Apheresis 092909 Hames

Apheresis

Fellowship lecture series

9/29/09

• Components of blood• Apheresis definitions• Methods of apheresis• Indications for apheresis• Dose of plasmapheresis/exchange• Anticoagulation• Routine medications• Complications of apheresis• Disease states• RBC exchange

Components of blood

• 45% cellular elements

• 55% plasma– 92% water– 8% solutes

• Proteins, non-protein nitrogen substances, food substances, regulatory substances, respiratory gases and electrolytes

– Plasma proteins include albumin, globulins, prothrombin and fibrinogen

Apheresis

• Apheresis originates from Greek roots meaning “to take away from”

• Apheresis = the separation of whole blood into its components– A selected component of blood is removed and the

remaining elements are recombined and returned to the donor or patient

• Concept of apheresis has been applied to blood donation as well as patient treatment

Apheresis

• 2 categories– Plasmapheresis

• Plasma exchange – large quantities of plasma are removed and replaced with a suitable replacement solution during a therapeutic procedure

– Cytapheresis• Leukapheresis• Thrombocytaphereis• Erythrocytapheresis

Methods of Apheresis

• Utilize peripheral or central line

• Centrifugation– Continuous or discontinuous

• Non-centrifugal based on sieving or “filtration technology”– Hollow-fibers or membranes

• Combination of both

*** PCMH uses a continuous centrifugation device

Separation of blood by centrifugal force

• Each blood component has a specific density and specific gravity

Constituent Specific Gravity (g/ml)

Plasma 1.025-1.029

Platelets 1.040

White Blood Cells

B-Lymphocytes 1.050-1.060

T-Lymphocytes 1.050-1.061

Blasts/Promyelocytes 1.058-1.066

Monocytes 1.065-1.066

Myelocytes/Basophils 1.070

Reticulocytes 1.078

Metamyelocytes 1.080

Bands and Segmented Neutrophils 1.087-1.092

Erythrocytes 1.078-1.114

Separation of blood by sieving

• Filtration technology separates plasma and the cellular components by sieving the cells from plasma

• Limited to plasmapheresis or donor platelet apheresis

• Pore size of the membrane separator is 6 microns

Component Diameter in Microns

Platelets 3 microns

Erythrocytes 7 microns

Lymphocytes 10 microns

Granulocytes 13 microns

Indications for Apheresis

• Category I – primary or 1st line adjunct to other treatments

• Category II – generally beneficial

• Category III – available trials insufficient to establish efficacy

• Category IV – available trials show lack of efficacy; should be done only w/an approved research protocol

Dose of Therapeutic plasma exchange

TBV = wt in kg x 70ml/kg (for adult)

TBV x (100 – hct%) = plasma volume

Plasma volume exchanged Plasma removed0.5 39%

1.0 63%

1.5 78%

2.0 86%

2.5 92%

3.0 95%

TBV = total blood volume

Estimated TBV is determined from wt/ht/age:

infant-child 100-75ml/kg teen 70-75ml/kg adult 65-80ml/kg

Anticoagulation for apheresis

• Regional anticoagulation– Citrate

• Used most commonly, enters the extracorporeal circuit at the first available opportunity

• Metabolized by the liver, kidney and muscles• Because citrate is plasma bound, only 15-18% is

returned

• Systemic anticoagulation– Heparin

• Used in liver failure, pediatrics

Anticoagulation in Apheresis

• Citrate– Binds to or “chelates” ionized calcium to

produce a soluble complex; this makes calcium unavailable for calcium-dependent clotting

– Remains active as long as the blood is in the extracorporeal circuit

Anticoagulation in Apheresis

• Citrate– Citric acid, citrate salts, citrate dextrose– Formulations:

• Anticoagulant citrate dextrose (ACD)– Contains citric acid, sodium citrate and dextrose

– Solution A 3% citrate concentration (21.4mg/ml)

– Solution B 2% citrate concentration (12.9mg/ml)

• Sodium citrate highly concentrated– 46.7% Trisodium citrate

For comparison, FFP is 4.10mg/ml and RBC with a Hct of 70% is .71mg/ml

Side-effects of Anticoagulation

• Citrate– Hypocalcemia is related to:

• Rate at which citrated blood is returned to the donor/patient• Length of the procedure• Use of FFP as replacement fluid• Metabolism (i.e. hepatic function)

– Infusion rates• 1mg/kg per minute or less harmless to most • > 1.7mg/kg per minute assoc. with mod to severe rxn• Limit for citrate infusions suggested as 4mg/kg per minute in

extreme circumstances

Side-effects of Anticoagulation

• Citrate infusion rates:– Cellular collections

Citrate infusion rate = [Cit] / Body wt. x [TFR/ n+1 – CFR / n- (n x Hct) +1] (mg/kg/minute)

– Plasma exchangesCitrate infusion rate = {[Cit] / Body Wt} X [TFR/ n+1 – PFR / n- (n x Hct) + 1] (mg/kg/minute)

TFR = the total flow rate into the system, including AC, in ml/min

[Cit] = citrate concentration of anticoagulant in mg/ml

CFR = the collection pump flow rate in ml/min

Hct = the hematocrit expressed as a decimal

n = the ratio of the rate of donor whole blood withdrawn to the rate of AC

Side-effects of AnticoagulationHypocalcemia

• Mild Circumoral paresthesia

Sneezing

Chewing on the lips

• Moderate paresthesia progressing to hands, feet, and/or chest

chills despite the use of a blood warmer

nausea and vomiting, abdominal cramping

vibrating sensation

lightheadedness and mild hypotension

restlessness

Side-effects of AnticoagulationHypocalcemia

• Severe muscle cramps, severe abdominal cramping

tremors

bladder and/or bowel incontinence

fear of impending doom

loss of consciousness

blurred or double vision

severe hypotension (BP < 90mmHg)

cardiac: arrhythmia, bradycardia, prolonged QT

interval, PVCs

Neuromuscular irritability

- chvostek’s sign

- trousseau’s sign

- seizure

Side-effects of AnticoagulationTreating hypocalcemia

• Keep pt warm with blankets• Blood warmers• Decrease BF rates• Decrease the AC:WB ratios to decrease citrate delivery• Calcium replacement

– Tums

– Oral calcium wafers

– IV calcium gluconate (1gm – 94mg Ca++)

– IV calcium chloride (1gm – 273mg Ca++)

• Terminate procedure

• Consider conditions that might exacerbate a citrate reaction: hyperventilation, hyperthermia, hypomagnesemia, hypoalbuminemia, using FFP as replacement fluid

Side effects of anticoagulation

• Other side effects of citrate– Hypomagnesemia– Hypokalemia– Decreased Ca/Mg can increase

parathormone

Other medications

• Medications that are free in the plasma and NOT bound to plasma protein are NOT efficiently removed during plasmapheresis

• Medications that are highly protein bound and slowly metabolized ARE more readily removed during plasmapheresis– If predominantly in the intravascular space, 70-80% of

drug will be removed in a 1 to 1.5 plasma volume exchange

• Not as big a problem with cytapheresis unless large volumes are processed

Other medications

• Irregardless, whenever possible, dose medications after pheresis

Apheresis - complications

• Early signs of a developing adverse reaction– Irregular breathing patterns– Hyperventilation– Tachycardia– Cold and clammy hands– Flushed or pale face– Restlessness– Abdominal cramping

Apheresis - complications• Hypocalcemia related to citrate toxicity (most

common)• Vasovagal and hypovolemic reactions• ACE-Inhibitors

– Bradykinin is produced as the blood is exposed to extracorporeal surface

– ACE-I decrease the rate of degradation of bradykinin– Potentiate allergic rxn (vasodilatation, hypotension,

flushing, bradycardia) due to increased levels of kinins– Usually this rxn occurs within minutes; procedure should

be terminated without blood return and rescheduled in 24-48hours

– Withhold ACE-I 24-48 hours prio to treatment or choose alternative agent

Apheresis - complications• Transfusion reactions (immediate within 15min or

delayed up to 12 hours)• Coagulopathy

– Removal of coagulation factors– A problem with albumin replacement– Fibrinogen level may decrease by 25-70% following a 1

to 1.5 plasma volume exchange• Recovers to baseline over 48-72 hours

– PT/PTT may be abnormal post pheresis • Recovers 4-24 hours

– 1-4 units of cryoprecipitate or FFP can be given at the end of the procedure as part of replacement fluids

• Air embolism (acute SOB, chest pain, diaphoresis, confusion, shock, syncope)

Apheresis - complications

• Catheter complications• Mechanical hemolysis• Aluminum bone deposits (albumin may be

contaminated with aluminum and other trace elements)

• Thrombocytopenia– Up to a 30-50% decrease in platelet count has been

reported• Removed with the plasma in plasma exchange• Removed with the red cells in RBC exchange• Become aggregated and caught in the machine centrifuge

chamber, tubing and filters

Disease states – Guillian Barre

• Benefit in controlled and uncontrolled studies

• North American Guillian Barre study group: Series of 5 exchanges compared to no exchanges but otherwise identical care– Plasma exchange has a role in tx of acute GBS– Greatest benefit w/disease duration < 1 wk and

who are not on a ventilator

• 5% Albumin replacement

Disease states – CIDP

• Regimen similar to North American Guillian Barre study group– 4-6 exchanges of 40 to 60 mL/kg in the 1st 2

weeks– Some follow with 1-2 exchanges weekly or at

larger intervals as needed to achieve maximal or stable response

• 5% Albumin replacement

Disease states – myasthenia gravis

• An autoimmune disease where pts have antibodies to the acetylcholine receptor (AChR)

• Treatment options:– Meds to enhance neuromuscular transmission (=anticholinesterase

drugs) -> facilitate more acetylcholine at the neuromuscular junction. i.e. mestinon=pyridostigmine, prostigmin=neostigmine

– Long-term immunosuppression– Short-term plasma exchange with albumin replacement– IVIG– thymectomy

• Indications– Not responding to drug therapy– In myasthenic crisis– Pre- and post- thymectomy

Disease states – myasthenia gravis

• Myasthenic crisis – exacerbation of myasthenia gravis

• Cholinergic crisis – identical symptoms but caused by excess of anticholinesterase medications: plasma exchange can precipitate this as it removes antibodies– Main difference between the 2 is HR should increase

with MC and should decrease with CC– Other symptoms of CC include abdominal cramps,

pallor, sweating, hypotension, respiratory arrest• Pregnant pt

– infant might be born with neonatal myasthenia gravis– can treat mom w/anticholinesterase drugs, steroids,

plasma exchange

Disease states – TTP

• Plasma exchange with FFP replacement is treatment of choice

• Should be an emergent transfer; utilize transfer to ED if beds full; tell outside hospital to hang 2-3 units of cryopoor (or regular if no cryopoor) FFP while awaiting emergent transfer

Blood 98 (6)

September 15 2001

Indications for Red Blood Cell Exchange

• Sickle cell disease

• Falciparum malaria

• Babesiosis

• Thalassemia

• CO poisoning

• methemaglobinemia

Red Blood Cell Exchange is used in sickle cell disease to:

• Alleviate an acute process– Impending stroke– Acute chest syndrome– Priapism– Retinal infarction– Hepatopathy– Severe liver disease– Refractory hematuria

• Prophylactic– To prevent a 2nd stroke

(goal HbS < 30-50%)– To alleviate chronic

pain crises– To prevent iron

overload

Red Blood Cell Exchange sickle cell disease

• Standard PRBC Hct is 70-80%– May be lower with leukoreduced (55%) or washed units

• To calculate amt of RBCs to be exchanged need to know wt, TBV (total blood volume), Hct and these will allow you to determine the RBCV (RBC volume)

• Pt’s with prior febrile transfusion reaction will need leukocyte-reduced RBCs

• For pts with RBC alloantibodies, antigen-negative RBCs will be needed

• Must use hemoglobin S negative blood• Must use standard blood filter on replacement line

Red Blood Cell Exchange sickle cell disease

• Example: RBC volume in a 36kg child with Hct 22%

• TBV=36kg x 80ml/kg=2880ml• RBCV=TBV x Hct = 2880ml x .22 = 633.6ml

• Unit of leukopoor RBC with 300cc and Hct 55% has RBCV of 165cc so for this child, ~3.8 units of PRBCs would be needed for exchange

Estimated TBV is determined from wt/ht/age:

infant-child 100-75ml/kg teen 70-75ml/kg adult 65-80ml/kg

THE END!!

History of Apheresis

• Ancient practice of bloodletting

• 1914 – first application of separation of blood components in uremic dogs


• During WWII, plasma needed

• Edwin J. Cohn adapted cream separator to separate plasma from whole blood


• 1948 – Cohn developed a closed-system whole blood separation device

• 1952 – sequential weekly plasma removal with red cell storage a week at a time

• 1962 – Mr. G. Judson (IBM) Dr. Emil Freireich (NCI) developed a continuous-flow blood component centrifuge


• 1960’s – Allen Latham, Jr and the Arthur D. Little Company developed a discontinuous-flow apparatus -> Soon to be Haemonetics corporation

• 1966 – 1st manual plasmapheresis using centrifugation device connected to integrated bag/tubing system

• 1984 – COBE bought IBM Biomedical systems division and eventually introduced COBE Spectra

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