American Society for Apheresis

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American Society for Apheresis
(ASFA)
Therapeutic Apheresis Waldenstroms
macroglobulinemia Cryoglobulinemia Post
Transfusion Purpura
A. Sergio Torloni MD Medical Director Transfusion
Services Therapeutic Apheresis Inova Fairfax
Hospital Falls Church - Virginia
sergio.torloni_at_inova.com
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Hyperviscosity
Hyperviscosity Syndromes

• Waldenstroms Macroglobulinemia
• Cryoglobulinemias
• Monoclonal Gamopathies (rare)
• Rheumatoid Arthritis

Viscosity resistance to the flow of a liquid
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Fluid Dynamics Compartments
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Fluid Dynamics made Simple
Capillary pressure
I
O
Plasma Oncotic Pressure
Interstitial fluid pressure
Interstitial fluid oncotic pressure
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Fluid Dynamics made Simple
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Capillary pressure
Interstitial fluid pressure
7
Interstitial fluid oncotic pressure
4.5
28.5
(outwards)
Plasma Oncotic Pressure
(inwards)
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Plasma Exchange Mathematical Models
Lymphatics
Immunoglobulins
INTRAVASCULAR
Interstitial
Catabolism
Intracellular
Modified from Weinstein, ApheresisPrinciples
and Practice- AABB press
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Hyperviscosity Protein Electrophoresis
Scanned Strip
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Hyperviscosity Protein Electrophoresis
Serum Protein Electrophoresis
Monoclonal Spike
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IgG 300 KDa
IgM 900KDa
Torlonib 2000 8
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Waldenstroms IgM
Torlonib 2000 9
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Hypervicosity Plasma Proteins
Protein mg/dl kDa IV
FCR TER
( /hr)
IgG 12.1 150 45 6.7
3 IgA 2.6 (160) 42 25
IgM 0.9 950 76 18
1-2 IgD 0.02 175 75 37 IgE
0.0001 190 41 94
FCR Fractional catabolic rate ( /day)
TER Transcapillary Escape Rate
From Principles of Apheresis, p266 AABB Press,
1997
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Waldenstroms Macroglobulinemia
A low grade, indolent lymphoma, characterized
by hyperproduction of IgM
CANCER FACTS National Cancer Institute National
Institutes of Health
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colloid-osmotic pressure
Intravascular Space
Extravascular Space
Torloni MD 2000 13
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Extravascular water
is drawn into the intravascular space
Torloni MD 2000 14
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Hyperviscosity Syndrome
Very High Plasma Protein Concentration

• Increased Resistance to Flow
• Ischemia
• Increased demand on CV system

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Hyperviscosity Syndrome
Symptoms
When do they occur ?

• When Viscosity is 4 x that of water

• Increased Plasma Volume
• CHF
• Vascular Resistance
• Neurologic
• Bleeding diathesis
• Retinopathy

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RBC deformability
NORMAL
Waldenstrom ( deformability )
Erythrocyte deformability in Waldenstrom's
macroglobulinemia Clin Hemorheol Microcirc
200022(1)17-20
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Waldenstroms Role of Aphreresis
Goal
Rapidly correct plasma viscosity and bleeding
diathesis
When should TPE be done ?
Risk of Stroke
Arboix A Besses C Cerebrovascular disease as
the initial clinical presentation of
haematological disorders. Eur Neurol
199737(4)207-11
Risk of Retinal complications
Avashia JH Fath DF Bilateral central retinal
vein occlusion in Waldenstrom's
macroglobulinemia. J Am Optom Assoc 1989
Sep60(9)657-8 Thomas EL, Olk RJ, Markman M,
Braine H, Patz A Irreversible visual loss in
Waldenstrom's macroglobulinaemia. Br J
Ophthalmol. 1983 Feb67(2)102-6.
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TPE Efficacy of Removal of Immunoglobulins
One 4 - 5 liter exchange.
Relief of symptom is usually achieved with
removal of 1-3 liters in many patients.
Beck et al Transfusion 198222 51-3
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Replacement Fluid(s)
Protein mg/dl kDa IV
FCR TER
IgM 0.9 950 76 18 1-2
Free water pulled into vessel
Free water pulled out of vessel
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REPLACEMENT FLUID(S)
5 Albumin alone or 5 Albumin Crystalloid
Frequency of Exchange
1 to 2 procedures ( 1 or 1.5 BV) will return
viscosity to WNL May have to repeat if therapy
is delayed and / or not effective (Taylored to
patients needs)
Grima, J. Clin Apheresis, vol 1 -2000 48-50.
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Waldenstroms TPE Category I

• Actual Plasma volume ? Calculated Plasma Volume
• If replacing with 5 albumin, replaced volume
  should be slightly less than
• volume removed
• Monitor Fluid Balance

( Albumin is slightly hyperosmotic )
Pay very close attention to Blood Pressure during
the procedure and afterwards !
( Be ready to bolus with Albumin if necessary )
GOAL of Exchange Relief of symptoms ( NOT
CURATIVE !)
Frequency 1 - 2 exchanges, sometimes
more Volume 1 Plasma Volume
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Cryoglobulinemia
Definition
Immunoglobulins that precipitate in the cold and
dissolve on rewarming.
P r e c I p I t a t I o n
37C
4C
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Cryoglobulinemia
Types of Proteins
C - Reactive Protein- Albumin complexes Cryofibrin
ogen Immuneglobulins
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Cryoglobulinemia
Cryoglobulins
Type I Single Monoclonal Type II Mixed
Monoclonal / Polyclonal Type III Mixed
Polyclonal
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Cryoglobulinemia
When do symptoms manifest ?
From Rossi EC et al Principles of Transfusion
Medicine, 2nd Ed. p573 William Wilkins Publishers
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Cryoglobulinemia
Type
Composition
Diseases
B - Cells Dyscrasias
IgM IgG IgA
I
Myeloma Waldenstroms CLL Hairy Cell
Leukemia Angioimmunoblastic Lymphadenopathy
Single Immunoglobulin
Monoclonal light chains
B - Cells Dyscrasias
IgM - IgG IgG - IgG IgA - IgG
II
Myeloma Waldenstroms CLL Mixed Essential
Cryoglobulinemia
Mixed Monoclonal Immunoglobulins
HAPS Education Resources www.haps.nsw.gov.au/educa
tion/newletters/cryoglobulins.html
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Cryoglobulinemia
Type
Composition
Diseases
Autoimmune Diseases
III
IgM - IgG IGM -IgG- IGA
SLE RA Sjogrens Syndrome Chronic Active
Hepatitis Primary Biliary Cyrrhosis
Mixed Monoclonal Immunoglobulins
Infections
EBV CMV Hepatitis Leprosy Lyme Disease Syphillis I
nfective Endocarditis Post- Strep. GN
HAPS Education Resources www.haps.nsw.gov.au/educa
tion/newletters/cryoglobulins.html
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Cryoglobulinemia Type II III
Most type II III are due to immune response
to Hepatitis C
1/3 Type II 2/3 Type III
127 patients with HCV 54 had
cryoglobulins
Lunel et al Cryoglobulinemia in Chronic Liver
Disease Gastroenterology 1994106 1291-6
Y


Anti HCV
IgM
HCV RNA
Cryoglobulin
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Cryoglobulinemia
Presentation
Cutaneous lesions 80 Vascular
Purpura 60 Distal Necrosis 14 Urticaria 10
Leg Ulcers 5 Raynauds phenomenon
50 Acrocyanosis 10 Arthralgia
35 Nephritis 20 Neurologic
17 Haemorrahge 7 Abdominal pain
2 Arterial thrombosis 1
HAPS Education Resources www.haps.nsw.gov.au/educa
tion/newletters/cryoglobulins.html
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Cryoglobulinemia
Findings
Type I
Type II III
HAPS Education Resources www.haps.nsw.gov.au/educa
tion/newletters/cryoglobulins.html
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Cryoglobulinemia
Effects of TPE
1) Rapidly reduces levels of circulating Ab,
IC, Inflammatory mediators 2) Removal of IC
can restore fx of RE system 3) Modifies size and
distribution of IC (inhibits immuneprecipitation)
4) Modifies quality of IC ( pre TPE ? post TPE)
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CASCADE FILTRATION
NOT USED IN THE U.S
From Valbonesi,et al Cascade Filtration
clinical application in 26 patients with
immune complex and IgM mediated diseases
Int. J. of Artif. Organs 6 6 1983
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Plasma in
CASCADE FILTER
YYYYYYYYYYYYYYYYYYYYYYY
YYYYYYYYYYYYYYYYYYYYYYY
Back to Patient
Pore size 0.01 - 0.02 micron

Albumin, IgA, IgG




IgM Lipoproteins Fibrinogen
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CRYOFILTRATION
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CRYOFILTRATION
The cryofilter and tubing before use top, and
after collecting cryoglobulins from the plasma
bottom.
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Cryoglobulinemia TPE
Manual exchange !

• Use 1000cc thoracic drain bottles or other
  calibrated container
• Draw appropriate volume
• Replace equal volume
• KEEP VERY ACCURATE TRACK OF EXCHANGE

Advantages Achieves relief of
symptoms Disadvantages - Very long procedure
. - Labor intensive .
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Post Transfusion Purpura
A mystery of alloimmunization
Pl-A2
Bak
Pl-A1
Pen
HLA
Autoantibody ?
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Post Transfusion Purpura
Mechanism ( how it should be)

• Majority of population is Pl-A1 positive
• Majority of donors are Pl-A1 positive
• Pl-A1 is a soluble antigen
• Pl-A1 negative individuals will receive PL-A1
  positive products
• Pl-A1 is recognized as a foreign and antibody is
  produced
• Antibody binds to PL-A1 antigen
• Pl-A1 antigen is removed from circulation

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Post Transfusion Purpura
Mechanism how it really is
Pl-A1 neg
Pl-A1 neg
Pl-A1 neg
Soluble Pl-A1 antigen
Recipients platelets (Pl-A1) negative
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Post Transfusion Purpura
Pl-A1 neg
Pl-A1 neg
Pl-A1 neg
2- Soluble Pl-A1 ag binds to patients Pl-A1
negative platelets...
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Pl-A1 neg
4- antibody binds to Pl-A1
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Pl-A1 neg
Pl-A1 neg
5- antibody coated platelets are removed by R.E.S
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Pl-A1 neg
Pl-A1 neg
Pl-A1 antigens re-circulates !
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Pl-A1 neg
Pl-A1 neg
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PTP Therapy
IVIG - Works well and rapidly
TPE

• Platelet counts usually 24 - 48 hours after
  TPE
• Works well ( 1-5 days post TPE)

How often ?

• Start promptly
• Daily or QOD exchanges till platelet count is
  greater than 20 K
• Replace with Albumin / Saline mixture (may add
  FFP)

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The End