Review Article

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Plasma products for transfusion: an overview

Erin E. Horstman, Christopher A. Tormey

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA
Contributions: (I) Conception and design: Both authors; (II) Administrative support: Both authors; (III) Provision of study materials or patients: None;
(IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: Both authors; (VII) Final approval
of manuscript: Both authors.
Correspondence to: Erin E. Horstman, MD. Department of Laboratory Medicine, Yale University School of Medicine, 333 Cedar Street, PO Box
208035, New Haven, CT 06520, USA. Email: erin.horstman@yale.edu.

Abstract: The use of plasma and cryoprecipitated blood components remains a vital part of transfusion
therapy for actively hemorrhaging patients, as well as for bleeding prophylaxis for patients at increased risk
of bleeding for a variety of reasons. Plasma also continues to be an essential replacement fluid for patients
undergoing therapeutic plasma exchange (TPE), among its many other applications. However, over the past
5–10 years, there have been numerous advancements in plasma and cryoprecipitated components, including
significant changes to the ways in which these products are collected, processed, modified, and manufactured
for human use. Moreover, our understanding of indications and dosing for these products has also evolved,
with more readily available evidence-based guidance and laboratory cutoffs. The last decade has also seen a
rise in pharmaceutical alternatives to plasma products. Knowledge of these products and their indications for
their use is critically important for transfusion consultants such that the most appropriate and best option
is ultimately chosen for the patient in need. Given these developments and the ever-changing nature of
transfusion therapy, the aim of this paper is to review the current state of, and recent advances in, plasma
and cryoprecipitated component therapy in order to ensure that our patients are receiving the best and most
appropriate product for their clinical situation.

Keywords: Plasma; cryoprecipitate; plasma derivatives; component therapy

Received: 28 February 2021; Accepted: 15 March 2022; Published: 31 March 2022.

doi: 10.21037/aob-22-7
View this article at: https://dx.doi.org/10.21037/aob-22-7

Introduction Plasma for transfusion

Plasma is a versatile and frequently used blood product with Overview

a myriad of uses. This, along with the variety of preparations
In the most general terms, plasma simply refers to the
and plasma derived products available, can lead to confusion
for clinicians and blood bankers alike when trying to select liquid portion of blood. However, a deeper look into its
the most appropriate product for patients. The goal of this composition and function reveals it to be anything but
review is to provide a clear and comprehensive overview simple. Containing numerous proteins (including albumin),
of the different plasma and plasma derived products that coagulation factors, complement, immunoglobulins, and
are available, as well as the indications and expected results enzymes (1), plasma contains much of what helps us stop
from their use. For the purposes of this review, regulations bleeding, prevents us from clotting, and keeps our immune
and standards referred to will apply specifically to those in systems functioning. Because there are so many different
the US; different products, technologies, and guidelines components with different half-lives and optimal storage
may be in use in other countries. conditions, different methods of processing, manufacturing

© Annals of Blood. All rights reserved. Ann Blood 2022;7:4 | https://dx.doi.org/10.21037/aob-22-7

Page 2 of 13 Annals of Blood, 2022

and storing plasma and plasma derived products are Plasma products
essential for optimal product function. In this section we
Fresh frozen plasma (FFP)
will start off by discussing plasma collection and move on to
FFP is the most well-known plasma product and the one
review each of these components and discuss the production
most requested by clinicians. It can be prepared from either
and storage conditions for that component. Cryoprecipitate,
whole blood or apheresis collections, and must be frozen at
a plasma derivative, will be briefly and separately discussed
−18 ℃ within 8 hours of collection. This short time interval
in a dedicated section.
is critical for preserving the function of the more labile
coagulation factors (Factor V, Factor VIII). After freezing,
Plasma collection FFP can be stored for up to 1 year at ≤−18 ℃, or with
special FDA approval, for up to 7 years at −65 ℃ (3).
Plasma donors are held to the same eligibility requirements
At the time of use, the FFP is thawed, either in a water bath
as all other blood donors as specified by the US Food
at 30–37 ℃, or utilizing another FDA approved thawing device.
and Drug Administration (FDA) (2). In addition to being
healthy and well at the time of donation and completing Once it has been thawed, its shelf life is reduced to 24 hours if
the Donor Health and History Questionnaire, individuals stored at 1–6 ℃, or 4 hours if stored at 20–25 ℃. It can also be
who plan to donate plasma products must be male, converted to Thawed Plasma and stored for a total of 5 days at
nulliparous females, or females who have been screened 1–6 ℃ if the product has been prepared in a closed system.
and found to be negative for human leukocyte antigen FFP contains adequate levels of all coagulation factors
(HLA) antibodies after pregnancy. This final requirement including Factor V and Factor VIII as well as antithrombin
is a fairly new addition to donor screening and serves as an and ADAMTS13 (1).
important strategy to decrease the incidence of transfusion
related acute lung injury (TRALI) (3). TRALI has Plasma frozen within 24 hours after phlebotomy (PF24)
historically been a leading cause of transfusion associated PF24 is defined as plasma that has been stored at 1–6 ℃
death and is attributed to the presence of HLA-antibodies within 8 hours of collection and frozen to −18 ℃ between
in donated plasma products. TRALI will be discussed in 8 and 24 hours after collection. It can be prepared from
more detail in the section regarding adverse reactions to both whole blood derived plasma or apheresis plasma,
transfusion. and is produced when there are logistical, technical, or
Plasma can be collected in two ways: as part of a whole transportation constraints that prevent freezing within
blood donation or by apheresis. Whole blood derived 8 hours (5). With the move to testing donors for HLA-
products make up the majority of plasma for transfusion antibodies prior to using their donated products, the
in the US (3). After a unit of whole blood is collected amount of PF24 being produced has increased. After
from a healthy donor, the entire collection is centrifuged collection, donor testing is performed, and if there are
to separate the components into red cells, and platelet antibodies present, that product is removed from the
rich plasma. That platelet rich plasma is transferred into donation pool and not frozen. Awaiting this testing delays
a satellite bag away from the red cells and centrifuged freezing of the product, and therefore, products are greater
again to further separate it into platelets and plasma. In than 8 hours from the time of collection when frozen (6).
an apheresis donation, only plasma is collected, and the PF24 is thawed in the same manner as FFP at the time
remainder of the blood components are returned. This of use and has the same storage and outdate requirements.
process also uses centrifugation to separate the plasma This product can also be relabeled as Thawed Plasma and
from the rest of the blood and leukoreduces the product be stored for an additional 4 days at 1–6 ℃ (1).
in the same process (4). Volume can be extremely variable Compared to FFP, PF24 contains decreased levels of
from unit to unit depending on the method of collection Factors V and VIII as well as Protein C but is otherwise
and can range from 250–300 mL (average volume) to equivalent (7,8).
400–600 mL for a unit collected by apheresis. After
plasma is obtained by either method of collection, it then PF24 held at room temperature up to 24 hours after
undergoes storing and/or product modification and is phlebotomy (PF24RT24)
labeled accordingly. PF24RT24 is plasma collected by apheresis or from whole

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Annals of Blood, 2022 Page 3 of 13

blood that is held at room temperature for up to 24 hours the expiration of the whole blood unit. Therefore, the
and then stored at −18 ℃ for up to 1 year (1). Unlike PF24, expiration date of the liquid plasma depends on the
this product is not refrigerated prior to freezing. preservative solution for the whole blood unit from which
Thawing standards, post thaw storage, and outdating are it was derived. Whole blood that was stored in acid-citrate-
the same as FFP. Coagulation factors are present in similar dextrose (ACD)/citrate-phosphate-dextrose (CPD) or
quantities as FFP with the exception of Factors V and VIII, citrate-phosphate-double dextrose (CP2D) has an expiration
and Protein S which are reduced (9). date of 21 days, so the liquid plasma collected from that
unit expires after 26 days. If the plasma is obtained from a
Plasma cryoprecipitate reduced unit of whole blood stored in citrate-phosphate-dextrose-
Also referred to as “cryo-poor plasma”, this plasma product adenosine (CPDA-1), the expiration date is 40 days
is what is left after cryoprecipitate is collected from whole- following collection (4).
blood derived FFP. The frozen FFP is partially thawed Factor levels in liquid plasma are normal initially but
to 1–6 ℃, the precipitate is removed, and the remaining do decrease over time (11). Of note, this product may
plasma must be refrozen with 24 hours (1). Cryoprecipitate contain viable lymphocytes and require irradiation prior to
will be discussed in detail in a later section. transfusion to eliminate the risk of transfusion associated-
The standards for storing and thawing plasma graft versus host disease (TA-GVHD) (3).
cryoprecipitate reduced are the same as the plasma products
previously discussed. Plasma derivatives
The removed cryoprecipitate contains large amounts In addition to being utilized in the form of plasma, FFP
of Factors VIII and XIII, fibrinogen, and von Willebrand is used to produce numerous products including albumin,
factor, so it follows that the remaining plasma has reduced intravenous immunoglobulin (IVIG) [formally labeled
levels of these factors. The levels of other factors present immune globulin (intravenous)] and factor concentrates.
are comparable to FFP (3). The frozen product is sent to a manufacturer who thaws
the plasma and combines them into a large pooled lot.
Thawed plasma Using a process called Cohn fractionation, the plasma
As discussed in the above sections, thawed plasma is FFP, is processed and purified to form the desired products.
PF24, PF24RT24 or plasma cryoprecipitate reduced that The purification steps are commonly performed using
has been thawed and stored at 1–6 ℃ for greater than immunoaffinity columns impregnated with factor specific
24 hours. After the initial 24 hours, this product can be antibodies (or in the case of some Factor VIII products,
relabeled and stored at 1–6 ℃ for an addition 4 days (5 days a von Willebrand factor antibody). As the plasma passes
total storage). This product is not licensed by the FDA through the column the target factor adheres to the
but is recognized by the AABB and regulation and labeling antibody, and the remaining plasma passes through.
requirements are included in the AABB Standards (Standard The factor is then eluted from the antibody to form a
5.7.4.12) (10). concentrated product (3).
Thawed plasma has adequate levels of non-labile factors
with decreased amounts of Protein S and Factors, V, VII, Plasma product modifications
and VIII. It can be used as a replacement fluid for patients Numerous safety measures are in place to protect recipients
undergoing therapeutic plasma exchange (TPE), especially of blood products from the time of collection through
for thrombotic thrombocytopenic purpura (TTP), or in transfusion. Pre-donation questionnaires and physical
bleeding patients with emergent need for plasma (3). examinations are in place to protect both the donor and
the recipients of the donated product, and significant
Liquid plasma infectious disease testing is performed on the collected
Unlike other plasma products, liquid plasma is unique products. Despite this extensive screening and testing, there
in that it is never frozen. This product is formed when is still a very small but real risk of transfusion transmitted
a unit of whole blood undergoes centrifugation and the disease from both known and emerging pathogens (12). In
plasma is removed. This can be done at any time during order to attempt to mitigate this risk, additional product
the acceptable storage period for whole blood, and the modification in the form of various types of pathogen
liquid plasma is stored at 1–6 ℃ for up to 5 days after inactivation can be performed prior to transfusion.

© Annals of Blood. All rights reserved. Ann Blood 2022;7:4 | https://dx.doi.org/10.21037/aob-22-7

Page 4 of 13 Annals of Blood, 2022

Pathogen reduction treated plasma a methodology for pathogen inactivation used primarily in
Although pathogen reduction technology is most frequently Europe. It is not currently approved for use in the US (3).
associated with platelets, it is also approved for and This process is similar to pathogen reduction using the
performed on plasma products. The INTERCEPT System INTERCEPT system but instead of using amotosalen,
from Cerus Corporation is the only system approved in methylene blue is added to thawed FFP and activated
the US by the FDA for pathogen reduction (3). It utilizes a using white light. After the activation, the methylene blue
psoralen based photoactivator (amotosalen) and ultraviolet is removed by filtration and the plasma is refrozen (15).
A (UVA) light to disrupt nucleic acids present in pathogenic Thawing of the frozen plasma product prior to methylene
organisms as well as leukocytes. Because of this effect blue addition is important to release any intracellular viral
on leukocytes, this process also eliminates the need for particles so they are exposed to the inactivation process.
irradiation in treated products to prevent TA-GVHD. Methylene blue treated plasma products are safe but
INTERCEPT is approved for use with platelets and contain 10% to 35% lower levels of Factor VIII and
plasma in the US, and it has been shown that post-treatment fibrinogen than plasma that has not been treated by this
levels and activity of factors in plasma are equivalent to methodology (16). While it is effective for pathogen
untreated plasma (13). inactivation, primarily on enveloped viruses with some
effect on non-enveloped viruses and bacteria, other methods
Solvent/detergent (S/D) treated plasma provide a more clinically effective plasma product (15).
In contrast to the pathogen reduction technology described
above, S/D treatment of plasma does not affect the nucleic
Laboratory studies for determining bleeding risk
acid of cells and pathogens, but rather disrupts the cell
membranes and viral envelopes (14). This product is Patients may require plasma administration in a variety of
produced by pooling hundreds of units of donated plasma clinical situations including congenital or acquired factor
that have been tested for infectious diseases and non- deficiency, anticoagulation therapy, or coagulopathy related
enveloped viruses. The pool plasma then undergo treatment to an underlying disease state. Aside from knowing the
with a solvent (1% tri-n-butyl phosphate) and detergent patient history, it is important to review basic coagulation
(1% Triton X-100) that disrupts the lipid membranes/viral laboratory results to determine the best and most
envelopes (3). Pooling of such large volumes of plasma also appropriate therapy for each patient.
serves to dilute any antigens that may be present in some of Since the goal of plasma administration in the settings
the units responsible for allergic reactions to transfusion, or of both bleeding prophylaxis or current active bleeding is
HLA antibodies implicated in TRALI (12). to replace or supplement absent or deficient coagulations
S/D plasma is packaged in uniform units of 200 mL factors, it is important to confirm that there is indeed
and are ABO blood group specific. Just like other plasma a deficiency to correct, and what degree of correction
products, it can be stored frozen at −18 ℃ for 12 months, is indicated. Following coagulation studies also allows
and after thawing should be used within 24 hours. It is not for monitoring after transfusion to determine the
typically considered for conversion to thawed plasma as effectiveness of the interventions. The most commonly
other plasma products are, however a recent study showed utilized coagulation tests to determine the necessity of
that it is equivalent to thawed plasma from other sources for plasma transfusion are the prothrombin time (PT) and
up to an additional 4 days after thawing (5 days total) (12). international normalized ratio (INR), and the activated
The majority of the coagulation factors present in partial thromboplastin time (aPTT).
S/D plasma are reduced between 5–15% causing a clinically The PT is performed using patient plasma (containing
insignificant decrease in their activity levels. Factor VIII is or lacking the coagulation factors present in the patient).
reduced by approximately 20% and levels of Protein S and The test evaluates the activity of the coagulation factors
alpha-2 antiplasmin are significantly reduced. Overall, S/D in the “extrinsic” and “common” coagulation pathways by
plasma is largely equivalent to FFP (14). incubating citrated patient plasma with tissue factor and
measuring the time to clot formation after adding excess
Methylene blue pathogen inactivation calcium chloride. Prolonged PTs indicate decreased levels
Methylene blue pathogen inactivation using the or function of Factors VII, X, V, II, and/or I (17). In order
THERAFLEX MB-plasma system from Maco-Pharma is for the PT to be affected, the factor(s) that are deficient/

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Annals of Blood, 2022 Page 5 of 13

defective must be functioning at <30% activity. Therefore, (if available) would likely be more beneficial and effective
mild factor deficiencies will not be picked up with this than plasma transfusions (20). In addition, patients
testing. predisposed to bleeding and/or clotting due to underlying
The INR allows for comparison of PTs between liver disease, antiphospholipid syndrome, etc. are also
laboratories by accounting for differences in reagents and unlikely to receive benefit from regular plasma transfusion.
instrumentation. It is a calculated value which utilizes
the PT, the average normal PT for that laboratory, and
Indications for use
the international sensitivity index (ISI) that has been
determined for the combination of reagents and instrument In the simplest terms, indications for plasma use can be
used to obtain the PT. The INR itself was not designed to broken down into two categories: prevention of bleeding
be used as a marker of bleeding risk, but rather as a way to or management of bleeding that is already ongoing. There
compare PT values between laboratories (17). However, are multiple subcategories within these areas which we will
due to its extensive use, it has become an important marker explore as well as the indications for the use of plasma as a
in attempting to predict bleeding in patients. PT values replacement fluid in TPE and the use of plasma derivatives.
>1.5–2.0 times the normal limits and INR values >1.7–2.0
are generally levels at which plasma transfusion can be Anticoagulation reversal
considered depending on the clinical and bleeding status One of the most well-known uses for plasma transfusion
of the patient (18). Specific “trigger” values vary between is anticoagulant reversal, and more specifically, reversal
institutions however. of vitamin K antagonists, i.e., warfarin. Warfarin works
Finally, aPTT is used to evaluate the activity of by inhibiting the enzyme vitamin K Reductase thereby
the coagulation factors making up the “intrinsic” preventing regeneration of the active form of vitamin K (21).
coagulation pathway (Factors XII, XI, IX, and VIII) The active form of Vitamin K is a required cofactor in
and the “common” pathway. This test is performed by the modification of glutamate residues of Factors II, VII,
incubating anticoagulated patient plasma (usually a citrate IX, and X as well as Protein C and Protein S. Therefore,
anticoagulant) with phospholipid and an activating agent inhibiting the regeneration of active vitamin K leads to
such as silica, kaolin, celite, or ellagic acid (this activation decreased function of these factors and is demonstrated in
step is the a in aPTT). As in the PT, excess CaCl2 is then laboratory testing by prolongation of the PT (and elevated
added and time to clot formation is measured. Also similar INR) as well as the aPTT (22).
to the PT, prolongation of the aPTT requires factor activity The low cost and convenience of the oral administration
to be below 15–35% depending on the factor affected (17). of warfarin is countered by the regular testing required to
An aPTT that is prolonged more than 1.5–2 times the maintain a therapeutic (but not dangerously high) INR,
upper limit of the reference range is usually an indication to possibly complicated dosing schedules and the impact
consider therapeutic plasma transfusion. that diet has on the effectiveness of the drug. Diets high
These laboratory values are important information in vitamin K blunt the inhibitory effect of the drug, and
to have when deciding on the appropriateness of plasma changes in diet often require changes in dosing. Given
transfusion, but need to be interpreted in the clinical all of these limitations, warfarin still remains a frequently
context of the patient at that time. For example, an INR used drug in patients requiring anticoagulation because the
of 1.4 is technically elevated (normal value is between 0.8 reversal agents are readily available and relatively easy to
and 1.2) but plasma transfusion is not indicated at this value administer.
simply because the average INR of a unit of plasma itself is A therapeutic INR for a person on warfarin is 2–3 or
in this range (19). Transfusion at this level exposes patients 2.5–3.5, depending on the indication for anticoagulation.
to the risks of transfusion without providing any significant When the value exceeds these goals, clinicians must decide
benefit in decreased bleeding risk. if reversal is indicated, and if so, what method should be
Other examples of cases in which a patient may have used. The first consideration is whether or not the patient
abnormal coagulation studies without indication for plasma is bleeding. In the absence of bleeding in a patient with
transfusion are patients on anticoagulants such as heparin an INR <10, current recommendations are simply to hold
or patients with a known factor deficiency. In these cases, warfarin and continue to closely monitor the patient. In
reversal of the anticoagulant or specific factor concentrates patients without bleeding and an INR >10, oral vitamin

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K supplementation is recommended. Only when patients but all acknowledge the importance of providing adequate
are bleeding is active replacement of vitamin K dependent amounts of plasma and therefore coagulation factors.
factors recommended (23). There have been many studies investigating the optimal
Four-factor prothrombin concentrate (4-FPCC) and ratio of products to transfuse and when to transfuse
plasma (24) are the two products of choice to reverse them in cases of massive hemorrhage, but there is little
vitamin K antagonists in actively bleeding patients. Both consensus beyond the above mentioned typical product
contain Factors II, VII, IX, and X in adequate levels when ratios. It is important to continue to monitor not only the
administered in proper doses. If it is available, 4-FPCC is patient’s vital signs and body temperature during these
typically the treatment of choice in warfarin reversal for massive transfusion events, but to continue to follow their
emergent procedures or large/life threatening bleeding laboratory values to make any adjustments or additions such
having been shown to act more quickly than plasma. as additional plasma or the use of cryoprecipitate.
However, it is significantly more expensive than plasma, In the case of bleeding in a patient with a congenital
and therefore is not always available. It should also be noted bleeding disorder, plasma is an option, but should be
that 4-FPCC has a higher thrombotic risk than plasma. No considered as a second choice if a factor concentrate for
matter which product is used, IV vitamin K is recommended the specific deficient factor is available. The use of a factor
in addition to factor replacement (23). concentrate rather than plasma has many possible benefits.
In patients who require rapid vitamin K antagonist First, the production of factor concentrates significantly
reversal for a procedure, plasma and vitamin K are typically decreases the risk of transfusion transmitted diseases.
preferred if the patient is able to tolerate the volume Second, the volume of infusion is smaller with factor
required. Discussion with transfusion medicine and/or concentrates than plasma. Finally, as the name states, factor
pharmacy services at your local institution is recommended. concentrates are a concentration of the specific factor that is
Plasma administration has little to no role in the reversal deficient or dysfunctional and leads to higher activity levels
of other anticoagulants including heparin, direct thrombin in the recipient than plasma (27).
inhibitors, and Factor Xa inhibitors. Given the mechanisms Currently, factor concentrates are available for all factors
of action of these drugs, plasma has minimal impact on with the exception of Factor II and Factor XI. Other factor
activity level of coagulation factors, and patients receive concentrates, such as Factor X, are commercially available,
more benefit from administration of the antidotes to the but not always stocked because the need is so low. If a factor
specific drugs if available (25). concentrate does not exist, or isn’t available, plasma is an
excellent substitute. If applicable, one can also consider
Bleeding 4-FPCC (27). Volume must be taken into consideration
There are numerous possible causes of bleeding that may when treating factor deficiencies with plasma though, as we
require transfusion support. Bleeding from both traumatic will address in the section on appropriate dosing of plasma
and non-traumatic causes as well as congenital bleeding products.
disorders can be severe enough to require transfusion of In patients with abnormal coagulation studies due to
not only red blood cells, but also platelets and plasma. underlying disease (such as liver disease) there is no need
Given that whole blood is not commonly used or available for treatment if the patient is not bleeding. Unfortunately,
in the majority of institutions in the US, it is important to there is a paucity of data related to use of plasma in these
understand how to administer separate blood components patients as prophylaxis for invasive procedures. Most
in a way that recapitulates whole blood lost by the patient institutions have developed internal guidelines pertaining
without exacerbating coagulopathy or hemodilution. to these cases, but more data is required to form definitive
Massive bleeding in both trauma and non-trauma recommendations.
settings are largely approached in the same way. The
majority of Massive Transfusion Protocols (MTPs; TPE
initiated when there is actual or anticipated loss of 10 or Plasma, and its derivative product albumin, are the primary
more units of blood) are designed to provide a 1:1:1 ratio replacement fluids used in TPE procedures (28). Albumin
of red cells:plasma:platelets (26). The exact contents of provides volume replacement as well as oncotic support after
these MTPs differ by institution, and sometimes within the removal of plasma in the majority of TPE procedures,
institutions based on the cause of the massive bleeding, however there are cases where replacement with plasma

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Annals of Blood, 2022 Page 7 of 13

is indicated. The most significant of these indications and indications for plasma transfusion, providing the
is TTP. In TTP, patients develop severe thrombotic patient with enough plasma to address their underlying
microangiopathy due to an inhibitor to ADAMTS13 coagulation issues without placing them at risk for volume
leading to accumulation of very large von Willebrand factor overload or giving unnecessary transfusions can be a tricky
multimers (29). TPE with plasma replacement provides balancing act.
the dual benefits of removing the inhibitor, and replacing The majority of coagulation factors will provide adequate
ADAMTS13 which is present at normal levels in plasma hemostasis at an activity level of 25–30%, so this is the goal
products. that we hope to reach when transfusing plasma. Weight-
Any of the plasma formulations described at the based dosing is a strategy that provides patient-specific
beginning of this review are adequate for replacement dosing based on each person’s individual plasma volume.
in TTP, but there are data showing that “cryo-poor” Calculating a patient’s plasma volume based on their
plasma may be associated with longer time to recovery height, body weight and hematocrit will allow one
and increased numbers of exacerbations, so it is not to calculate the most accurate volume of plasma for
recommended as a first line replacement fluid if others are transfusion. In other words, a volume of transfused plasma
available (30). equal to 30% of the patients’ blood volume will replace
Providing a continuous infusion of plasma (and therefore 30% of the activity of all coagulation factors (31).
a continuous infusion of functional ADAMTS13) is If only the patients’ weight is available, a simpler,
recommended in cases where TPE is not immediately but less exact, formula will provide similar transfusion
available. recommendations. Dosing plasma at 10–15 mL/kg also
Other indications for full or partial replacement with replaces approximately 30% of the coagulation factor
plasma in TPE treatments are conditions such as anti- activity, but may overestimate the volume infused.
glomerular basement membrane syndrome that may have a
component of alveolar hemorrhage, and other thrombotic Product selection and preparation
microangiopathies. Plasma can also be used if there are any After determining the appropriate dose of plasma for
indications that there is bleeding secondary to removal of transfusion, the product is thawed and prepared in the
coagulations factors in the plasma exchange; specifically, if blood bank. When selecting products to prepare, one must
there is bleeding during or after exchange (29). It should also consider ABO compatibility. Plasma is an acellular blood
be noted that in cases where there is concern for thrombosis, product, but does contain a variety of antibodies including
such as catastrophic antiphospholipid syndrome, full or ABO antibodies. When determining which plasma units are
partial replacement with plasma in combination with albumin compatible, the interactions between these antibodies and
should be considered. In this case, the concern is depletion of the antigens must be considered or the patient is at risk of
anticoagulant factors (Proteins C and S) rather than the levels receiving an incompatible transfusion.
of procoagulant factors. In the reverse of ABO matching for red blood cells,
There are benefits to replacing the plasma removed with group AB plasma is “universal donor” plasma due to the
donor plasma, but there are also risks that must also be absence of anti-A and anti-B antibodies (31). When the
taken into consideration. The most significant of these risks patient ABO type is known, the best plasma product for
is the exposure of the recipient to large volumes of donor them is one that is ABO identical/ABO compatible. In cases
plasma from numerous different donors. Patients must be of urgent or emergent transfusion when the ABO type
monitored for possible transfusion reactions, and these must of the patient isn’t available, best practice is to supply AB
be investigated as any other possible transfusion reaction plasma. This however, is not always possible. Given that
would be investigated. Also present is the risk of citrate only approximately 4% of people in the US are blood group
toxicity given that citrate is used both as an anticoagulant AB, and that an even smaller number of these group AB
during the TPE procedure and in the transfused plasma individuals are plasma donors, large volumes of AB plasma
products. are frequently not available or sustainable for long periods
of transfusion. In these cases, practice has been to utilize
plasma from group A donors. Studies have shown that there
Dosing and administration of plasma products
is no evidence of poorer outcomes or increase in mortality
As seen in the previous sections on coagulation testing when group A plasma is administered to non-group A

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Page 8 of 13 Annals of Blood, 2022

patients in the setting of emergent, traumatic bleeding (32). transfusion transmitted infections and transfusion reactions
Liquid plasma, which is unique among the plasma such as transfusion associated circulatory overload (TACO),
products having never been frozen, potentially contains TRALI, and allergic transfusion reactions. Each of these
some intact red blood cells from the donor. This adverse events is relatively uncommon, but they should
raises concern not of hemolysis, but rather of Rh(D) always be considered when deciding if a transfusion is
alloimmunization of the recipient in cases of transfusion of warranted.
Rh(D)+ plasma to an Rh(D)- individual. For this reason, it is
recommended that fresh/liquid plasma products be matched Infectious disease risk
for Rh(D), especially in children or women of childbearing Transfusion may transmit viruses, bacteria, parasites,
age (3). Plasma products that have been frozen have not and prions. The consequences of transmission of one of
shown significant residual Rh(D) antigen, and do not these diseases from a donor to a recipient can be severe,
require matching for Rh(D) (33). Other non-ABO blood so multiple layers of screening and testing are used in
group antigens do not need to be considered when choosing an attempt to mitigate this risk. As a result, transfusion-
a plasma product for transfusion regardless of the type of transmitted diseases have thankfully become a rare
plasma. Donors are screened for red cell alloantibodies, complication of blood transfusion (31).
and those with antibodies detected are excluded from the Donors are screened prior to donation though a detailed
plasma donor pool. Therefore, crossmatching of plasma set of questions covering behaviors, medical histories, and
components is unnecessary. travel histories that may put the donor at a higher risk for
After the appropriate product has been selected, carrying, and therefore transmitting, an infectious agent. If
the frozen products require thawing. Thawing can be the risk is deemed to be significant, the donor is unable to
performed by using water baths, dry tempering platforms, or donate and is deferred either temporarily or indefinitely (34).
microwave devices designed specifically for plasma thawing. Additional detailed discussion of donor product testing is
Regardless of the device used, thawing must take place beyond the scope of this review, but while a small risk of
between 30–37 ℃ in order to preserve the functionality and disease transmission is present, this has thankfully become a
safety of the product. Given that thawing can range from very rare occurrence.
10–30 minutes, having thawed or liquid plasma in inventory
can be prudent in order to be prepared for cases of urgent TACO
or emergent transfusion. After the plasma product is fully TACO is a transfusion reaction that can occur with any
thawed, the bag is carefully inspected to ensure its integrity, blood product, including plasma. It is caused by vascular
and if it is intact, it is ready to be released from the blood volume overload, and has a mortality rate of 5–15%.
bank (3). Patients most at risk are those who are at the extremes of
Consistent with transfusion requirements for other age, or who have underlying cardiac dysfunction/risk for
blood products, plasma must be transfused through a filter, volume overload. Close monitoring of patients during
and cannot be administered in the same line as anything their transfusion, especially those who are receiving large
except normal saline. The infusion must be completed volumes of plasma, can lead to early recognition and
within 4 hours after it has been started, although the treatment of volume overload. These patients can be
rate of infusion will vary depending on the clinical status treated with diuretics and supplemental oxygen, and future
of the patient. In a stable adult, a unit of plasma can be transfusions should be given in smaller volumes over longer
safely infused over 30–120 minutes, and in stable pediatric periods of infusion (31).
patients, the recommended rate is over 2–3 hours. Patients
at risk for volume overload, or those that have renal and/or TRALI
cardiovascular deficiencies will likely require infusion over a In contrast to TACO, TRALI is a noncardiogenic process
longer period of time, even up to 4 hours (27). leading to pulmonary edema. The mechanism is not fully
understood, but is believed to be related to HLA and
human neutrophil antigens (HNA) antibodies in transfused
Contraindications and complications in plasma transfusion
blood products containing plasma. TRALI mitigation
As with any blood product or medical therapy, there are strategies, including utilizing only male and nulliparous
risks associated with plasma transfusion. These risks include females (as well as females tested for the presence of HLA

© Annals of Blood. All rights reserved. Ann Blood 2022;7:4 | https://dx.doi.org/10.21037/aob-22-7

Annals of Blood, 2022 Page 9 of 13

or HNA antibodies after each pregnancy) as donors for derivatives are smaller volume (generally, an average of
plasma and plasma containing products and deferring any 15 mL/individual unit) and contain a more limited profile
donors who have had products associated with TRALI, have of procoagulants, most prominently fibrinogen and
significantly decreased the incidence of this potentially fatal fibronectin (1). In addition, the cryoprecipitation process
reaction (3). also yields a concentrated dose of Factor VIII, von
Willebrand factor, and Factor XIII.
Allergic reactions
Allergic transfusion reactions range from mild to severe,
Cryoprecipitate components
though thankfully most fall into the mild-moderate range.
They occur when there is a reaction between preformed The most widely used formulation is cryoprecipitated
antibodies in the recipient and antigen that is present in antihemophilic factor (AHF), often abbreviated as
the transfused product. Mild-moderate allergic reactions ‘cryoprecipitate’ or sometimes simply as ‘cryo’. After
are characterized by itching, rash, and/or urticaria. They thawing traditional plasma at 1–6 ℃, the precipitate is
typically resolve with cessation of the transfusion and extracted and frozen within an hour after removal. US
administration of anti-histamines (31). These reactions standards indicate that each unit of cryoprecipitate must
are not uncommon, and aside from close monitoring and contain at least 80 IU of Factor VIII and at least 150 mg of
consideration of premedication with future transfusions, do fibrinogen (1). Beyond these single units, in recent years a
not typically impact the ability to transfuse a patient in the pre-storage pooled product has been available from blood
future. suppliers in the US and internationally, which typically
Severe allergic reactions are characterized by consists of five individual units pooled together at donor
anaphylaxis (35). The most famous of these reactions is sites and issued to hospital transfusion services in the pre-
related to immunoglobulin A (IgA)-deficient patients who pooled state (36). Similar to processes used for plasma, there
have developed anti-IgA antibodies who are transfused with are also applications of pathogen-reduction technologies to
blood products containing IgA. In these cases, patients can cryoprecipitated products (37).
be transfused plasma products from other IgA-deficient
individuals if they require transfusion (31). Laboratory studies for determining bleeding risk and
In many cases, the cause of severe anaphylactic allergic cryoprecipitate use
reaction cannot be determined. In these cases, avoiding
transfusion is always the safest course, but if this isn’t As a component with a limited scope of procoagulants, the
possible, generous use of antihistamines and/or steroids is laboratory studies used to influence decision-making for
recommended along with slow infusion rates and very close cryoprecipitate tend to be much more limited as well and
monitoring. much more specific in scope. As primarily a fibrinogen
In summary, plasma is a deceptively complex blood concentrate, fibrinogen levels (either via the Clauss method
product that is often underestimated in its versatility. or PT-derived method) are an important determinant
Understanding when to use, and when not to use, plasma for utilization of cryoprecipitate. Thrombin times and/
or reptilase times may be equally important for use of
and plasma products is extremely important in the
cryoprecipitate in the setting of dysfibrinogenemia (38).
management of bleeding patients or those who are at risk
While no true prospective studies have been performed,
of bleeding. The purpose of this overview was to attempt
goals for active bleeding or prophylaxis aim to increase
to clarify some of the confusion surrounding these issues
fibrinogen to above 100–150 mg/dL for most indications,
and to provide a review of the latest developments and
with some authors suggesting even higher goals for clinical
recommendations in transfusion of these products.
settings such as hypofibrinogenemia associated with major
obstetric hemorrhage (39). This will be discussed further in
Cryoprecipitated products the section on ‘Indications for use’.
Because of its additional contents, and in the absence of
Overview
specific factor concentrates, Factor XIII levels can also be of
Prepared from thawing traditional plasma units (as described importance in determining whether cryoprecipitate infusion
above) at 1–6 ℃, cryoprecipitated plasma products/ may be appropriate (40). Historically, cryoprecipitate

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Page 10 of 13 Annals of Blood, 2022

was the main source for Factor VIII and von Willebrand Factor XIII replacement
factor, and thus studies of these factors were critical to Individuals can (rarely) present with bleeding due to
determine appropriateness of this component. However, congenital Factor XIII deficiency or, somewhat more
and as discussed later, use of cryoprecipitated products for commonly, due to acquired defects (e.g., in the setting
Hemophilia A and von Willebrand disease has largely been of disseminated intravascular coagulation) (44). While a
abandoned and replaced by therapy with specific factor dedicated, purified Factor XIII concentrate is available
concentrates (41). for congenital deficiencies, cryoprecipitate would be
appropriate if such a concentrate is not available, and for
acquired forms of Factor XIII deficiency.
Indications for use

Fibrinogen replacement Uremic bleeding

Due to its small volume and concentrated nature, Increasingly, there is strong evidence that renal failure and
cryoprecipitate products remain the treatment of choice uremia contribute to platelet dysfunction associated with
for acquired disorders of fibrinogen, most prominently potentially severe bleeding. While platelet transfusion is not
hypofibrinogenemia, but also dysfibrinogenemia. In of particular benefit in this setting (since transfused platelets
bleeding individuals, who may have consumption of acquire a similar defect), data suggest that ‘overloading’ von
fibrinogen, dilution of fibrinogen, or some combination of Willebrand factor via cryoprecipitate transfusion may help
the above, most guidance and experience-based approaches overcome acquired uremic defects (45).
suggest cryoprecipitate use to maintain fibrinogen levels
>150 mg/dL (36). One important exception is bleeding Bleeding associated with tissue plasminogen activator
associated with major obstetric hemorrhage, wherein rapid (tPA)
and profound decreases in fibrinogen can be seen. In such Individuals with thrombotic occlusive events (e.g., stroke)
settings, some authors and guidance have suggested targets may be administered tPA to ‘lyse’ the thrombus and restore
of >200–250 mg/dL to assure appropriate hemostasis (42). normal blood flow. Unfortunately, in upwards of 10% of
Finally, there are no strong recommendations for fibrinogen tPA uses, severe bleeding complications can arise, including
goals for prophylactic, non-bleeding patients (e.g., in the gastrointestinal hemorrhages and even hemorrhagic
setting of surgical interventions), but many authors and strokes. Because the mechanism of action of tPA is to
guidance suggest considering transfusion, if appropriate, activate fibrinolytic pathways, expert guidance suggests
once fibrinogen levels drop to <100 mg/dL (36). cryoprecipitate may be of benefit in promoting hemostasis
With the evolution of dedicated, pharmaceutical- in such circumstances, by replenishing fibrinogen and
grade fibrinogen concentrate therapies, most guidelines Factor XIII (46).
suggest use of such specific therapies for congenital
fibrinogen disorders, particularly entities such as congenital Hemophilia A and von Willebrand disease
afibrinogenemia or hypofibrinogenemia (40). However, With the evolution of dedicated, purified factor concentrates
are such purified concentrates more appropriate, or (some even fully recombinant), the use of cryoprecipitated
even superior to, cryoprecipitated products for treating products for treating hemophilia A or von Willebrand
acquired disorders? At least one clinical trial in the setting disease is sharply in decline. However, in emergency
of cardiac surgery found non-inferiority of fibrinogen situations where a dedicated or purified factor concentrate
concentrate in this setting, and with the added benefit of may not be immediately available, cryoprecipitate can
less likelihood of transfusion-transmitted illness due to the certainly be employed to replenish Factor VIII and/or von
purification associated with preparing this concentrate (43). Willebrand factor.
Nonetheless, and to date, there are no compelling data
suggesting that fibrinogen concentrates are superior to
Dosing and administration of cryoprecipitated products
cryoprecipitate, and the advent of a pathogen-reduced
product has reduced concerns for infectious disease General considerations
transmission. As such, and until better data are available, As a small volume product, with limited ABO antibodies,
continued use of cryoprecipitate for acquired fibrinogen there are reports of ABO incompatible cryoprecipitate
disorders appears safe and appropriate (39). products being administered without serious adverse

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Annals of Blood, 2022 Page 11 of 13

events in adults (47). Nonetheless, whenever possible (and normal hemostasis. As such, guidance suggests 3–5 units
certainly for small recipients like neonates and children), of cryoprecipitate is likely sufficient to achieve normal clot
ABO compatible products are preferred (1). As an acellular formation, with repeated doses as clinically appropriate (40).
product, there is no need to Rh match and also no need to
irradiate cyroprecipitated products. Given small component Hemophilia A and von Willebrand disease
volumes, and in order to achieve meaningful increment in As discussed previously, purified human-derived or
procoagulants like fibrinogen, cryoprecipitated products recombinant factor concentrates have become the preferred,
are typically pooled prior to administration for adults, while first-line therapy for individuals requiring transfusion or
individual units may be used for children. Once thawed, infusion therapy. Such products should always be employed
cryoprecipitated units should not be refrigerated, lest the if available. However, in settings where there is bleeding or
components re-precipitate (48). In the US, if a product is need for urgent transfusion, and a dedicated concentrate is
pooled on site post-thawing, then such components expire not immediately on hand, then cryoprecipitate can certainly
within 4 hours of thaw, while pre-storage pooled products be utilized. Current guidance suggests the cryoprecipitate
have a 6-hour expiration window (1,2). Pathogen-reduced dosage for Factor VIII should be as follows for adults (1):
products with much longer expiration periods are being
studied (37). Desired increasein FVIII × 40 × Body weight ( kg )
Number of bags = [1]
Average FVIII content per cryounit

Fibrinogen replacement For the above calculation, it is prudent to recall that

The most comprehensive data regarding appropriate dosing each unit of cryoprecipitate should contain at least 80 IU
for cryoprecipitate derive from fibrinogen replacement of Factor VIII per regulatory standards. Regarding von
studies. There are very useful equations available, which Willebrand factor replacement with cryoprecipitate in
can be employed to calculate an exact dose of cryo, typically adults, and similar to other approaches, guidance suggests
requiring knowledge of a patient’s: pre-infusion fibrinogen employing 1 unit of cryo per 10 kg body weight while
levels, goal levels, plasma volume, and the average content closely following laboratory studies and clinical status after
of fibrinogen in an individual cryo unit. Online applications dosing (1). Pediatric dosing for the above generally suggests
and calculators are available to assist in dosing (49). If formal 1–2 units/10 kg body weight (1).
data or calculators are not available, a general rule of thumb
for adult patients is that one individual unit per 10 kg body
Acknowledgments
weight of the recipient should increase fibrinogen levels by
50–75 mg/dL (1). Thus, for most patients, starting doses of Funding: None.
10 units (or a 10-unit pool) is appropriate.

Footnote
Other acquired defects—uremic bleeding, tPA reversal,
FXIII replacement Provenance and Peer Review: This article was commissioned
There are limited prospective data on appropriate starting by the Guest Editor (Paul D. Mintz) for the series
doses for cryoprecipitated products for other acquired “Transfusion Therapy: Principles and Practices” published
forms of bleeding. For uremia, most evidence-based in Annals of Blood. The article has undergone external peer
guidance suggests starting with a 10-unit pooled dose for review.
adult patients with repeated doses as clinically warranted
based on degree of bleeding, recovery of renal function, Conflicts of Interest: Both authors have completed the
and/or implementation of other, more definitive therapies ICMJE uniform disclosure form (available at https://aob.
(e.g., renal replacement therapy) (45). For tPA reversal, amegroups.com/article/view/10.21037/aob-22-7/coif). The
a similar approach of 10 units pooled cryoprecipitate is series “Transfusion Therapy: Principles and Practices” was
appropriate in order to achieve replacement of at least 2,000 commissioned by the editorial office without any funding or
mg of fibrinogen in this setting. Repeated dosing would sponsorship. The authors have no other conflicts of interest
also be considered for ongoing hemorrhage or evidence to declare.
of persistent hypofibrinogenemia (46). Finally, generally
only low levels of Factor XIII are required to maintain Ethical Statement: The authors are accountable for all

© Annals of Blood. All rights reserved. Ann Blood 2022;7:4 | https://dx.doi.org/10.21037/aob-22-7

Page 12 of 13 Annals of Blood, 2022

aspects of the work in ensuring that questions related coagulation factors in plasma prepared after a 24-hour
to the accuracy or integrity of any part of the work are room temperature hold. Transfusion 2010;50:1934-42.
appropriately investigated and resolved. 10. Standards for Blood Banks and Transfusion Services. 32nd
ed. Bethesda: AABB Press, 2020.
Open Access Statement: This is an Open Access article 11. Gosselin RC, Marshall C, Dwyre DM, et al. Coagulation
distributed in accordance with the Creative Commons profile of liquid-state plasma. Transfusion 2013;53:579-90.
Attribution-NonCommercial-NoDerivs 4.0 International 12. Racine-Brzostek SE, Canver MC, DeSimone RA, et al.
License (CC BY-NC-ND 4.0), which permits the non- Thawed solvent/detergent-treated plasma demonstrates
commercial replication and distribution of the article with comparable clinical efficacy to thawed plasma. Transfusion
the strict proviso that no changes or edits are made and the 2020;60:1940-9.
original work is properly cited (including links to both the 13. Cushing MM, Pagano MB, Jacobson J, et al. Pathogen
formal publication through the relevant DOI and the license). reduced plasma products: a clinical practice scientific
See: https://creativecommons.org/licenses/by-nc-nd/4.0/. review from the AABB. Transfusion 2019;59:2974-88.
14. Prowse C. Properties of pathogen-inactivated plasma
components. Transfus Med Rev 2009;23:124-33.
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© Annals of Blood. All rights reserved. Ann Blood 2022;7:4 | https://dx.doi.org/10.21037/aob-22-7