An Overview ofTherapeutic Plasma Exchange
Betty L Fife RN, HP (ASCP)Clinical Specialist, CaridianBCTTherapeutic 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.
• CaridianBCT’s 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• ASFA’s 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 body’s 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 patient’s 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.
Clotting factors 25 – 50% 80 – 100%
Fibrinogen 63% 65%
Immunoglobulins 63% 45%
Paraproteins 20 – 30% Variable %
Liver Enzymes 55 – 60% 100%
Bilirubin 45% 100%
C3 63% 60 – 100%
Platelets 25 – 30%* 75 – 100%
Constituent Decrease Recovery-48hrs
From: McLeod B, Price T, Weinstein R. Apheresis, Principles and Practice. AABB Press
Alteration in Blood Constituents after a one PV Exchange
* Apheresis instrument dependent
Separation of Blood
successions 2
Separation of Blood Components
Centrifugal force separates cells based on their specific gravity
*Average specific gravity of cell type shown
Plasma
Packedred cells
Buffycoat
Granulocytes1.085*
Monocytes1.065*
Lymphocytes1.071*
Platelets 1.048*
Procedural Aspects
• Frequency of the procedure• Amount of plasma to remove• Hemostasis and Anticoagulation• Fluid balance • Replacement Fluid• Patient monitoring and care• Vascular access
Therapeutic Plasma Exchange – Procedural Considerations
• TPE – dual access procedure
• The type of vascular access device needed will depend on patient condition and length of time TPE is needed
Vascular Access
4. Khatri BO, “Vascular Access Via Temporary Radial Artery Catheterization for Therapeutic Plasma Exchange.” Journal of Clinical Apheresis 2003; 18: 134.
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.
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
XIIaXI
IXXIa
IXaX
Xa
Thrombin
Fibrin
Fibrinogen
Prothrombin
VIII, Ca++ ,PI
V, Ca++ ,PI
Ca++
Ca++
Platelets and calcium (Ca+2) are needed for many of the reactions in the coagulation cascade
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 non-
physiological 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 responseo 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 Low body weight o Women o Older patients o Hepatic disease o 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 systemicallyoMetabolized slowly (1 to 2 hours)
• Can cause heparin induced thrombocytopenia
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 intravascularo Procedure may be done less frequently
• IgG removal: Predominantly extravascularo Procedure may be done more frequently
Therapeutic Plasma Exchange – Duration
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 Physician’s 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
TBV
6000 mL
Plasma volume
3600 mL
RBC Volume2400 mL
60%
40%
Patient SexHeightWeight
Total blood volume* (TBV)
TBV x (1-Hct) = Plasma volumeTBV x (1-Hct) = Plasma volume
6000 x 0.60 = 3600 ml6000 x 0.60 = 3600 ml
TBV and plasma volume are calculated by the apheresis device
*based on Nadler/Allen nomogram
Procedural considerations
Replacement fluid:• Crystalloids – contain no
proteino 0.9% NaCl
• Colloids – contain proteino 5% Albumino Plasma Substitutes (PPF)o Fresh Frozen Plasma
Procedural Considerations – Replacement Fluid
Replacement fluids contain citrate!!
0
2
4
6
8
10
12
14
16
18
Plasma Albumin Saline
Procedural Considerations – Fluid Balance
Fluid balance:
Isovolemia:
Fluid removed = Fluid replaced
Hypovolemia
Fluid removed > Fluid replaced
Hypervolemia
Fluid removed < Fluid replaced
Fluid (AC and replacement fluid) Given to patient
Fluid (Plasma) Removed from patient
Pre-procedure
• CBC
• Electrolyte panel• Coagulation studies• Disease specific indicators
Procedural Considerations – Patient Monitoring
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• P lasma bound drugs
Therapeutic Plasma Exchange –Procedural Considerations
Adverse reactions
• Chilling (feeling cold)• Hypocalcemia• Hypotension• Vascular access related• Allergic reactions
Procedural Considerations: Adverse Events
Symptoms:• Numbness and tingling• Chills• Chest wall vibrations• Tetany• Cardiac arrythmias
Intervention:• Slow or pause the
procedure• Oral or IV calcium
Hypocalcemia
Procedural Considerations: Adverse Events
Symptoms:• Lightheadedness• Increased pulse rate• Shallow respirations• Perspiration
Hypotension
Intervention:• Lower head/raise feet• Give fluids either
crystaloid or colloid
Procedural Considerations: Adverse Events
Symptoms:• Hives• Rash• Swelling• Difficulty breathing
Intervention:• Stop procedure• Contact physician for
treatment
Allergic reaction
The Immune System
Need
Normal Immune Response
• 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 non-self cells
Plasma cells
Antibodies
Helper T-cells
Macrophage
B-cells
Dendritic cell
Foreign Ag
Normal Immune Response
• TH cells also play a role in the generation of cytotoxic T cells (CTLs)
• CTLs directly lyse infected
cells.
Cytotoxic T cells
Infected cell
APC presenting AgTo TH cell
Dendritic 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 byo Fevero Paino 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
2. T cells activate B cells to produce antibodies against the self cells
3. An immune response is initiated with resulting inflammatory effects:
• Fever• Pain• Swelling
4. Self cell is destroyed
Immune Complex Disease
1. An antibody and an antigen combine to form a complex
2. Middle-size complexes become entrapped in blood vessels in the skin and kidneys, and in synovial membrane of the joints
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 Grade 2C *Positive panel reactive antibodies (PRA)
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.
Dahlbäck 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 Practice—Evidence-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 Categories—Introduction 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 Physician’s 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.