3 P’S IN A POD

Plasma exchange: concepts, mechanisms, and an overview

of the American Society for Apheresis guidelines
Jeffrey L. Winters1

1Department of Laboratory Medicine and Pathology, Division of Transfusion Medicine, Mayo Clinic,
Rochester, MN

Plasma exchange is a therapeutic procedure used to treat a variety of diseases through the bulk removal of plasma. To
apply this treatment to patients appropriately, it is essential to understand the methods to remove plasma, its effects
on normal plasma constituents, the role of replacement fluids in the treatment, and the risks associated with the
procedure. To facilitate the appropriate evidence-based use of plasma exchange and to encourage research, the
American Society for Apheresis has published guidelines providing practical guidance and information to those
responsible for ordering or providing this treatment.

Introduction must be replaced with some form of replacement fluid.2 Plasmaphere-

The word “apheresis” is derived from the Greek word “aphairesis,” sis removes a smaller amount of plasma, usually less than 15% of
which means “to separate,” “to take away by force,” or “to remove.” the patient’s blood volume, and therefore does not require replace-
This term was originally used by Abel, Rowntree, and Turner to ment of the removed plasma. The most common plasmapheresis
describe manual plasma exchange, the removal of units of whole procedures performed in the United States are those in which
blood anticoagulated with heparin followed by centrifugation to plasma is collected from healthy donors for transfusion or manufac-
separate the blood into the cellular elements and plasma.1 The ture into products such as albumin, IVIG, factor concentrates, and
cellular elements were then mixed with a replacement for the laboratory reagents. In common usage, the terms plasma exchange
discarded plasma and reinfused. Since this initial use, the term has and plasmapheresis are used interchangeably, although the 2 proce-
been used more broadly to describe several procedures, all of which dures are different. The lack of clarity in usage of these 2 terms
involve the separation of whole blood into its components with could result in problems when searching the medical literature.
removal or modification of one or more of these components. Table Plasmapheresis and plasma exchange are 2 separate Medical
1 lists the apheresis procedures performed commonly within the Subject Headings (MeSH) in the National Library of Medicine. The
United States.2 incorrect usage of the terms by authors has led to incorrect
categorization, meaning that literature searches should include both
Of the procedures listed in Table 1, therapeutic plasma exchange terms to identify all relevant literature. For the remainder of this
(TPE) is the procedure that is performed most commonly. As article, only TPE will be discussed, because the devices used to
defined in Table 1, TPE is a procedure in which a large volume of perform therapeutic plasmapheresis procedures, other than the
plasma is removed from a patient.2 The volume removed is such that devices used to perform low-density lipoprotein apheresis, have not
if it were not replaced, significant hypovolemia resulting in been approved by the Food and Drug Administration for use in the
vasomotor collapse would occur. As a result, the removed plasma United States.

Table 1. Apheresis procedures performed commonly in the United States2

Procedure name Description
Leukocytapheresis A procedure in which the WBCs are separated from the blood. The cells may be discarded, as
when used to decrease WBC count in acute leukemia, or used for transfusion, as in the case
of granulocyte collection or the collection of hematopoietic progenitor cells.
Extracorporeal photopheresis (ECP) A type of leukocytapheresis in which the cells collected are treated with a psoralen compound,
exposed to ultraviolet A light, and reinfused to induce an immunomodulatory effect.
Platelet apheresis A donor procedure in which platelets are removed to produce a platelet product for transfusion.
Thrombocytapheresis A therapeutic procedure in which platelets are removed and discarded from a thrombocythemic
patient.
Erythrocytapheresis A donor procedure in which the equivalent of 1 or 2 units of RBCs are removed to produce
RBCs for transfusion.
RBC exchange A therapeutic procedure in which abnormal RBCs are removed and replaced by donated RBCs.
Plasmapheresis A procedure in which plasma is separated from the blood and retained without replacing the
removed volume.
LDL apheresis A type of plasmapheresis procedure in which the removed plasma is modified to remove LDL
cholesterol and then returned to the patient.
Plasma exchange A procedure in which a large volume of plasma is removed, usually 1-1.5 plasma volumes. The
removed plasma is replaced with a replacement fluid.

LDL indicates low-density lipoprotein.

Hematology 2012 7
Table 2. Diseases and disorders treated with plasma exchange2
Disease ASFA category* Recommendation grade†
ABO-incompatible hematopoietic stem cell transplantation
BM II 1B
Peripheral blood II 2B
ABO-incompatible solid organ transplantation
Kidney II 1B
Heart (age ⬍ 40 mo) II 1C
Liver III 2C
Acute disseminated encephalomyelitis II 2C
Acute inflammatory demyelinating polyradiculopathy (Guillain-Barré Syndrome) I 1A
ANCA-associated rapidly progressive glomerulonephritis/vasculitis
(Wegener granulomatosis)
Dialysis independent I 1A
Alveolar hemorrhage I 1C
Dialysis dependent III 2C
Antiglomerular basement membrane disease (Goodpasture syndrome)
Dialysis independent I 1A
Alveolar hemorrhage I 1B
Dialysis dependent IV 1A
Aplastic anemia III 2C
Autoimmune hemolytic anemia
Warm III 2C
Cold agglutinin disease (life threatening) II 2C
Catastrophic antiphospholipid Ab syndrome II 2C
Chronic focal encephalitis (Rasmussen encephalitis) II 2C
Chronic inflammatory demyelinating polyradiculopathy I 1B
Cryoglobulinemia I 1B
Focal segmental glomerulosclerosis (recurrent) I 1C
Hemolytic uremic syndrome
Complement factor gene mutations II 2C
Autoantibody to factor H I 2C
Diarrhea associated IV 1C
Hypertriglyceridemic pancreatitis III 2C
Hyperviscosity in monoclonal gamopathies
Symptomatic I 1B
Prophylactic for rituximab treatment I 1C
Multiple sclerosis
Acute CNS demyelination unresponsive to steroids II 1B
Chronic progressive III 2B
Myeloma cast nephropathy II 2B
Neuromyelitis optica II 1C
Paraproteinemic polyneuropathies
IgG/IgA I 1B
IgM I 1C
Multiple myeloma III 2C
Pediatric autoimmune neuropsychiatric disorders associated with I 1B
streptococcal infections (PANDAS)
Phytanic acid storage disease (Refsum disease) II 2C
Posttransfusion purpurea III 2C
RBC alloimmunization in pregnancy II 2C
Renal transplantation, Ab-mediated rejection I 1B
Renal transplantation desensitization II 1B
Scleroderma IV 1A
Sepsis with multiorgan failure III 2B
Systemic lupus erythematosus
Severe complications of vasculitis II 2C
Nephritis IV 1B
Thrombotic thrombocytopenic purpura I 1A
Thyroid storm III 2C

*Please see Table 5 for a description of ASFA categories.

†Please see text for a description of recommendation grades.

A wide variety of diseases seen by different medical specialists can (ASFA) are listed in Table 2. This list does not represent all of the
be treated with TPE. The diseases/disorders treated with TPE that diseases and disorders to which TPE has been applied, only those
have been categorized by the American Society for Apheresis for which sufficient published literature exists to provide guidance

8 American Society of Hematology

for the use of TPE. The treatment of specific diseases or disorders absolute amount removed becomes lower, although removal of a
will not be discussed herein, but rather the general concepts and fixed 60%-70% still occurs.8 For this reason, routine practice is to
mechanisms of TPE, including the mechanism of action, important exchange only 1-1.5 plasma volumes during a TPE.2 Treating
patient care concepts, and complications of TPE. The purpose and volumes beyond 1.5 plasma volumes removes smaller, less clini-
structure of the ASFA guidelines will also be reviewed. cally important amounts of pathologic substance present in the
plasma while prolonging the procedure and exposing the patient to
more replacement fluid and anticoagulant. The result is an increas-
Mechanism of action of plasma exchange
ing risk of complications without increasing benefit to the patient.
TPE, through the bulk removal and replacement of plasma, removes
There are diminishing returns in treating beyond 1.5 plasma
pathologic substances such as pathologic Abs, immune complexes,
volumes.
and cytokines. It has been presumed that the removal of these
substances represents the major mechanism of action of TPE.
The equation provided in the preceding section assumes that there is
However, this mechanism does not explain the length of response
no exchange between the intravascular and extravascular compart-
seen in some disorders. Additional evidence suggests that TPE may
ments during the procedure. However, this assumption is not valid
have an immunomodulatory effect beyond the removal of Ig.
for all substances, so the amount removed and the concentration in
Reported effects of TPE on immune function include T-cell
the plasma at the end of the procedure may not match that predicted.
modulation with a shift from in the Th1/Th2 balance with a shift
For example, IgG is evenly distributed between the intravascular
toward Th2,3 suppression of IL-2 and IFN-␥ production,4,5 and in
space and the extravascular space and can move between these
vitro cultures demonstrating an increase in concanavalin A–induced
compartments. During TPE, as the concentration of IgG in the
suppressor cell function.6
intravascular space decreases, IgG within the extravascular space
moves into the intravascular space. After the procedure, the plasma
Mechanism of plasma removal concentration of IgG will be greater than predicted, suggesting that
Devices used to perform TPE can be divided into 2 broad categories, the TPE was not as efficient as expected.8 This has led some to
those that separate the plasma from the cellular components based believe that the removal of such molecules is less efficient and that
on size and those that separate components based on density.7 greater volumes should be treated, but the amount of IgG in the
Devices separating based on size use filters, whereas those separat- waste bag is actually greater than predicted, indicating that TPE was
ing by density use centrifugation. In the former, whole blood flows more efficient than expected due to redistribution during the
over a membrane that separates the plasma from the cellular procedure, with removal of IgG from both the intravascular and
elements, which are then returned to the patient. Different configu- extravascular compartments.8
rations of filters have been used to separate plasma from cellular
elements and all have similar capabilities. Filtration-based apheresis Because TPE involves the bulk removal of plasma, anything
devices for performing TPE-utilizing filters are not widely used in circulating in the plasma will be removed. The procedure is
the United States.7 nonselective, removing both normal and pathologic plasma compo-
nents. For example, during a 1 plasma volume exchange using
The predominant method used for TPE in the United States is albumin as the replacement fluid, coagulation factor activity de-
centrifugation. In these apheresis devices, whole blood is pumped creases and coagulation tests may become abnormal. Significant
into a rapidly rotating separation chamber. Components separate declines in factor V (FV), FVII, FVIII, FIX, FX, and VWF activity
into layers based upon their density, with the most dense element, occurs.9-11 Activities of FVIII, FIX, and VWF return to normal
RBCs, migrating the furthest from the axis of rotation and the least within 4 hours after TPE, whereas the remaining coagulation factors
dense portion, plasma, layering closest to the axis of rotation. achieve pre-TPE activity levels by 24 hours.9 The exception to this
Intermediate layers, moving from the axis of rotation outward, are is fibrinogen, which reaches 66% of pre-apheresis levels by
platelets, lymphocytes, and granulocytes.7 In TPE, the plasma layer 72 hours.10 Additional substances removed include inhibitors of
is removed and discarded and the remaining cellular elements are coagulation such as antithrombin11,12 and the pseudocholinesterase
mixed with a replacement fluid and returned to the patient. It is necessary for metabolism of some drugs.13,14 Theoretically, the
important to realize that there is some mixing that occurs at the removal of inhibitors of coagulation could predispose patients to
interface between the layers in the centrifuge. The implication of thrombosis, but this has not been demonstrated definitively.11,12
this is that some platelets may be present in the plasma layer and, Reports of prolonged neuromuscular blockade due to decreased
depending upon several factors, there may be a resulting loss of pseudocholinesterase activity have been reported.13,14 The bulk
platelets during TPE.7 removal and replacement of plasma also has implications for
laboratory testing. The removal of Abs from the patient can result in
The fact that a replacement fluid is necessary to perform TPE and false negative tests for infectious diseases, autoantibodies, alloanti-
that it is administered while the procedure is occurring has bodies, and enzyme and coagulation factor activity. Samples for
implications for the removal of substances circulating in the plasma. such testing should be collected before the initiation of TPE.
The removal of a substance in the plasma and limited to the Finally, in addition to the removal of these normal components of
intravascular space can be described by the following exponential plasma, TPE may also remove medications. Although the effect of
equation: Y/Y0 ⫽ e⫺x, where Y is the final concentration of a TPE on the majority of medications is unknown due to limited
substance, Y0 is the initial concentration, and X is the number of pharmacokinetic studies, some drugs have been reported to have
times the patient’s plasma volume is exchanged.8 Because of the significant removal.15-17 Drugs that have been reported to be
dilution of the plasma by the replacement fluid, the substance of removed by TPE are listed in Table 3.
interest cannot be completely removed from the circulation. For
each 1-1.5 plasma volume exchanged, approximately 60%-70% of As has been stated, TPE requires the replacement of the removed
substances present in the plasma at the start of that plasma volume plasma. The composition of the replacement fluid, as alluded to in
will be removed. As additional plasma volumes are exchanged, the the section describing the removal of coagulation factors, influences

Hematology 2012 9
Table 3. Medications reportedly removed by TPE14,16,17 number of disorders, for example, to replace ADAMTS13 when
Basiliximab
treating thrombotic thrombocytopenic purpura, to treat coagulation
Ceftriaxone factor deficiencies, and to prevent dilutional coagulopathy in
Ceftazidime patients with active bleeding.20
Chloramphenicol
Cisplatin To perform TPE, it is necessary to obtain vascular access. It is
Diltiazem frequently assumed that central venous access is required and that
IFN-␣ every patient must have a central venous line to have a successful
IVIG course of TPE. However, this perception is not supported by the
Palivizumab published literature.21-23 The Canadian Apheresis Study group
Propoxyphene found that 67% of 5234 TPE procedures could be completed
Propranolol
successfully with peripheral venous access alone.21 In a clinical trial
Rituximab
of the use of TPE to treat multiple sclerosis, 96% of patients
Tobramycin
Verapamil
considered for enrollment had adequate peripheral vascular access
Vincristine and, of those enrolled, only 4% could not complete the trial due to
inability to obtain peripheral venous access.22 In another study of
patients with neurologic disorders undergoing TPE, 50% could
the effects of TPE on the patient. It is important to realize that complete their entire course of therapy using only peripheral venous
one-third of the replacement fluid administered at the beginning of access.23 Why is it important to consider peripheral access in the
the TPE will be present by the end, with the majority having been performance of TPE? Studies examining the complication rates of
removed. Administering plasma as a replacement fluid at the apheresis procedures have found that the frequency of complica-
beginning of a TPE results in exposure of the patient to blood tions due to the placement of central venous catheters exceed the
products without benefit. frequency of complications directly related to the procedure.24 In
one study, all serious complications were related to central venous
The most commonly used replacement fluid is 4%-5% human access, including a death due to a hemopneumothorax.24 Central
albumin in physiologic saline. This solution has the advantage of venous access has also been identified as a major risk factor for
avoiding disease transmission and transfusion reactions (eg, transfu- complications of TPE in other studies.19,25
sion-related acute lung injury), both of which can occur with
plasma. The main disadvantage of albumin is its expense relative to Complications of TPE
plasma. This replacement fluid is slightly hyperoncotic compared The frequency of complications associated with TPE reported in the
with plasma and may therefore expand intravascular volume. This literature is variable and is dependent upon what is or is not
effect can be beneficial in avoiding hypovolemia. Because the considered a reaction or an expected physiologic response. In an
albumin replacement fluid is the most expensive component of a early study in which complications of central venous catheters were
TPE procedure18 and use of 100% albumin as a replacement does considered as being related to the procedure, the rate of complica-
expand intravascular volume, some practitioners will use lower tions was 17%, of which 6.14% were severe, requiring hospitaliza-
albumin concentrations, such as 70% albumin and 30% saline. tion or significant intervention.24 More recent studies have seen
When this is done, the albumin and saline are alternated, with the markedly divergent reaction rates ranging from 4.75%25 to 36%.19
majority of the albumin being given at the end of the procedure to The study demonstrating the rate of 36% did not report any severe
avoid hypovolemia from redistribution of the crystalloid. It should reactions, with those that did occur being mild and easily treated.19
be noted that the use of albumin and saline has been associated with Table 4 summarizes the reported types of reactions and their
a greater frequency of hypovolemic reactions compared with using frequencies in these series. The most common reaction seen are
albumin alone.19 Plasma is used as a replacement fluid in a limited paresthesias related to hypocalcemia resulting from the use of citrate

Table 4. Reactions due to TPE

Study
Reaction Couriel and Weinstein19 Basic-Jukic24 Shemin25
No. of TPE procedures 381 4857 1727
Paresthesias 5.5% 2.7% 7.3%
Urticaria 0.26% 1.6% 7.4%
Hypofibrinogenemia 3.67% NR NR
Hypotension 2.1% NR 5.6%
Vasovagal reactions 0.5% NR NR
Nausea 2.9% NR 3.2%
Vomiting 0.5% NR 2.7%
Hemothorax 0.26% NR NR
Catheter site infection 0.26% 0.06% NR
Bleeding/hematoma 0.26% 2.46% NR
Pneumothorax 0.26% 0.04% NR
Other NR Clotting, 1.7% Fever, 7.7%
Pruritus, 5.8%
Tachycardia, 5.6%

NR indicates not reported.

10 American Society of Hematology

anticoagulant to keep blood from clotting in the apheresis device. Table 5. ASFA categories2
The reactions reported are, for the most part, mild and easily treated. Category Definition
Risk factors for reactions include the use of plasma as a replacement
fluid,19,24,25 central venous access,19,24 and the presence of neuro- I Disorders for which apheresis is accepted as first-line
logic disease.19 therapy, either as a primary stand-alone treatment
or in conjunction with other modes of treatment.
II Disorders for which apheresis is accepted as second-
The American Society of Apheresis clinical guidelines line therapy, either as a stand-alone treatment or in
The ASFA is a professional society composed of physicians, conjunction with other modes of treatments.
scientists, and allied health professionals. It was founded in 1982 III Optimum role of apheresis therapy is not established;
when the Society of Hemapheresis Specialists, an allied health decision-making should be individualized.
organization, and the American Society for Apheresis Symposia, a IV Disorders in which published evidence demonstrates
physician and scientist organization, merged. Since that time, a goal or suggests apheresis to be ineffective or harmful.
of ASFA has been to advance the “science of apheresis medicine.” Institutional review board approval is desirable if
A difficulty with this goal is the lack of randomized controlled apheresis is undertaken in these circumstances.
clinical trials examining the use of apheresis to treat disease.
Shehata et al performed a systematic review to identify all
randomized controlled trials involving apheresis published between low-quality evidence, respectively.2 The finalized fact sheets are
1976 and 1999.26 A total of 592 articles were identified, of which then sorted alphabetically by disease name and compiled into a
only 85 (14%) were randomized controlled trials.26 As is demon- document that is then published in the Journal of Clinical Aphere-
strated by this review, the quality of the medical literature for sis. The ASFA guidelines are revised and published every 3 years,
therapeutic apheresis is limited. Because the diseases treated with with the next publication scheduled to occur in June of 2013.
apheresis are rare, for many diseases, the published evidence may
consist solely of case reports or small case series. Whereas The ASFA guidelines have been recognized worldwide and have
controlled trials may exist for more common diseases, randomized been translated into Spanish and Russian, with plans for translation
trials are uncommon.26 into simplified Chinese. Several international apheresis societies
have endorsed or adopted these guidelines. Finally, many third-
To provide practical, evidence-based guidance to the apheresis party payers are basing their coverage decisions upon the informa-
practitioner and to encourage critical science in the field of apheresis tion included in the guidelines.
medicine, ASFA has published guidelines on the use of therapeutic
apheresis in clinical practice. The latest guidelines, published in Summary
2010, are the 5th edition.2 Plasma exchange is a therapeutic procedure used to treat a wide
variety of diseases through the bulk removal of plasma. Whereas the
To create these guidelines, a group of 10-12 apheresis experts mechanism of action has been thought to be the removal of
reviews the previous guidelines and suggestions from the ASFA pathologic Igs, there is evidence suggesting an immunomodulatory
membership or interested parties to determine which diseases and effect. The procedure is safe, with the majority of reactions and
disorders should be evaluated. The members are then each assigned complications being mild, easily treated, and of limited duration.
6-10 specific diseases. They are asked to review the English Unfortunately, the published evidence supporting the use of plasma
language literature related to the use of therapeutic apheresis in their exchange is of limited quality. To assist the practitioner in the
assigned disorders. The individual committee members draft a determining the appropriate use of plasma exchange and other
standardized, single-page “fact sheet.” This document includes apheresis treatments, and to promote additional studies of the role of
information such as the disease name, incidence, apheresis proce- apheresis, the ASFA has created evidence-based guidelines that
dure used to treat the disorder, summary of published evidence, have been accepted internationally as indications for the use of
description of the disease, brief description of nonapheresis treat- apheresis in clinical medicine.
ments, rationale for the use of apheresis in treating the disorder
including important publications, technical notes on the perfor- Disclosures
mance of the apheresis procedure, and guidance on the duration and
Conflict-of-interest disclosure: The author is on the board of
discontinuation of the procedure. These “fact sheets” are then
directors or an advisory committee for ASFA, has received research
reviewed by 2 other committee members, with input being used to
funding from Fenwal Inc and Asahi Kasei Corporation, and has
generate a second draft. This is then reviewed by the entire
received honoraria from Fenwal Inc and Terumo BCT. Off-label
committee, with additional input creating a third draft. After this,
drug use: None disclosed.
based upon consensus of the committee, each disorder is assigned
an ASFA category and recommendation grade.2 The ASFA cat-
egory provides a description of the role of apheresis in the treatment Correspondence
of a disease. The categories are defined in Table 5. The recommen- Jeffrey L. Winters, MD, Division of Transfusion Medicine, Mayo
dation grade is based upon the Grading of Recommendations Clinic, 200 First St SW, Rochester, MN 55905; Phone: 507-538-
Assessment, Development and Evaluation (GRADE) system27 and 1707; Fax: 507-284-1399; e-mail: [email protected].
provides the strength of recommendation and an indication of the
quality of evidence supporting the use of the apheresis treatment. A References
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Hematology 2012 11
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12 American Society of Hematology