Therapeutic Apheresis

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Therapeutic Apheresis

• Inside the black box

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• 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

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History of Apheresis
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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)

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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

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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 1980s

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History

• 1959 Skoog and Adams used manual plasmapheresis
  in patient with Waldenstroms to reduce serum
  viscosity
• Followed by use in treatment of Rh sensitized
  pregnant women to prevent hemolytic disease of
  newborn with variable outcomes

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History

• Earliest work in early 1950s 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

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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

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Principle of Operation
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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)

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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

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Principle of Operation

• Gambro Spectra
• Continuous automated centrifugal separator

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Plasma collect bag
Waste bag
272ml ECV 52ml RBC ECV
Inlet Pump
ACD pump
Plasma pump
Centrifuge channel
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Physiology of Apheresis
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• 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

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• 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

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• 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 patients total plasma volume
  is exchanged

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• 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

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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 53 240
A2 macroglobulin 100 constant 820
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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

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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 gt40g/L)
• Some myeloma patients have higher proportion of
  IgG in intravascular space (56-85)
• As remove paraprotein in TPE, plasma volume
  progressively decreases

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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

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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

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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

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• 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

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• 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

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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)

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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

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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

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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 lt150

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Removal of Autoantibodies

• Monoclonal immunoglobulins
• Paraproteins
• Polyclonal autoantibodies
• Antibodies in immune complexes

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• 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

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• 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

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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

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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

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TBV calculations

• Calculate TBV by Nadlers 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

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TBV calculations

• Other methods
• Gilchers Rule of 5s

BLOOD VOLU ME (ml/kg) of Body wt
Fat Thin Normal Muscular
Male 60 65 70 75
Female 55 60 65 70
Infant / child - - 80/70 -
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• 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 lt24, the PLEX may not be tolerated
• Acute onset anemia less tolerated on exchange

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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

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Volume Replacement

• Up to 2/3 of anticoagulant volume may be retained
  in removed plasma
• Dont 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

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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

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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

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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

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Anticoagulant

• Citrate infusions 65-95mg/kg/hour are safe
• gt100mg/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)

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Anticoagulant

• Variables affecting symptoms
• Absolute amount of calcium
• Rate of decrease
• Serum pH
• Decrease in Mg, K, Na
• sedatives

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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

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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)

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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

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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

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Vascular Access

• Return lines
• 17-18 G for gt80ml/min
• 19 G for lt 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

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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

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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

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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 80s to 90s due
  to improvement in technical issues
• Severe events 0.3

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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

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Complications

• Rare events
• Allergic reactions due to ethylene oxide used in
  sterilization of apheresis kit
• Hemolysis in tubing
• Air embolism
• Circuit clotting

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Indications
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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

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Renal and Metabolic

• Antiglomerular basement membrane (Goodpastures)
• Rapidly progressive GN
• HUS
• Renal tx
• Rejection
• Sensitization
• Recurrent FSGS

• I
• II
• III
• IV
• III
• III

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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

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Autoimmune and Rheumatic

• Cryoglobulinemia
• ITP
• Raynaud
• Vasculitis
• Autoimmune hemolytic anemia
• Rheumatoid Arthritis

• II
• II (adsorption)
• III
• III
• III
• II (adsorption)
• IV (PLEX)

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Autoimmune and Rheumatic

• Scleroderma
• SLE
• Bullous pemphigoid
• Pemphigus Vulgaris

• III
• III
• NR (AABB) /II (ASFA)
• II

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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

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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

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Hematologic

• Malaria
• babesiosis

• III
• III

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Neurologic

• Acute/chronic inflamatory demylinating
  polyradiculoneuropath
• Lambert-Eaton myasthenia
• Multiple Sclerosis
• Myasthenia Gravis

• I
• II
• III
• I

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Neurologic

• Acute CNS inflammatory demylinating
• Paraneoplastic neurologic syndrome
• Demylinating polyneuropathy IgG and IgA
• Sydenham chorea

• II
• III
• I
• II

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Neurologic

• Polyneuropathy with IgM
• Cryoglobulinemia with polyneuropathy
• Myeloma with polyneuropathy
• POEMS
• AL amyloidosis

• II
• II
• III
• III
• IV

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Neurologic

• Polymyositis
• Dermatomyositis
• Inclusion body myositis
• Rasmussens encephalitis
• Stiff man syndrome
• PANDAS
• ALS

• III
• III
• III
• III
• III
• II
• IV