An Overview of Therapeutic Plasma Exchange

1. An Overview ofTherapeutic Plasma Exchange Betty L Fife RN, HP (ASCP)Clinical Specialist, CaridianBCTTherapeutic Apheresis and Cell Therapy

2. 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. 

3. Presentation Overview • Plasma Exchange Procedure • definition, rationale and procedural aspects • Immune Response • ASFA’s Evidence Based-Approach guidelines to the use of TA

4. 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.

5. 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

6. 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. • McLeod BC (editor), et al., Apheresis: Principles and Practice. 2003, second edition, American Association of Blood Banks (AABB), AABB Press, Bethesda, Maryland, United States.

7. Types of TA Procedures: • Therapeutic Plasma Exchange (TPE) • Selective Extraction • Red Blood Cell Exchange (RBCX) • Cellular Depletions

8. 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

9. 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

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

11. Autoimmune Therapy • Purpose: • Suppress the abnormal immune response • Remove the causative factor • Relieve/eliminate symptoms • Therapy: • Drugs • Surgery • Drugs and TPE

12. 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.

13. Constituent Decrease Recovery-48hrs 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% Alteration in Blood Constituents after a one PV Exchange * Apheresis instrument dependent From: McLeod B, Price T, Weinstein R. Apheresis, Principles and Practice. AABB Press

14. Separation of Blood

15. Separation of Blood Components Centrifugal force separates cells based on their specific gravity *Average specific gravity of cell type shown Platelets 1.048* Lymphocytes 1.071* Plasma Monocytes 1.065* Buffy coat Granulocytes 1.085* Packed red cells successions 2

16. Procedural Aspects

17. 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

18. 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) • 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.

19. Hemostasis

20. 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

21. XII XIIa XI XIa IX IXa X VIII, Ca++ ,PI Xa Prothrombin V, Ca++ ,PI Thrombin Fibrinogen Fibrin Coagulation Cascade Ca++ Ca++ Platelets and calcium (Ca+2) are needed for many of the reactions in the coagulation cascade

22. 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

23. 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 !!

24. Anticoagulation

25. Anticoagulation in Apheresis

26. 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

27. Anticoagulation • ACD-A • Heparin • Combinations of ACD-A and Heparin

28. Anticoagulation in Apheresis ACD-A for TPE Procedures • Acid Citrate Dextrose Solution A (ACD-A) • 10,665 mg citrate/500 mL • Acts as an extracorporeal anticoagulant by: • Binding ionized calcium (Ca++) in the extracorporeal circuit • Inhibiting platelet aggregation response • 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

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

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

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

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

33. 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 • Procedure may be done less frequently • IgG removal: Predominantly extravascular • Procedure may be done more frequently

34. 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

35. Procedural Considerations: Amount of Plasma to RemoveThe 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

36. Plasma volume 3600 mL 60% TBV 6000 mL RBC Volume 2400 mL 40% 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 and plasma volume are calculated by the apheresis device *based on Nadler/Allen nomogram

37. Procedural considerations

38. Procedural Considerations – Replacement Fluid Replacement fluid: • Crystalloids – contain no protein • 0.9% NaCl • Colloids – contain protein • 5% Albumin • Plasma Substitutes (PPF) • Fresh Frozen Plasma Replacement fluids contain citrate!!

39. Procedural Considerations – Fluid Balance Fluid (Plasma) Removed from patient Fluid (AC and replacement fluid) Given to patient Fluid balance: Isovolemia: Fluid removed = Fluid replaced Hypovolemia Fluid removed > Fluid replaced Hypervolemia Fluid removed < Fluid replaced

40. 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

41. 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

42. Therapeutic Plasma Exchange –Procedural Considerations Adverse reactions • Chilling (feeling cold) • Hypocalcemia • Hypotension • Vascular access related • Allergic reactions

43. 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

44. Procedural Considerations: Adverse Events Hypotension Symptoms: • Lightheadedness • Increased pulse rate • Shallow respirations • Perspiration • Intervention: • Lower head/raise feet • Give fluids either crystaloid or colloid

45. Procedural Considerations: Adverse Events Allergic reaction Symptoms: • Hives • Rash • Swelling • Difficulty breathing • Intervention: • Stop procedure • Contact physician for treatment

46. The Immune System Need

47. 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 non-self cells Dendritic cell Helper T-cells B-cells Antibodies Plasma cells

48. Normal Immune Response • TH cells also play a role in the generation of cytotoxic T cells (CTLs) • CTLs directly lyse infected cells. APC presenting Ag To TH cell Dendritic cell Cytotoxic T cells Infected cell

49. 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 • Fever • Pain • Swelling

50. Abnormal Immune Response