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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 % intravascular Change in Molecular
in plasma catabolism with weight
(mg/mL) decrease conc. (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 53 240
A2 100 constant 820
macroglobulin
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
Male 60 65 70 75
Female 55 60 65 70
Infant / - - 80/70 -
child
• 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 I
basement membrane
(Goodpastures)
• Rapidly progressive II
GN
III
• HUS
• Renal tx:
– Rejection
IV
– Sensitization III
– Recurrent FSGS III
Renal and Metabolic
• Heart transplant III
rejection
• Acute hepatic failure III
• Familial I (adsorption)
hypercholesterolemia II (PLEX)
• Overdose/poisoning III
• Phytanic Acid storage I
disease
• Lupus Nephritis
IV
Autoimmune and Rheumatic
• Cryoglobulinemia II
• ITP II (adsorption)
• Raynaud III
• Vasculitis III
• Autoimmune III
hemolytic anemia
• Rheumatoid Arthritis II (adsorption)
IV (PLEX)
Autoimmune and Rheumatic
• Scleroderma III
• SLE III
• Bullous pemphigoid NR (AABB) /II (ASFA)
• Pemphigus Vulgaris II
Hematologic
• ABO mismatched I (RBC removal marrow)
BMT
• PCV II
• Leuko/thrombocytosis I
• TTP I
• Post transfusion I
purpura
• Sickle Cell I
• Myleoma II
(hyperviscosity)
Hematologic
• Myeloma (ARF) II
• Coagulation factor II
inhibitors
• Aplastic anemia III
• Pure RBC aplasia III
• Cutaneous T cell I (photopheresis)
lymphoma
• HDN III
• PLT alloimmunization III
Hematologic
• Malaria III
• babesiosis III
Neurologic
• Acute/chronic I
inflamatory
demylinating
polyradiculoneuropath
• Lambert-Eaton
myasthenia II
• Multiple Sclerosis III
• Myasthenia Gravis I
Neurologic
• Acute CNS II
inflammatory
demylinating
• Paraneoplastic III
neurologic syndrome
• Demylinating
polyneuropathy IgG I
and IgA
• Sydenham chorea II
Neurologic
• Polyneuropathy with II
IgM
• Cryoglobulinemia with II
polyneuropathy
• Myeloma with III
polyneuropathy
• POEMS
III
• AL amyloidosis
IV
Neurologic
• Polymyositis III
• Dermatomyositis III
• Inclusion body III
myositis
• Rasmussen’s III
encephalitis
• Stiff man syndrome III
• PANDAS II
• ALS IV