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Fresh frozen plasma

Fresh frozen plasma (FFP) is the fluid portion of a unit of that is separated and frozen within 8 hours of collection to preserve labile factors, including all clotting factors except platelets, as well as fibrinogen, , , , , and pathway inhibitors. It is stored at -18°C or colder and serves as a critical for transfusion in clinical settings to replace proteins and correct coagulopathies.

Preparation and Storage

FFP is prepared by centrifuging to separate the , which is then rapidly frozen to maintain the activity of factors that degrade at . A standard unit contains approximately 200 to 250 milliliters of fluid and is free of erythrocytes and leukocytes. Before , it is thawed using a water bath at 30°C to 37°C for 20 to 30 minutes or an FDA-approved for faster thawing in 2 to 3 minutes. Once thawed, FFP must be used immediately or stored at 1°C to 6°C for up to 24 hours, though some guidelines extend this to 5 days for thawed . Variants include frozen within 24 hours (PF24), which has similar uses but may not be suitable for production.

Clinical Uses and Indications

FFP is primarily indicated for patients with coagulation factor deficiencies accompanied by active bleeding or abnormal coagulation tests, such as prolonged (PT) or activated (aPTT) greater than 1.5 times normal. Common applications include reversal of warfarin-induced anticoagulation in cases of bleeding, particularly ; treatment of (TTP); management of massive transfusion protocols in to prevent dilutional ; and correction of congenital or acquired factor deficiencies when specific concentrates are unavailable. A typical adult dose is 10 to 20 mL/kg (4 to 6 units), which raises factor levels by about 20% and provides volume expansion of around 250 mL per unit. It is administered intravenously over 30 minutes, with ABO compatibility preferred to minimize reactions, though type A or AB may be used in emergencies.

Risks and Considerations

While effective, FFP transfusion carries risks including allergic reactions, transfusion-related acute injury (TRALI), (TACO), and rare infections from donors. It is not recommended for volume expansion alone, protein supplementation without , or routine reversal of without . Monitoring post-transfusion involves assessing for cessation and repeating studies. Guidelines emphasize restrictive use to balance benefits against potential harms, particularly in non- scenarios like or non-massive surgical .

Introduction

Definition

Fresh frozen plasma (FFP) is the fluid portion of human separated from a unit of by or collected via and frozen within 8 hours of collection at a of −18°C or colder to preserve labile clotting factors such as factors V and VIII. This process ensures the retention of essential components, distinguishing FFP as a key for transfusion . In contrast, plasma frozen within 24 hours after (PF24) is held at refrigerated temperatures (1–6°C) for up to 16 additional hours before freezing, resulting in slightly reduced activity of factors V and VIII compared to FFP. The U.S. (FDA) regulates FFP under 21 CFR Part 640, requiring compliance with standards for collection, processing, and storage to maintain product integrity and safety for intravenous use. Additionally, FFP is listed on the (WHO) Model List of as a vital blood and blood component for managing deficiencies in factors. A standard unit of FFP typically contains 200–300 mL of with a straw-yellow color, which is thawed and administered intravenously to restore plasma volume and clotting function in patients with .

Historical Development

The use of in began in with the development of methods to separate and store from , initially focusing on liquid and dried formulations to address challenges in transportation and preservation. During , gained widespread adoption by American and British military forces for treating hemorrhagic shock and blood loss on the battlefield, where its ability to expand plasma volume without the logistical issues of proved invaluable, saving countless lives in combat zones. In 1935, the introduction of the (PT) test by Armand Quick provided a critical tool for assessing extrinsic pathways, enhancing the monitoring of therapy and underscoring the therapeutic potential of products. This was followed in 1961 by the development of the activated partial thromboplastin time (aPTT) test by Samuel I. Rapaport and colleagues, which standardized evaluation of the intrinsic pathway and facilitated more precise use of plasma transfusions to correct coagulopathies. The late 1950s marked the emergence of fresh frozen plasma (FFP) as a key treatment for bleeding disorders, particularly , where it served as the primary source of clotting factors before more concentrated options became available. In 1964, Judith Pool discovered while studying the thawing process of FFP, yielding a concentrated form rich in that revolutionized hemophilia management by allowing targeted dosing with reduced plasma volume. Post-1960s advancements included standardized freezing protocols, typically at -18°C or below within 8 hours of collection, which preserved labile factors and supported broader clinical application; by the , FFP usage surged due to these improvements and expanded surgical practices, reaching nearly 2 million units transfused annually by the mid-1980s. The epidemic in the 1980s profoundly impacted FFP safety, as thousands of hemophilia patients and other recipients contracted through unscreened plasma-derived products, prompting urgent regulatory responses including donor screening and the introduction of antibody testing for blood donations in 1985. This crisis accelerated pathogen inactivation methods and viral testing protocols, fundamentally enhancing the safety of FFP and all plasma components.

Preparation and Storage

Production Methods

Fresh frozen plasma (FFP) is primarily produced from donations collected via a single uninterrupted , ensuring minimal damage and manipulation of the donor's blood cells. The process begins with the collection of approximately 450-500 mL of into an anticoagulant solution, such as citrate-phosphate-dextrose, to prevent clotting during handling. This method yields plasma as one component alongside red blood cells and platelets. Following collection, the unit undergoes to separate the from cellular components. Typically, a two-step process is employed: an initial light spin to separate red blood cells, followed by a heavier spin to isolate platelets if needed, leaving the supernatant . This separation must occur within 8 hours of to preserve the labile factors, such as factors V and VIII. The is then transferred to a storage container and prepared for freezing. Freezing of the initiates promptly after separation, with placed in a controlled environment to achieve a core of -18°C or colder within 8 hours of the initial collection. Plasma freezers or dry -ethanol baths are commonly used to ensure rapid and uniform freezing, preventing the formation of that could degrade proteins. Once , the product is quarantined pending testing before release for . An alternative production method involves , where is collected directly using an automated that separates and returns cellular components to the donor. This yields higher volumes of per donation (400 to 600 mL) without collecting , and the collected follows similar if needed and freezing protocols to meet . Apheresis-derived FFP is therapeutically equivalent to -derived FFP in terms of factor content. Prior to freezing and release, all plasma units undergo rigorous , including testing for infectious diseases such as , and C, human T-lymphotropic virus, and , in accordance with FDA regulations. These tests employ amplification and serological methods to detect pathogens, ensuring the safety of the product; units testing positive are discarded. Additional checks verify volume, appearance, and sterility. A variation in production involves solvent-detergent (S/D) treated , where pools of up to 1,500 individual units (matched by ABO group) are thawed, treated with agents like tri(n-butyl) and to inactivate lipid-enveloped viruses, and then refrozen into smaller units. This pathogen-reduced product maintains factor activity while enhancing beyond standard testing.

Storage Requirements

Fresh frozen plasma (FFP) must be stored in a frozen state at temperatures of -18°C or colder to preserve its factors and proteins, with a of up to 12 months from the date of collection. According to guidelines from the Joint and Tissue Transplantation Services Professional Advisory Committee (JPAC), FFP can be stored at -25°C or below for up to 36 months, provided the storage equipment maintains consistent temperatures without fluctuations that could compromise product integrity. Some facilities use ultra-low temperature freezers reaching -30°C or lower to extend viability, but all frozen units require protection from and stress during storage. Thawing of FFP is performed to prepare it for transfusion, typically in a water bath maintained at 30-37°C for 20-30 minutes while the unit remains in its protective overwrap to prevent . Alternatively, FDA-cleared thawing devices can accelerate the process to 2 to 3 minutes by ensuring uniform heat distribution without exceeding safe temperatures. The thawing method must avoid overheating, as temperatures above 37°C can degrade labile clotting factors, and partial thawing during handling should be prevented by immediate refreezing if not fully utilized. Once thawed, FFP is stored at 1-6°C and must be transfused within 24 hours to minimize and factor degradation, as per standard FDA regulations. Recent FDA approvals in have extended post-thaw storage to up to 5 days at 1-6°C for certain thawed variants, such as pathogen-reduced or cryoprecipitate-reduced products, enabling greater flexibility in emergency settings while maintaining hemostatic efficacy. Transportation of frozen FFP requires maintaining the unit in a fully frozen state using in insulated containers or specialized cryogenic freezers capable of sustaining -18°C or lower. temperature monitoring with loggers is essential during transit to detect any excursions above -18°C that could lead to partial thawing and loss of potency, ensuring the product arrives viable at its destination.

Composition

Biochemical Makeup

Fresh frozen plasma (FFP) consists primarily of , accounting for approximately 90-92% of its , with the remaining 8-10% comprising dissolved solids such as proteins, electrolytes, nutrients, and metabolites. The total protein concentration in FFP is typically 6-8 g/dL, which includes at 3.5-5 g/dL and globulins at 2-3.5 g/dL, contributing to and transport functions. These proteins, along with other non-coagulation elements, maintain the structural and osmotic integrity of the . Electrolytes in FFP include sodium at 150-170 mEq/L and at 3-5 mEq/L, reflecting concentrations influenced by the collection process. Nutrients such as glucose (approximately 500-550 mg/dL) and are present, supporting metabolic needs upon transfusion, while metabolites like and are also retained. The osmolarity of FFP ranges from 280-320 mOsm/L, closely mirroring normal to ensure isotonicity, and its pH is maintained between 7.2 and 7.4. FFP is anticoagulated using citrate-phosphate-dextrose (CPD) or analogous solutions during collection, which chelates calcium and results in low ionized calcium levels (<0.5 mmol/L). The freezing process preserves additional constituents, including hormones, vitamins, and trace minerals, which remain stable for storage. In contrast to , FFP retains fibrinogen and other clotting precursors within its protein fraction, distinguishing it as a complete derivative.

Coagulation Factors and Proteins

Fresh frozen plasma (FFP) contains a range of factors essential for , categorized as labile or stable based on their sensitivity to processing and storage conditions. Labile factors, particularly factor V and , are preserved effectively when plasma is separated and frozen within 8 hours of collection, maintaining activities typically between 50% and 150% of normal levels. These factors are critical for the intrinsic and common pathways of , with their rapid freezing preventing significant degradation during initial handling. Stable factors, including factors , VII, IX, and X, exhibit near 100% activity in FFP, approaching levels found in fresh whole . Fibrinogen concentrations range from 200 to 400 mg/dL, providing a substrate for clot formation, while is also retained at approximately 100% activity to support platelet adhesion. These components remain robust due to their inherent stability during the freezing process at -18°C or below. FFP also preserves natural anticoagulants such as antithrombin III, , and , which are maintained at levels sufficient for treating hereditary or acquired deficiencies. These inhibitors regulate and other procoagulant enzymes, ensuring a balanced hemostatic profile in transfused patients. In comparison to FFP, plasma frozen within 24 hours (PF24) shows a 20-30% decline in factor V and VIII activities due to room-temperature holding prior to freezing, though other factors remain comparable. Post-thaw, labile factors like V and VIII undergo further degradation, with significant losses occurring within 24 hours at 1-6°C, necessitating prompt use to retain efficacy. When frozen promptly after collection, FFP retains more than 70% of original factor levels, particularly for , aligning with quality standards for therapeutic use.

Clinical Applications

Indications and Uses

Fresh frozen plasma (FFP) is primarily indicated for the treatment of multiple deficiencies in patients with active or those requiring invasive procedures when the international normalized ratio (INR) exceeds 1.5. This approach addresses complex coagulopathies where specific concentrates are unavailable or inappropriate, ensuring rapid replacement of labile clotting factors to prevent or control hemorrhage. In emergency settings, FFP is recommended for reversing warfarin-induced , particularly in cases of life-threatening such as , often in combination with . For specific rare deficiencies, FFP serves as a source of antithrombin III when concentrates are not accessible, and it is used for Factor V deficiency due to the lack of commercial concentrates. Additionally, FFP is integral to plasma exchange procedures in (TTP), where it replaces deficient enzyme and removes autoantibodies. In massive transfusion protocols for trauma-induced coagulopathy, FFP is administered as part of balanced resuscitation, typically in a 1:1:1 ratio with red blood cells and platelets to mitigate dilutional coagulopathy. Current guidelines emphasize a restrictive approach to FFP use, recommending it only for active bleeding rather than prophylaxis in non-bleeding patients with abnormal coagulation tests, based on evidence from the AABB's 2010 standards and ongoing endorsements through 2025. The World Health Organization supports essential access to FFP in low-resource settings to ensure safe and rational transfusion practices, prioritizing evidence-based indications to optimize outcomes and minimize risks.

Administration and Dosage

Fresh frozen plasma (FFP) is typically administered intravenously to replace factors in patients with deficiencies and active or those requiring reversal of effects. The standard therapeutic dose is 10-20 mL/kg body weight, which generally raises factor levels by approximately 20-30%. For adults, this equates to 4-6 s, totaling 800-1500 mL, depending on unit volume (typically 200-250 mL per ). Dosing should be guided by clinical response and laboratory parameters rather than fixed volumes to avoid unnecessary transfusion. FFP must be ABO-compatible with the recipient's , with group plasma preferred for universal compatibility if type-specific is unavailable. begins immediately after thawing, starting at a rate of 10-20 mL/min for the first 15-30 minutes to monitor for , then increasing to 30 mL/min if tolerated, completing each unit over 30-60 minutes. The total infusion time should not exceed 4 hours to minimize bacterial contamination risk. Premedication with antihistamines or acetaminophen is not routinely required for FFP transfusion, as prophylactic use does not significantly reduce reaction rates in most patients. However, for individuals with a history of allergic reactions to blood products, premedication with an such as diphenhydramine may be considered on a case-by-case basis. During and after infusion, patients should be monitored for signs of transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), or allergic responses, with checked every 15 minutes initially. Post-infusion coagulation studies, including (PT), international normalized ratio (INR), and activated (aPTT), are recommended to assess efficacy, targeting values less than 1.5 times the upper limit of normal. In special populations, dosing adjustments account for body size and clinical context. For pediatric patients, a dose of 10-15 mL/kg is standard, often used in neonates for or exchange transfusions. In , particularly for major postpartum hemorrhage, FFP is administered at 12-15 mL/kg or in a 1:1 ratio with red blood cells as part of massive transfusion protocols, per guidelines from organizations like the American Association of Blood Banks () and Royal College of Obstetricians and Gynaecologists (RCOG).

Risks and Complications

Adverse Reactions

Fresh frozen plasma (FFP) transfusion carries several potential adverse reactions, primarily related to infectious , immunologic responses, , coagulation disturbances, and other complications. Although modern screening has greatly reduced infectious risks, they remain a concern. The risk of transmitting is approximately 1 in 7.8 million units, hepatitis B virus about 1 in 153,000 units, and hepatitis C virus around 1 in 2.3 million units, thanks to nucleic acid testing (NAT) and other donor screening measures implemented since the early 2000s. Immunologic adverse reactions include transfusion-related acute injury (TRALI), a serious condition characterized by acute respiratory distress occurring within 6 hours of transfusion, with an incidence of approximately 1 in 5,000 units transfused. TRALI is often mediated by donor anti-leukocyte antibodies and is a leading cause of transfusion-related fatalities, though mitigation strategies like male-only donation have reduced its occurrence. Allergic and anaphylactoid , manifesting as urticaria, pruritus, nausea, or respiratory distress, occur in about 1.37% of FFP units transfused, particularly in patients receiving multiple units. Volume-related complications, such as (TACO), arise from the rapid infusion of FFP's fluid volume, leading to and , especially in elderly patients or those with cardiac or renal impairment; incidence rates vary but can reach 1% among transfused patients receiving plasma products. Coagulation-related issues include paradoxical due to the procoagulant factors in FFP, such as fibrinogen and , which may promote clot formation in susceptible individuals, with studies showing increased postoperative deep vein risk following intraoperative FFP administration. Other reactions encompass febrile non-hemolytic transfusion reactions, involving fever and chills without , reported in up to 1-2% of transfusions; acute from ABO incompatibility, which can cause severe intravascular destruction if mismatched units are given; and citrate toxicity during rapid or massive infusions, leading to , arrhythmias, and due to citrate's calcium-binding properties, necessitating calcium supplementation in high-volume scenarios.

Contraindications

Fresh frozen plasma (FFP) is contraindicated in cases of isolated deficiencies that can be effectively treated with specific concentrates, such as recombinant for hemophilia A, rather than broad-spectrum therapy. Similarly, FFP should not be used for hypofibrinogenemia alone, where is the preferred agent due to its higher fibrinogen concentration and targeted efficacy. Prophylactic administration of FFP in non-bleeding patients, including for mild or elevated INR without active hemorrhage, is also contraindicated, as it offers no proven benefit and may increase risks such as mortality and transfusion-related acute lung injury. Relative contraindications include conditions predisposing to volume overload, such as or renal impairment, where the large fluid volume of FFP (typically 200-250 mL per unit) can precipitate or exacerbate cardiac strain. In patients with to plasma components or IgA deficiency, FFP is relatively contraindicated due to the risk of severe allergic reactions. For stable warfarin reversal without , FFP is not recommended; instead, prothrombin complex concentrates () are preferred per updated 2025 guidelines, which emphasize faster and more reliable anticoagulation correction with lower volume. Regarding and , there are no established absolute contraindications for FFP, but its use should be limited to situations where benefits clearly outweigh potential risks, as safety data remain limited. Overall, these contraindications underscore the need for targeted therapies to minimize unnecessary exposure to FFP's risks.

Current Usage and Alternatives

In the United States, fresh frozen plasma (FFP) usage peaked around 2008-2010 with approximately 4.5 million units transfused annually, reflecting increased adoption in trauma and surgical settings. By 2019, national surveys indicated a continued downward trend in plasma transfusions, with distributions stabilizing but overall usage declining due to stricter clinical guidelines; this pattern persisted post-2020 amid ongoing emphasis on evidence-based restrictions. For instance, the 2021 National Blood Collection and Utilization Survey reported about 2.2 million units transfused, a notable reduction from the prior decade's highs. The 2023 National Blood Collection and Utilization Survey reported 1,882,000 units transfused (95% CI: 1,765,000–1,998,000), indicating further modest decline and stabilization. In the United States, FFP usage expanded dramatically from 2000 to 2010, increasing roughly tenfold to meet rising demands in management and for plasma-derived therapies. However, between 2020 and 2025, trends shifted toward stabilization or modest decline, driven by the of alternatives and refined transfusion protocols, though discard rates remain elevated in high-volume settings like trauma centers. The temporarily disrupted collections in 2020, with a minimal annualized drop in donations and transfusions compared to 2019, followed by recovery to pre-pandemic levels by 2023 as supply chains adapted. Key factors influencing these patterns include guidelines promoting evidence-based plasma transfusion, which have curtailed prophylactic use by emphasizing targeted indications to minimize risks without proven benefits. In the , pediatric applications account for a substantial share; according to a 2010 study using 2002-2009 data, about 53% of FFP infusions occurred in infants under 1 year, often in neonatal intensive care units for management. Market indicators underscore sustained infrastructure investment despite clinical usage moderation; the global FFP freezer sector is projected to reach $1.6 billion by 2025, supporting storage needs for ongoing distributions.

Alternatives

Prothrombin complex concentrates (PCCs), particularly four-factor formulations, serve as a targeted alternative to fresh frozen plasma (FFP) for rapid reversal of warfarin-associated bleeding, offering faster correction of international normalized ratio (INR) with lower infusion volumes compared to FFP. The 2020 American College of Cardiology (ACC) expert consensus pathway recommends four-factor PCC over FFP for vitamin K antagonist reversal in most cases due to its efficacy and reduced risk of fluid overload. A 2025 systematic review further supports PCC's benefits in oral anticoagulant-related intracranial hemorrhage, highlighting its speed and lower volume requirements. Liquid (LP), a never-frozen variant stored refrigerated, provides an accessible alternative to FFP in and massive transfusion protocols, with a 26-day that facilitates prehospital and use without thawing delays. U.S. adoption of LP expanded from 2023 to 2025, as outlined in Central Command protocols, due to its extended stability and equivalence in factor activity to thawed FFP. Cryoprecipitate-poor (CPP) offers a volume-reduced option for therapeutic plasma exchange in (TTP), demonstrating similar efficacy to FFP in reducing mortality and relapse rates per a 2023 . Cryoprecipitate is a concentrated source for fibrinogen replacement in hypofibrinogenemia, delivering 200-250 mg of fibrinogen per unit to correct deficiencies more efficiently than FFP in scenarios like massive hemorrhage. Recombinant factor VIII concentrates treat hemophilia A by providing the missing clotting protein without plasma-derived risks, marking a standard since their 1992 FDA approval and ongoing use in prophylaxis. Fibrinogen concentrates have shown equivalence to partial FFP replacement in maintaining levels above 1 g/L during therapeutic plasma exchange for patients with mild-to-moderate bleeding risk, as evidenced by a 2024 pilot study. Non-product strategies, such as patient blood management programs incorporating viscoelastic testing (e.g., or ), guide targeted transfusions to minimize FFP use by assessing real-time and reducing overall allogeneic product requirements in and settings. Recent advancements include extending thawed to 5 days at refrigerated temperatures while preserving key factors, as confirmed in 2025 studies supporting its utility in urgent care. Synthetic clotting agents, such as platelet-mimicking nanoparticles, are in phase I/II trials for -induced , demonstrating potential to stabilize clots and reduce in preclinical models from 2023-2025. These alternatives contribute to observed declines in FFP utilization trends.

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