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Therapeutic Apheresis
Inside the black box
• Apheresis is a process by which blood
being removed from a subject is
continuously speparated into component
parts, usually to allow a desired
component(s) to be retained while the
remainder is returned to the subject
• Plasmapheresis from greek apairesos or
Roman aphairesis meaning to take away
by force
History of Apheresis
History
• Earliest continuous flow centrifugation
device was hand cranked cream separator
in 1877 by Dr. Carl Gustav Patrik De Laval
• Applications of flow centrifugation in:
– Petroleum industry (separate impurities)
– Nuclear fuels (separate uranium isotopes)
– Waste management (separate solid and liquid
wastes)
History
• Plasmapheresis (removal of plasma with
return of RBC) first performed 1914 John
Abel at Johns Hopkins University in a dog
in context of artificial kidney research
History
• Developed manual plasmapheresis where
blood drawn from donor (vein then kept
open by IV saline)
• Centrifuge blood in blood bank
• RBC then reinfused with saline
• Plasma stored for use
• Major method of collecting source plasma
from paid donors until early 1980’s
History
• 1959 Skoog and Adams used manual
plasmapheresis in patient with
Waldenstrom’s to reduce serum viscosity
• Followed by use in treatment of Rh
sensitized pregnant women to prevent
hemolytic disease of newborn with
variable outcomes
History
• Earliest work in early 1950’s by Dr. Edwin
Cohn at Harvard
– Devised fractionation scheme for plasma and
important in providing albumin for WWII
– Developed the Cohn centrifuge in response to
need for cellular components that might be
needed in event of nuclear war
– Blood into conical centrifugal separation
chamber
History
• 1962 IBM engineer son dx with CML
• Together with Dr. Emil Freireich and IBM
developed NCI-IBM (2990) at National
Cancer Institute
• Initially process 11L of blood from CML
patients for leukopheresis
• 1964 studies on CLL patient leukopheresis
• 1969 1st automated plasma exchange
procedures
Principle of Operation
Principle of Operation
• Blood reaching equilibrium after application of
centrifugal force:
Plasma (1.025-1.029 specific gravity)
Platelet (1.040)
Mononuclear (lymph, mono, PBSC,blast)
(1.070)
Granulocyte (neut, baso, eos) (1.087)
Neocyte RBC
RBC (1.093-1.096)
Principle of Operation
• Intermittent flow
– Blood processed in discrete batches
– Separation until container filled with dense
component (RBC)
– Needs to empty before next batch
• Continuous flow
– All fractions can be removed in ongoing
manner
• Do not need to empty container until end of
procedure
Principle of Operation
Gambro Spectra:
• Continuous automated centrifugal
separator
Waste bag
Plasma collect bag
272ml ECV
52ml RBC ECV
Inlet Pump
ACD pump
Plasma pump
Centrifuge channel
Physiology of Apheresis
Effectiveness of TPE depends on:
• Volume of plasma removed relative to total
plasma volume
• Distribution of substance to be removed
– Between intra and extravascular
compartments
• Speed at which the substance equilibrates
between compartments
• Rate at which substance is synthesized
• Mathematical models used to predict TPE
outcome assume the intravascular plasma
volume is a closed compartment
• Also assumes that steady state between
synthesis and catabolism is not altered
during TPE
• The equation that describes the removal of a
substance in PLEX is:
Y = Y0e-x
Y = final concentration
Y0 = initial concentration
e = base of natural logarithms (2.718…..)
X = number of times patient’s total plasma volume
is exchanged
• Assumes no equilibration with
extravascular stores
• Assumes no further substance is produced
• Predicts 37% of substance remains at end
of 1 plasma volume exchange
• 22% remaining after 1.5 PV exchange
• 14% remaining after 2.0 PV exchange
Metabolic Characteristics of
Plasma Proteins
Protein
Concentration
in plasma
(mg/mL)
% intravascular
Change in
catabolism with
decrease conc.
Molecular
weight
(kDa)
IgG
12.1
45
Decrease
150
IgA
2.6
42
Constant
160
IgM
0.9
76
Constant
950
IgD
02.6.02
75
Increase
175
IgE
0.0001
41
Increase
190
Albumin
42
40
Decrease
66
Fibrinogen
2-4
80
Constant
340
C3
1.5
53
A2
macroglobulin
100
240
constant
820
Normal Immunoglobulins
One plasma volume exchange:
• IgG drops to 34% of baseline
• IgA drops to 39% of baseline
• IgM drops to 31% of baseline
• Varying reports as to time to recovery of Ig
• Ranges from 3 days to 5 weeks to full recovery
– Variation due to different methods of calculating
recovery, some patients on immunosuppressive
medications
Paraproteins
• Removal of paraproteins (ie myeloma) is 50% of
predicted
– Some cases can have greater removal than predicted
(see last 2 reasons)
• Due to:
– Increase in plasma volume (up to 1.5x greater,
especially if IgG >40g/L)
– Some myeloma patients have higher proportion of
IgG in intravascular space (56-85%)
– As remove paraprotein in TPE, plasma volume
progressively decreases
Complement and Immune
Complexes
• C3 has equal distribution between
intra/extravascular space
• Decrease to 37% of baseline with 1
plasma volume exchange
• Recovery to 90% at 24 hours and 100% at
48 hours
• Similar results for circulating immune
complexes
Coagulant Proteins
Fibrinogen:
• Decrease to 25% of pretreatment with
single exchange of 1 PV
• Decrease to 10-30% of pretreatment with
consecutive daily 1 PV exchange
• recover to 100% of pretreatment levels by
2-3 days
Coagulant Proteins
Prothrombin:
• Decreased to 30% of baseline
Factor VII & factor VIII:
• Decreased to 45-50% of baseline
Factor IX:
• Decreased to 60% of baseline
Factor V, X, XI:
• Decrease to 38% of baseline
Antithrombin:
• Activity to 40%, Ag to 70%
• Recovery to 85-100% of baseline within 24
hours
• Elevation of PTT, PT, TT post exchange
• PTT,TT returned to normal 4 hours post
exchange
• PT returned to normal 24 hours post
exchange
• While decreases in coagulation proteins,
large studies have not shown increased
bleeding risks in patients undergoing
repeat exchanges
• Concern if preexisting hemostatic risk:
– Currently bleeding, surgical procedure within
last 24 hours, preexisting coagulopathy
Electrolytes
• Potassium decrease (minimal)(0.25meq/L
with albumin and up to 0.7meq/L with FFP
• No change in sodium and glucose
• Bicarbonate decrease 6meq/L and
chloride increase 4meq/L with albumin and
this reverses with FFP (more citrate in
FFP)
Other plasma proteins and
molecules
• LDL cholesterol, ALP, ALT decrease to
37% after 1 PV exchange
• AST, LDH,amylase, CK, ferritin, transferrin
decrease to 47% after 1 PV exchange
• ALT, AST, amylase 100% recovery in
48hrs
• LDH, ALP,CK 60% recovery in 48hrs
• LDL cholesterol 44% recovery in 48hrs
CBC
RBC:
• Up to 12% decrease in Hb immediately
after 1 PV exchange
• Recovery to 100% within 24 hours
• Felt to be due to expansion of plasma
volume with albumin more than FFP
WBC:
• Some have shown increase in neutrophils
(up to 2x109/L), while others have not
CBC
Platelets:
• 15-50% reductions have been seen post
1PV exchange
• With 5-10 repeated exchanges platelets
may drop to 20-25% pretreatment levels
• Recover to 70-85% by 24 hours and 100%
by 72-96 hours
• Platelets may fall by smaller amount if
baseline platelets <150
Removal of Autoantibodies
•
•
•
•
Monoclonal immunoglobulins
Paraproteins
Polyclonal autoantibodies
Antibodies in immune complexes
• IgG 45% intravascular
• 1.25 plasma volume exchange removes 32% of
total body IgG
• Reequilibration between intra/extravascular
compartments may be complete by 24 hours
• To deplete total body IgG by 85% requires 5
exchanges of 1.25 plasma volumes on alternate
day schedule
• 21 day resynthesis half life
• IgM 75% intravascular
• Faster rate of synthesis than IgG at 5-6
day resynthesis half life
• To reduce to 85% requires 3-4 exchanges
of 1.25 plasma volumes
Hyperviscosity Syndrome
• Concentration of paraprotein at which
patients develop clinical hyperviscosity is
variable
• For IgM, reduction of serum viscosity may
occur with removal of 0.5 plasma volume
Drug Removal
• Can remove:
– ASA, tobramycin, dilantin, vancomycin, propranolol
• May reduce plasma levels of enzymes that metabolize
drugs
• May reduce plasma levels of proteins that bind and
transport drugs
• Depends on distribution of drug between
intra/extravascular space, half life of drug in circulation,
timing of administration of drug, protein bound status, not
lipid or tissue bound
• 1% of prednisone removed
• IVIG mainly removed as remains intravascularly
• Ideally give medications after exchange
TBV calculations
• Calculate TBV by Nadler’s formula
• For male: (0.006012xht3) / (14.6xwt) + 604
= TBV(ml)
• For female: (0.005835xht3) / (15xwt) +183
= TBV (ml)
– Will overestimate obese patient blood volume
and underestimate muscular patient blood
volume
TBV calculations
• Other methods:
• Gilcher’s Rule of 5’s:
BLOOD
VOLU
ME
(ml/kg)
of
Body
wt
Fat
Thin
Normal
Muscul
ar
Male
60
65
70
75
Female
55
60
65
70
Infant /
child
-
-
80/70
-
• Extracorporeal blood volume limited to 15% of
TBV
– To limit hypovolemia
– Can prime with RBC if extracorporeal RBC volume is
more than 15% of RBC volume
– Intraprocedure hematocrit:
(RCV-extracorporeal RCV)/TBV x100
– If this is <24%, the PLEX may not be tolerated
– Acute onset anemia less tolerated on exchange
Replacement Fluid
• Need replacement fluid to exert oncotic
pressure to replace removed plasma
– 5% albumin exerts oncotic pressure resulting
in slight reequilibration of fluid into
intravascular space at end of PLEX
– FFP
– Pentastarch
Volume Replacement
• Up to 2/3 of anticoagulant volume may be
retained in removed plasma
– Don’t have to replace this whole volume
• Hypovolemic exchanges
– Potential for hypotension even if volume
overloaded at start of exchange
– PLEX modulates intravascular volume only
• Unlike hemoperfusion or hemodialysis
Anticoagulant
• Citrate
• Chelates calcium and block calcium
dependent clotting factor reactions
– Ensures extracorporeal blood remains in fluid
state
– Minimize activation of platelets and clotting
factors
Anticoagulant
• 40% plasma calcium bound to albumin
• 47% free plasma calcium
– Target of chelation by citrate
– Will decrease with little decrease in total
calcium
• 13% complexed to
citrate/phosphate/lactate
• Ionized calcium decrease 0.1mmol/L for
each 0.5-0.6 nmol/L rise in plasma citrate
Anticoagulant
• Dilution, redistribution, removal, metabolism and
excretion of infused citrate are factors protecting
against severe hypocalcemia
• Much of infused citrate is discarded with
separated plasma
• Usually 23-33% reduction in ionized calcium
• Most rapid decrease in 1st 15 mins
• Serum citrate levels return to normal 4 hours
post exchange
Anticoagulant
• Citrate infusions 65-95mg/kg/hour are safe
• >100mg/kg/hr lead to increased side
effects
• Hypomagnesemia can worsen symptoms
• Duration of procedure increases risk of
symptoms
• 5% albumin can bind ionized calcium and
contribute (more than FFP which contains
citrate)
Anticoagulant
Variables affecting symptoms:
• Absolute amount of calcium
• Rate of decrease
• Serum pH
• Decrease in Mg, K, Na
• sedatives
Anticoagulant
•
•
•
•
•
•
•
•
•
Oral, acral paresthesia
Nausea and vomiting
Lightheadedness
Shivering, twitching, tremors
Worsening of myasthenia gravis during exchange
Muscle cramping
Tetany
QT prolongation
May cause metabolic alkalosis if renal disease and using
FFP
Vascular Access
• Blood flow rates for adults ~60-150 ml/min
• For small children may be down to
10ml/min
• Flow rate depends on:
– Vascular access
– Ability to tolerate citrate (related to TBV)
Vascular Access
• Peripheral veins when possible
• Draw site:
– 16-18 G steel needle allows flows up to
120ml/min
– Antecubital fossa
• Medial cubital, cephalic, basilic
– Disorders of autonomic nervous system have
poor vascular tone, peripheral neuropathies;
may be unable to maintain good flow rates
Vascular Access
• High Hct or hyperviscous patients may
need 16 G
• 18 G can be used for normal viscosity or
Hct to get flow up to 110 ml/min
• Soft plastic IV will colapse
Vascular Access
•
•
•
•
•
Return lines:
17-18 G for >80ml/min
19 G for < 70 ml/min
Can be used in other arm veins
If use same arm, return line should be
above (downstream) from draw line to
decrease recirculation
Vascular Access
• Central lines:
• Large bore allows faster flow rates up to
150ml/min
• Less concern re: loss of site or vasospasm
• Increased concern re: infection and/or
thrombosis
• Need hard plastic hemodialysis type line
• Red port: shorter draw line
• Blue port: longer return line
Complications
AABB survey (1999):
• 3429 therapeutic apheresis procedures
• 6.8% of 1st time procedures
• 4.2% of repeat procedures
–
–
–
–
–
1.6% transfusion reactions (in plasma)
1.2% citrate related nausea/vomiting/paresthesia
1.0% hypotension
0.5% vasovagal event
0.5% diaphoresis and pallor
Complications
AABB survey (contd):
–
–
–
–
0.4% tachycardia
0.3% respiratory distress
0.2% tetany/seizure
0.2% chills or rigors
• Other registry data; Canadian, Swedish
demonstrate roughly same event rates
• Rates of events decreased from 80’s to 90’s due
to improvement in technical issues
• Severe events ~0.3%
Complications
Mortality rates:
• French registry: 1-2/10,000
• Swedish registry: 0/14,000
• American data: 3/10,000
–
–
–
–
–
–
–
60% cardiac or respiratory
Mainly in FFP replacement
Anaphylaxis
Spesis
PE
Line related
Risks increase in FFP exchanges
Complications
Rare events:
– Allergic reactions due to ethylene oxide used
in sterilization of apheresis kit
– Hemolysis in tubing
– Air embolism
– Circuit clotting
Indications
AABB / ASFA Guidelines
Category I:
• Considered primary or standard therapy usually
on basis of controlled trials
Category II:
• Supportive or adjunctive to other therapy
Category III:
• Insufficient data to determine effectiveness;
results of clinical trials may be conflicting or
uncontroled anecdotal reports of efficacy
Category IV:
• do not respond to apheresis therapy
Renal and Metabolic
• Antiglomerular
basement membrane
(Goodpastures)
• Rapidly progressive
GN
• HUS
• Renal tx:
– Rejection
– Sensitization
– Recurrent FSGS
I
II
III
IV
III
III
Renal and Metabolic
• Heart transplant
rejection
• Acute hepatic failure
• Familial
hypercholesterolemia
• Overdose/poisoning
• Phytanic Acid storage
disease
• Lupus Nephritis
III
III
I (adsorption)
II (PLEX)
III
I
IV
Autoimmune and Rheumatic
•
•
•
•
•
Cryoglobulinemia
ITP
Raynaud
Vasculitis
Autoimmune
hemolytic anemia
• Rheumatoid Arthritis
II
II (adsorption)
III
III
III
II (adsorption)
IV (PLEX)
Autoimmune and Rheumatic
•
•
•
•
Scleroderma
SLE
Bullous pemphigoid
Pemphigus Vulgaris
III
III
NR (AABB) /II (ASFA)
II
Hematologic
• ABO mismatched
BMT
• PCV
• Leuko/thrombocytosis
• TTP
• Post transfusion
purpura
• Sickle Cell
• Myleoma
(hyperviscosity)
I (RBC removal marrow)
II
I
I
I
I
II
Hematologic
• Myeloma (ARF)
• Coagulation factor
inhibitors
• Aplastic anemia
• Pure RBC aplasia
• Cutaneous T cell
lymphoma
• HDN
• PLT alloimmunization
II
II
III
III
I (photopheresis)
III
III
Hematologic
• Malaria
• babesiosis
III
III
Neurologic
• Acute/chronic
inflamatory
demylinating
polyradiculoneuropath
• Lambert-Eaton
myasthenia
• Multiple Sclerosis
• Myasthenia Gravis
I
II
III
I
Neurologic
• Acute CNS
inflammatory
demylinating
• Paraneoplastic
neurologic syndrome
• Demylinating
polyneuropathy IgG
and IgA
• Sydenham chorea
II
III
I
II
Neurologic
• Polyneuropathy with
IgM
• Cryoglobulinemia with
polyneuropathy
• Myeloma with
polyneuropathy
• POEMS
• AL amyloidosis
II
II
III
III
IV
Neurologic
• Polymyositis
• Dermatomyositis
• Inclusion body
myositis
• Rasmussen’s
encephalitis
• Stiff man syndrome
• PANDAS
• ALS
III
III
III
III
III
II
IV