C. Taylan and S. M. Sutherland

928

a
Fraction of plasma component (%)

100
90
80
70
60
50
40
30
20
10
0
0

1

2

3
Days

4

5

6

b
100
Fraction of plasma component (%)

Fig. 48.2 Comparison
of daily and alternate
day plasma exchange
regimens. Figure 48.2a
depicts daily, single-­
volume exchanges
whereas Fig. 48.2b
depicts alternate-day
exchanges of 1.5x
volume. Similar
effective clearances can
be achieved over 4 or
7 days, respectively.
While alternate day
regimens allow greater
inter-treatment rebound
of pathologic blood
components (i.e.,
autoantibodies), they
also allow for synthesis
and reaccumulation of
physiologic compounds
necessary for
hematologic

homeostasis (i.e.,
clotting factors)

90
80
70
60
50
40
30
20
10
0
0

1

2

cient disease management than that achieved
with manual transfusion approaches. Automated
exchange transfusions also prevent dramatic
increases in effective circulating volume and are
associated with reduced risk for iron overload
[18, 19].

Leukapheresis
Leukapheresis is the process by which leukocytes are removed from whole blood while the
plasma, platelets, and red cells are returned to the
patient. Historically, the most common indication

for ­leukapheresis has been malignancy-associ-

3

4

5
Days

6

7

8

9

10

ated hyperleukocytosis. Hyperleukocytosis in the
setting of leukemia can cause severe pulmonary
and neurologic complications; traditionally, rapid
reduction of the leukocyte count by automated
therapeutic leukapheresis was thought to reduce
the risk of these complications through a reduction in circulating WBC mass and blood viscosity [20–22]. Newer data, however, has suggested
that leukapheresis may not significantly improve
outcomes [23–25]. Based upon the best currently
available data, leukapheresis tends to be considered when the WBC count is >300–400×109/L
[26–28]; if initiated, it is often performed until
the WBC falls below 50–100×109/L [26, 28].

Though its use in pediatric hematologic malig-


48  Therapeutic Apheresis in Children

nancies can be debated, there is ample data to suggest that it can be performed safely even in very
small children [26, 29]. Additionally, variations
of this leukapheresis technique can be used to
harvest peripheral blood mononuclear cells from
allogeneic or autologous donors for stem cell
transplantation or cell-based therapies [30, 31].
Leukapheresis allows harvest of peripheral blood
progenitor cells which can then be used in stem
cell transplantations. Alternatively, leukapheresis
can be used to harvest T-cell lymphocytes which
are manipulated ex-vivo and used therapeutically
in the setting of malignancy [32, 33].

Plateletpheresis
In plateletpheresis whole blood from healthy
donors is separated into platelet-poor plasma
(PPP), platelet-rich plasma (PRP), and red cells.
The PRP is retained as a single-donor platelet concentrate, while the PPP and red cells are
returned to the donor. This is the single most
frequent application of apheresis technology
and harvested platelets are used to treat thrombocytopenia of various causes and severities.
Plateletpheresis can also be used as a therapeutic procedure to remove excess platelets from the
circulation in patients with symptomatic thrombocytosis [34, 35].

Photopheresis

Photopheresis is a specialized variation of the
leukapheresis procedure. In photopheresis, leukocytes are collected and then exposed to a photosensitizing agent and ultraviolet A light; the
photo-activated leukocytes are then returned to
the patient [36]. When it was first introduced, the
photosensitizing agent was administered systemically (orally); however, the currently employed
procedure utilizes an agent which can be administered to the leukocytes ex vivo during the procedure [37]. This has increased effectiveness
and tolerability, the latter of which is especially
significant in pediatric patients [10, 37]. This
therapy was first employed in the setting of cuta-

929

neous T-cell lymphoma [38–41] and has since
been used to treat graft-versus-host disease, solid
organ allograft rejection, and some autoimmune
diseases [36, 38, 42–48]; in children, the most
common indications are graft versus host disease
and acute rejection of solid organ transplants [10].
Although it has been utilized since the 1980s, the
mechanism of action remains poorly understood
[10, 37–39, 49, 50]. The prevailing data suggests
that the procedure mediates immunomodulation
via induction of lymphocyte apoptosis [36, 37].
At our institution (SMS), a closed photopheresis system is utilized (CELLEX®, Therakos,
Mallinckrodt Pharmaceuticals, Bedminster NJ,
USA). This device has a priming volume of ~
250 mL and a blood prime is recommended for
patients <35  kg [51]. The manufacturer recommends heparin anticoagulation; however, the use
of citrate has been successfully described [52].
Although special accommodations are required,

this technique can be performed effectively
and safely in small children with appropriately
trained staff [10, 52, 53].

Lipoprotein Apheresis
Lipid apheresis (also described as LDL apheresis) refers to the process by which circulating
lipoproteins are removed from the circulation
via an extracorporeal circuit [54]. The definitive indication for LDL apheresis is familial
­hypercholesterolemia (FH), an autosomal dominant form of hypercholesterolemia. At our institution (CT), its heterozygous form has an estimated
prevalence of approximately 1 in 500 persons, but
a prevalence as high as 1 in 72 persons has been
described in certain populations; the reported
prevalence of the homozygous form ranges from
1 in 30,000 to 1 in 860,000 [55]. Patients with FH
experience increased LDL-cholesterol (LDL-C)
levels, extraplasmatic deposition of LDL-C, and
an increased risk for premature coronary heart
disease (CHD). In general, this risk and the atherosclerotic burden are dependent on the severity of the disease and the duration of exposure to
elevated LDL-C levels [56]. Although CHD generally does not manifest before adulthood, two


930

indicators of early atherosclerotic development,
namely, endothelial dysfunction and thickening of
the arterial vessel wall, can be found in children
with the homozygous form of the disease [57]; it
is particularly important to identify these cases
early so that aggressive lipid-lowering therapies
can begin promptly in childhood [58]. Although

LDL apheresis can be used in other forms of
hypercholesterolemia, this approach is not as universally accepted and should not be considered
unless patients have failed medical management.
When performed, LDL-apheresis treatments
take between 2 and 4  hours depending on the
system and regimen. The goal of each treatment
is a reduction in LDL-C of at least 60% and, in
patients with established atherosclerotic lesions,
target LDL cholesterol levels should be <100 mg/
dL. Of note, inter-treatment rebound is common
and variable amongst patients. Thus, if therapeutic targets are not met, the frequency should be
increased to weekly or, if necessary, twice weekly
[58]. It is important to note that in 2015, the FDA
approved a medical anti-LDL therapy which may
be used in lieu of LDL-­apheresis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
can be used in patients with FH or in those with
clinical evidence of atherosclerotic cardiovascular
disease who have inadequately controlled LDL
levels despite optimized statin therapy. These
inhibitors bind and inactivate PCSK9 which augments LDL receptor recirculation and increases
LDL-C clearance [59, 60].
Although a complete discussion of LDL
apheresis is beyond the scope of this chapter, it is
important to highlight the various LDL apheresis
removal techniques:
1. Immunoadsorption
columns
containing
matrix-bound sheep antiapoB antibodies.
After plasma separation, the elimination of

LDL and Lp (a) particles occurs by binding to
polyclonal sheep anti-human apolipoprotein
B-100 antibodies. Since the mechanism is
very specific for apoB-100-containing particles, there is no significant elimination of
other plasma components such as HDL and
fibrinogen. Therefore, there is no restriction
regarding the treated plasma volume.

C. Taylan and S. M. Sutherland

2. Direct adsorption of lipoprotein using hemoperfusion. In this method, whole blood passes
through an absorber containing porous polyacrylamide beads having polyacrylic acid on
their surface. The negatively charged polyacrylic acid reversibly binds the apolipoprotein-­B100 portion of LDL and Lp(a) and little
fibrinogen.
3. Heparin extracorporeal LDL precipitation. In
this LDL-Apheresis method the separated
blood plasma is buffered with heparin acetate,
lowering the plasma pH which results in
crosslinking of LDL, fibrinogen and Lp(a)
with heparin. This precipitate is then eliminated by a filter and excess heparin is removed
by adsorption.
4. Double Filtration Plasmapheresis (DFPP).
After separation, plasma is processed through
a second hollow fiber filter which is permeable to particles with a molecular weight
below 50,000–100,000  Da; HDL, albumin,
and smaller immunoglobulins pass through
and are returned to the patient, whereas LDL,
Lp(a), VLDL, and chylomicrones (as well as
larger immunoglobulins like IgM) are retained
and discarded.

5. Dextran sulfate columns. In this method, positively charged apolipoprotein B-100 contained in LDL, VLDL, and Lp(a) is bound to
immobilized,
negatively
charged
­low-­molecular-­weight dextran. There are 2
different methods to achieve this. Whole
blood can be passed directly through an
absorber or, alternatively, plasma can be separated first via a membrane plasma separator;
the separated plasma is then passed through
the absorber before being returned to the
whole blood.

Immunoadsorption
Immunoadsorption refers to the selective removal
of a plasma constituent. In this technique, plasma
is separated from the other blood components
and then passed into a plasma absorption column. Pathogenic substances bind to the column
(absorption) and are removed based upon the


48  Therapeutic Apheresis in Children

931

selective binding between ligands on a given column and the pathogenic substances themselves.
Unlike the non-selective substance removal
achieved with plasmapheresis, immunoadsorption selectively removes specific protein types
such as IgG or even individual (such as ABO)
antibodies. In addition to its high efficiency,
the technique maintains fluid homeostasis without the requirement of a replacement fluid and

avoids exposure of the patient to foreign plasma,
minimizing the risks of sensitization, allergic
reactions, and infection. Hence, if available,
immunoadsorption should be considered as a
first-line option when the underlying disease
is supposed to be caused by circulating agents
that can be removed from the blood. The technical suitability of immunoadsorption in children
depends on the size of the absorber and the resul-

tant extracorporeal volume, which should not
exceed 15% of the patient’s total blood volume.
Columns are commercially available for both
single use and patient-specific re-use. The binding capacity of a column is limited to about 2 g
of human IgG so two columns are often utilized;
multiple-use absorbers can be regenerated during
the treatment and the flow of plasma is diverted
from the saturated column to the newly stripped
one. The columns can be preserved and reused
following a session; columns are typically reused
5 to 20 times depending on the system employed.
Several of the more commonly used absorption
columns are described in Table 48.3.
Immunoadsorption is associated with the standard side effects of extracorporeal procedures
including hypotension, anemia, clotting, vascular access problems, and hemolysis. Notably,

Table 48.3 Plasma adsorbers used for immunoadsorption
Adsorber
Coraffin

Matrix

Sepharose/synthetic
peptide
Pure synthetic
peptide
Peptid GAMđ
Sepharose/BG
antigen

Binding
ò1-adrenerge receptor Ab

Immunosorba

Sepharose/
Staphylococcus
protein A

Immusorba
PH 350 L

Phenylalanine
immobilized
polyvinylalcohol gel

High affinity to Fc fraction
of IgG immunoglobulins of
the subclasses IgG1, IgG2,
and IgG4
Immune complexes and
anti-DNA antibody


Immusorba
TR 350 L

Tryptophan
immobilized
polyvinylalcohol gel
Dextran sulfate/
cellulose

Anti-acetylcholine receptor
antibodies and immune
complexes
DNA-Ab, Cardiolipin-Ab,
immune complexes

Sepharose/polyclonal
sheep-IgG

IgG (subclasses 1–4)
IgM, IgA, IgE, IgD,
circulating immune
complexes
Rheumatoid factors
Fragments of
immunoglobulins

Globaffin

Glycosorb


Selesorb

Therasorb

IgG1, IgG2, IgG4

Anti-A/anti-B-Ab

Remark
PV 60
Dilatative cardiomyopathy
Multiple use
PV 60 ml
Single use
PV 150 ml
AB0 incompatible transplantation
Multiple use
PV 63 ml

Single use
PV 300 ml
Autoimmune diseases (systemic lupus
erythematosus, malignant rheumatoid
arthritis, Guillain-Barré syndrome,
chronic inflammatory demyelinating
polyneuropathy, multiple sclerosis
Single use
PV 300 ml
Neurologic antibody-mediated disease

Multiple use
PV 150 ml
Systemic lupus erythematosus
Multiple use
PV 300 ml


C. Taylan and S. M. Sutherland

932
Table 48.4  Indications for immunoadsorption by system
Dermatology

Hematology
Nephrology

Neurology

Ophthalmology
Otorhinolaryngology

Dermatomyositis/polymyositis
Pemphigus vulgaris/foliaceus and bullous pemphigoid
Atopic dermatitis
Thrombotic microangiopathies
Acquired inhibitory hemophilia
ABO incompatible kidney transplantation
Antibody-mediated rejection
ANCA-associated vasculitis
Cryoglobulinemic vasculitis

Focal segmental glomerulosclerosis
Multiple sclerosis
Myasthenia gravis and Lambert Eaton myasthenia syndrome
Neuromyelitis optica
Chronic inflammatory demyelinating polyneuropathy
Age-related macular degeneration (AMD)
Acute hearing loss, idiopathic sudden sensorineural hearing loss (SSHL)

angiotensin-­
converting enzyme (ACE) inhibitors have been associated with potentially severe
reactions which occur shortly after the start of the
apheresis procedures. The belief is that the contact
of the blood with the negatively charged surfaces
of the absorber activates bradykinin release; ACE
inhibitors, in turn, block bradykinin degradation
resulting in hypotension, dizziness, vomiting, and
skin rashes. Because of this, ACE inhibitors must
be stopped 24  hours before an immunoadsorption procedure is performed; angiotensin-receptor
blockers (ARBs) are not associated with this issue
and can be prescribed in lieu of ACE inhibitors
if similar antihypertensive effect is required. The
use of immunoadsorption is growing and indications are becoming more common. A decade ago,
its use was limited to rheumatoid arthritis, hemophilia, and a few kidney diseases. However, immunoadsorption has become an important part of the
overall therapeutic paradigm in a number of different diseases across a spectrum or organ systems
(Table 48.4) [61–72].

Indications for Apheresis
Techniques
The American Society for Apheresis periodically
publishes guidelines on indications for therapeutic apheresis; the most recent update was in

2019 [17]. Guidelines such as these are extraordinarily important since although apheresis has
many theoretical applications, in practice, only

some are supported by existing data. These particular guidelines classify indications by category
(Table 48.5) which define disorders according to
whether therapeutic apheresis is a first-line therapy (Category I), a second-line therapy (Category
II), a therapy of uncertain benefit (Category III),
or a therapy known to be harmful or ineffective
(Category IV). Therapeutic apheresis should be
used for all Category I and II indications and
considered for Category III indications; it should
not be employed to treat Category IV disorders.
The guidelines also describe each therapeutic
­recommendation as strong (Grade 1) or weak
(Grade 2) and the data supporting the recommendation as high (A), moderate (B), or low quality
(C). Using this combined rating system, one is
capable of determining the likely benefit of any
given therapy in any given disease. The Category
I indications (therapeutic apheresis in first line
therapy) are shown in Table  48.6; Category II
indications (therapeutic apheresis is second-line
therapy) are shown in Table  48.7 [17]. A complete discussion of all the potential indications
for therapeutic apheresis is beyond the scope of
this chapter; however, we have included more indepth discussions of some of the more common
pediatric indications below.

ANCA-Associated Glomerulonephritis
Antineutrophil cytoplasmic antibody (ANCA)–
associated diseases are vasculitides which affect



48  Therapeutic Apheresis in Children
Table 48.5  Indications and grading of recommendations
for therapeutic apheresis
Categories of therapeutic indications
I
Disorders for which apheresis is accepted as
first-line therapy, either as a primary standalone
treatment or in conjunction with other modes of
treatment
II
Disorders for which apheresis is accepted as
second-line therapy, either as a standalone
treatment or in conjunction with other modes of
treatment
III Optimum role of apheresis is not established.
Decision making should be individualized
IV Disorders in which published evidence
demonstrates or suggests apheresis to be
ineffective or harmful. IRB approval is desirable
if apheresis treatment is undertaken in these
circumstances.
Grading of recommended indications
1A Strong recommendation
High-­
quality
evidence
1B Strong recommendation
Moderate-­
quality

evidence
1C Strong recommendation
Low-quality
evidence
2A Weak recommendation
High-­
quality
evidence
2B Weak recommendation
Moderate-­
quality
evidence
2C Weak recommendation
Low-quality
evidence
Adapted from Padmanabhan et al. [17]

small and medium-sized blood vessels. The two
most common diseases, granulomatosis with
polyangiitis (GPA) and microscopic polyangiitis
(MPA), present primarily with glomerulonephritis, severe renal failure, and pulmonary hemorrhage [73]. The prompt diagnosis and treatment
of these diseases is crucial as delays increase
the risk for morbidity and mortality. The cornerstone of ANCA-associated disease management
is systemic immunosuppression; commonly this
involves the use of high-dose corticosteroids
and an additional agent, typically cyclophosphamide or rituximab [74–77]. However, there
is ample data to suggest additional benefit from
therapeutic apheresis in certain circumstances.
The majority of prospective studies suggest that
while plasma exchange is not beneficial in milder


933
Table 48.6  Category I apheresis indications
Therapeutic Plasma Exchange
Disease
 Acute inflammatory demyelinating
polyradiculoneuropathy/Guillain-Barre
syndrome
 Acute liver failure (high-volume TPE)
 ANCA-associated rapidly progressive
glomerulonephritis (microscopic
polyangiitis, granulomatosis with
polyangiitis, renal limited vasculitis)
   Diffuse alveolar hemorrhage
  
Creatinine ≥5.7 mg/dL or dialysis
dependence
 Anti-glomerular basement membrane
disease (Goodpasture syndrome)
   Diffuse alveolar hemorrhage
   Dialysis independence
 Catastrophic antiphospholipid syndrome
(CAPS)
 Chronic inflammatory demyelinating
polyradiculopathy
 Focal segmental glomerulosclerosis
recurrence in renal transplant
(+/− immunoabsorption)
 Hyperviscosity in
hypergammaglobulinemia

   Symptomatic
   Prophylaxis for rituximab
 Liver transplantation (desensitization of
ABO incompatible living donor)
 Myasthenia gravis (acute short-term
treatment +/− immunoabsorption)
 N-methyl D-aspartate receptor antibody
encephalitis (+/− immunoabsorption)
 Paraproteinemic demyelinating
neuropathies/chronic acquired
demyelinating polyneuropathy
   IgG/IgA/IgM
 Renal transplant
  
Antibody-mediated rejection
(+/− immunoadsorption)
  
Desensitization, living donor
(+/− immunoadsorption)
  
ABO incompatible, living donor
(+/− immunoadsorption)
 Thrombotic microangiopathy, complement
mediated (factor H antibody)
 Thrombotic microangiopathy, drug
mediated (ticlopidine)
 Thrombotic thrombocytopenic purpura
 Wilson’s disease, fulminant
Photopheresis
 Cutaneous T-cell lymphoma, mycosis

fungoides, Sezary syndrome
(erythrodermic)

Grade
1A

1A
1C
1A

1C
1B

2C
1B
1B

1B
1C

1C
1B
1C
1B

1B
1B
1B

2C

2B
1A
1C
1B

(continued)