ACKD

Therapeutic Plasma Exchange in the Critically

Ill Patient: Technology and Indications
Amber P. Sanchez and Rasheed A. Balogun

Therapeutic plasma exchange (TPE) is frequently the most common Apheresis Medicine technique used for extracorporeal ther-
apy of a wide variety of renal, neurological, hematological, and other clinical indications. Many of these clinical indications
require intensive care during critical illness. Conventional TPE uses one of two main technical methods to achieve the goal
of removing known disease mediators from the plasma: using centrifugal forces to separate and remove components of blood,
or a membrane filtration method that separates plasma from the cellular components of blood. The following review discusses
the basic principles of TPE, the technological aspects, and relevant clinical scenarios encountered in the intensive care unit,
including relevant guidelines and recommendations from the American Society for Apheresis.
Q 2021 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Therapeutic plasma exchange, Plasmapheresis, Critical care nephrology, Apheresis

dense cellular components.7 In mTPE, a nonselective

T herapeutic plasma exchange (TPE) is an extracorporeal
blood purification technique used to remove patho-
genic substances from the plasma, with many potential in-
dications in the critical care setting.1,2 Conventional TPE is
performed either by centrifugal- or membrane-based tech-
nology to separate the plasma from the cellular blood ele-
ments.2,3 Additional columns and filters have been
employed to further process plasma for more selective
removal of a specific component, although these selective
procedures have limited availability in the United States.3
This review will discuss techniques in use for TPE, consid-
erations for the critically ill patient, current recommenda-
tions from the American Society for Apheresis (ASFA),
and recent advances employed in the field of apheresis
medicine in the intensive care unit (ICU) setting.
PRINCIPLES OF THERAPEUTIC PLASMA EXCHANGE
TPE has the ability to remove larger substances
(.15,000 Da), such as antibodies, cytokines, endotoxins,
immune complexes, and lipids, or those that are highly
protein bound, unlike dialysis which is more useful for
the removal of smaller molecular weight components.4 Po-
tential beneficial effects of TPE include the rapid removal
of a circulating factor, replenishment of specific plasma
factors, and possible direct immunomodulatory effects.5
However, the ability of TPE to successfully treat a specific
disease requires an understanding of the underlying dis-
ease pathophysiology, the role of concomitant immuno-
suppression, and the kinetics of production, removal,
and redistribution of a target substance between the intra-
vascular and extravascular compartments.
TECHNOLOGY: CENTRIFUGAL- VS MEMBRANE-
BASED PLASMA SEPARATION
TPE is performed either via centrifugal-based (cTPE) or
membrane-based (mTPE) plasma separation. Although
the indications for TPE and the choice of replacement
fluids are similar between cTPE and mTPE, there are
fundamental differences in the mechanism of separation,
anticoagulation, blood flow, vascular access requirements,
and equipment needed (see Table 1). With cTPE, whole
blood is spun in an extracorporeal centrifuge so that the
blood components are separated in order of increasing
specific gravity, separating the plasma from the more
microporous membrane allows passage of proteins to
pass through the membrane, with a sieving coefficient of
0.9-1.0, allowing for a filtrate that is nearly identical to
plasma.7,8 In a randomized prospective crossover study
comparing cTPE and mTPE, both treatments had compa-
rable removal efficiency of immunoglobulin G (IgG) and
immunoglobulin M (IgM).9 In the USA, the majority of
TPE procedures are carried out via cTPE, however, in other
countries, such as Japan and Germany, 90% of TPE treat-
ments are membrane-based.10
TPE is a nonselective apheresis procedure, as all plasma
components (including albumin, clotting factors, and im-
munoglobulins) are collected and discarded, which re-
quires the use replacement solutions, such as albumin or
donor plasma. Additional adsorptive columns can be
added to cTPE or mTPE circuits to remove a specific
plasma component, known as selective apheresis or im-
munoadsorption (IA), minimizing the need for replace-
ment solutions. The technique known as double filtration
plasmapheresis (DFPP) refers to a system that uses
membrane-based plasma separation followed by a second-
ary plasma fractionator selected to remove a specific sub-
stance based on molecular size and weight.11
Disadvantages of the selective apheresis procedures
include high costs, limited availability, complexity of cir-
cuits, and potential need for regeneration and storage of
select columns.12
From the Division of Nephrology and Hypertension, Department of Internal
Medicine, University of California San Diego Health System, San Diego, CA
(A.P.S.); Division of Nephrology, University of Virginia (R.A.B.); and Apheresis
Unit & Extracorporeal Therapies, University of Virginia Health, Charlottesville,
VA (R.A.B.).
Financial Disclosure: The authors declare that they have no relevant finan-
cial interests.
Address correspondence to Rasheed A. Balogun, MD, FACP, FASN, HP
(ASCP), Division of Nephrology, University of Virginia School of Medicine,
Medical Director, Apheresis Unit & Extracorporeal Therapies, Division of
Nephrology, University of Virginia Health System, P O Box 800133, Charlottes-
ville, VA, 22908. E-mail: rb8mh@virginia.edu
Ó 2021 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2021.03.005

Adv Chronic Kidney Dis. 2021;28(1):59-73 59

60 Sanchez and Balogun

PRESCRIPTION: CALCULATING THE PLASMA SPECIAL CONSIDERATIONS IN THE CRITICALLY ILL

VOLUME, CHOICE OF REPLACEMENT SOLUTIONS, PATIENT
AND FREQUENCY TPE is relatively safe and well tolerated in the ICU setting;
When prescribing TPE, one must determine the desired however, special considerations must be made, as the criti-
plasma volume to remove, the choice of replacement fluid cally ill patient is more likely to experience hemodynamic
to be given, and the frequency at which the procedure will instability, coagulation disorders, or electrolyte abnormal-
be delivered. A typical TPE treatment calls for a 1.0 to 1.5 ities. The overall adverse event rate during TPE is approxi-
times the total plasma volume (TPV). To calculate the TPV, mately 4-5% in the general population, and in the ICU
one must first calculate the total blood volume (TBV) then setting serious adverse event rates have been reported to
multiply the TBV by (1-hematocrit). One method used to be as low as 1-2% of procedures.16-18 Adverse events
calculate the TBV is Gilcher’s rule of fives (see Table 2). 13
during TPE occur more frequently with the first
For instance, a 1.0 x TPV for a 70 kg man with a hematocrit procedure, with certain diagnoses (ie. when autonomic
of 40% is calculated as: TBV (70 kg 3 70 mL/kg ¼ 4900 mL) instability is present), with a low starting hematocrit
x (1-0.4 ¼ 0.6) ¼ TPV of 2940 mL, or approximately a 3 L (increased hypotension), and when plasma is used for
exchange. Replacement fluid should be both isotonic and replacement (see Table 3).19-21 Plasma should be avoided
isosmotic to avoid hypotension and edema. A solution of unless it is required to correct a complement or
5% human albumin in saline is often used. Replacement coagulation factor deficiency, or needed to prevent
with plasma should be avoided unless it is specifically bleeding complications. TPE can also remove
indicated to treat a disease (eg. thrombotic thrombocyto- pharmacologic agents, which may reduce critical
penia purpura [TTP]), required to correct a complement medications to subtherapeutic levels, such as certain
or coagulation factor deficiency, or needed to prevent a antibiotics; however, it can also be favorable, as in drug
depletion coagulopathy in a patient who is actively overdoses.22,23 The medications most susceptible to removal
bleeding (eg. diffuse alveolar by plasma exchange are those
hemorrhage) or surrounding that are highly protein bound
CLINICAL SUMMARY (.80%) and those with a low
an invasive surgery or pro-
cedure (eg. renal biopsy). Vd (,0.2 L/kg) (see
Practice habits vary  Therapeutic plasma exchange (TPE) constitutes an Table 4).22,25 Rituximab is
extracorporeal removal of large molecular weight often used in the manage-
regarding threshold pre-
constituents of plasma that are mediators of disease.
TPE fibrinogen levels (the ment of acquired TTP, and
slowest of the clotting factors  Antibodies, cytokines, endotoxins, immune complexes, while TPE has been demon-
to regenerate) with surveys lipoproteins. and highly protein bound substances in the strated effective in its
indicating that most practi- intravascular space are common targets for removal by removal, depletion of
tioners would add some TPE. CD191 and CD201 B lym-
plasma or cryoprecipitate at  Critically ill patients may have indications for TPE and other phocytes occurs within a
the end of the procedure extracorporeal therapies like hemodialysis simulteneously. mean of 3 days after adminis-
when the preprocedure tration (range 1-14 days);
 Special attention should be placed to effect of TPE on
fibrinogen is less than medications used in critically ill patients.
therefore, it is recommended
100 mg/dL due to recent to perform TPE 24 hours after
TPE.14 Factors that influ- administration of rituxi-
ence the frequency at which mab.26,27 In patients who
the procedure is performed include: the size of the require both intermittent hemodialysis and TPE, in general
pathogenic substance being removed, production and it is recommended to perform TPE first, followed by inter-
catabolic rates, and its volume of distribution. For mittent hemodialysis in order to correct any electrolyte,
instance, in IgM mediated hyperviscosity a substantial acid-base, or excess volume-related issues that occur as a
and sustained reduction in IgM can typically be result of TPE. In patients who require both continuous
achieved within 1-3 procedures as IgM is largely intra- kidney replacement therapy (CKRT) and TPE, options
vascular. However, when the desired substance has a include discontinuing the CKRT therapy for the duration
larger volume of distribution, such as IgG, there will of the TPE, or running the 2 procedures simultaneously
be significant rebound post procedure and more either via parallel or in-series circuits.28 Figure 1 depicts
frequent and prolonged duration of procedures may combined CKRT and TPE in both series and parallel circuits
be required. In multiple myeloma, production rates of for centrifugal-based TPE systems, though performing via
light chains may overwhelm the ability of TPE to main- mTPE is also feasible.28,29 Additionally, in patients on extra-
tain a sufficient and sustained reduction and may corporeal membrane oxygenation support, with special con-
require daily TPE therapy with a documented sus- siderations and modifications, TPE has been successfully
tained decrease in light chains .50% in order to have performed while connected to the extracorporeal membrane
a renal benefit from TPE.15 oxygenation circuit.30

Adv Chronic Kidney Dis. 2021;28(1):59-73

 TPE in ICU 61

INDICATIONS FOR TPE IN CRITICALLY ILL PATIENTS

Abbreviations: cTPE, centrifugal therapeutic plasma exchange; PIVs, peripheral intravenous catheters; AVF, arteriovenous fistula; AVG, arteriovenous graft; ACD-A, anticoagulant
Systemic anticoagulation required
TPE can be a first-line therapeutic intervention in the ICU

Removal efficiency of a particular

removal ¼ longer treatment time
in certain disorders, but it is also increasingly being used as
an adjuvant therapy in conditions with high mortality
available to nephrologist

substance can be limited

rates such as sepsis and acute liver failure. Every 3 years,
Disadvantages

Due to lower PER, must

achieve desired plasma

Central access required
Equipment may not be

ASFA publishes an updated comprehensive “Guidelines

Risk for citrate toxicity

process higher TBV to

citrate dextrose – A; TBV, total blood volume; TPV, total plasma volume; PER, plasma extraction ratio; mTPE, membrane-based therapeutic plasma exchange.
capacity of the filter
on the Use of Therapeutic Apheresis in Clinical Practice”.1

by pore size and

In this special issue, indications for apheresis are assigned
one of the 4 categories of recommendation, with an as-
signed grade as to the level of evidence that is available
(See Table 5). This review will focus on many of the dis-
eases in which critically ill patients may benefit from
TPE, as well as some novel and future indications.
Prismaflex & PrisMax Equipment often available

Table 6 includes a list of the indications discussed in this re-

Regional anticoagulation
Access can be peripheral

view, including the ASFA category and grade, rationale,

to the Nephrologist

and technical notes, such as frequency and number of pro-

Equipment can also
Higher PER ¼ faster
Advantages

cellular depletions

cedures typically performed and replacement solutions

treatment time

given.
be used for

ANTIGLOMERULAR BASEMENT MEMBRANE

DISEASE
Antiglomerular basement membrane (anti-GBM) disease
is a rare autoimmune disorder that leads to a rapidly pro-
(Fresenius Medical
Optia (Terumo BCT)

(Baxter), NxStage
Equipment (USA)

gressive glomerulonephritis as well as diffuse alveolar

Amicus (Fresenius)

hemorrhage (DAH), which can be rapidly fatal.33 The

(Haemonetics)
NexSys PCSÒ

term Goodpasture’s syndrome implies both kidney and

lung involvement. Gold standard for treatment includes
an aggressive regimen of corticosteroids, cyclophospha-
Care)

mide, and TPE. Prior to the use of TPE in anti-GBM dis-

Table 1. Comparison of Centrifugal- and Membrane-Based Plasma Exchange Techniques

ease, nearly 90% of patients would either die or develop

end-stage renal disease (ESRD).34 The 5-year survival
(10-100 mL/min)
Typical Blood

100-250 mL/min

rate now exceeds 80% and fewer than 30% of patients

require long-term dialysis.33 The addition of TPE provides
80%, typically 1 mL/kg/min
Flow

a decreased likelihood of ESRD, reduces mortality, and

achieves a more rapid resolution of hemoptysis in cases
with DAH.35-38 When TPE is applied early in the course
of anti-GBM disease along with aggressive immunosup-
1.5x TBV6

pression, renal recovery is more likely.37,39 Patients who

Ratio (per)
Extraction

3 x TBV6
Plasma

30%, must

present with a creatinine .5.7 mg/dL or are dialysis

dosed proportional process

process

dependent at the time of TPE initiation generally do not

recover renal function. In this situation, TPE should only
be performed if DAH is present.32 IA and DFPP have
to incoming blood

been used in small case series with efficient removal of

Anticoagulation

anti-GBM antibodies and clinical response; however, no

proportional to
PIVs, certain ports, Citrate (ACD-A)

comparative studies have been performed.40

body weight
Heparin dosed
Typical

ANTINEUTROPHIL CYTOPLASMIC ANTIBODY

(ANCA)-ASSOCIATED VASCULITIS
ANCA-associated vasculitis (AAV) is a major cause of
rapidly progressive glomerulonephritis characterized by
a necrotizing vasculitis that can affect any organ, but
dialysis-type

commonly involves the kidneys (70%) and lungs

Access

Dialysis-type

AVF/AVGs
catheters,

catheters,

(.50%).41 Untreated, 80% will progress to ESRD with a

AVF/AVG

mean survival of 5 months. When treated with rituximab

or cyclophosphamide in addition to steroids, remissions
occur in 80-90% of cases; however, relapse is common
and maintenance immunosuppression is required. TPE
Method

mTPE

has been shown to be of benefit during the induction phase

cTPE

in patients with DAH, severe renal disease (creatinine

.5.7 mg/dL), and when anti-GBM antibodies are also

Adv Chronic Kidney Dis. 2021;28(1):59-73

62 Sanchez and Balogun
Table 2. Gilcher’s Rule of 5’s: Blood Volume (mL/kg of Body
Weight)
Patient Obese Thin Normal Muscular
Male 60 65 70 75
Female 55 60 65 70
Infant/child — — 80/70 —
present.42 However, long-term follow-up studies have
failed to show the benefit of TPE on mortality or
ESRD.43-45 Additionally, recent results of the Plasma
Exchange and Glucocorticoids for Treatment of Anti-
Neutrophil Cytoplasm Antibody (ANCA) – Associated
Vasculitis (PEXIVAS) RCT also failed to find benefit of
TPE in reducing the composite outcome of ESRD or
death.46 Subgroup analysis of patients with a
Cr $ 5.7 mg/dL or DAH also failed to show a statistically
significant benefit of TPE. However, much debate has
ensued, as there was a lack of power to detect significant
in these 2 subgroups, and enrollment was not limited to
initial presentation, nor was renal biopsy required. Subse-
quently, in 2020, ASFA updated the AAV Fact Sheet down-
grading the indication for TPE in severe renal involvement
from a Category I to a Category II indication.47 Although
no controlled studies have been performed specifically ad-
dressing DAH, the available evidence suggests that in pa-
tients with pulmonary hemorrhage secondary to AAV,
TPE was associated with improved in-hospital mortality
rates.47,48
CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME
Catastrophic antiphospholipid syndrome (CAPS) is a rare
event defined as the acute onset of multiple thromboses in
at least 3 organ systems over a period of days to weeks, in
patients with antiphospholipid antibodies. Clinically this
can manifest with renal failure, pulmonary embolism,
acute respiratory distress syndrome, myocardial infarc-
tion, heart failure, stroke, and encephalopathy and carries
a high mortality.49,50 Optimal treatment of CAPS is un-
known but is focused on treating any precipitating factors,
preventing and controlling thrombosis with anticoagula-
tion, and suppression of the excessive cytokine produc-
tion. CAPS registry data supports a lower mortality rate
with a triple therapy approach that includes anticoagula-
tion, glucocorticoids, and TPE and/or intravenous immu-
noglobulin (IVIG).51
HYPERVISCOSITY SYNDROME
Hyperviscosity syndrome is an oncologic emergency, most
commonly caused by Waldenstrom’s macroglobulinemia
that classically presents with the triad of neurologic defi-
cits (eg. altered mental status, seizures, headaches), visual
changes, and mucosal bleeding. Other manifestations can
include heart failure, respiratory compromise, coagulation
abnormalities, anemia, fatigue, and neuropathy.52 In Wal-
denstrom’s macroglobulinemia, the large IgM pentamers
are highly viscous with symptoms occurring at levels
exceeding 4 g/dL. A single TPE can reduce serum viscosity
by 20-30% and promptly reverse symptoms, and should be
performed as soon as the diagnosis is made, followed by
chemotherapy to control the monoclonal protein produc-
tion.53 Transient increases in IgM are seen post rituximab
administration, and prophylactic TPE before rituximab is
recommended when serum viscosity is . 3.5 cp or IgM
level is . 4 g/dL.54
CRYOGLOBULINEMIC VASCULITIS
Cryoglobulins can induce a small-vessel vasculitis known
as cryoglobulinemic vasculitis that mainly involves the
skin, joints, peripheral nervous system, and the kidneys.55
Symptoms range from mild to fulminant life-threatening
organ involvement (glomerulonephritis, limb necrosis, or
systemic vasculitis involving lung, heart, or central ner-
vous system). Severe disease warrants immunosuppres-
sion, treatment of hepatitis C when present, and
consideration of TPE. Numerous case reports and series
have documented clinical improvement in up to 70-80%
of patients treated with adjunctive TPE when severe active
disease is present.56 DFPP and a technique called cryofil-
tration have also been used to treat cryoglobulinemia. Cry-
ofiltration is a selective technique where the plasma is
cooled in an extracorporeal circuit in order to precipitate
and remove the cryoglobulins; then, the remaining plasma
is warmed and returned to the patient.57 Additionally, IA
has been demonstrated to be effective in lowering cryoglo-
bulins.58
THROMBOTIC MICROANGIOPATHIES
Thrombotic microangiopathy (TMA) syndromes are
defined by the presence of microangiopathic hemolytic
anemia that leads to organ injury due to widespread
thrombi in the microcirculation. While TMA syndromes
share clinical, laboratory, and biological features, each syn-
drome has a distinct pathophysiology and it is essential
that the underlying cause be identified quickly as optimal
treatment varies considerably based on diagnosis.59 TPE is
commonly requested when a patient is discovered to have
TMA, often before the underlying cause has been eluci-
dated.
TTP is a life-threatening systemic thrombotic illness pri-
marily affecting small vessels, characterized by a severe
deficiency in the ADAMTS13 enzyme activity (,10 IU/
dL) most often due to an acquired antibody to the
ADAMTS13 enzyme.60,61 When there is clinical suspicion
for TTP, the decision to start TPE emergently should not
wait for the confirmatory laboratory data. TPE has
decreased the overall mortality of TTP from uniformly
fatal to ,10-20%.62 Additional management strategies
include steroids, rituximab, and caplacizumab.
Hemolytic uremic syndrome (HUS) is a potentially life-
threatening TMA that has been further divided into
Shiga-toxin induced HUS (STEC-HUS) or atypical HUS
(aHUS). The presence of oliguric/anuric renal failure dis-
tinguishes HUS from TTP, and in general ADAMTS13
levels are normal to slightly decreased.63,64 During a large
STEC-HUS outbreak in Europe in 2011, addition of TPE did
not have an overall beneficial impact on outcomes.65 How-
ever, during the same outbreak, TPE and IA appeared to
improve the course in patients with neurologic
Adv Chronic Kidney Dis. 2021;28(1):59-73
 TPE in ICU 63

involvement, indicating a potential limited role for TPE in

STEC-HUS, though further data are needed.66-68 Atypical
Bruising, pain, vasovagal syncope,

HUS (aHUS), while rare, tends to be a chronic condition

interrupted procedure if access

of uncontrolled activation of the alternative complement

pathway due to genetic or acquired defects, and
Vascular Access

mortality and ESRD rates historically have approached

65% within the first year of diagnosis.59,69 In the past,
TPE played a larger role in the management of aHUS; how-
Pneumothorax
ever, in the era of eculizumab, its use has become more
Peripheral veins

limited.70 TPE is often employed early in the course while

Thrombosis

Malfunction
problematic
Central access

Bleeding
Infection

awaiting investigations for TTP and other forms of TMA, or

when eculizumab is not available.
HELLP (hemolysis, elevated liver enzymes and low
platelets) syndrome is a TMA that typically occurs in the
third trimester of pregnancy but up to 25% of patients
may present postpartum. Patients with severe HELLP
Hemorrhage (vascular access, disease

can develop multiorgan failure and disseminated intravas-

Hemolysis: high membrane pressure

cular coagulopathy. ADAMTS13 is typically low but

or hypotonic replacement fluids
Hematologic/Immunologic

detectable and autoantibodies have not been identified.

Definitive treatment is prompt delivery to avoid increased
Thrombocytopenia (heparin)
related, heparin induced)

Immunoglobulin depletion

maternal and perinatal mortality. While data are limited,

Depletion coagulopathy

multiple case reports, case series, and a retrospective

controlled trial TPE appears to confer benefit when used
in severe postpartum cases of HELLP.71
Urticaria/allergy

HEPARIN-INDUCED THROMBOCYTOPENIA
Thrombosis

Heparin-induced thrombocytopenia (HIT) classically oc-

Anemia

curs 5-10 days after heparin exposure with an observed

mortality rate of 10% and a thrombosis rate of 30%.72
Management includes discontinuation of heparin and
administration of a nonheparin-based anticoagulant. If
Metabolic alkalosis (citrate)

there is an urgent need for cardiopulmonary bypass

Electrolyte/Acid Base

(which requires heparin use) during acute or subacute

Hypocalcemia (citrate)

HIT, TPE may be considered to remove HIT antibodies

Hypomagnesemia

before the surgery. The largest case series available

demonstrated no cases of HIT post cardiopulmonary
Hypokalemia

bypass when TPE was employed preoperatively, though

no RCT have been performed.73 In another small study,
early initiation of TPE (within 4 days of onset of thrombo-
cytopenia) conferred an improved 30-day mortality rate
in progressive thrombosis due to HIT that was deemed
Table 3. Complications of Therapeutic Plasma Exchange

life or limb threatening.74

Hemorrhage (disease related, heparin induced,

ACUTE INFLAMMATORY DEMYELINATING

Disease-related (eg. autonomic dysfunction in

POLYRADICULONEUROPATHY
Delayed, inadequate or hypo-oncotic fluid

Acute inflammatory demyelinating polyradiculoneurop-

Anaphylaxis (plasma, ethylene oxide,

athy or Guillain-Barre syndrome is an acute, symmetrical,

and ascending paralyzing autoimmune disorder that pro-
Arrhythmia/myocardial ischemia
Cardiovascular

bioincompatible membranes)

gresses over a period of hours to days, requiring mechan-

Transfusion-related lung injury

ical ventilation in 25% of cases. Severe autonomic

Guillain-Barre syndrome)
depletion coagulopathy)

dysfunction can lead to life-threatening variability in

blood pressure and heart rate, with mortality estimates
at 3-5%. TPE was the first therapeutic modality to impact
Pulmonary embolus

the disease favorably and several major RCTs have

replacement

confirmed its efficacy, including decreasing time on the

Hypovolemia
Hypotension

ventilator when instituted within 7 days of disease

onset.75,76 Additionally, several cases series and one
controlled trial have demonstrated similar efficacy of IA
to TPE for management of acute inflammatory demyelin-
ating polyradiculoneuropathy.77,78

Adv Chronic Kidney Dis. 2021;28(1):59-73

64 Sanchez and Balogun

Table 4. Drug Removal by Therapeutic Plasma Exchange

Drug Class Significant Removal by TPE Possible Removal by TPE Insignificant Removal by TPE
Anti-infective agents Ampicillin Amphotericin B Acyclovir
Ceftriaxone* Vancomycin Cefepime
Chloramphenicol Ceftazidime
Gentamicin Dapsone
Tobramycin Zidovudine
Immunosuppressants and Cisplatin Calcineurin inhibitors‡
chemotherapeutic agents Methotrexate Mycophenolate mofetil
Monoclonal antibodies Prednisone/prednisolone
(rituximab, basiliximab, Sirolimus
natalizumab)
Vincristine
Cardiovascular agents Amlodipine Digoxin† Amiodarone
Diltiazem Metoprolol
Propranolol
Verapamil
Antiepileptics Carbamazepine Oxcarbazepine
Phenytoin Phenobarbital
Valproic acid
Homeostatic agents Dalteparin Aspirin
Lepirudin Heparinx
Miscellaneous Diclofenac Metformin Acetaminophen
IVIG Theophylline Quinine
Propoxyphene Thyroxine

*When TPE initiated within 3 hours of administration.

†Possible role of TPE in overdose situations in combination with digoxin immune antigen-binding fragments.
‡50% distributed in erythrocytes; therefore, red blood cell exchange has been used in overdoses.
xWhen FFP used for replacement during TPE, infusion rate of heparin should be increased by 65% during the procedure.24

MYASTHENIC CRISIS
Myasthenic crisis is a serious, life-threatening event that
can lead to airway compromise and can require mechan-
ical or noninvasive ventilation due to autoantibodies
interfering at the skeletal neuromuscular junction. Mor-
tality rate has improved from 75% to ,5% due to the
use of immunomodulatory therapies.79 Although the ab-
solute antibody levels in myasthenia gravis (MG) do not
correlate well with disease severity, MG has a well-
documented and quick response to TPE or IA (trypto-
phan-IA column).78 TPE has been shown more effective
if initiated earlier in hospital admission in severe cases
and may be more effective than IVIG when antibodies
to muscle-specific tyrosine kinase (MuSK-Ab) are pre-
sent.80,81 IA and DFPP have exhibited equal efficacy
compared to TPE and for acute MG.1
ACUTE DISSEMINATED ENCEPHALOMYELITIS
Acute disseminated encephalomyelitis is an acute inflam-
matory demyelinating disease of the CNS predominantly
affecting the white matter of the brain and spinal cord,
often occurring after an immune trigger, such as an infec-
tion or a vaccination. Clinical presentation is of an acute
encephalopathy accompanied by multifocal neurologic
deficits (ie. ataxia, dysarthria, dysphagia, cranial nerve
palsies, seizures) with a favorable prognosis but typically
requires ICU level care. While no RCTs exist, therapies
are targeted at decreasing the CNS inflammatory reaction
with IV steroids and IVIG. Several case series and retro-
spective studies have found that patients who have failed
steroids and/or IVIG may benefit from TPE, particularly
when it has been initiated within 15 days of disease
onset.82-84
AUTOIMMUNE ENCEPHALITIS
Autoimmune encephalitis is a severe inflammatory disor-
der of the brain commonly seen in children and young
adults and up to 70% will require intensive care. An
increasing array of autoantibodies have been associated,
with N-methyl D-aspartate receptor encephalitis being
the most frequent. Symptoms progress over a period of
weeks to days, often initially presenting with neuropsychi-
atric symptoms, then progressing to include autonomic
dysfunction, decreased level of consciousness, seizures,
and coma, with mortality in the range of 4%. First-line ther-
apy includes high-dose steroids, IVIG, and TPE/IA, fol-
lowed by cyclophosphamide or rituximab as second-line
treatment.85 Often there is an underlying tumor that is
thought to serve as the antigenic stimulus for antibody for-
mation.86,87 TPE can lead to clinical improvement when
combined early in the disease course with immunosup-
pression and tumor removal, if present.85,88,89 Individual
comparisons of TPE vs IA (tryptophan-IA column) for
autoimmune encephalitis have been shown to have near
equal efficacy (60-88% response rates, some reports in
favor of IA).86,90
ACUTE LIVER FAILURE
Severe cases of acute liver failure can result in multior-
gan failure, including cardiovascular instability, acute
kidney injury, and brain edema with mortality rates

Adv Chronic Kidney Dis. 2021;28(1):59-73

 TPE in ICU 65

Figure 1. Combining centrifugal TPE and continuous dialysis. Reproduced with permission from Apheresis Standard Oper-
ating Procedures Manual, 1st Edition, 2019 American Society for Apheresis. Original graphic credit: David M. Ward, MD,
FRCP. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this
article.)

of up to 50-90%.91 Treatment is supportive, and in se-
vere cases, liver transplantation can improve survival
rates. Many extracorporeal liver support systems have
been trialed, but thus far, such procedures have been
unable to consistently demonstrate improvement in sur-
vival.92-94 Aggressive TPE has been used as a bridge to
liver transplant. Several studies have shown that TPE is
associated with an improvement in mean arterial blood
pressure, increased hepatic blood flow, cerebral blood
flow, perfusion pressure, and metabolic rate, but the
impact of TPE on clinical improvement in acute liver
failure is still unclear.95-98 An RCT of high-volume
plasma exchange (TPE-HV), defined as an exchange
of 8-12L or 15% of ideal body weight with fresh-
frozen plasma, reported improved transplant-free sur-
vival rates at 3 months.99
THYROID STORM
Thyroid storm is a rare life-threating condition with mor-
tality rates of 10-30% characterized by the severe clinical

Adv Chronic Kidney Dis. 2021;28(1):59-73

66 Sanchez and Balogun
Table 5. ASFA Guidelines on Indication and Level of Evidence
Category
Category I: Disorders for which apheresis is accepted as a first-
line therapy, either as a primary standalone treatment or in
conjunction with other modes of treatment.
Category II: Disorders for which apheresis is accepted as a
second-line therapy, either as a standalone treatment or in
conjunction with other modes of treatment.
Category III: Optimum role of apheresis therapy is not
established. Decision-making should be individualized.
Category 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.
manifestations of thyrotoxicosis, including arrhythmias,
heart failure, and delirium which can progress to multior-
gan failure.100 Treatment involves a multifaceted approach
in the ICU.101 No RCTs have evaluated the benefit of TPE
compared to standard therapy but there have been multi-
ple case series and case reports demonstrating benefit
when one fails to quickly respond to first line therapy, or
when it is contraindicated, or in the setting of
amiodarone-induced thyrotoxicosis.102-105
HYPERTRIGYCERIDEMIC PANCREATITIS
Acute pancreatitis due to hypertriglyceridemia has a mor-
tality rate up to 30%. Treatment involves insulin, bowel
rest, heparin, cholesterol-lowering medications, and occa-
sionally TPE. Use of TPE in this setting has been controver-
sial as there have been no RCTs; however, there have been
multiple case reports, case series, and one nonrandomized
control trial published. TPE can be performed for hypertri-
glyceridemia with either cTPE or mTPE; however, effi-
ciency is improved in cTPE as triglycerides (TG) tend to
clog the pores of the mTPE plasma separator. In a case se-
ries of 103 patients, the authors found that while TPE
reduced TG 2 times more than medications alone, the TG
level did not correlate with clinical severity by APACHE
II score, and there was no difference in mortality if TPE
was started within 36 hours of diagnosis vs later.106 In
the setting of pregnancy, one might consider the addition
of TPE as fibrates are teratogenic.107 It is important to
note that the TPE effect of lowering TG is transient, and
the efficacy of mTPE for this indication is impaired as the
chylomicrons clog the plasma separator and therefore
cTPE is preferred.
SEPSIS WITH MULTIORGAN FAILURE
Severe sepsis remains a leading cause of death in patients
admitted to the ICU worldwide, with an average mortality
of approximately 33%.108,109 Case reports and small obser-
Grading Recommendations
1A – Strong recommendation, high-quality evidence
1B – Strong recommendation, moderate-quality evidence
1C – Strong recommendation, low-quality or very low-quality
evidence
.delete this square in reformatting (ie only 2 rows in column 2,
2A – Weak recommendation, high-quality evidence
2B – Weak recommendation, moderate-quality evidence
2C – Weak recommendation, low-quality or very low-quality
evidence
.delete this square in reformatting,
vational studies of early use of TPE in septicemia or menin-
gococcemia suggest a survival benefit when compared to
expected survival rates; however, other RCTs have had
conflicting outcomes.110-112 The results of a 2014
systematic review and meta-analysis of patients (adult
and pediatric) with severe sepsis, septic shock, or dissem-
inated intravascular coagulopathy due to infection, found
that the use of TPE was not associated with a significant
reduction in all-cause mortality, except in adults; however,
their conclusion was that there is still insufficient evidence
to recommend TPE as an adjunctive therapy in septic
shock.113 Other blood purification techniques have been
trialed in sepsis, including adsorption columns designed
to bind and neutralize endotoxins or cytokines; however,
data have been limited, with conflicting reports of benefit
on 28-day mortality.114-116
DRUG OVERDOSE, ENVENOMATION, AND
POISONING
Drug overdoses, envenomation, or poisoning can lead to
tissue injury and potential systemic effects. While treat-
ment is often supportive, TPE has been employed in the
management of certain drug overdoses, with case reports
of success with overdoses of cisplatin, vincristine, amio-
darone, verapamil, diltiazem, amitriptyline, theophylline,
and carbamazepine though the data have been too limited
to warrant individual category indications in the ASFA
guidelines.22,23,117,118 TPE can be more effective than he-
modialysis in removal of substances that are larger, more
highly protein bound (.80%), with a low volume of distri-
bution (,0.2 L/kg).119 Amanita phalloides mushroom
poisoning is the most frequent clinical diagnosis where
TPE has been utilized with large case series showing
decreased mortality among patients who received early
TPE (within the first 24-48 hours) when compared to his-
torical controls.118 Other environmental exposures where
TPE has been employed include ricin toxicity following
Adv Chronic Kidney Dis. 2021;28(1):59-73
Adv Chronic Kidney Dis. 2021;28(1):59-73

Table 6. Common Indications for TPE in the ICU Setting Adapted From the 2019 ASFA Guidelines
Disease Rationale Indication Category Grade Technical Notes
Antiglomerular basement Removal of pathogenic anti- DAH I 1C Frequency: daily or every other
membrane disease GBM antibodies that bind Dialysis independence I 1B day for 14 days or until anti-
type IV collagen in the GBM Dialysis dependence, no DAH III 2B GBM undetectable
and alveolar basement Replacement solution: albumin,
membrane plasma if DAH or recent biopsy
ANCA-associated vasculitis: Removal of cytotoxic ANCA DAH I 1C Frequency: every other day for 7
MPA, GPA, RLV, and eGPA antibodies (MPO and PR3) RPGN, Cr $ 5.7 mg/dL or on II 1B exchanges over 2 weeks,
dialysis III 2C when DAH present, perform
RPGN, Cr , 5.7 mg/dL III 2C TPE daily
eGPA Replacement solution: albumin,
plasma if DAH or recent biopsy
Catastrophic Removal of antiphospholipid CAPS I 2C Frequency: daily or every other
Antiphospholipid antibodies, cytokines, tumor day until clinical response
Syndrome (CAPS) necrosis factor-a, and (minimum of 3-5 days up to 1-
complement 3 weeks)
Replacement solution: plasma
alone or in combination with
albumin
Hyperviscosity syndrome Reduce viscosity by removing Symptomatic I 1B Frequency: 1-3 treatments, daily

Cryoglobulinemic vasculitis
Thrombotic
thrombocytopenic purpura
(TTP)
large IgM molecules in
Waldenstrom’s
macroglobulinemia or
monoclonal IgA or IgG3 in
multiple myeloma
Removal of cryoglobulins in
order to alter the antigen-
antibody ratio, eliminate
cytokines, and increase
immune-complex
clearance.31
Removal of ADAMTS13
autoantibodies while
replacing deficient
ADAMTS13 protease activity
Prophylaxis for rituximab
Severe/symptomatic (TPE)
Severe/symptomatic (IA)
TTP
TPE in ICU
I 1C or every other day, until
symptoms abate
Replacement: albumin, plasma
if daily
II 2A Frequency: daily or every other
II 2B day for 3-8 procedures, or
until clinical response
Some cases requiring longer
term or chronic therapy (ie.
neuropathy or recurrent
symptoms)
Replacement: TPE: albumin; IA:
N/A
Replacement fluids, return lines,
and room should be warmed to
avoid precipitation of
cryoglobulins32
I 1A Frequency: daily until platelets
.150K and LDH near normal
for 2-3 consecutive days,
taper vs abrupt
discontinuation practices vary
Replacement solution: plasma
(Continued )

67
 Table 6. Common Indications for TPE in the ICU Setting Adapted From the 2019 ASFA Guidelines (Continued )

68
Disease Rationale Indication Category Grade Technical Notes
Thombotic microangiopathy, Removal of cytokines, ULvWFM STEC-HUS, severe (TPE/IA) III 2C Frequency: daily until
infection associated and Stx that damage the pHUS (TPE) III 2C improvement, no
endothelium. For pHUS, TPE standardized approach exists
may remove antibodies Replacement: STEC-HUS:
directed against the exposed plasma; pHUS: albumin (avoid
T-Ag and circulating bacterial plasma in this group to prevent
neuraminidase passive transfer of anti-T in
normal plasma)
Thrombotic Remove autoantibodies or Factor H autoantibody I 2C Frequency: daily until clinical
microangiopathy, defective complement Complement factor gene III 2C response (complement
complement or coagulation regulators with replacement mutations III 2C mediated), daily or every
mediated (aHUS) of exogenous complement THBD, DGKE, and PLG other day for coagulation-
factors mutations (coagulation- mediated TMA
mediated TMA) Replacement: plasma or
plasma/albumin
Thrombotic Extrapolated from TTP data, Ticlopidine I 2B Frequency: daily or every other
microangiopathy, drug direct rationale unclear given Clopidogrel III 2B day until clinical
associated lack of ADAMTS13 deficiency Gemcitabine/quinine IV 2C improvement, followed by
or presence of inhibitors taper vs abrupt

Sanchez and Balogun

(except with ticlopidine), but discontinuation
overall thought to be an Replacement: plasma
immune-mediated reaction
HELLP syndrome Removal of circulating protein Postpartum III 2C Frequency: daily if no
bound platelet aggregating Antepartum IV 2C improvement 48-72 hours
and procoagulant factors after delivery, perform until
released from activated platelet count .100K or LDH
platelets and endothelial cells normalized
Replacement: plasma
Heparin-induced Removal of antibodies to Precardiopulmonary bypass III 2C Frequency: daily or every other
Thrombocytopenia platelet factor 4 (PF4) Thrombosis III 2C day until antibody titers
undetectable (typically 1-5
procedures)
Adv Chronic Kidney Dis. 2021;28(1):59-73

Replacement: albumin, plasma

Acute inflammatory
demyelinating
polyradiculoneuropathy
(Guillain-Barre syndrome)
Myasthenia gravis
Removal of antibodies targeted
against peripheral nerve
myelin
Removal of antibodies, such as
AChR, MuSK, and LRP4
autoantibodies
Primary treatment: TPE I 1A Frequency: 5-6 procedures daily
Primary treatment: IA I 1B or every other day over 10-
14 days, relapses are common
requiring additional courses
Replacement: TPE: albumin/
plasma; IA: N/A
Acute, short-term treatment I 1B Frequency: acute attack: 3-6
Long-term treatment, refractory II 2B treatments over 10-14 days;
to immunosuppression N/A N/A chronic treatment: 1-2 x a
Pre-thymectomy week; pre-thymectomy: 3-5
treatments
Replacement: TPE: albumin; IA:
N/A
(Continued )
 Table 6. Common Indications for TPE in the ICU Setting Adapted From the 2019 ASFA Guidelines (Continued )
Adv Chronic Kidney Dis. 2021;28(1):59-73

Disease Rationale Indication Category Grade Technical Notes

Acute disseminated
encephalomyelitis
Autoimmune encephalitis
Acute liver failure (ALF)
Thyroid storm
Removal of potential antibodies
against myelin
oligodendrocyte glycoprotein
or other autoantigens
Removal of autoantibodies
Removal of inflammatory
mediators, albumin-bound
and unbound toxins, and
restoration of hemostasis
Wilson disease: removal of
serum copper and large
molecular weight toxins
Removal of T3 and T4 bound to
plasma proteins, removal of
amiodarone in cases of
amiodarone-associated
thyrotoxicosis, removal of
Steroid refractory II 2C Frequency: every other day for
5-7 treatments
Replacement: albumin
NMDAR encephalitis (TPE/IA) I 1C Frequency: 5-12 treatments
Paraneoplastic (TPE/IA) II 2C daily or every other day over
1-3 weeks
Replacement: TPE: albumin; IA:
N/A
ALF – TPE III 2B Frequency: daily until transplant
ALF – TPE-HV I 1A or clinical improvement (TPE);
ALF due to fulminant Wilson I 1C for TPE-HV perform 3
Disease consecutive treatments
Replacement:
plasma . albumin; with TPE-HV
target 8-12L exchange
Thyroid storm failing to respond II 2C Frequency: daily to every 3 days
to first-line therapy within 24- guided by control of systemic
48 hours or when first-line symptoms
therapy contraindicated Replacement: albumin/plasma.
Plasma increases thyroid-

TPE in ICU
autoantibodies in Graves’ binding globulin; however,
disease, catecholamines, and albumin provides more low-
cytokines affinity binding sites for thyroid
hormone
Hypertriglyceridemic Rapid reduction in triglyceride Severe III 1C Frequency: daily for 1-3 days for
pancreatitis levels Prevention of relapse III 2C severe pancreatitis
Replacement: albumin, plasma
Sepsis with multiorgan Removal of inflammatory and Severe sepsis III 2B Frequency: daily up to 14 days
failure antifibrinolytic mediators and or resolution of symptoms
restoration of homeostasis Replacement: plasma
Drug overdose, Removal of toxic substance, Mushroom poisoning II 2C Frequency: daily until clinical
envenomation, and drug, or inflammatory Envenomation III 2C symptoms improved
poisoning mediators Drug overdose/poisoning III 2C Replacement: albumin, plasma,
targeting a 1 – 2 TPV exchange

Abbreviations: GBM, glomerular basement membrane; DAH, diffuse alveolar hemorrhage; ANCA, antineutrophil cytoplasmic antibody; MPA, microscopic polyangiitis; GPA,
granulomatosis with polyangiitis; RLV, renal limited vasculitis; eGPA, eosinophilic granulomatosis with polyangiitis; MPO, myeloperoxidase; PR3, serine protease 3; RPGN,
rapidly progressive glomerulonephritis; Cr, creatinine; TPE, therapeutic plasma exchange; IA, immunoadsorption; ULVWFM, unusually large von Willebrand factor multimers;
Stx: shiga toxin; pHUS, thrombotic microangiopathy due to Streptococcus Pneumoniae; STEC-HUS, shiga-like toxin producing E. coli hemolytic uremic syndrome; aHUS, atypical
HUS; TMA, thrombotic microangiopathy; HELLP, hemolysis elevated liver enzymes and low platelets; AChR, acetylcholinesterase receptor; MuSK, muscle-specific kinase; LRP4,
lipoprotein receptor-related protein 4; NMDAR, N-methyl D-aspartate receptor; TPE-HV, therapeutic plasma exchange-high volume; TPV, total plasma volume.

69
70 Sanchez and Balogun
castor bean ingestion and pesticide/organophosphate
poisoning.120,121 TPE has also been used for toxin removal
following envenomation from snake, brown recluse spider
bites, and scorpion or Africanized bee stings.122
EMERGING INDICATIONS FOR TPE IN THE
CRITICALLY ILL PATIENT
With emerging global zoonotic infections on the rise, that
display high morbidity and mortality rates and limited
treatment options, novel therapeutic approaches must be
considered. A selective apheresis column has been devel-
oped that has a high affinity for glycoproteins on the sur-
face of enveloped viruses and has been successfully used
to treat a patient with severe Ebola virus disease, as well
as trialed in Middle East respiratory syndrome coronavi-
rus (MERS-CoV), and Marburg Virus (MARV).123,124
Additionally, conventional TPE has been utilized as a suc-
cessful rescue strategy in 3 children with 2009 H1N1 influ-
enza A related acute lung injury and hemodynamic
compromise.125 Experimental trials in blood purification
techniques have begun in the current SARS-CoV-2
(COVID-19) global pandemic as well.126 At time of this
publication, there have been several case reports and series
describing the use of TPE in severe COVID-19 associated
acute respiratory distress syndrome, the largest of which
demonstrated higher extubation rates and lower 14-day
and 28-day mortality in the TPE group.127,128 Current ran-
domized controlled trials in severe COVID-19 infection are
underway utilizing both conventional TPE and a second-
ary plasma cartridge (D2000, Marker Therapeutics AG,
Switzerland) that removes a range of inflammatory cyto-
kines from the plasma (clinicaltrials.gov identifier:
NCT04358003).129 In April 2020, this cartridge received
emergency use authorization from the FDA to treat acute
respiratory failure in COVID-19 in the USA. Similar to
the use of TPE in septic shock, the potential benefit of
TPE in this setting is postulated to be due to removal of in-
flammatory cytokines, stabilization of endothelial mem-
branes, and resetting the hypercoagulable state.126
SUMMARY
TPE should be considered an additional tool in the man-
agement of select patients in the ICU setting. It is impor-
tant to be aware of the techniques of apheresis available,
including centrifugal- and membrane-based systems, as
well as the special considerations with each technique
that must be made for the critically ill patient. The ASFA
guidelines are an excellent resource to provide a quick
reference for the indications for TPE, the level of evidence
supporting that indication, and technical aspects of the
prescription and performance of the procedure. There is
increasing interest in the use of TPE or selective plasma
processing for the management of severe and emerging
global infections.
REFERENCES
1. Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on
the Use of therapeutic apheresis in clinical practice - evidence-
based approach from the Writing Committee of the American
Society for apheresis: the Eighth special issue. J Clin Apher.
2019;34(3):171-354.
2. Okafor C, Ward DM, Mokrzycki MH, Weinstein R, Clark P,
Balogun RA. Introduction and overview of therapeutic apheresis.
J Clin Apher. 2010;25(5):240-249.
3. Stegmayr B, Ramlow W, Balogun RA. Beyond dialysis: current and
emerging blood purification techniques. Semin Dial. 2012;25(2):207-
213.
4. Williams ME, Balogun RA. Principles of separation: indications
and therapeutic targets for plasma exchange. Clin J Am Soc Nephrol.
2014;9(1):181-190.
5. Reeves HM, Winters JL. The mechanisms of action of plasma ex-
change. Br J Haematol. 2014;164(3):342-351.
6. Ward DM. Conventional apheresis therapies: a review. J Clin Apher.
2011;26(5):230-238.
7. Burgstaler EA, Sanchez AP. Apheresis instrumentation. In:
Balogun RA, ed. Principles Apher Technology. ed 7. American Society
for Apheresis; 2020:21-36.
8. Gashti CN. Membrane-based therapeutic plasma exchange: a new
Frontier for Nephrologists. Semin Dial. 2016;29(5):382-390.
9. Hafer C, Golla P, Gericke M, et al. Membrane versus centrifuge-
based therapeutic plasma exchange: a randomized prospective
crossover study. Int Urol Nephrol. 2016;48(1):133-138.
10. Malchesky PS, Koo AP, Roberson GA, Hadsell AT, Rybicki LA, In-
ternational Apheresis R. Apheresis technologies and clinical appli-
cations: the 2005 International apheresis registry. Ther Apher Dial.
2007;11(5):341-362.
11. Siami GA, Siami FS. Membrane plasmapheresis in the United
States: a review over the last 20 years. Ther Apher. 2001;5(4):315-320.
12. Sanchez AP, Cunard R, Ward DM. The selective therapeutic apher-
esis procedures. J Clin Apher. 2013;28(1):20-29.
13. Neyrinck MM, Vrielink H, Joint Task Force for E, Certification. Cal-
culations in apheresis. J Clin Apher. 2015;30(1):38-42.
14. Zantek ND, Pagano MB, Rollins-Raval MA, et al. Hemostasis
testing and therapeutic plasma exchange: results of a practice sur-
vey. J Clin Apher. 2019;34(1):26-32.
15. Leung N, Gertz MA, Zeldenrust SR, et al. Improvement of cast ne-
phropathy with plasma exchange depends on the diagnosis and on
reduction of serum free light chains. Kidney Int. 2008;73(11):1282-1288.
16. Lemaire A, Parquet N, Galicier L, et al. Plasma exchange in the
intensive care unit: technical aspects and complications. J Clin
Apher. 2017;32(6):405-412.
17. Mortzell Henriksson M, Newman E, Witt V, et al. Adverse events in
apheresis: an update of the WAA registry data. Transfus Apher Sci.
2016;54(1):2-15.
18. Yilmaz AA, Can OS, Oral M, et al. Therapeutic plasma exchange in
an intensive care unit (ICU): a 10-year, single-center experience.
Transfus Apher Sci. 2011;45(2):161-166.
19. Mokrzycki MH, Kaplan AA. Therapeutic plasma exchange: com-
plications and management. Am J Kidney Dis. 1994;23(6):817-827.
20. Norda R, Stegmayr BG, Swedish Apheresis G. Therapeutic apher-
esis in Sweden: update of epidemiology and adverse events. Trans-
fus Apher Sci. 2003;29(2):159-166.
21. Sanchez AP, Crookston K. Introduction to therapeutic apheresis. In:
Schwartz J, ed. Therapeutic Apheresis—A Physician’s Handbook. ed 6.
AABB/ASFA; 2019.
22. Ibrahim RB, Liu C, Cronin SM, et al. Drug removal by plasmaphe-
resis: an evidence-based review. Pharmacotherapy. 2007;27(11):1529-
1549.
23. Cheng CW, Hendrickson JE, Tormey CA, Sidhu D. Therapeutic
plasma exchange and its impact on drug levels: an ACLPS critical
review. Am J Clin Pathol. 2017;148(3):190-198.
24. Kaplan A, Raut P, Totoe G, Morgan S, Zantek ND. Management of
systemic unfractionated heparin anticoagulation during therapeu-
tic plasma exchange. J Clin Apher. 2016;31(6):507-515.
Adv Chronic Kidney Dis. 2021;28(1):59-73
 TPE in ICU
25. Ibrahim RB, Balogun RA. Medications in patients treated with ther-
apeutic plasma exchange: prescription dosage, timing, and drug
overdose. Semin Dial. 2012;25(2):176-189.
26. Benhamou Y, Paintaud G, Azoulay E, et al. Efficacy of a rituximab
regimen based on B cell depletion in thrombotic thrombocytopenic
purpura with suboptimal response to standard treatment: results
of a phase II, multicenter noncomparative study. Am J Hematol.
2016;91(12):1246-1251.
27. Sayani FA, Abrams CS. How I treat refractory thrombotic thrombo-
cytopenic purpura. Blood. 2015;125(25):3860-3867.
28. Balogun RA, Sumner K, Harris R, Sanchez AP. Combined continuous
renal replacement (CRRT) and therapeutic plasma exchange (TPE) in
parallel (Chapter 55); Combined continuous renal replacement
(CRRT) and therapeutic plasma exchange (TPE) in series (Chapter
56). In: Wu Y, ed. Apheresis Standard Operating Procedures Manual. 1st
ed. American Society for Apheresis; 2019:168-169. 170-171.
29. Ponikvar R, Kandus A, Urbancic A, Kornhauser AG, Primozic J,
Ponikvar JB. Continuous renal replacement therapy and plasma ex-
change in newborns and infants. Artif Organs. 2002;26(2):
163-168.
30. Tufan Pekkucuksen N, Sigler KE, Akcan Arikan A, Srivaths P.
Tandem plasmapheresis and continuous kidney replacement
treatment in pediatric patients. Pediatr Nephrol. 2021;36(5):
1273-1278.
31. Rockx MA, Clark WF. Plasma exchange for treating cryoglobuline-
mia: a descriptive analysis. Transfus Apher Sci. 2010;42(3):247-251.
32. Sanchez AP, Ward DM. Therapeutic apheresis for renal disorders.
Semin Dial. 2012;25(2):119-131.
33. Greco A, Rizzo MI, De Virgilio A, et al. Goodpasture’s syndrome: a
clinical update. Autoimmun Rev. 2015;14(3):246-253.
34. Rosenblatt SG, Knight W, Bannayan GA, Wilson CB, Stein JH.
Treatment of Goodpasture’s syndrome with plasmapheresis. A
case report and review of the literature. Am J Med.
1979;66(4):689-696.
35. Lockwood CM, Rees AJ, Pearson TA, Evans DJ, Peters DK,
Wilson CB. Immunosuppression and plasma-exchange in the
treatment of Goodpasture’s syndrome. Lancet. 1976;1(7962):711-
715.
36. Johnson JP, Moore J Jr, Austin HA 3rd, Balow JE, Antonovych TT,
Wilson CB. Therapy of anti-glomerular basement membrane anti-
body disease: analysis of prognostic significance of clinical, patho-
logic and treatment factors. Medicine (Baltimore). 1985;64(4):219-227.
37. Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of
anti-glomerular basement membrane antibody disease treated
with plasma exchange and immunosuppression. Ann Intern Med.
2001;134(11):1033-1042.
38. Simpson IJ, Doak PB, Williams LC, et al. Plasma exchange in Good-
pasture’s syndrome. Am J Nephrol. 1982;2(6):301-311.
39. Salama AD, Levy JB, Lightstone L, Pusey CD. Goodpasture’s dis-
ease. Lancet. 2001;358(9285):917-920.
40. Biesenbach P, Kain R, Derfler K, et al. Long-term outcome of anti-
glomerular basement membrane antibody disease treated with im-
munoadsorption. PLoS One. 2014;9(7):e103568.
41. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International
Chapel Hill consensus conference Nomenclature of Vasculitides.
Arthritis Rheum. 2013;65(1):1-11.
42. Geetha D, Jefferson JA. ANCA-associated vasculitis: Core Curricu-
lum 2020. Am J Kidney Dis. 2020;75(1):124-137.
43. Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood CM. Plasma
exchange in focal necrotizing glomerulonephritis without anti-
GBM antibodies. Kidney Int. 1991;40(4):757-763.
44. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of
plasma exchange or high-dosage methylprednisolone as adjunctive
therapy for severe renal vasculitis. J Am Soc Nephrol.
2007;18(7):2180-2188.
Adv Chronic Kidney Dis. 2021;28(1):59-73
71
45. Walsh M, Casian A, Flossmann O, et al. Long-term follow-up of pa-
tients with severe ANCA-associated vasculitis comparing plasma
exchange to intravenous methylprednisolone treatment is unclear.
Kidney Int. 2013;84(2):397-402.
46. Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocor-
ticoids in severe ANCA-associated vasculitis. N Engl J Med.
2020;382(7):622-631.
47. Balogun RA, Sanchez AP, Klingel R, et al. Update to the ASFA
guidelines on the use of therapeutic apheresis in ANCA-
associated vasculitis. J Clin Apher. 2020;35(5):493-499.
48. Uechi E, Okada M, Fushimi K. Effect of plasma exchange on in-
hospital mortality in patients with pulmonary hemorrhage second-
ary to antineutrophil cytoplasmic antibody-associated vasculitis: a
propensity-matched analysis using a nationwide administrative
database. PLoS One. 2018;13(4):e0196009.
49. Cervera R, Bucciarelli S, Plasin MA, et al. Catastrophic antiphos-
pholipid syndrome (CAPS): descriptive analysis of a series of 280
patients from the "CAPS Registry. J Autoimmun. 2009;32(3-4):240-
245.
50. Cervera R, Rodriguez-Pinto I, Espinosa G. The diagnosis and clin-
ical management of the catastrophic antiphospholipid syndrome: a
comprehensive review. J Autoimmun. 2018;92(Aug):1-11.
51. Rodriguez-Pinto I, Moitinho M, Santacreu I, et al. Catastrophic
antiphospholipid syndrome (CAPS): descriptive analysis of 500 pa-
tients from the International CAPS Registry. Autoimmun Rev.
2016;15(12):1120-1124.
52. Gertz MA. Acute hyperviscosity: syndromes and management.
Blood. 2018;132(13):1379-1385.
53. Treon SP. How I treat Waldenstrom macroglobulinemia. Blood.
2015;126(6):721-732.
54. Ansell SM, Kyle RA, Reeder CB, et al. Diagnosis and management
of Waldenstrom macroglobulinemia: Mayo stratification of macro-
globulinemia and risk-adapted therapy (mSMART) guidelines.
Mayo Clin Proc. 2010;85(9):824-833.
55. Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D. Cryo-
globulinemia vasculitis. Am J Med. 2015;128(9):950-955.
56. De Vita S, Quartuccio L, Isola M, et al. A randomized controlled
trial of rituximab for the treatment of severe cryoglobulinemic
vasculitis. Arthritis Rheum. 2012;64(3):843-853.
57. Siami GA, Siami FS. Current topics on cryofiltration technologies.
Ther Apher. 2001;5(4):283-286.
58. Stefanutti C, Vivenzio A, Di Giacomo S, et al. Immunoadsorption
apheresis and immunosuppressive drug therapy in the treatment
of complicated HCV-related cryoglobulinemia. J Clin Apher.
2009;24(6):241-246.
59. Adamski J. Thrombotic microangiopathy and indications for ther-
apeutic plasma exchange. Hematol Am Soc Hematol Educ Program.
2014;2014(1):444-449.
60. Sadler JE. What’s new in the diagnosis and pathophysiology of
thrombotic thrombocytopenic purpura. Hematol Am Soc Hematol
Educ Program. 2015;2015(1):631-636.
61. Joly BS, Coppo P, Veyradier A. An update on pathogenesis and
diagnosis of thrombotic thrombocytopenic purpura. Expert Rev
Hematol. 2019;12(6):383-395.
62. Brunskill SJ, Tusold A, Benjamin S, Stanworth SJ, Murphy MF. A
systematic review of randomized controlled trials for plasma ex-
change in the treatment of thrombotic thrombocytopenic purpura.
Transfus Med. 2007;17(1):17-35.
63. Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis
and management of thrombotic thrombocytopenic purpura and
other thrombotic microangiopathies. Br J Haematol.
2012;158(3):323-335.
64. Hunt BJ, Lammle B, Nevard CH, Haycock GB, Furlan M. von Wil-
lebrand factor-cleaving protease in childhood diarrhoea-associated
haemolytic uraemic syndrome. Thromb Haemost. 2001;85(6):975-978.
72 Sanchez and Balogun
65. Menne J, Nitschke M, Stingele R, et al. Validation of treatment stra-
tegies for enterohaemorrhagic Escherichia coli O104:H4 induced
haemolytic uraemic syndrome: case-control study. BMJ.
2012;345(19):e4565.
66. Colic E, Dieperink H, Titlestad K, Tepel M. Management of an
acute outbreak of diarrhoea-associated haemolytic uraemic syn-
drome with early plasma exchange in adults from southern
Denmark: an observational study. Lancet. 2011;378(9796):1089-1093.
67. Greinacher A, Friesecke S, Abel P, et al. Treatment of severe neuro-
logical deficits with IgG depletion through immunoadsorption in
patients with Escherichia coli O104:H4-associated haemolytic urae-
mic syndrome: a prospective trial. Lancet. 2011;378(9797):1166-
1173.
68. Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological
involvement in diarrhea-associated hemolytic uremic syndrome.
Clin J Am Soc Nephrol. 2010;5(7):1218-1228.
69. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic comple-
ment abnormalities in sporadic and familial aHUS and their impact
on clinical phenotype. Clin J Am Soc Nephrol. 2010;5(10):1844-1859.
70. Krishnappa V, Gupta M, Elrifai M, et al. Atypical hemolytic uremic
syndrome: a meta-analysis of case reports Confirms the Prevalence
of genetic Mutations and the Shift of treatment regimens. Ther
Apher Dial. 2018;22(2):178-188.
71. Eser B, Guven M, Unal A, et al. The role of plasma exchange in
HELLP syndrome. Clin Appl Thromb Hemost. 2005;11(2):211-217.
72. Dhakal B, Kreuziger LB, Rein L, et al. Disease burden, complication
rates, and health-care costs of heparin-induced thrombocytopenia
in the USA: a population-based study. Lancet Haematol.
2018;5(5):e220-e231.
73. Welsby IJ, Um J, Milano CA, Ortel TL, Arepally G. Plasmapheresis
and heparin reexposure as a management strategy for cardiac sur-
gical patients with heparin-induced thrombocytopenia. Anesth An-
alg. 2010;110(1):30-35.
74. Robinson JA, Lewis BE. Plasmapheresis in the management of
heparin-induced thrombocytopenia. Semin Hematol. 1999;36(1
Suppl 1):29-32.
75. Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-
Barre syndrome. Cochrane Database Syst Rev. 2017;2(2):CD001798.
76. Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group,
Randomised trial of plasma exchange, intravenous immunoglob-
ulin, and combined treatments in Guillain-Barre syndrome. Plasma
Exchange/Sandoglobulin Guillain-Barre Syndrome Trial Group.
Lancet. 1997;349(9047):225-230.
77. Okamiya S, Ogino M, Ogino Y, et al. Tryptophan-immobilized
column-based immunoadsorption as the choice method for plas-
mapheresis in Guillain-Barre syndrome. Ther Apher Dial.
2004;8(3):248-253.
78. Haupt WF, Rosenow F, van der Ven C, Birkmann C. Immunoad-
sorption in Guillain-Barre syndrome and myasthenia gravis. Ther
Apher. 2000;4(3):195-197.
79. Juel VC. Myasthenia gravis: management of myasthenic crisis and
perioperative care. Semin Neurol. 2004;24(1):75-81.
80. Mandawat A, Mandawat A, Kaminski HJ, Shaker ZA, Alawi AA,
Alshekhlee A. Outcome of plasmapheresis in myasthenia
gravis: delayed therapy is not favorable. Muscle Nerve.
2011;43(4):578-584.
81. Sanders DB, Wolfe GI, Benatar M, et al. International consensus
guidance for management of myasthenia gravis: Executive sum-
mary. Neurology. 2016;87(4):419-425.
82. Llufriu S, Castillo J, Blanco Y, et al. Plasma exchange for acute at-
tacks of CNS demyelination: predictors of improvement at 6
months. Neurology. 2009;73(12):949-953.
83. Koelman DL, Chahin S, Mar SS, et al. Acute disseminated enceph-
alomyelitis in 228 patients: a retrospective, multicenter US study.
Neurology. 2016;86(22):2085-2093.
84. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M,
Weinshenker BG. Plasma exchange for severe attacks of CNS demye-
lination: predictors of response. Neurology. 2002;58(1):143-146.
85. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prog-
nostic factors for long-term outcome in patients with anti-NMDA
receptor encephalitis: an observational cohort study. Lancet Neurol.
2013;12(2):157-165.
86. Fassbender C, Klingel R, Kohler W. Immunoadsorption for autoim-
mune encephalitis. Atheroscler Suppl. 2017;30(Nov):257-263.
87. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at
diagnosis and during follow-up of anti-NMDA receptor encephali-
tis: a retrospective study. Lancet Neurol. 2014;13(2):167-177.
88. Suppiej A, Nosadini M, Zuliani L, et al. Plasma exchange in pedi-
atric anti-NMDAR encephalitis: a systematic review. Brain Dev.
2016;38(7):613-622.
89. DeSena AD, Noland DK, Matevosyan K, et al. Intravenous methyl-
prednisolone versus therapeutic plasma exchange for treatment of
anti-N-methyl-D-aspartate receptor antibody encephalitis: a retro-
spective review. J Clin Apher. 2015;30(4):212-216.
90. Heine J, Ly LT, Lieker I, et al. Immunoadsorption or plasma ex-
change in the treatment of autoimmune encephalitis: a pilot study.
J Neurol. 2016;263(12):2395-2402.
91. Stravitz RT, Lee WM. Acute liver failure. Lancet.
2019;394(10201):869-881.
92. Saliba F, Camus C, Durand F, et al. Albumin dialysis with a noncell
artificial liver support device in patients with acute liver failure: a
randomized, controlled trial. Ann Intern Med. 2013;159(8):522-531.
93. Demetriou AA, Brown RS Jr, Busuttil RW, et al. Prospective, ran-
domized, multicenter, controlled trial of a bioartificial liver in treat-
ing acute liver failure. Ann Surg. 2004;239(5):660-667. discussion
667-670.
94. Shen Y, Wang XL, Wang B, et al. Survival benefits with artificial
liver support system for acute-on-chronic liver failure: a time
series-based meta-analysis. Medicine (Baltimore). 2016;95(3):e2506.
95. Larsen FS, Hansen BA, Ejlersen E, et al. Cerebral blood flow,
oxygen metabolism and transcranial Doppler sonography during
high-volume plasmapheresis in fulminant hepatic failure. Eur J
Gastroenterol Hepatol. 1996;8(3):261-265.
96. Wiersema UF, Kim SW, Roxby D, Holt A. Therapeutic plasma ex-
change does not reduce vasopressor requirement in severe acute
liver failure: a retrospective case series. BMC Anesthesiol.
2015;15:30.
97. Huang YK, Tan DM, Xie YT, et al. Randomized controlled study of
plasma exchange combined with molecular adsorbent re-
circulating system for the treatment of liver failure complicated
with hepatic encephalopathy. Hepatogastroenterology.
2012;59(117):1323-1326.
98. Li MQ, Li JQ, Shi ZX, et al. Efficacy of various combined blood pu-
rification techniques for treating patients with non-viral acute liver
failure. Cell Biochem Biophys. 2014;68(3):571-575.
99. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma
exchange in patients with acute liver failure: an open randomised
controlled trial. J Hepatol. 2016;64(1):69-78.
100. Chiha M, Samarasinghe S, Kabaker AS. Thyroid storm: an updated
review. J Intensive Care Med. 2015;30(3):131-140.
101. Satoh T, Isozaki O, Suzuki A, et al. 2016 guidelines for the manage-
ment of thyroid storm from the Japan thyroid association and Japan
Endocrine Society (first edition). Endocr J. 2016;63(12):1025-1064.
102. Simsir IY, Ozdemir M, Duman S, Erdogan M, Donmez A,
Ozgen AG. Therapeutic plasmapheresis in thyrotoxic patients.
Endocrine. 2018;62(1):144-148.
103. Diamond TH, Rajagopal R, Ganda K, Manoharan A, Luk A. Plas-
mapheresis as a potential treatment option for amiodarone-
induced thyrotoxicosis. Intern Med J. 2004;34(6):369-370. author
reply 370-361.
Adv Chronic Kidney Dis. 2021;28(1):59-73
 TPE in ICU
104. Ezer A, Caliskan K, Parlakgumus A, Belli S, Kozanoglu I,
Yildirim S. Preoperative therapeutic plasma exchange in patients
with thyrotoxicosis. J Clin Apher. 2009;24(3):111-114.
105. Garla V, Kovvuru K, Ahuja S, Palabindala V, Malhotra B, Abdul
Salim S. Severe hyperthyroidism complicated by agranulocytosis
treated with therapeutic plasma exchange: case report and review
of the literature. Case Rep Endocrinol. 2018;2018:4135940.
106. Gubensek J, Buturovic-Ponikvar J, Romozi K, Ponikvar R. Factors
affecting outcome in acute hypertriglyceridemic pancreatitis
treated with plasma exchange: an observational cohort study.
PLoS One. 2014;9(7):e102748.
107. Basar R, Uzum AK, Canbaz B, et al. Therapeutic apheresis for se-
vere hypertriglyceridemia in pregnancy. Arch Gynecol Obstet.
2013;287(5):839-843.
108. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ.
Two decades of mortality trends among patients with severe
sepsis: a comparative meta-analysis*. Crit Care Med.
2014;42(3):625-631.
109. Singer M, Deutschman CS, Seymour CW, et al. The Third Interna-
tional consensus Definitions for sepsis and septic shock (Sepsis-3).
JAMA. 2016;315(8):801-810.
110. Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmaphe-
resis in severe sepsis and septic shock: a prospective, randomised,
controlled trial. Intensive Care Med. 2002;28(10):1434-1439.
111. Sevketoglu E, Yildizdas D, Horoz OO, et al. Use of therapeutic
plasma exchange in children with thrombocytopenia-associated
multiple organ failure in the Turkish thrombocytopenia-
associated multiple organ failure network. Pediatr Crit Care Med.
2014;15(8):e354-e359.
112. Lima LM, McCracken CE, Fortenberry JD, Hebbar KB. Use of
plasma exchange in pediatric severe sepsis in children’s hospitals.
J Crit Care. 2018;45:114-120.
113. Rimmer E, Houston BL, Kumar A, et al. The efficacy and safety of
plasma exchange in patients with sepsis and septic shock: a sys-
tematic review and meta-analysis. Crit Care. 2014;18(6):699.
114. Chang T, Tu YK, Lee CT, et al. Effects of polymyxin B hemoperfu-
sion on mortality in patients with severe sepsis and septic shock: a
systemic review, meta-analysis update, and disease severity sub-
group meta-analysis. Crit Care Med. 2017;45(8):e858-e864.
115. Kuriyama A, Katsura M, Urushidani S, Takada T. Impact of poly-
myxin B hemoperfusion in the treatment of patients with sepsis
and septic shock: a meta-analysis of randomized controlled trials.
Ann Transl Med. 2018;6(11):206.
116. Monard C, Rimmele T, Ronco C. Extracorporeal blood purification
therapies for sepsis. Blood Purif. 2019;47(Suppl 3):1-14.
Adv Chronic Kidney Dis. 2021;28(1):59-73
73
117. Ozkale M, Ozkale Y. The role of therapeutic plasma exchange in
the treatment of childhood Intoxication: a single-center experience.
Pediatr Crit Care Med. 2020;21(11):e988-e995.
118. Nenov VD, Marinov P, Sabeva J, Nenov DS. Current applications
of plasmapheresis in clinical toxicology. Nephrol Dial Transpl.
2003;18(Suppl 5):v56-v58.
119. Samtleben W, Mistry-Burchardi N, Hartmann B, Lennertz A,
Bosch T. Therapeutic plasma exchange in the intensive care setting.
Ther Apher. 2001;5(5):351-357.
120. Wang CF, Nie XJ, Chen GM, et al. Early plasma exchange for treat-
ing ricin toxicity in children after castor bean ingestion. J Clin
Apher. 2015;30(3):141-146.
121. Disel NR, Akpinar AA, Sebe A, et al. Therapeutic plasma exchange
in poisoning: 8 years’ experience of a university hospital. Am J
Emerg Med. 2015;33(10):1391-1395.
122. Zengin S, Yilmaz M, Al B, et al. Plasma exchange as a comple-
mentary approach to snake bite treatment: an academic emer-
gency department’s experiences. Transfus Apher Sci.
2013;49(3):494-498.
123. Buttner S, Koch B, Dolnik O, et al. Extracorporeal virus elimina-
tion for the treatment of severe Ebola virus disease–first experi-
ence with lectin affinity plasmapheresis. Blood Purif. 2014;38(3-
4):286-291.
124. Koch B, Schult-Dietrich P, Buttner S, et al. Lectin affinity plasmaphe-
resis for Middle East respiratory syndrome-coronavirus and Mar-
burg virus glycoprotein elimination. Blood Purif. 2018;46(2):126-133.
125. Patel P, Nandwani V, Vanchiere J, Conrad SA, Scott LK. Use of ther-
apeutic plasma exchange as a rescue therapy in 2009 pH1N1 influ-
enza A–an associated respiratory failure and hemodynamic shock.
Pediatr Crit Care Med. 2011;12(2):e87-e89.
126. Keith P, Day M, Perkins L, Moyer L, Hewitt K, Wells A. A novel
treatment approach to the novel coronavirus: an argument for
the use of therapeutic plasma exchange for fulminant COVID-19.
Crit Care. 2020;24(1):128.
127. Keith P, Day M, Choe C, et al. The successful use of therapeutic
plasma exchange for severe COVID-19 acute respiratory distress
syndrome with multiple organ failure. SAGE Open Med Case Rep.
2020;8:2050313X20933473.
128. Khamis F, Al-Zakwani I, Al Hashmi S, et al. Therapeutic plasma ex-
change in adults with severe COVID-19 infection. Int J Infect Dis.
2020;99:214-218.
129. Faqihi F, Alharthy A, Alodat M, et al. A pilot study of therapeutic
plasma exchange for serious SARS CoV-2 disease (COVID-19): a
structured summary of a randomized controlled trial study proto-
col. Trials. 2020;21(1):506.