An Overview of Therapeutic Plasma Exchange

Betty L Fife RN, HP (ASCP) Clinical Specialist, CaridianBCT Therapeutic Apheresis and Cell Therapy

Disclosure
Employed by CaridianBCT, Inc. CaridianBCT manufactures and sells the COBE Spectra and Spectra Optia Apheresis Systems To date, therapeutic apheresis systems are cleared by FDA as tools for the conduct of therapeutic apheresis procedures. CaridianBCTs device labeling does not include specific therapeutic indications for use. The appropriate clinical application of therapeutic apheresis is left to the treating physician, as a part of his or her practice of medicine.

Presentation Overview
Plasma Exchange Procedure
definition, rationale and procedural aspects

Immune Response ASFAs Evidence Based-Approach guidelines to the use of TA

Learning Objectives
Participants will be able to: Define and state the rationale for a TPE procedure Discuss procedural aspects of a TPE procedure State two cell types that play important roles in the immune response State role of TPE associated with Pre and Post Renal Transplant.

Definition of a TA Procedure
The removal of a blood component from a patient using apheresis technology for the purpose of removing defective cells or depleting a disease mediator

Rationale For Performing a TA Procedure1

An apheresis procedure can more effectively remove a pathogenic substance in the circulating blood that contributes to a disease state than the bodys own homeostatic mechanisms can. The patient may benefit from both the removal of the blood component and replacement fluid given.
1. McLeod BC (editor), et al., Apheresis: Principles and Practice. 2003, second edition, American Association of Blood Banks (AABB), AABB Press, Bethesda, Maryland, United States .

Types of TA Procedures:
Therapeutic Plasma Exchange (TPE) Selective Extraction Red Blood Cell Exchange (RBCX)

Cellular Depletions

Therapeutic Plasma Exchange (TPE)

The removal of large volumes of patient plasma and replacement of the plasma with appropriate fluids.
Diseases treated with TPE:
Neurologic disorders Renal and metabolic diseases Hematologic diseases

Therapeutic Plasma Exchange

The most common use of TPE is for the treatment of autoimmune or immune mediated diseases or disorders.
TPE removes: Monoclonal antibodies Paraproteins Autoimmune antibodies Antigen-antibody complexes

Take Home Message

The production of antibody to self is responsible for many of the disorders treated with Therapeutic Plasma Exchange (TPE).

Autoimmune Therapy
Purpose:
Suppress the abnormal immune response Remove the causative factor Relieve/eliminate symptoms

Therapy:
Drugs Surgery Drugs and TPE

Therapeutic Plasma Exchange

Removing the patients plasma removes disease mediators circulating in the plasma, including:
Alloantibodies, autoimmune antibodies and antigen-antibody complexes Abnormal or increased amount of plasma proteins

Very high cholesterol levels

High levels of plasma metabolic waste products Plasma bound drugs or poisons

Decreasing levels of disease mediator can relieve symptoms but is not curative.

Alteration in Blood Constituents after a one PV Exchange

Constituent
Clotting factors Fibrinogen Immunoglobulins Paraproteins Liver Enzymes Bilirubin C3 Platelets

Decrease
25 50% 63% 63% 20 30% 55 60% 45% 63% 25 30%*

Recovery-48hrs
80 100% 65% 45% Variable % 100% 100% 60 100% 75 100%

* Apheresis instrument dependent

From: McLeod B, Price T, Weinstein R. Apheresis, Principles and Practice. AABB Press

Separation of Blood

Separation of Blood Components

Centrifugal force separates cells based on their specific gravity

Platelets
1.048*

Lymphocytes
1.071*

Plasma Buffy coat Packed red cells

*Average specific gravity of cell type shown
successions 2

Monocytes
1.065*

Granulocytes
1.085*

Procedural Aspects

Therapeutic Plasma Exchange Procedural Considerations

Frequency of the procedure Amount of plasma to remove Hemostasis and Anticoagulation Fluid balance Replacement Fluid Patient monitoring and care Vascular access

Vascular Access
TPE dual access procedure

The type of vascular access device needed will depend on patient condition and length of time TPE is needed

Types of access:
Peripheral veins (inserted for each procedure) Femoral or Central venous catheter (dialysis type catheter short term / long
term)

Implanted ports3 Graft/fistula (long term surgically implanted) Radial artery cannulation4 (requires trained physician to insert prior to each
procedure)

3.Gonzales A, et al., Long-Term Therapeutic Plasma Exchange in the Outpatient Setting Using an Implantable Central Venous Access Device. Journal of Clinical Apheresis 2004; 19: 180-184. 4. Khatri BO, Vascular Access Via Temporary Radial Artery Catheterization for Therapeutic Plasma Exchange. Journal of Clinical Apheresis 2003; 18: 134.

Hemostasis

Hemostasis
Primary hemostasis Vascular response Platelet plug formation

Secondary hemostasis Activation of the coagulation cascade Balance of clot formation and breakdown
*Anticoagulation is needed to keep blood in the apheresis device from
clotting

Coagulation Cascade
XII XI IX
Ca++

XIIa
Ca++

XIa IXa
VIII, Ca++ ,PI

X
Prothrombin

Xa
V, Ca++ ,PI Thrombin

Fibrinogen Fibrin

Platelets and calcium (Ca ) are needed for many of the reactions in the coagulation cascade

+2

Summary
Hemostasis is a complex mechanism whereby the body arrests bleeding from damaged blood vessels and maintains adequate blood flow Coagulation is part of hemostasis and involves a cascade of clotting factors and the activation, adhesion and aggregation of platelets

Take home message

There is a potential for clotting to occur in the tubing set as well as in the patient in response to:
Damage to the blood vessel Exposure of clotting factors and platelets to nonphysiological surfaces like plastic tubing or a catheter in a vein

Adequate anticoagulation is crucial !!

Anticoagulation

Anticoagulation in Apheresis

Anticoagulation in Apheresis
Factors impacting the microenvironment include:
Mechanism of action of the anticoagulant chosen
Concentration of anticoagulant The optimal anticoagulation for apheresis provides a microenvironment in the extracorporeal circuit in which all cells remain in suspension during separation and harvesting Hemostatic status of the donor or patient undergoing the apheresis procedure

Anticoagulation
ACD-A
Heparin Combinations of ACD-A and Heparin

Anticoagulation in Apheresis
ACD-A for TPE Procedures Acid Citrate Dextrose Solution A (ACD-A)
o 10,665 mg citrate/500 mL

Acts as an extracorporeal anticoagulant by:

o Binding ionized calcium (Ca++) in the extracorporeal circuit o Inhibiting platelet aggregation response o Inhibiting activation of calcium dependent plasma coagulation factors

Lowers the pH of whole blood to further prevent aggregation and keep platelets in suspension. Most common method of anticoagulation used for apheresis

AC Ratio
Determines the AC concentration in the extracorporeal circuit Lower platelet counts allow higher ratios

AC Infusion Rate
Dose Individuals at risk for citrate toxicity
o o o o o Low body weight Women Older patients Hepatic disease Renal disease

Heparin
Heparin for TPE Procedures Requires pre and post labs (PT,PTT, Coagulation factors) Mixed with ACD-A or Heparin drip Physician directed

Heparin Review
Complexes with antithrombin and increases its activity, which inactivates thrombin and other factors and prevents thrombus formation1 Anticoagulates systemically o Metabolized slowly (1 to 2 hours) Can cause heparin induced thrombocytopenia

Therapeutic Plasma Exchange Duration

Frequency of procedures

The frequency of TPE procedures can be disease specific and relates to the type of antibody present and the rate at which it equilibrates (redistributes or rebounds)
IgM removal: Predominantly intravascular
o Procedure may be done less frequently

IgG removal: Predominantly extravascular

o Procedure may be done more frequently

TPE and Removal of Proteins

Substance depletion by TPE depends on its distribution between intravascular and extravascular compartments. Larger molecular weight proteins (IgM, Fibrinogen) that reside mostly in the intravascular compartment, are more easily removed. IgG, which has a larger extravascular distribution, is less efficiently removed, requiring multiple procedures.
Therapeutic Apheresis : A Physicians Handbook 1st Edition, 1st Chapter, Page 5

Procedural Considerations: Amount of Plasma to Remove

The success of a TPE procedure is dependent on:
Distribution of disease mediator
Between intravascular and extravascular space Rate of re-equilibration between the intravascular and extravascular space

Amount of plasma removed

Calculation of Total Blood Volume and Plasma Volume

Patient Sex Height Weight

Total blood volume* (TBV)

TBV x (1-Hct) = Plasma volume 6000 x 0.60 = 3600 ml

TBV 6000 mL

60%

Plasma volume 3600 mL

RBC Volume 2400 mL

40%

TBV and plasma volume are calculated by the apheresis device

*based on Nadler/Allen nomogram

Procedural considerations

Procedural Considerations Replacement Fluid

Replacement fluid: Crystalloids contain no protein o 0.9% NaCl Colloids contain protein o 5% Albumin o Plasma Substitutes (PPF) o Fresh Frozen Plasma

Replacement fluids contain citrate!!

18 16 14 12 10 8 6 4 2 0 Plasma Albumin Saline

Procedural Considerations Fluid Balance

Fluid balance:
Fluid (Plasma) Removed from patient Fluid (AC and replacement fluid) Given to patient

Isovolemia:
Fluid removed = Fluid replaced

Hypovolemia
Fluid removed > Fluid replaced

Hypervolemia
Fluid removed < Fluid replaced

Procedural Considerations Patient Monitoring

Pre-procedure CBC
Electrolyte panel Coagulation studies Disease specific indicators

During the procedure Monitoring for comfort

Vital signs

Post procedure Center and patient specific

Therapeutic Plasma Exchange Procedural Considerations

TPE is a non-specific therapy:

It also removes normal plasma components important in the maintenance of homeostasis:
Immunoglobulins (IgG, IgM, IgA) Cholesterol Albumin Fibrinogen Urea, Creatinine Electrolytes Plasma bound drugs

Therapeutic Plasma Exchange Procedural Considerations

Adverse reactions
Chilling (feeling cold) Hypocalcemia Hypotension Vascular access related Allergic reactions

Procedural Considerations: Adverse Events Hypocalcemia

Symptoms: Numbness and tingling Chills Chest wall vibrations Tetany Cardiac arrythmias Intervention: Slow or pause the procedure Oral or IV calcium

Procedural Considerations: Adverse Events

Hypotension
Symptoms: Lightheadedness Increased pulse rate Shallow respirations Perspiration Intervention: Lower head/raise feet Give fluids either crystaloid or colloid

Procedural Considerations: Adverse Events Allergic reaction

Symptoms: Hives Rash Swelling Difficulty breathing Intervention: Stop procedure Contact physician for treatment

The Immune System

Need

Normal Immune Response

Foreign Ag Macrophage

Antigen presenting cells (APCs) circulate through the body touching and capturing antigen (Ag) APCs process and present self and non-self Ag to T helper (TH) cells If APCs receive the correct chemical signals, an appropriate mix of T-helper cells are produced TH cells signal B cells to develop into plasma cells and produce antibodies Antibodies mediate a number of different processes to destroy nonself cells

Dendritic cell

Helper T-cells

B-cells

Antibodies

Plasma cells

Normal Immune Response

Dendritic cell

APC presenting Ag To TH cell

Cytotoxic T cells

TH cells also play a role in the generation of cytotoxic T cells (CTLs) CTLs directly lyse infected cells.

Infected cell

Normal Immune Response

As non-self Ags are eliminated, APCs stop presenting Ag to TH cells, returning the body to its normal state

Cell and antibody mediated immune responses destroy non-self cells and cause an inflammatory response

The inflammatory response results from chemicals released by phagocytic cells and by products of phagocytosis

It is characterized by o Fever o Pain o Swelling

Abnormal Immune Response

Autoimmune Disease
Occurs when an adaptive immune response is triggered inappropriately against self antigens Antigen cannot be cleared by normal immune processes resulting in a sustained immune response, chronic inflammation and injury to involved tissues

Types of Autoimmune Disease

Cellular-mediated
Disease resulting from an individual's white blood cells (T cells) recognizing the body's own tissues as foreign and attacking them.

Direct antibody mediated

Disease resulting from an immune reaction produced by antibodies acting on the body's own tissues or extracellular proteins.

Immune complex disease

Disease resulting from the deposition of antigen-antibody-complement complexes in the microvasculature of tissues. Complement initiates inflammation.

Autoimmune Disease Sequence of Events

1. Self cells are inappropriately identified as non-self cells T cells activate B cells to produce antibodies against the self cells

2.

3.

An immune response is initiated with resulting inflammatory effects: Fever Pain Swelling
Self cell is destroyed

4.

Immune Complex Disease

1.

An antibody and an antigen combine to form a complex Middle-size complexes become entrapped in blood vessels in the skin and kidneys, and in synovial membrane of the joints

2.

Effects:
Vasculitis Nephritis Arthritis

American Society for Apheresis

Journal of Clinical Apheresis

Volume 25- Issue 3- 2010 A Modified Approach Indications for TA
Level of evidence Grading recommendations (Guyatt et al.)

ASFA Guidelines
Categories- Redefinition of the Indications Evidence-Based Assessment of the Therapeutic Apheresis Literature Recommendations-Sub-Categories Focus on Treatment Approach to a given Clinical Condition Fact Sheets

ASFA Categories Category I- Apheresis is accepted as first-line therapy

(primary or in conjunction with other modes of treatment)
Grade 1A- Strongly recommended, high quality evidence Grade 1B- Strongly recommended, moderate quality evidence Grade 1C- Strongly recommended. low to very low quality evidence

ASFA Categories Category II- Apheresis is accepted as secondline

therapy, either as standalone treatment or in conjunction with other modes of treatment.
Grade 2A- Weak recommendation, high quality evidence Grade 2B- Weak recommendation, moderate quality evidence Grade 2C- Weak recommendation, low or very low quality evidence

ASFA Categories
Category III- Optimum role of Apheresis is not
established. Decision making should be individualized

Category IV- Published evidence demonstrates or

suggests Apheresis to be ineffective or harmful. IRB approval is desired

Tissue Typing: Determination of Eligibility

ABO (Blood Type) Compatibility -Same or compatible blood type
-RH factor not a consideration

Cross Match Compatibility -Humoral immune reponse

-Detects antibodies against donor cells -Test (mixture of donor and recipient blood)

Human Leukocyte Antigens (HLA) Tissue Typing

-Unique protein markers on cells

-Graft rejection- Self identifies non-self and destroys -Acute or chronic

TPE for ABO Incompatibility

Solid Organ- Kidney Category II, Grade 1B Shortage of kidney transplants Major incompatibility against A and/or B blood groups Adjunct therapy to reduce anti-A or anti-B antibodies Preconditioning protocols using TPE to lower antibody titers <4, prior to transplant Volumes- 1-1.5 TPV Frequency- Daily or QOD (Post transplant-taper with titer reduction)

TPE for Renal Transplant

CATEGORIES for Treatment with TPE
-Antibody mediated rejection(AMR)Category I, Grade 1B *Preconditioning protocols using TPE to lower antibody titers
*Post transplant-taper with titer reduction

-Desensitization, Category II, Grade 1B

*Positive cross match, reduce donor specific antibody (DSA) *Convert from positive to negative pre transplant

-High PRA; cadaveric donor, Category III

*Positive panel reactive antibodies (PRA)

Grade 2C

Thank you

References
The Biology Department Development Team, University of Arizona, The Biology Project, University of Arizona, revised October 26, 2002, http://www.biology.arizona.edu/immunology/tutorials/immunology/page3.html Carter PM, Immune Complex Disease, Annals of the Rheumatic Diseases 1973, 32: 265-271. Dahlbck B, Blood Coagulation, The Lancet 2000; 355 (9215): 1627-1632. Green D, Coagulation Cascade, Hemodialysis International 2006; 10 (Suppl. 2): S2-S4. Gonzales A, et al., Long-Term Therapeutic Plasma Exchange in the Outpatient Setting Using an Implantable Central Venous Access Device. Journal of Clinical Apheresis 2004; 19: 180-184. Janeway C, Immunobiology. 2001, fifth edition, Garland Science Publishing, New York, New York, United States. Khatri BO, Vascular Access Via Temporary Radial Artery Catheterization for Therapeutic Plasma Exchange. Journal of Clinical Apheresis 2003; 18: 134.

References
McLeod BC (editor), et al., Apheresis: Principles and Practice. 2003, second edition, American Association of Blood Banks (AABB), AABB Press, Bethesda, Maryland, United States. Szczepiorkowski ZM, et al., Guidelines on the Use of Therapeutic Apheresis in Clinical PracticeEvidence-Based Approach From the Apheresis Applications Committee of the American Society for Apheresis. Journal of Clinical Apheresis 2007; 22: 106-175. Szczepiorkowski ZM, et al., The New Approach to Assignment of ASFA CategoriesIntroduction to the Fourth Special Issue: Clinical Applications of Therapeutic Apheresis. Journal of Clinical Apheresis 2007; 22: 96-107. Szczepiorkowskial, Zbigniew M. Special Issue: Applications of Therapeutic Apheresis. Journal of Clinical Apheresis 2010; Volume-25, Issue 3. Tormey CA, et al., Improved Plasma Removal Efficiency for Therapeutic Plasma Exchange Using a New Apheresis Platform. Transfusion 2009, in press. Winters JL, (editor), Therapeutic Apheresis: A Physicians Handbook. 2008, second edition, American Association of Blood Banks (AABB), AABB Press, Bethesda, Maryland, United States. Zimmerman LH, Causes and Consequences of Critical Bleeding and Mechanisms of Blood Coagulation. Pharmacotherapy 2007, 27 (Suppl. 9, part 2), 45S-56S.