Therapeutic Pheresis: A Residents Guide

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Therapeutic Pheresis A Residents Guide

• Lloyd Cook, MD
• James Fulcher, MD

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Transfusion Medicine
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Examples of Evil Humors
Waste bag from CAD
Leukoreduction for blast crisis
Platelet reduction
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Apheresis Methods
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Separation Method

• Apheresis Machines are basically centrifuges that
  can move a certain part of the blood based on
  density.
• The assorted tubes and pumps are there to
  maintain proper flow into/from the body.

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Ideal Solutes
Ideal doesnt mean risk free
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Ideal Solute Discontinous exchange
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Ideal Solute
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Ideal Solutes- as defined before Examples
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Apheresis Setup for RBC Exchange in S.C. Crisis
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Plasma Exchange with 5 albumin for M.G.
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Apheresis Complications
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Apheresis Complications Procedure Related
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Apheresis Complications Procedure Related

• Central lines
• Problem two 16g steel needles
• Femoral vs. IJ vs. subclavian
• Hemorrhage (placement, anticoagulation)
• Pneumothorax
• Thrombosis and embolism
• Sepsis

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Apheresis Complications Procedure Related

• Chills
• Afferent tubing, efferent tubing, centrifuge RT
• Can use blood warmers
• Anything that can go wrong, will go wrong
• Blankets
• Disease relevance
• Cold-type autoimmune hemolytic anemia
• Cryoglobulinemia

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Apheresis Complications Procedure Related

• Citrate toxicity
• Pathophysiology chelation, hypocalcemia
• Symptoms circumoral paresthesias, tetany
• Treatment
• Slow down the procedure
• Oral calcium carbonate (Tums)
• IV calcium gluconate
• Clear symptoms
• Low ionized Ca2
• Attending approval

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Apheresis Complications Procedure Related

• Other metabolic changes
• Fibrinogen
• Drugs
• IVIG
• Dilantin no problem
• Antimicrobials
• No information for most

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Apheresis Complications Procedure Related

• Plasma exchange with FFP (e.g. TTP)
• Infectious risk reduced but still a
  concern
• Allergic transfusion reactions
• RBC exchange (e.g. Hgb SS disease)
• Hemolytic transfusion reactions
• Febrile transfusion reactions
• Allergic transfusion reactions
• Transfusion-transmitted diseases
• Etc.

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Final procedural point

• Choice of solute depends on disease treated
• TTP/HUS- FFP-allergy/infection risk worth
  replacing vital clotting factors
• Guillain Barré- 5 albumin- reduce
  infection/allergy risk
• Myasthenia Gravis- 5 albumin- reduce
  infection/allergy risk

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Indications/ Link to Insurance Website

• TTP- plasma
• Guillain Barré- plasma
• Myasthenia Gravis- plasma
• Leukocytosis- Cytapheresis
• Sickle Cell- Red cell exchange
• Multiple autoimmune neuropathies
• Atena Policy on Apheresis

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Review of the Diseases Commonly Treated by
ApheresisDiscussion will follow in this order

• TTP/HUS
• Guillain-Barre
• Myasthenia Gravis

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Eli Moschcowitz (1879-1964) In hospitals,
people should be treated and not diseases.

• Emigrated from Hungary to America at age 2
• Qualified in Medicine at Mount Sinai Hospital
  1903
• Studied Pathology with Ludwig Pick in Berlin
• Brother Alexis Victor was clinical professor of
  Surgery
• Many contributions to medical knowledge

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Thrombotic thrombocytopenic purpura
An 18 year old girl presented with abrupt onset
of fever, anemia, renal dysfunction, CNS
impairment and cardiac failure. She died 2
weeks later.
Moschcowitz, E. Arch Int Med 1925 3689-93.
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Thrombotic thrombocytopenic purpuraDemographics

• Incidence 1100,000 - 1500,000
• Malefemale 12
• Age
• Most common in 30-40 year olds
• 90 of patients less than 60 years old
• No racial differences
• No seasonal difference

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Thrombotic Thrombocytopenic Purpura

• Clinical findings
• Fever
• Neurological changes
• Renal impairment
• Laboratory findings
• Microangiopathic hemolytic anemia
• Thrombocytopenia

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Laboratory Findings in TTP

• Thrombocytopenia
• Anemia
• Reticulocytosis
• LDH increased
• Indirect/direct bilirubin increased (depends on
  liver function)
• Haptoglobin deceased

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Schistocytes Microangiopathic hemolytic anemia
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Defining the diagnosis of TTP

• Anemia may not be apparent at diagnosis
• Alternative diagnoses may only be apparent after
  treatment has begun
• The initial diagnosis should be considered
  tentative
• Remain vigilant for an alternative diagnosis
• MCG recently had a case of TTP that was most
  likely HIT.

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Alternative diagnoses of patients who have
clinically suspected TTP/HUS

• Apparent after the plasma exchange has begun
• Autoimmune disorders
• Systemic lupus erythematosus
• Scleroderma
• Anti-phospholipid antibody syndrome
• Sepsis
• Malignant hypertension
• Heparin-induced thrombocytopenia/thrombosis
• Disseminated malignancy

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Presentations of TTP/HUSThrombotic
microangiopathy

• Idiopathic
• No apparent etiology or associated condition
• Drug-induced
• Allergic Quinine, ticlopidine
• Dose-related Mitomycin, gemcitabine, cyclosporin
• Pregnancy/postpartum
• Diarrhea-associated
• Bone marrow transplantation
• Congenital

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Changing incidence and clinical spectrum of
TTP-HUS

• Methods
• 168 consecutive patients over 10 years (U
  Oklahoma)
• BMT patients excluded
• Results
• Incidence 4.9/million/year - 9.5/million/year
• Associated findings Alternative diagnosis 49
  (29)
• Idiopathic 70 (42) Autoimmune disease 23
• Drug-induced 19 (11) Sepsis 10
• Pregnancy 18 (11) Malignancy 6
• Bloody diarrhea 12 (7) HIT 4
• Malignant HTN 3
• 
  HIV 2
• 
  MOF 1

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Changing incidence and clinicalspectrum of
TTP-HUS

• Conclusions
• The diagnosis of TTP-HUS is increasing
• This may be related to over-diagnosis
• This may be related to more drug-induced cases

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ADAMTS13, VWF, and TTP

• Structure and function of ADAMTS13
• Mutations in congenital TTP
• Pathophysiology of microangiopathy
• Treatment of TTP

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The Von Willebrand Factor Precursor
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Weibel-Palade Bodies

• Storage granules present in endothelial cells.
  They are a component of the secretory pathway of
  endothelial cells.
• Contain Factor VIII, von Willebrand factor,
  P-selectin, interleukin-8 and endothelin
• The vWF contained in the W-P bodies is the
  highly-active large multimer variety
• The production, release and processing of the vWF
  multimers is critical in TTP and vWF disease

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Weibel-Palade Bodies
0.5 mm
Courtesy of Elizabeth Cramer
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von Willebrand Factor Multimers
120 nm
Adapted from Fowler et al, J Clin Invest
761491-1500, 1985
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VWF Multimers in TTP
Endothelial Cell
Normal Plasma
Active
Remission
Unusually large Multimers
Moake et al, NEJM 3071432, 1982
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VWF and Platelet Adhesion
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Shear and VWF Proteolysis

• Proteolysis increased by
• Shear stress, denaturants
• VWD type 2A mutations

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VWF, ADAMTS13, and TTPFeedback Regulation of
Platelet Adhesion

• VWF Multimer Assembly
• Conserved mechanism
• Prevents multimerization in the ER
• Enables disulfides to form in the Golgi

• Proteolysis by ADAMTS13
• Cleaves VWF Tyr1605-Met1606
• Increase causes VWD (type 2A)
• Decrease causes TTP

Control of VWF multimer size is essential
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VWF, Proteolysis, and Platelet Adhesion
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VWF Cleaving Protease in Plasma

• Discovered in 1996 by Tsai and by Furlan
• Requires Ca2 and Zn2 ions
• Cleaves VWF between Tyr1605 - Met1606
• Activated by shear stress, mild denaturants

Absent in children with congenital TTP
Absent in most adults with idiopathic
TTP (acquired IgG autoantibody inhibitor)
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VWF Cleaving Protease(ADAMTS13)
Chromosome 9q34
Zheng and Chung et al, J Biol Chem 2001
27641059-41063
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VWF Cleaving Protease(ADAMTS13)
Metalloprotease
Thrombospondin 1
Disintegrin
A Disintegrin-like And Metalloprotease with
ThromboSpondin-1 repeats
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VWF Cleaving Protease(ADAMTS13)
Ligand binding?
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Mechanisms of Thrombotic Microangiopathy
ADAMTS13-Dependent (TTP)

• Lesions rich in VWF and platelets, poor in fibrin
• Exacerbated by stress, endothelial injury
• Inherited ADAMTS13 deficiency
• Responds to plasma infusion
• Autoimmune ADAMTS13 deficiency
• Idiopathic - majority
• Drug-associated - ticlopidine, clopidogrel
• Responds to plasma exchange
• May benefit from immunosuppression

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Non-ADAMTS13 Dependent Causes
Factor V Leiden-Dependent (TTP)
V Leiden V Leiden 0 16 4 7 Contro
ls 6 180
TTP and ADAMTS13 TTP and ADAMTS13
P Raife et al, Blood 2002 99 437-442
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Non- ADAMTS13 dependent causes
Complement Factor H Deficiency (HUS)

• Impaired inactivation of C3b, C4b
• Complement-mediated tissue injury
• Microvascular thrombosis
• Lesions rich in fibrin, poor in VWF and platelets
• Relatively severe renal damage
• Uncertain relationship to ADAMTS13 or VWF
• May respond to plasma infusion

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Non-ADAMTS13 causes
Verotoxin-induced (HUS)

• Lesions rich in fibrin, poor in VWF and platelets
• Relatively severe renal damage
• Epidemic bloody diarrhea (e.g., E. coli O157H7)
• Verotoxin is cytotoxic
• Binds globotriaosylceramide on endothelium
• Inhibits protein synthesis
• No demonstrated role for plasma therapy

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Initial treatment of TTP

• Plasma exchange
• Replace 1-1.5 volume of plasma daily
• Adjunctive therapy
• Glucocorticoids
• Aspirin
• Dipyridamole

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Response to initial therapy

• Rapid response (1-2 days)
• Non-focal neurologic symptoms
• Moderate response (3-10 days)
• Thrombocytopenia
• Parameters of hemolysis (LDH)
• Slow response (weeks-months)
• Anemia
• Renal insufficiency (unpredictable and often
  incomplete)

Treatment requires persistence and patience
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Complications of plasma exchange treatment
Approximate Complication frequency
() Central-venous catheter related
Procedure(Pneumothorax,Hemorrhage) 1-4
Infection 10-15 Thrombosis
(Catheter or venous)
10 Plasma-related Allergic (Urticaria,hypotens
ion, hypoxia) 4 Alkalosis Volume
depletion Transfusion-transmitted infection
Unintentional platelet pheresis ?
Rizvi, MA et al. Transfusion 2000 40896-91.
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Follow-up and outcome

• Follow up
• Duration of initial treatment is undefined
• Monitor CBC and LDH
• Outcome
• Relapse rates 29-82
• Chronic renal insufficiency (25)
• Long term neurologic effects (incidence ?)

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Approach to treatmentRelapse or refractory
patients

• Continue/intensify plasma exchange
• Aspirin/dipyridamole/glucocorticoids
• Splenectomy
• Immunosuppressive therapy
• Vincristine
• Other
• Intravenous immunoglobulin (IVIg)

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TTP and ADAMTS13

• Plasma exchange does not address the underlying
  autoimmune disorder
• Refractory disease may benefit from
  immunosuppression
• ADAMTS13 and inhibitor assays may become useful
  to guide therapy

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TTP treatment and ADAMTS13

• Plasma exchange does not address the underlying
  autoimmune disorder
• Refractory disease may benefit from
  immunosuppression
• ADAMTS13 and inhibitor assays may become useful
  to guide therapy

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Next Indication Guillain-Barre(Acute
inflammatory demyelinating polyradiculoneuropathy
AIDP)

• Thought to be a post infectious peripheral
  polyneuritis characterized by a rapidly
  progressive ascending peripheral nerve
  dysfunction leading to paralysis.
• Triggering events
• viral infections -lymphoma
• bacterial infections -surgery
• vaccines - trauma

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Polyneuropathy

• ADIP- Acute inflammatory demyelinating
  polyneuropathy- Most common in USA
• AMAN- Acute motor axonal neuropathy- Developing
  countries, Campylobacter jejuni association
• AMSAN- Acute motor/sensory axonal neuropathy
• MFS- Miller Fisher variant- ataxia,
  opthalmoplegia and areflexia without weakness

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Pathophysiology of AIDP

• Though to be an autoimmune response to antibodies
  present from a recent illness.
• The autoimmune response acts to breakdown the
  myelin sheath which functions to promote rapid
  conduction of nerve impulses. Axonal damage may
  also occur. The myelin sheath regenerates. The
  axons do not. Thus the amount of residual
  dysfunction is related to the amount of axonal
  damage that occurs.

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Assessment and Diagnosis of AIDP

• Signs and Symptoms
• motor weakness
• paresthesias
• sensory changes
• cranial nerve dysfunction
• Progression Abrupt onset of lower extremity
  dysfunction travelling upward. The accent is
  bilateral.

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Medical and Nursing Management

• Supportive measures as the disease runs its
  course and the myelin sheath regenerates.
• Ventilator support
• maintaining, joint, muscle and skin integrity
• nutritional support by enteral feedings
• Plasmapheresis To remove the antibodies.
• Immunoglobulin
• Steroids

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Next Indication Myasthenia Gravis

• A chronic, progressive, neuromuscular disease
  caused by an autoimmune disorder. The body
  produces antibodies that destroy the
  acetylcholine receptor sites of the neuromuscular
  junctions.
• Involves only skeletal muscles and frequently
  involves the muscles of chewing, swallowing, and
  speaking, and the facial and eye muscles.

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Signs and Symptoms of Myasthenia Gravis

• Muscle weakness (frequently of a specific muscle
  group).
• The weakness is worse after use and is relieved
  by rest.
• The weakness is usually worse later in the day.
• No sensory loss or pupil changes.
• May have difficulty holding their head up.

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Tensilon Test

• Injection of Tensilon, a fast acting
  acetylcholinesterase inhibitor, will reduce
  symptoms for about 5-10 minutes in a positive
  test.
• Atropine should be on hand in case of a
  cholinergic reaction
• Remember the neurotransmitter of the
  neuromuscular junction (Ach) is the major
  transmitter of the cholinergic system.

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Electromyography

• Takes advantage of the partial blockade in
  myasthenia
• Repeated stimulation leads to decremental
  response
• Testing done on several muscles

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Management of Myasthenia Gravis

• Anticholinesterase medications (acts to increase
  the acetylcholine that is available at the
  neuromuscular junction.
• Mestinon
• Mytelase
• Prostigmine
• Cholinergic medications
• Immunosuppressive therapy given to reduce the
  autoimmune response.

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Management of Myasthenia Gravis

• Plasmapheresis
• Patient teaching regarding airway management.
• Potential complications of MG are secondary to
• impaired swallowing
• weak cough
• inability to cough and deep breath
• frequent respiratory infections.

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Myasthenia Crisis vs Cholinergic Crisis

• Myasthenia Crisis onset of sudden muscular
  weakness usually the result of increased stress
  or under medication
• Cholinergic Crisis Same clinical manifestations
  as myasthenia crisis. Caused by over medication
  of cholinergic meds.
• Tensilon test is done to differentiate between
  the two.

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Works Cited

• Aetna Insurance Home page.
• Blinder, Morey. An Update on the Treatment and
  Pathogenesis of TTP. Hematology.im.wustl.edu
• Clinical Diagnosis and Management by Laboratory
  Methods. Henry, John. 20th Ed
• Clinical Laboratory Pearls. Jones, Steven.
• Other online sources cited in text
• UpToDate. Internet Resources. Vol 12 3.

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Any Questions?