The Rationale for
Therapeutic Plasma Exchange
Stuart L. Goldstein, MD
Professor of Pediatrics
Baylor College of Medicine
Medical Director, Renal Dialysis and Pheresis Service
Texas Children’s Hospital
Houston, Texas
Outline
• Principles of TPE
– Centrifugal TPE
– Membrane TPE
• What rationale exists for TPE?
– When should TPE be considered
– AABB, ASFA classifications
• Specific disease entities
Membrane vs. Centrifugation
• In the US, most TPE is performed by
centrifugation.  One machine can do
all apheresis procedures.
• Double filtration method: first membrane
separates plasma from cellular portion
and second membrane separates
globulin from albumin.
Blood Components Separated by Centrifugation
Platelets
Plasma
Lymphocytes
Monocytes
Granulocytes
Neocytes
Erythrocytes
Plasma Exchange
TPE: Available techniques
techniques...
• Cascade or secondary filtration: Separated
blood is perfused through a plasma filter (1)
to remove certain plasma elements. The
second column (2) (cascade) absorbs the
element and the plasma is returned to the
patient.
1
2
PATIENT
Plasma removal is affected by:
• Qb
• Hct
• Pore Size
• TMP
=Plasma effluent
Qb 100-150
Hct 25-45%
Pore Size
TMP <50 mmHg
Efficiency of removal is greatest early in the procedure and
diminishes progressively during the exchange
Plasma Volume Exchange
Plasma Volume
Exchange
0
0.5
1.0
1.5
2.0
2.5
3.0
Percent Removed
100%
39.3%
63.2%
77.7%
86.5%
91.8%
95.0%
Small vs. Large Volume
Exchange
• 1.0 plasma volume exchange: minimizes
time required for each procedure but may
need more frequent procedures.
• 2.0 – 3.0 plasma volume exchange:
greater initial diminution of pathologic
substance but requiring considerably more
time to perform the procedure.
Rationale of Plasma Exchange
• The existence of a known pathogenic
substance in the plasma.
– IgG, IgM, phytanic acid, cytokines (?)
• The possibility of removing this substance
more rapidly than it can be renewed in
the body.
Mechanical Removal of Antibodies
• When antibody is rapidly and massively
decreased by TPE, antibody synthesis
increases rapidly.
• This rebound response complicates
treatment of autoimmune diseases.
• It is usually combined with immune
suppressive therapy.
Indication for TPE
Category 1: Standard acceptable therapy
• Chronic idiopathic demyelinating polyneuropathy
(CIDP)
• Cryoglobulinemia
• Goodpasture syndrome
• Guillain-Barre syndrome
• Recurrent FSGS
• Myasthenia gravis
• Post transfusion purpura
• Refsum’s disease
• TTP
Indication for TPE
Category 2: Sufficient evidence to suggest efficacy
as adjunctive therapy
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•
•
•
•
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ABO incompatible organ transplant
bullous pemphigoid
coagulation factor inhibitors
drug overdose and poisoning (protein bound)
Eaton-Lambert syndrome
HUS
monoclonal gammopathy with neuropathy
Sydenham’s chorea
RPGN
Systemic vasculitis
Indication for TPE
Category 3: Inconclusive evidence of efficacy or
uncertain risk/benefit ratio.
TPE can be considered for the following occasions:
1. Standard therapies have failed.
2. Disease is active or progressive.
3. There is a marker to follow.
4. It is agreed that it is a trial of TPE and when to stop.
5. Possibility of no efficacy is understood by the patient.
Indication for TPE
Category 4: Lack of efficacy in controlled trials.
• Examples: AIDS, amyotrophic lateral
sclerosis, lupus nephritis, psoriasis, renal
transplant rejection, schizophrenia,
rheumatoid arthritis
Thrombotic Syndromes
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•
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TTP-HUS complex
Sepsis
Malignancy
Drugs
Pancreatitis
Pregnancy
ADAMTS-13 and vWF
the 13th member of a disintegrin and metalloprotease family with thrombospondin domains (ADAMTS-13)
Plasma Exchange and TTP
• One major comparative trial
– (Rock et al NEJM, 1991)
– TPE (centrifugation) vs. FFP infusion
– 1.5 volume exchange
– Mean 15.8 exchanges
– Outcomes
• Increased platelets (TPE 40/51 vs. FFP 25/51, p<0.005)
• Survival (TPE 40/51 vs. FFP 32/51, p<0.05)
TPE in TTP: Different Replacement Fluids
• Concerns raised regarding exposure to large volumes of
FFP and inherent infectious risks
• Randomized double-blind trial for TTP with FFP vs.
photo-chemically treated FFP (Mintz: Transfusion, 2006)
TPE in Sepsis
• Significant debate over the risks/benefits
of TPE in sepsis and MODS
• Could this be of benefit in prothrombotic
forms of sepsis and MODS?
• The risk of the increased
immunosuppressive effect
• What parameter to follow?
Asanuma et al: Ther Apher Dial. 2004
• Retrospective review
– 33 patients with sepsis and MODS secondary to
acute peritonitis
– 18 patients with necrotizing pancreatitis
• All patients received surgery
Busund: Intens Care Med, 2002
• Proespective randomized trial of standard
therapy + TPE in Russia
• 106 patients
• One TPE treatment followed by another in
24 hours if no clinical improvement noted
• Primary end-point was 28 day survival
Busund: Intens Care Med, 2002
Busund: Intens Care Med, 2002
Busund: Intens Care Med, 2002
Busund: Intens Care Med, 2002
Busund: Intens Care Med, 2002
Stegmayr: Crit Care Med, 2003
• Retrospective review of 76 patients with
DIC and MODS (at least ARF) who
received TPE
• 66/76 (83%) with septic shock
• Median 2 TPE Rxs (range 1-14)
• Outcome was mortality compared to the
literature based on similar diagnoses and
APACHE II scores
Stegmayr: Crit Care Med, 2003
• Pediatric patients (Pittsburgh)
• TAMOF
– Period 1
• OFI > 2
• Thrombocytopenia (< 100,000)
– Period 2
• OFI > 3
• Thrombocytopenia (< 100,000)
• AKI (SCr > 1, oliguria)
• ULVWF seen in 15/25
patients with decreased
ADAMTS-13 activity and
TAMOF (technique?)
• All four pts with activity
<10% had ULVWF (dose
effect?)
10 patients (5 in each group)
TPE in Transplantation
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Recurrent FSGS
Other recurrent GN
ABO incompatibility
Humoral transplant rejection
FSGS and Renal Transplant:
NAPRTCS
• FSGS erases LD
transplant survival
advantage
• Reasons for graft
failure
– Similar ATN incidence
– Increased recurrence
(FSGS 6.1% vs 0.7%)
Baum MA et al: Kid Int 2001
Baum MA et al: Ped Transplant 2002
Increased Recurrence with Higher Permeability
Activity
Savin V et al: NEJM 1996
TPE Decreases PA: HD Patient
Savin V et al: NEJM 1996
TPE Decreases PA and Proteinuria: 6 TX
Patients
Savin V et al: NEJM 1996
TPE to Treat Recurrent FSGS: Review
• No controlled trials
• Meta-analysis of case reports and series in 2001
to guide TPE treatment numbers
• NAPRTCS does not collect data regarding
recurrent FSGS occurrence rates, only if
recurrent FSGS was cause of graft failure
TPE for Recurrent FSGS: MetaAnalysis
• Inclusion criteria
– ESRD secondary to FSGS AND
– Renal transplantation AND
– Recurrence of FSGS
• Nephrotic range proteinuria OR
• Biopsy confirmation
– TPE provision
– Cases with secondary diagnoses included
• TPE response
– 50% reduction in proteinuria
Davenport R: J Clin Apher 2001
Meta-Analysis Results
• 44 cases from 12 reports satisfied inclusion
criteria
• Median time to recurrence was 21 days
• Median time from diagnosis to TPE was 9
days
– Range 0 – 91 days
• 32/44 cases responded
– Median time from diagnosis to TPE for responders vs.
non-responders was 10 vs. 19 days (NS)
Davenport R: J Clin Apher 2001
Meta-Analysis Results
Davenport R: J Clin Apher 2001
Meta-Analysis Results
Davenport R: J Clin Apher 2001
Meta-Analysis Results
• Biopsy with sclerosis or inadequate
material
– 3/26 responders vs. 9/10 non-responders
(p<0.05)
• Unable to evaluate effect of treatment
regimen on outcomes (response or
relapse)
– 11 different treatment regimens used in 12
studies
Davenport R: J Clin Apher 2001
TPE for Recurrent FSGS – 2001 to
2006
• Four case series; 2 case reports
(prolonged TPE)
• 54 patients in case series
– 42 children/ 12 adults
– Remission achieved in 40-60% of patients
TPE for Prevention of Recurrent FSGS
• Ohta et al (Transplantation 2001)
– Retrospective
– Pediatric
– Recurrence rates
• 4/6 in non-PP group
• 5/15 in PP group (2-3 TPE Rx)
• High risk patient recurrence
• Gohh et al (Am J Trans 2005)
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Prospective
High risk patients
Previous allograft lost to recurrent FSGS
Rapid progression to ESRD (<3 years)
Prospective TPE Prophylaxis for Recurrent
FSGS
Gohh RY et al: Am J Trans 2005
TPE Prophylaxis for Recurrent FSGS
Gohh RY et al: Am J Trans 2005
TPE for ABO Incompatible
Transplantation
• Common for emergent hepatic transplantation
• More common in Japan for LRD renal transplantation
where DD kidney availability is poor
– 10% of all DD transplants from 1989 to 2002
• UNOS data demonstrate O and B patients wait twice as
long as A patients for a DD kidney
• ABO antigens are located on the vascular endothelium
of convoluted distal and collecting tubules
Protocols
• Pre-transplant TPE
– Single or double filter pheresis on Day -4, -2
and -1
– Albumin as replacement fluid except for last
TPE
• Immunoadsorption
– Anti A or Anti B linked to a silica column
• Splenectomy?
– Infectious risk
– Not universally advocated
• Anticoagulation
TPE for ABO Incompatible
Transplantation: Long-Term Outcomes
• 564 Japanese
patients1
• 1989 - 2003
1. Takahashi K: Xenotransplantation 2006
TPE for ABO Incompatible
Transplantation: Long-Term Outcomes
Takahashi K: Xenotransplantation 2006
TPE for ABO Incompatible
Transplantation: Long-Term Outcomes
Takahashi K: Xenotransplantation 2006
Anticoagulation
Takahashi K: Xenotransplantation 2006
Summary
• Few randomized controlled trials to provide conclusive
evidence for the rationale for TPE
• TPE is probably rational for disease states in which a
causative factor is known and a clinical biomarker is
available for response assessment
• TPE must be combined with other immunosuppression
for realize prolonged remission
• “We have to do something” is not a justification to
subject patients and our healthcare system to TPE
without and endpoint