Journal of Clinical Apheresis 15:1–5 (2000)
Introduction to the Third Special Issue:
Clinical Applications of Therapeutic Apheresis
Bruce C. McLeod1,2*
Guest Editor
1
Blood Center, Rush Presbyterian-St. Luke’s Medical Center,
Chicago, Illinois
2
Rush Medical College, Chicago, Illinois
Welcome to the Special Issue on Therapeutic Apher-
esis for 2000. This is the third in a series of such issues,
the first having appeared in 1986 with Dr. Harvey Klein
as editor and the second in 1993 under the direction of
special editor Dr. Ronald G. Strauss. The ASFA Board of
Directors, cognizant of numerous new developments in
apheresis since the last issue, determined that it was time
for another and invited me, as chair of the Education
Committee, to serve as editor. I agreed, counting it an
honor to be numbered with these predecessors. I subse-
quently enlisted the talented, distinguished authors who
have helped to plan and write the issue.
GUIDE TO CONTENTS
The present Special Issue contains seven articles. Fol-
lowing this introduction is an article by Dr. Eleftherios
Vamvakas that will serve as a guide to evaluation of
primary publications of trials and other reports on thera-
peutic apheresis (TA). There follow four subspecialty-
oriented articles with disease-specific discussions writ-
ten by Dr. Kathleen Grima, Dr. Anna Koo, Dr. Alvaro
Pineda, Dr. Robert Weinstein, Dr. Jeffrey Winters, and
myself. Each disease category is covered to an extent
commensurate with its current importance in the field.
Thus, neurological diseases, which historically have ac-
counted for the majority of TA procedures, have received
the most extensive coverage, while rheumatic diseases,
in which enthusiasm for TA has generally waned, are
covered more briefly. Readers familiar with the previous
edition will find that some disease categories, such as
“HIV-associated,” have been omitted, while others have
been condensed or moved to a different article. The for-
mat for discussion of individual diseases remains the
same, with sections on the pathophysiology and clinical
features of the disease, the overall treatment strategy, the
role and technical details of TA, and finally the refer-
ences cited. The last article, also a new feature, is a
discussion of pediatric TA by Dr. Haewon Kim.
© 2000 Wiley-Liss, Inc.
INDICATION CATEGORIES
Each disease-specific section in the following articles
includes an indication category (I through IV) for each
TA modality that is applicable. These are compiled in
Table I of this article. The categories are those described
previously by committees of both ASFA [1] and AABB
[2] and used in the previous special editions. The cat-
egory definitions will also be summarized here for con-
venience.
Category I includes diseases for which TA is standard
and acceptable, either as a primary therapy or a valuable
first-line adjunct therapy. Note that this designation need
not imply that TA is mandatory in all cases. The percep-
tion of efficacy in these disorders is usually based on
well-designed randomized controlled trials or on a broad
and non-controversial base of published experience.
Category II denotes diseases for which TA is gener-
ally accepted but considered to be supportive or adjunc-
tive to other, more definitive treatments, rather than a
primary first-line therapy. Randomized controlled studies
are available for some of these disorders, but in others the
literature contains only small series or informative case
studies.
Category III diseases are those in which there is a
suggestion of benefit for which existing evidence is in-
sufficient, either to establish the efficacy of TA or to
clarify the risk/benefit (or sometimes the cost/benefit)
ratio associated with TA. Included are disorders in which
controlled trials have produced conflicting results or for
which anecdotal reports are too few or too variable to
support an adequate consensus. Therapeutic apheresis
may reasonably be used in such patients when conven-
tional therapies do not produce an adequate response or
as part of an IRB-approved research protocol.
Category IV indicates disorders for which controlled
trials have not shown benefit or anecdotal reports have
*Correspondence to: Bruce C. McLeod, M.D., Rush Medical Center,
1753 W. Congress Parkway, Chicago, IL 60612. E-mail: bmcleod@rush.edu
2 McLeod

TABLE I. Indication Categories for Therapeutic Apheresis

Disease Procedure Indication category
Renal and metabolic diseases
Anti-glomerular basement membrane antibody disease Plasma exchange I
Rapidly progressive glomerulonephritis Plasma exchange II
Hemolytic uremic syndrome Plasma exchange III
Renal transplantation
Rejection Plasma exchange IV
Presensitization Plasma exchange III
Recurrent focal glomerulosclerosis Plasma exchange III
Heart transplant rejection Plasma exchange III
Photopheresis III
Acute hepatic failure Plasma exchange III
Familial hypercholesterolemia Selective adsorption I
Plasma exchange II
Overdose poisoning Plasma exchange III
Phytanic acid storage disease Plasma exchange I
Autoimmune and rheumatic diseases
Cryoglobulinemia Plasma exchange II
Idiopathic thrombocytopenic purpura Immunoadsorption II
Raynaud’s phenomenon Plasma exchange III
Vasculitis Plasma exchange III
Autoimmune hemolytic anemia Plasma exchange III
Rheumatoid arthritis Immunoadsorption II
Lymphoplasmapheresis II
Plasma exchange IV
Scleroderma/progressive systemic sclerosis Plasma exchange III
Systemic lupus erythematosus Plasma exchange III
Hematological diseases
ABO incompatible marrow transplant Red cell removal (marrow) I
Plasma exchange (recipient) II
Erythrocytosis/polycythemia vera Phlebotomy I
Erythrocytapheresis II
Leukocytosis and thrombocytosis Cytapheresis I
Thrombotic thrombocytopenia purpura Plasma exchange I
Post-transfusion purpura Plasma exchange I
Sickle cell diseases Red cell exchange I
Myeloma/paraproteins/hyperviscosity Plasma exchange II
Myeloma/acute renal failure Plasma exchange II
Coagulation factor inhibitors Plasma exchange II
Aplastic anemia/pure red cell aplasia Plasma exchange III
Cutaneous T-cell lymphoma Photopheresis I
Leukapheresis III
Hemolytic disease of the newborn Plasma exchange III
Platelet alloimmunization and refractoriness Plasma exchange III
Immunoadsorption III
Malaria/babesiosis Red cell exchange III
Neurological disorders
Chronic inflammatory demyelinating polyradiculoneuropathy Plasma exchange I
Acute inflammatory demyelinating polyradiculoneuropathy Plasma exchange I
Lambert-Eaton myasthenic syndrome Plasma exchange II
Multiple sclerosis
Relapsing Plasma exchange III
Progressive Plasma exchange III
Lymphocytapheresis III
Myasthenia gravis Plasma exchange I
Acute central nervous system inflammatory demyelinating disease Plasma exchange II
Paraneoplastic neurologic syndromes Plasma exchange III
Immunoadsorption III
Demyelinating polyneuropathy with IgG/IgA Plasma exchange I
Immunoadsorption III
Sydenham’s chorea Plasma exchange II
Polyneuropathy with IgM (± Waldenström’s) Plasma exchange II
Immunoadsorption III
(Continued)

TABLE I. (Continued) Indication Categories for Therapeutic Apheresis
Disease
Cryoglobulinemia with polyneuropathy
Multiple myeloma with polyneuropathy
POEMS syndrome
Systemic (AL) amyloidosis
Polymyositis or dermatomyositis
Inclusion-body myositis
Rasmussen’s encephalitis
Stiff-Man syndrome
PANDAS
been discouraging. TA for these disorders is discouraged
and should be carried out only in the context of an IRB-
approved research protocol, if at all.
The categories assigned in this issue should not be
construed as standards of practice promulgated by
ASFA. Rather, they represent the considered opinion of
the authors and the editor based on review of the pub-
lished literature currently available. Most of the assign-
ments coincide with those in prior ASFA or AABB pub-
lications; however, there are a few alterations and
additions based on recent data. Physicians using these
assignments for clinical decision making should also
bear in mind the need to interpret them in light of indi-
vidual patient data and the latest information.
PROVISION OF THERAPEUTIC APHERESIS
Organizational Guidelines
ASFA has recently published guidelines for the orga-
nization of TA facilities that will be summarized here [3].
The guidelines suggest that each TA facility be directed
by a licensed physician who provides TA as a consulta-
tive service. The director should be knowledgeable in the
relevant disciplines and should be qualified by training
and/or experience to evaluate patients, plan their treat-
ment, and manage complications.
Nonphysician staff should be adequately trained and
have documented competency in each type of procedure
that they perform without immediate supervision. They
should be capable of establishing vascular access, moni-
toring patients, keeping records, and coping with minor
reactions and instrument malfunctions. Certification as a
Hemapheresis Practitioner, offered by the American So-
ciety of Clinical Pathologists by means of a computer-
ized exam, can document knowledge and skills in this
area; eligible individuals are encouraged to seek such
certification.
TA procedures should be performed in an environ-
ment that is safe for both patients and employees, and in
which adequate back-up is available to handle a severe
adverse effect should one arise. There should be a pro-
cedure manual that describes all routine activities, and
Introduction 3
Procedure Indication category
Plasma exchange II
Plasma exchange III
Plasma exchange III
Plasma exchange IV
Plasma exchange III
Leukapheresis IV
Plasma exchange III
Leukapheresis IV
Plasma exchange III
Plasma exchange III
Plasma exchange II
records of each procedure should be created and main-
tained. Comprehensive programs should be in place for
quality control and quality improvement, and to assure
compliance with the guidelines.
Blood Component Exchange
Plasmapheresis, or therapeutic plasma exchange
(TPE), is the most frequently performed TA procedure.
Its effects on patient blood composition can be predicted
with reasonable accuracy on the basis of operative math-
ematical principles. These have been described previ-
ously in detail [4] but will be reviewed here for conve-
nience. Analogous concepts applicable to red cell
exchange are noted where appropriate.
Estimating vascular compartment volumes. Total
blood volume for adults of medium build may be esti-
mated at 65 mL/kg for females or 70 mL/kg for males;
however, this method overestimates blood volume in
both obese and thin patients, and underestimates it in
muscular patients [5]. A formula based on height and
weight, which compensates for moderate variation in
body habitus, has been devised [6] and has been pub-
lished in the form of a convenient nomogram [7].
If the hematocrit is known, estimates of plasma and
red cell volume can be calculated or read from the no-
mogram; however, even these estimates may need ad-
justment. Actual volumes may be overestimated in de-
hydrated patients and underestimated in patients with
polycythemia, hyperproteinemia and overhydration.
Exchange efficiency. Plasma and red cell exchange
procedures become less efficient as the procedure pro-
gresses. This is true regardless of whether the perceived
goal is removal or provision of either a plasma macro-
molecule or a particular red cell type. Stated simply, the
reason is that a steadily increasing proportion of the ma-
terial removed is replacement medium infused earlier in
the procedure, rather than patient material. Mathematical
analysis predicts that under such conditions the concen-
tration of a relevant blood constituent will decrease as-
ymptotically, such that the blood level of a substance
absent in the replacement medium will decrease by about
65% when one patient plasma (or red cell) volume has
4 McLeod
been exchanged. Similarly, the concentration of a sub-
stance absent in the patient’s blood will rise, after an
exchange of one plasma (or red cell) volume, to about
65% of the level in the replacement medium. For re-
moval of IgG, of which about half is extravascular, most
practitioners choose to stop at one plasma volume ex-
changed (or at most 1.5) and wait for a day or 2 until
equilibration with extravascular material has raised the
plasma IgG concentration before proceeding with the
next in a series of exchanges. For a predominantly intra-
vascular material, such as IgM (or red cells), it may
sometimes be beneficial to push beyond this point.
Choice of replacement medium. The standard re-
placement formula for TPE has been 5% human serum
albumin, although substitution of 25–50% of the volume
removed with normal saline has been reported successful
in certain patient groups [8,9]. Albumin has been pre-
ferred over plasma as a source of replacement colloid
because it is pasteurized to eliminate infectious agents,
because it can be given without regard to blood type, and
because it does not require thawing or other preparation
prior to use. Adverse reactions can occur but their inci-
dence is very low [10]. One group has observed signs of
a kinin-induced reaction in patients on ACE inhibitors
with certain lots of albumin [11]. Notable exceptions to
the preference for albumin are 1) thrombotic microangi-
opathies, in which plasma is preferred because of abun-
dant evidence that it works better for TTP [12], and 2)
patients with a pre-existing bleeding diathesis, who may
not tolerate the temporary deficiency of clotting factors
that follows an albumin/saline exchange. One group has
tried reinfusing a solution of hydroxyethyl starch, a less
expensive volume expander, instead of albumin in the
early part of an exchange and has reported satisfaction,
albeit with a higher evidence of adverse effects [13].
Course of treatment. The expected outcome of a se-
ries of plasma exchanges is usually dependent on the
difference in half-life between IgG and most other
plasma constituents. With repeated exchanges, there is a
progressive drop in IgG that is fairly selective over time
because IgG is resynthesized so much more slowly than
the other plasma proteins that are not replaced. Many
prior discussions of TPE refer to a “rebound” phenom-
enon, whereby the IgG synthetic rate is increased in re-
sponse to depletion by TPE. However, recent evidence,
derived from genetically altered mice that hypercatabo-
lize IgG but do not increase synthetic rate, indicates that
“rebound” probably does not happen [14].
Cytoreduction Procedures
These are usually performed with a target value in
mind for the post treatment level of the cell being re-
moved, such as <100,000 leukemic blasts per ␮L or
<1,000,000 platelets per ␮L. The outcome of a procedure
is difficult to predict because the efficiency of cell re-
moval is variable from patient to patient and because
cells may be mobilized into the bloodstream during a
procedure. Fortunately the progress of cytoreduction can
almost always be closely monitored during a procedure
with STAT cell counts to determine when the target
value has been reached [15]. Peripheral blood progenitor
cell collections, which are often classified as therapeutic
procedures, are an important exception to this rule, since
rapid turnaround is typically not available for CD34+ cell
enumeration; however, precollection blood CD34+ cell
counts are usually reasonably predictive of yield [16].
Further Processing
Some apheresis therapies include further processing of
a separated component, either on-line or off-line, with
subsequent return of processed autologous material to the
patient. These currently include 1) photopheresis, in
which mononuclear cells collected by apheresis are ex-
posed to UVA light in the presence of a psoralen, and 2)
selective extraction of plasma constituents, in which
pathogenic material is depleted from autologous plasma
that can then be returned to the patient. Noteworthy ad-
vances have occurred in the latter field since the previous
special edition. A device for selective depletion of low
density lipoproteins has gained FDA approval [17], while
new indications, including rheumatoid arthritis, have
been explored for protein A-containing affinity columns
[18]. Photopheresis, meanwhile, has been investigated as
a means to prevent or reverse solid organ transplant re-
jection [19]. These developments will be discussed in
greater detail in the appropriate disease-specific articles.
Adverse Effects
Apheresis procedures are reasonably safe, even when
they are carried out on patients. Despite occasional re-
ports of serious reactions and deaths, most adverse ef-
fects are mild and easily reversible [20]. The incidence of
reactions during plasma exchange is higher if donor
plasma is given as replacement; this is due almost en-
tirely to the occurrence of urticarial reactions in such
patients [21]. Other notable adverse effects are severe
citrate reactions, which are also more common when do-
nor plasma is given, and vasovagal/hypotensive reac-
tions, which are more likely in patients with neurological
disease [21]. A recent study found that the evidence of
adverse effects in PBPC collections is lower than in clas-
sic therapeutic techniques [21].
ACKNOWLEDGMENTS
Thanks to all the contributing authors, as well as to
their secretaries, for their efforts on behalf of this Special
Issue. It is our collective hope that the issue will, like the
previous Special Issues, be an asset to the apheresis com-
munity, not only for patient care but also for teaching and
training.

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Introduction 5
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