrial applications of blood fractionation extend to animal-derived products, where plasma serves as a key ingredient in additives. Spray-dried animal plasma, obtained by fractionating from sources, enhances the nutritional profile and palatability of pet s, providing highly digestible proteins that support and immunity in companion animals. This process transforms otherwise discarded into a functional additive, improving texture in wet formulations and delivering essential without synthetic alternatives. Emerging uses include research leveraging fractionated blood, which yields hematopoietic and non-hematopoietic progenitors for regenerative studies. The mononuclear fraction of contains approximately 1% stem and progenitor cells, comparable to , facilitating investigations into tissue repair and immune modulation. In , fractionated plasma components such as are integrated into media to promote mammalian cell growth and viability, reducing reliance on while maintaining metabolic support. Plasma protein fractions have been shown to effectively supplement media for hybridoma and recombinant , enhancing in serum-free environments. In the United States, plasma collection for industrial fractionation purposes reached approximately 60 million liters annually as of , underscoring the scale of this resource-intensive process.

Safety and Regulation

Contamination Risks

Blood fractionation, the process of separating or plasma into components, carries inherent risks of that can lead to transmission of infectious agents or adverse reactions in recipients. Biological hazards primarily involve blood-borne pathogens, including viruses such as human immunodeficiency virus (), hepatitis B virus (), and hepatitis C virus (), which can persist in plasma pools despite screening efforts. Prions, such as those associated with variant Creutzfeldt-Jakob disease (vCJD), pose a theoretical risk through transfusion of plasma-derived products, as these infectious proteins can be present in donors and survive standard processing. Bacterial often arises from poor collection practices, including inadequate skin disinfection or unrecognized donor bacteremia, introducing like coagulase-negative staphylococci into the product during . In the 1980s, non-heat-treated clotting factor concentrates transmitted to thousands of hemophilia patients, underscoring early vulnerabilities in before viral inactivation was routine. Chemical contaminants in fractionated products stem from processing agents and formulation additives. The Cohn cold ethanol fractionation method, widely used to isolate plasma proteins, involves concentrations that are effectively removed during processing. Stabilizers and excipients added to final products, such as amino acids or sugars in immunoglobulin preparations, have been linked to rare allergic reactions, including urticaria or , particularly in patients with prior sensitivities. Notable transmission incidents highlight ongoing challenges. In the 1990s, outbreaks of hepatitis C infections were traced to immune globulin intravenous (IGIV) derived from imported plasma pools contaminated due to inadequate donor screening in source countries, affecting hundreds of recipients in the United States and prompting product recalls. More recently, in the 2020s, emerging pathogens like raised concerns about potential in donors, though transfusion transmission risk remains minimal based on low viral loads in blood; early pandemic disruptions nonetheless amplified fears of undetected contamination in fractionated plasma. Beyond direct contaminants, inherent risks include immunological reactions and weaknesses. Transfusion-related acute lung injury (TRALI) arises from donor antibodies in plasma components, such as anti-HLA or anti-neutrophil antibodies, which activate recipient neutrophils and cause non-cardiogenic shortly after infusion. vulnerabilities, including gaps in donor screening for travel history or emerging infections, can introduce contaminated material upstream, as seen in disruptions from global events that compromise testing reliability. These risks emphasize the need for vigilant monitoring throughout the fractionation pipeline to protect vulnerable patient populations.

Quality Standards and Oversight

Donor screening is a foundational step in ensuring the safety of blood products for fractionation, involving comprehensive health questionnaires and laboratory testing to identify potential infectious risks. In the United States, the Food and Drug Administration (FDA) mandates nucleic acid testing (NAT) for viruses such as HIV-1/2, hepatitis B virus (HBV), and hepatitis C virus (HCV) on all donations, often using pooled or individual samples to detect viral RNA or DNA with high sensitivity. Similarly, the World Health Organization (WHO) recommends standardized donor selection criteria, including deferral for individuals with recent travel to malaria-endemic areas or other high-risk behaviors, to minimize transmission of pathogens like HIV through fractionated products. Processing safeguards during fractionation further mitigate contamination risks through validated viral inactivation and removal techniques integrated into manufacturing protocols. Common methods include heat , typically at 60°C for 10 hours for heat-stable proteins like , which effectively inactivates enveloped and non-enveloped viruses without significantly degrading product . Solvent-detergent (S/D) treatment, using agents like tri(n-butyl) and , targets lipid-enveloped viruses such as and HBV by disrupting their membranes, while nanofiltration employs filters with pore sizes around 20-35 nm to physically remove viruses and particulates. Quality control measures enforce rigorous standards throughout production to verify product safety, purity, and potency. Facilities must adhere to (GMP) guidelines, as outlined by the WHO and FDA, which cover premises design, equipment validation, and personnel training to prevent cross-contamination. Lot release testing, required prior to distribution, assesses parameters such as purity, which must exceed 96% for therapeutic use, alongside potency assays and sterility checks to ensure compliance. Global oversight harmonizes these standards across regions to facilitate safe international trade in plasma products. The FDA regulates U.S. plasma collection and fractionation through biologics licensing and inspections, while the oversees plasma-derived medicinal products via the Plasma Master File (PMF) system, established in the early 2000s, which compiles data on plasma sourcing, testing, and processing for certification. The WHO promotes international alignment through guidelines on GMP and viral safety, supporting from donor to final product. As of 2025, advancements in include the integration of (AI) for enhanced contamination detection, such as models that analyze blood counts and morphological irregularities in real-time during screening and processing to improve accuracy over traditional methods.

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