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.