Therapeutic Plasma Exchange

Ovidiu Bedreag
UMF ”V. Babes” Timisoara

Chisinau, 24 nov 2022

© 2008, Gambro
Definitions
Apheresis:
- refers to a procedure by which plasma or cellular components
are separated from circulating whole blood.

• Donor Apheresis
Used for the preparation of transfusion products.

• Therapeutic Apheresis
Used for the treatment of diseases.

© 2008, Gambro
Two techniques of Aphaeresis

Centrifugation Plasmafiltration

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Definitions

Plasmapheresis:
- Separation of plasma from whole blood.

Plasma exchange:
- procedure in which the patient’s plasma is separated from
whole blood. The removed plasma is replaced on a 1:1 ratio by a
replacement solution of same osmotic pressure as plasma. The red
blood cells; white blood cells, and platelets are returned to the
patient.

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 Definitions:

Cytapheresis:
- selective removal of cellular components from the
blood (RBC’s, WBC’s, Platelets)

• Leukocytapheresis: separation and removal of WBC’s.

• Thrombocytapheresis: separation and removal of
platelets.
• Erythrocytapheresis: separation and removal of RBC’s.

© 2008, Gambro
TPE – membrane filtration technique

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 Filtration
Blood In

Effluent
• Use semi permeable
Out membrane to separate the
smallest component (plasma)
from larger one (cells)

• A negative pressure is applied

Plasma out
via the effluent pump to
remove plasma from the blood
side of the membrane.
Blood Out
© 2008, Gambro
 Filter Specification
Specification TPE CRRT
• Molecular Wt. Cut-off 3 million Daltons 30,000 Daltons

• Hollow Fibers 3,000 6,000

• Membrane Semi-permeable Semi-permeable

• Maximum Pore size 0.5 um <0.01 um

•
• Circuitry differences • No dialysate line • Dialysate line in
• Replacement line given place
post-filter • Replacement line
• Extra fluid line attached usually given pre-filter
to access line.
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 Therapeutic Plasma Exchange

• Simple plasma exchange by single

membrane filtration…
=Plasma
membrane
Whole blood

Packed Cells

© 2008, Gambro
 Factors affecting plasma removal

Plasma removal is affected by: Qb, Hct, Pore Size, TMPa

=Plasma effluent
Pore Size

membrane
Qb 100-150 Cell rich
blood
Hct 25-45%
membrane

TMPa < limit depending on QB

© 2008, Gambro
Membrane / pore size Platelets ~ 3 µm
RBC~ 7 µm
Lymphocytes ~ 10 µm
Membrane pore size : 0.5 µm Granulocytes ~ 13 µm

Red Blood cells

150µm

2.0µm 7.5µm

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Molecular Weights
1,000,000 – 3,000,000 Molecules target for TPE

}
100,000
50,000 • Albumin (55,000 - 60,000)

“large”
•

}
Beta 2 Microglobulin (11,800)
10,000
5,000 • Inulin (5,200)
molecular weight,
Daltons
1,000 • Vitamin B12 (1,355)
“middle”
500 • Aluminum/Desferoxamine Complex (700)

}
• Glucose (180)
100 • Uric Acid (168)
• Creatinine (113)
• Phosphate (80)

50 • Urea (60)
“small”
• Potassium (35)
• Phosphorus (31)
10 • Sodium (23)

5
0

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Indications for TPE (1)
• Guillain-Barre
• Remove antibodies • MG
• Lambert-Eton Syn.
• Goodpasture’s Syn.

• Removal of immune
complexes • S.Lupus Eryth.
• Rheumatoid vasculitis
• Removal of inflammatory
mediators
• Goodpasture’s Syn.
• Sepsis

© 2008, Gambro
Indications (2)

• Replacement of • Thrombotic
plasma thrombocytopenic
purpura (TTP)
deficiencies

• Removal of plasma • Poisons

constituents • Protein-bound drugs

© 2008, Gambro
 Principles of Treatment
1. Therapy should almost always include
immuno – suppression
(i.e. Cortico steroid treatment).
- this will reduce the rate of resynthesis of pathologic antibodies production.

2. Diseases that respond to TPE should be treated early to halt

inflammatory response that often contributes to the disease progression.
- (i.e. TPE of anti – GMB disease is most effective if therapy is initiated
when the patient’s serum Creatinine is less than 381 mmol/L (5 mg/dl).

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 Principles of Treatment

3. Knowledge of the Kinetics of immunoglobulin removal;

a. Immunoglobulins have a long half life;

- 21 days for IgG
- 5 days for IgM

- The plasma half life will determine how quickly the plasma level of the
pathogen will rebound and how often subsequent TPE sessions will
have to be performed

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 Principles of Treatment

3. Knowledge of the Kinetics of immunoglobulin removal;

b. Immunoglobulins have substantial extravascular distribution. The

extent of intravascular vs. extravascular distribution – this will
determine how effectively they can be removed in the course of
single TPE session.

Example:

Extravascular Distribution of IgG = 50%

IgM = 20%
Therefore; depletion of IgM occurs more quickly than that of IgG.

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 Important Point!

• TPE performed with a CRRT filter would be ineffective.

• CRRT performed with dedicated TPE filter would be life
endangering due to constant albumin loss without
replacement.

For safety reasons;

• Prisma “Set Recognition” test will induce warning.
• TPE has RED safety warning sheet covering the filter.

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Physicians Order

• Vascular Access
• Plasma Volume Exchange
• Number of Exchanges
• Determination of TBV and PV
• Pre-treatment Hematocrit
• Anticoagulation
• Replacement fluid
• Machines settings

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 Components of Therapy
• Calculating the Plasma Volume to be removed.
• Replacement Solution
• Anticoagulation
• Vascular Access
• Warming Device

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 Estimated Plasma Volume (PV) to exchange:

• Use nomogram and equations using height, weight and

hematocrit in the literature;

• Useful Rule of thumb is to consider Plasma Volume (PV) to be

approximately: 40 ml/kg of body weight.
Example:
70 kg patient, the PV would be;
70 kg x 40 ml/Kg = 2800 ml or 3000 ml.

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Estimated Plasma Volume (PV) to exchange:

Another Formula:

Total Blood Volume (TBV) = Pt’s Wt. In Kg x 70 ml/kg

Plasma Volume (PV) = TBV x (100 – Hct.%)

Example: 70 Kg patient, Plasma Volume would be;

TBV = 70 Kg x 70 ml/Kg = 4900 ml

PV = 4900 ml x (100 – 41%) = 2891 ml or 3000 ml.

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How to Calculate Plasma Volume:

Step 2: Calculate the amount of plasma to

exchange/replace.
= Plasma Volume x Number of exchanges

Ex: 4060 ml x 1.5 (or 150%) = 6090 ml

Total plasma volume to exchange :

6090 ml.

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Estimated Plasma Volume (PV) to exchange:

Physician’s Order;
1.0 or 1.5 Plasma Volume to be
Exchanged
For a 70 Kg patient;

A 1.0 or 100% PV exchange would

be 3000 ml.
A 1.5 or 150% PV exchange would
be 4500 ml.

Ensure that you follow the physician’s

order for PV to be exchanged.

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 Exchange orders
Number of Exchanges based on diseases process and
goals

1 X PV removes 50-65 % of plasma concentration of the targeted

substance
2 X PV removes 85 % of plasma concentration of the targeted substance
3 X PV removes 95 % of plasma concentration of the targeted substance

Typically Exchange of Plasma Volume =

1.4

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Vascular Access for adequate BFR

Blood Flow Rate : 1 ½ - 2 X patient weight

Eg. 70Kg X 2 = 140 mL/min

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Anticoagulation

HEPARIN
In general, plasmafiltration devices use heparin

CITRATE
Centrifugal devices most commonly operate with citrate.

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 Heparinization
• Much larger amount of heparin required for TPE than in CRRT.
• Dose should be sufficient to double the activated clotting time
(ACT) or (APTT)
• It is recommended to add Heparin to priming solution, if not
contraindicated.
• The recommended dosing for Bolus: 40 u/Kg of BW.
• Continuous infusion rate: 20 u/Kg of BW.

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 Heparinization
Monitoring the Heparin:

1. Activated Clotting Time (ACT)

Normal Value: <100 sec
Target range: 1.5 to 2.0 X the pre procedure ACT (150-220)

2. Activated Partial Thromboplastin Time (aPTT)

Normal Value: 45 to 70 sec
Target range: 1.5 to 2.0 X the normal values.

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Replacement Fluids

Restore Volume
Restore Oncotic Pressure
Restore Protein Concentration
Supply Coagulation Factors
Supply Immunoglobulins

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 Colloid Solutions - Albumin (5%)
 used in most plasmapheresis procedures
5% albumin provides adequate osmotic pressure

Advantages Disadvantages

• Occasional hypotension, bradykinin like reaction

• Most commonly used
• Safe (no viral transmission)
• Less expensive than FFP
• Maintains stable blood volume
• Pulmonary oedema following rapid increase in
albumin
• Post treatment coagulopathy related to removal
of clotting factors
• Loss of immunoglobulins

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 Colloid Solutions - Fresh Frozen
Plasma (FFP)
 when coagulation factors have been reduced more than 20% of normal value,
when fibrinogen level is low (<125mg/dl) or when platelet count is reduced

Advantages Disadvantages

• Replaces plasma clotting • Anaphylactoid reactions

factors • ABO matching
• No post-pheresis coagulopathy • Viral transmission (rare)
• No immunoglobulin deficiencies • Citrate toxicity
• Expensive

 Indicated for treatment of TTP and HUS

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 Medications and TPE
ACE Inhibitor:

• Patients receiving ACE Inhibitor with Albumin as replacement are at high risk
for anaphylactic or atypical reactions such as; flushing, hypotension,
bradycardia and dyspnea.
• Fragments of Prekallikrein – Activating Factor present in human albumin leads
to bradykinin release.
• Severity of reactions depends on different variables, including drug type and
lot of albumin.

• Recommended that ACE Inhibitors be withheld for at least 24 - 48

hours prior to TPE procedure.

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 Medications and TPE

Lasix:

• Avoid the use of diuretics just prior to and during TPE as this will
change the patient’s hematocrit value (Increased).

• Changed the estimated PV.

• Whenever possible, all medications should be administered after TPE.

(Follow physician’s order).

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Diseases treated by TPE…

Removal of antibodies Guillain-Barre

Myasthenia Gravis
Lambert-Eton Syn.
Goodpasture’s Syn.

Removal of immune Systemic Lupus

complexes Erythematosus.
Rheumatoid Vasculitis

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Diseases treated by TPE…

Removal of inflammatory Sepsis

mediators Goodpasture’s Syn.
Transplant Rejection????

Replacement of plasma Thrombotic thrombocytopenic

deficiencies purpura (TTP)

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Diseases treated by TPE…

Removal of other plasma Poisons

constituents Protein-bound drugs

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The American Society for Apheresis evidence-based guidelines Category
I

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Diseases treated by TPE:

A. Category I – considers that TPE is proven effective therapy;

1. Guillain – Barre Syndome

2. Good Pasture’s Syndrome
3. Cryoglobulinemia
4. Hyperviscosity Syndrome
5. Thrombotic Thrombocypenic Purpura (TTP)
6. Myasthenia gravis

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The American Society for Apheresis evidence-based guidelines Category II

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Diseases treated by TPE:

B. Category II – considers that TPE is on second line of therapy

1. Drug Overdose and Poisoning
2. Hemolytic Uremic Syndrome
3. Systemic Vasculitis
4. Systemic Lupus Erythematosus
5. Rapid Progressive Glomerulonephritis

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Diseases treated by TPE:

C. Category III – considers inconclusive evidence;

1. Multiple Sclerosis
2. Progressive Systemic Sclerosis
3. Warm Autoimmune Hemolytic Anemia
4. ABO Incompatibilities
5. Coagulation Factor Inhibitors

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Diseases treated by TPE:

D. Category IV – lack of conclusive evidence

1. Auto Immune Deficiency Syndrome
2. Aplastic Anemia
3. Rheumatoid Arthritis
4. Fulminant Hepatic Failure
5. Renal Transplant Rejection

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 Category I: TTP/HUS
(Thrombotic Thrombocytopenic Purpura)

Thrombotic thrombocytopenic purpura/Hemolytic

Uremic Syndrome
Comprises about 27% of TPE treatments
Characterized as platelet aggregation in the
microcirculation, leading to organ dysfunction
Caused by release of abnormally large chains of
von Willebrand factor (vWF)
TPE goal: replace platelets and reductase
enzyme, which reduces large vWF to their
normal size

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Category I: Myasthenia Gravis

Comprises approximately 15% of TPE treatments, includes

Lambert-Eton Syndrome
Characterized by muscle weakness caused by IgG antibodies
which attack the acetylcholine receptor molecule (AchR).
Considered fatal in the past
TPE goal: Remove IgG antibodies

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Neurotransmission…

Normally, ACh will

attach, here.

IgG antibodies attack the receptor molecule on

the cell membrane, so ACh may not attach itself.

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 Category I: Guillain-Barre Syn.
And CIDP
Characterized by weakness and paralysis of lower
limbs, which may spread to arms, face, and
respiratory system.
The most common cause of acute paralysis in the USA
and Europe.
Mortality rate is about 5%.
Caused by antibodies that attack the myelin sheath
of nerves, preventing nerve conduction.
TPE goal: remove antibodies GM1 and anti-alpha-
GQ1b.

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Guillain-Barre Syndrome
(GBS) and
Chronic Inflammatory
Demyelinating Poly-
Neuropathy (CIDP)

Autoantibodies
attack myelin
sheath and nerve
impulse is unable to be
conducted.

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 Category III: Drug overdose and poisoning

Effective in removing highly protein-bound

toxins
Limitations to removal:
> Agents are not lipid soluble or tissue-
bound
> Agents have a low volume of distribution,
outside of the bloodstream.

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Highly protein-bound drugs or drugs
removed efficiently by TPE

Antimicrobials: Anticoagulants: Miscellaneous:

Doxycycline Coumadin Dephenhydramine
Clindamycine Dicumarol Clofibrate
Cardiac: Anticonvulsants: Amanita (mushroom)
Digitoxin Phenytoin Sodium Chlorate
Chemotherapeutics: Valproic Acid Methylparathion
Cisplatin Hypoclycemics: Paraquat
Vincristine Glyburide Barbiturates
Diuretics: Anti-inflammatories: Chloredecone
Acetazolamide Phenylbutazone Aluminum
Furosemide Indomethacin Tricyclic antidepressant
Chlorthalidone Fenoprofen Benzodiazepines
Metolozone Ibuprofen Quinine
Naproxen

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Therapeutic plasma exchange key messages

1 TPE is recommended as part of a first-line treatment strategya for a number of diseases and conditions

TPE is associated with positive clinical outcomes in the treatment of Guillain–Barré syndrome, TTP, MG, and
2 Goodpasture’s syndrome

3 TPE using membrane filtration has a known safety profile

Membrane TPE can be delivered using existing infrastructure to help reduce the need for additional training
4 and investment

Membrane TPE is associated with similar patient outcomes at lower direct costs compared with IVIg in the
5 treatment of patients with Guillain–Barré syndrome

Abbreviations: ASFA, American Society for Apheresis; IVIg, intravenous immunoglobulin; MG, myasthenia gravis; TPE, therapeutic plasma exchange;
TTP, thrombotic thrombocytopenic purpura.
a
As per ASFA guidance, please refer to Schwartz J, et al. J Clin Apher. 2016; 31:141–338 for details and recommendations, as well as relevant country-specific guidance. Accepted as first-line therapy, either as the primary standalone treatment or in conjunction with other modes of treatment.

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