Apheresis Principles (April 9, 2013) - 0

Principles of Therapeutic Apheresis:
A Method to the Madness
Paul Yenson, MD FRCPC

Clinical Hematology,
Vancouver General Hospital
April 9, 2013
Tuesday, 9 April, 13
Disclosures
Unrestricted educational grant from Octapharma Canada.
Objectives
By the end of this presentation, you should be able to:
Understand an abbreviated history of therapeutic apheresis.
List 2 different methods of blood separation.
Describe the physiologic effects of therapeutic apheresis, including

anticoagulation, fluid balance, plasma dilution and cellular loss.
List the most common indications and side effects of therapeutic

apheresis.
Outline an approach to a therapeutic apheresis consultation.
Case
66yo F, end-stage liver disease secondary to primary biliary cirrhosis.
Past Hx: hypertrophic cardiomyopathy.
Patient blood group A POS.
Undergoes cadaveric liver transplant.
Apheresis Physician contacted 1 hour post-op when surgeon realizes that

liver is group AB.
Plasma exchange requested to prevent hyperacute graft rejection due to

major ABO incompatibility.
History of Apheresis
Apheresis = separation
Greek apairesos / Roman aphairesis: to take away
Process in which blood is removed from a patient and continuously

separated into component parts; allowing a component to be retained
while the remainder is returned to the patient.
The History of Apheresis
1971
1950 MD Andersen
Glass bottles performs first
replaced with peripheral blood
1960 1980s
plastic bags. stem cell collection.
1914 Schwab and Fahey
Refinements to IBM
John Abel describes machine lead to
perform plasmapheresis on
manual plasmapheresis introduction of COBE
patient with Waldenstroms
procedure in dogs. Spectra in 1987.
macroglobulinemia.
1966 1978 2013

1940-1941
Freireich performs first Membrane
Edwin Cohn develops
leukapheresis in CML patient plasmapheresis
cold ethanol fractionation
using centrifugal blood introduced as new
to produce albumin.
separator developed by IBM. method for TPE.
Isodor Ravdin uses
Plasmapheresis introduced
albumin to treat shock
as a means of collecting
at Pearl Harbor.
plasma for fractionation.
Methods of Separation
Centrifugation
VS
Membrane
Separation
Methods of Separation:
Centrifugation
Separation of blood components according to density.
HEMATOCRIT
0%
2%
3%
100%
Centrifugation
Calcium
(other fluids) Anticoagulant Waste
2
5 1 3
Centrifuge
Replacement
Fluid
Blood ECV
Warmer ~180mL
4 3
Membrane Filtration
Separation of blood components according to molecular size.
Extracorporeal blood pumped across a hollow-fibre, capillary plasma filter

with varying pore sizes.
Membrane Filtration
Hur M et al. ABO-incompatible kidney transplantation. 2011.
Therapeutic Apheresis:
Physiologic Considerations and Effects
The Importance of Factor IV
Heparin use limited by the degree of
systemic anticoagulation and
concerns regarding HIT.
With centrifuge devices, citrate is

the anticoagulant of choice.
Chelates ionized calcium thereby

blocking all calcium-dependent
steps in coagulation cascade.
Mild, transient hypocalcemia can

occur; usually well-tolerated and
responds to oral or intravenous
calcium supplementation.
Anticoagulation
Citrate is rapidly metabolized by the liver (normal levels

within 4 hours).
Hepatic dysfunction severe hypocalcemia
Citrate metabolism consumes hydrogen ions

bicarbonate production
Renal failure metabolic alkalosis
Factors affecting citrate dose/risk of toxicity:

- Duration of procedure - Rate blood is drawn from pt
- Type of procedure - AC ratio
- ?Patient weight
Fluid Balance and Shifts
Apheresis procedures cause hemodynamic changes.
{
+250
Primed fluid Rinseback

Fluid
-----------------------------------------
}
Balance 0
(mL) Initial n
io
Diversion
~ECV
infus
CD
/A
-193 l cium
Ca
Start Finish
Procedure Time
Fluid Balance and Shifts
Procedural variability:
Cytoreduction procedures have net fluid removal

(e.g. stem cell collection bag 300-400 mL)
Plasma exchange usually results in net fluid gain

(Fluid balance can be modified to a modest degree, generally 90-110%)
Granulocyte collections require use of starch (volume

expander).
Dilutional Effects on Plasma
Primarily seen with plasma exchange using 5% albumin /

crystalloid.
Removal of plasma constituents depends on extent of re-

equilibration between intravascular and extravascular
compartments:
Fibrinogen + other coagulation factors
Immunoglobulins
Enzymes (e.g. transaminases)
Electrolytes
Dilutional Coagulopathy
Fibrinogen levels reduced to 25% after single exchange; below

10% with consecutive daily exchanges. Recovery on average
by 3 days.
Coagulation factor levels drop 40-60%; most normalize within

24 hours.
Clotting assays will be abnormal following PLEX but normalize

within 24-48 hrs.
Clinically significant abnormalities in hemostasis are

uncommon.
Cellular Loss
Procedure, operator and method of separation dependent.
Intentional: platelet donation, PBSC collection, granulocyte

collection, red cell exchange.
Generally, minimal red cell loss with platelet collections and

plasma exchange.
Platelet loss can be significant with stem cell collections (up

to 50%) and to lesser degree, plasma exchange.
- Platelet recovery usually by 2-3 weeks.
Adverse Effects
Vasovagal reactions
Common; spectrum includes nausea, hypotension, syncope, convulsions.
Citrate toxicity
Hypocalcemia ( citrate dose), metabolic alkalosis.
Vascular access complications
Up to 20% of patients will require a central venous catheter (dual-lumen,

large bore = ID 1.3mm, dialysis catheter).
Hemorrhage, thrombosis, infection, pneumothorax, etc.
Adverse Effects
1995 survey of 18 apheresis centres; 3429 procedures.
Overall incidence of AEs 4.75%

1.6% Transfusion reactions (pre-leukoreduction)
1.2% Citrate toxicity
1% Hypotension (SBP <80)
1% Other vasovagal symptoms
<0.5% Respiratory distress; seizure; rigors
3 deaths, none procedure related.
McLeod et al. Transfusion 1999.
Centrifugation
VS
Membrane
Separation
Centrifugation Membrane Separation
Higher plasma extraction efficiency Lower plasma extraction efficiency
Low blood flow rate (50-100mL/min) High blood flow rate (400-600mL/min)
Peripheral (or central) venous access Central venous access
Citrate (usually) Heparin (usually)
Risk of cellular loss Risk of hemolysis
Selective cell removal Selective plasma protein removal
Specifically designed machines Use on existing dialysis machines
Therapeutic Apheresis: Why, When and How?
Apheresis Applications
1. Plasmapheresis
2. Cytapheresis Plateletpheresis Therapeutic plateletpheresis
Single donor platelet collection
Leukapheresis Leukoreduction
PBSC collection
Donor lymphocyte collection
(Granulocyte collection)
Erythrocytapheresis RBC exchange
RBC depletion
3. Photopheresis
4. Selective plasma LDL-pheresis
adsorption Staphylococcal protein A columns
Plasma Exchange:
Therapeutic Considerations
1. Is the medical condition an appropriate indication?
2. Is the patient a suitable candidate?
3. What type of vascular access is required?
4. What dose of PLEX should be prescribed?
Case
66yo F, end-stage liver disease secondary to primary biliary cirrhosis.
Past Hx: hypertrophic cardiomyopathy.
Patient blood group A POS.
Underwent cadaveric liver transplant.
Apheresis Physician contacted 1 hour post-op when surgeon realizes that

liver is group AB.
Plasma exchange requested to prevent acute graft rejection.
Therapeutic Plasma Exchange (TPE)
Rationale for therapeutic plasma exchange
1) Removal of pathogenic antibody.

(autoAb, alloAb, monoclonal protein)
2) Removal or alteration of immune complexes.
3) Removal of toxin / compound / lipid.
4) Replacement / infusion of a plasma component.
Therapeutic Plasma Exchange:
Indications
Paucity of evidence to support the use of plasma

exchange in many conditions.
Difficulties with randomized assessments: require sham

exchanges to control for placebo effect.
PLEX often used as last ditch maneuver in sick patients.
Anectodal reports of success set precedent for use.
Plasma Exchange:
McLeods Criteria
Plausible The current understanding of the disease
Pathogenesis process supports a clear rationale for the
use of therapeutic apheresis (TA).
Better Blood The abnormality, which makes TA plausible,
can be meaningfully corrected by its use.
Perkier Patients There is a strong evidence that TA confers

benefit that is clinical worthwhile and not
just statistically significant.
McLeod BC. J Clin Apher 2002.
ASFA Guidelines (J Clin Apher 2010)
Category I: Standard and acceptable therapy, generally based on randomized

controlled trials or a broad, non-controversial base of published experience.
Category II: Generally accepted in a supportive role, occasionally supported

by a randomized controlled trial.
Category III: Suggestion of benefit for which existing evidence is insufficient.
Category IV: No benefit by randomized controlled trial or anecdotal reports

have been discouraging.
Category I Indications for Therapeutic Apheresis
Plasmapheresis Cytapheresis
Thrombotic thrombocytopenic purpura Hyperleukocytosis syndrome
Guillain-Barre Syndrome Sickle cell disease (life-threatening complications)
Chronic inflammatory demyelinating polyneuropathy ABO mismatched marrow transplant
Demyelinating polyneuropathy with IgG and IgA Cutaneous T-cell lymphoma, erythrodermic (ECP)
Myasthenia gravis Heart transplant rejection prophylaxis (ECP)
Anti-GBM disease
Hyperviscosity syndrome in monoclonal gammopathies
Cryoglobulinemia
Familial hypercholesterolemia (selective adsorption)
PANDAS
Category II Indications for Therapeutic Apheresis
Plasmapheresis Cytapheresis
ABO incompatible alloSCT Malaria / babesiosis
ABO incompatible solid organ transplant Polycythemia vera
Wegeners granulomatosis Acute and chronic GVHD (ECP)
Familial hypercholesterolemia (heterozygote) Essential thrombocytosis
Heart transplant (treatment of rejection)
Eaton-Lambert Syndrome
Multiple sclerosis (acute CNS relapse)
Phytanic acid storage disease
Rasmussens encephalitis
Red cell alloimmunization in pregnancy
Renal transplant AMR and HLA desensitization
Most Common Indications
(CAG 2010)
Diagnosis n
TTP-HUS 211
Myasthenia gravis 179

Chronic inflammatory demyelinating
81
polyneuropathy
Renal transplant AMR 35
Hyperviscosity syndrome 19
Neuromyelitis optica /transverse myelitis 15
Plasma Exchange:

- Cardiorespiratory status?
- Fluid balance?
- Liver or renal failure?
- Coagulopathy
- Medications (antihypertensives, anticoagulation)
Plasma Exchange:
Vascular Access
Resistance Viscosity x Length

Radius4
Peripheral Central
Short (3 inches) 1. Dialysis catheter (large diameter)
2. Central venous catheter

3. Implanted ports
4. PICC
Plasma Exchange:
Therapeutic Plasma Exchange (TPE)
Efficacy of TPE depends on:
1) Volume of plasma removed relative to total plasma volume.
2) Distribution of substance to be removed between

intravascular and extravascular compartments.
3) Re-equilibration rate between compartments.
Plasma Volume
What is a plasma volume Plasma Protein Removal

and how do you estimate it? 100
90
Mean TBW = 70kg 80
70
Estimated TBV = 70mL/kg 60
50
TBV = 70mL/kg x 70kg
40
= 4900mL
30
PV = TBV x (1-Hct) 20
= 4900mL x (1-0.40) 10
= 2940mL 0
0 0.5 1.0 1.5 2.0 2.5 3.0
Plasma Volume
Protein Kinetics
Protein Intravascular Component (%)

IgM 76%
IgG 45%
Albumin 40%
/ Light chain 15%
IgM is removed more efficiently than IgG; both re-equilibrate within 24-48 hrs
To effectively deplete total body IgG by ~85% requires 5 exchanges q2 days; only
2-3 exchanges for IgM.
Effect of plasma exchange is temporary (T of normal IgG ~21 days, IgM 7-10
days)
Replacement Fluid
Category Product Indication

Plasma Frozen plasma TTP, bleeding or periop patients
Solvent-detergent plasma TTP/HUS, RIBD w/ allergy, pre-
existing lung d/o, ?AB blood group.
Cryosupernatent plasma TTP
Colloid 5% albumin All others
Starches ?Jehovahs Witness
(e.g. Voluven, Pentaspan)
Crystalloid Normal saline
Ringers lactate
512 512
PE 1.0 plasma volume
AB plasma 5% albumin
ATG ATG ATG ATG ATG
Intraprocedural Ca2+ levels
PE PE PE PE PE PE PE IVIG IVIG
256
Anti-B IgM
Anti-B IgG
192
128
64
0
20 21 22 23 24 25 26 27 28 29 30 1 2 3 4 5 6 7 8 9 10
TACROLIMUS, MYCOPHENOLATE, PREDNISONE
September October
Summary
Therapeutic apheresis is performed via either centrifugation or membrane

separation with the principle advantage being selective cellular vs protein
removal respectively.
The primary physiologic effects of therapeutic apheresis include citrate

anticoagulation, fluid balance, plasma dilution and potential for cellular loss.
The most common indications in Canada include TTP/HUS, myasthenia

gravis and CIDP.
The most common side effects include vasovagal reaction, citrate toxicity
(hypocalcemia) and tranfusion reactions.
An Approach to the Therapeutic Apheresis Patient
Thank you! Questions?

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Principles of Therapeutic Apheresis:

A Method to the Madness

Paul Yenson, MD FRCPC

Unrestricted educational grant from Octapharma Canada.

By the end of this presentation, you should be able to:

Understand an abbreviated history of therapeutic apheresis.

List 2 different methods of blood separation.

Describe the physiologic effects of therapeutic apheresis, including

List the most common indications and side effects of therapeutic

Outline an approach to a therapeutic apheresis consultation.

66yo F, end-stage liver disease secondary to primary biliary cirrhosis.

Past Hx: hypertrophic cardiomyopathy.

Patient blood group A POS.

Undergoes cadaveric liver transplant.

Apheresis Physician contacted 1 hour post-op when surgeon realizes that

Plasma exchange requested to prevent hyperacute graft rejection due to

Greek apairesos / Roman aphairesis: to take away

Process in which blood is removed from a patient and continuously

1966 1978 2013

Separation of blood components according to density.

Separation of blood components according to molecular size.

Extracorporeal blood pumped across a hollow-fibre, capillary plasma filter

Hur M et al. ABO-incompatible kidney transplantation. 2011.

With centrifuge devices, citrate is

Chelates ionized calcium thereby

Mild, transient hypocalcemia can

Citrate is rapidly metabolized by the liver (normal levels

Citrate metabolism consumes hydrogen ions

Renal failure metabolic alkalosis

Factors affecting citrate dose/risk of toxicity:

Apheresis procedures cause hemodynamic changes.

Primed fluid Rinseback

Cytoreduction procedures have net fluid removal

Plasma exchange usually results in net fluid gain

Granulocyte collections require use of starch (volume

Primarily seen with plasma exchange using 5% albumin /

Removal of plasma constituents depends on extent of re-

Fibrinogen + other coagulation factors

Enzymes (e.g. transaminases)

Fibrinogen levels reduced to 25% after single exchange; below

Coagulation factor levels drop 40-60%; most normalize within

Clotting assays will be abnormal following PLEX but normalize

Clinically significant abnormalities in hemostasis are

Procedure, operator and method of separation dependent.

Intentional: platelet donation, PBSC collection, granulocyte

Generally, minimal red cell loss with platelet collections and

Platelet loss can be significant with stem cell collections (up

Common; spectrum includes nausea, hypotension, syncope, convulsions.

Hypocalcemia ( citrate dose), metabolic alkalosis.

Vascular access complications

Up to 20% of patients will require a central venous catheter (dual-lumen,

Hemorrhage, thrombosis, infection, pneumothorax, etc.

Overall incidence of AEs 4.75%

3 deaths, none procedure related.

McLeod et al. Transfusion 1999.

Centrifugation Membrane Separation

Higher plasma extraction efficiency Lower plasma extraction efficiency

Peripheral (or central) venous access Central venous access

Citrate (usually) Heparin (usually)

Risk of cellular loss Risk of hemolysis

Selective cell removal Selective plasma protein removal

Specifically designed machines Use on existing dialysis machines