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Clinical Applications Of Therapeutic Apheresis
- 1. Clinical Applications of TherapeuticApheresis Raul H. Morales-Borges, MD Medical Director Blood Services American Red Cross of Puerto Rico
- 2. Origin of theWord “APHERESIS” Greek Means “Withdrawal Blood components are separated by centrifugation accordingly to relative density.
- 3. Density of bloodcomponents Plasma 1.025-1.029 Platelets 1.040-1.045 Lymphocytes 1.050-1.061 Granulocytes 1.087-1.092 Erythrocytes1.078-1.114
- 4.
- 5. Definition of TPE •Removalof large volumes of patient plasma and replacement of the plasma with appropriate fluids. Specialty areas: •Renal and metabolic diseases •Hematologic diseases •Neurologic disorders
- 6. Therapeutic Apheresis (TA) Whole blood is removed from the patient into an instrument that separates its components via a centrifugation process. The goal is to selectively remove a substancial proportion of one or more components causing disease while returning the remaining components to the patient, with or without replacement of the removed component.
- 7. TA Technologies Membrane Centrifugation Prisma Gambro BCT Asahi Plasma Flow Cascade apheresis for selective plasma component removal Specialized devices
- 8. Apheresis in ClinicalPractice Sickle Cell Dis. Malaria Thrombocytosis RBC WBC PLT Plasma Leukemias TTP Cell Therapies Guillain Barre Syn. Myasthenia Gravis Goodpasture’s Syn. Waldenstrom’s
- 9.
- 10. “When it comesto bloodletting four questions must be answered” Who? When? How much? Which Fluids?
- 11. Removed with Plasma •Immune complexes •Immunoglobulins (IgG, IgM, IgA) •Abnormal/increased amounts of plasma protein •Cholesterol • •Plasma metabolic waste products •Plasma protein bound poisons
- 12. Access Plamapheresis is an extracorporeal theapy and as such is dependent on adequate central vascular access. As plasmapheresis results in profound immunosuppression, a tunnelled line is preferred. Baxter/Edwards Bloodlines are used. Apheresis/dialysis-compatible catheter vendors include MedComp, Quinton Intruments, Vascath, Arrow, and Vaxcel.
- 13. A “perfect” apheresiscatheter: Dual lumen Staggered ports Large-bore lumens Minimal length Sufficient firmness Biocompatibility Infection resistance
- 14. How much? Volume of exchange • 1-1.5 plasma volume Calculation depends on numerous factors • Frequency of procedures • Duration of therapy
- 15. Important Formulas Total Blood Volume= 0.065 x Kg Plasma Volume=(0.065 x Kg) x (1 – Hct in decimal number) Red Cell Volume= Hct in decimal x TBV
- 16. Efficiency of Plasmapheresis What is being Efficiency of Plasmapheresis removed? 70 60 • IgG - mainly 50 40 1 plasma vol 1.5 plasma vol extravascular Percent 30 2 plasma vol 20 • IgM – mainly 10 0 intravascular
- 17. Frequency of Procedures Disease specific: IgM removal: Predominantly intravascular Procedure may be done every other day. IgG removal: Predominantly extravascular Procedure may be done daily.
- 18. Exchange Fluids 5% Albumin • Best choice • Dilute only with saline Combination of saline and albumin FFP Cryopoor plasma Cryoprecipitate (vWF mediates in recurrent TTP; also used to avoid fluid overload)
- 19. Replacement Fluid Crystalloids: Containno protein. Normal saline 0.9% Ex: in combination with albumin replacement Colloids: Contain protein 5% albumin Ex: Guillian-Barré, myasthenia gravis Fresh frozen plasma/cryo-poor plasma Ex: TTP, HUS (thrombotic microangiopathies) 6% hetastarch, pentastarch
- 20. Anticoagulant •ACD-A: Binds to Ca++. Lowers pH of the blood. Inhibits platelet clumping. Acts as an extracorporeal anticoagulant. May cause hypocalcemia. •Heparin: Complexes with antithrombin and increases its activity which inactivates thrombin and other factors and prevents thrombus formation.* Acts as a systemic anticoagulant. There are individual sensitivities and elimination rates. Can cause heparin induced thrombocytopenia. *Essentials of hemostasis and thrombosis drugs used in management of thrombosis.
- 21. Diseases Treated withTA Guillain-Barre Syndrome 11% Guillain-Barre Syndrome 11% Myasthenia Gravis 12% Myasthenia Gravis 12% CIDP 8% CIDP 8% Cryoglobulinemia 30% Cryoglobulinemia 30% Anti-GBM Disease 30% Anti-GBM Disease 30% Pauci-immune RPGN 13% Pauci-immune RPGN 13% SLE nephropathy 10% SLE nephropathy 10% Myeloma kidney 7% Myeloma kidney 7% Recurrent FSG 5% Recurrent FSG 5% Renal transplantation 5% Renal transplantation 5%
- 22. American Society forApheresis (ASFA) Guidelines Indications by Category (there are 4 categories). There are 3 levels of evidence. There are 2 grade recommendations.
- 23. Category I: Apheresisis considered primary or standard. Category II: There is sufficient evidence to suggest efficacy, usually in an adjunctive role. Category III: Insufficient data to determine effectiveness. Isolated published studies have indicated that it may be of benefit as a “last-ditch” effort. Category IV: Controlled trials have not shown benefit.
- 24. Renal and metabolicdiseases: Antiglomerular basement membrane antibody disease (cat. I) Rapidly progressive glomerulonephritis (cat. II) Familial hypercholesterolemia (cat. II) Cryoglobulinemia (cat. II)
- 25. Hematologic diseases: ABO-mismatched marrow transplant (cat. II) Thrombotic thrombocytopenia purpura (cat. I) Myeloma, paraproteins, or hyperviscosity (cat. II) Coagulation factor inhibitors (cat. II)
- 26. Neurologic disorders: Guillain-Barré syndrome (Acute inflammatory demyelinating polyradiculoneuropathy)(cat. I) Chronic inflammatory demyelinating Polyradiculoneuropathy (cat. I) Myasthenia gravis (cat. I) Cryoglobulinemia with polyneuropathy (cat. II)
- 27. Modified McLeod’s Criteriafor Evaluation of Efficacy of Therapeutic Apheresis Evidence Mc Leod’s Explanation Criteria Mechanism Plaussible Clear Pathogenesis Rationale Correction Better Blood Meaningfully Corrected Clinical Effect Perkier Clinically Patients Worthwhile
- 28. ASFA 2010 IndicationCategories for TA There are 68 diseases. There are many TA accordingly to the diseases. Few of the procedures are: • Total Plasma Exchange (TPE) • RBC Exchange • Extracorporeal Photopheresis (ECP) • Immunoadsorption (IA) • Thrombocytapheresis & Leukocytapheresis • Selective removal methods • Adoptive Cytapheresis • Membrane differential filtration • Cryofiltration apheresis
- 29. General Issues tobe Considered When Evaluating a New patient for Initiation of TA Rationale Impact Technical Issues Therapeutic Plan Clinical and/or laboratory end-points Timing & Location
- 30. Risks / Sideeffects of TA The overall rate is < 5%. Transfusion Reactions Nausea/Vomiting Hypotension, hypovolemia, fluid overload Vasovagal reactions Pallor, tachycardia, respiratory distress, muscle spasm, chills, rigors Hematomas, venous sclerosis, thrombosis, bleeding, infection Hypocalcemia from citrate
- 31. Use of Calciumin Preventing Symptoms TUMS 1000 mg po 30 minutes prior the procedure and halfway of the procedure (As recommended by Medical Directors Consensus from ARC) Or Use Calcium Gluconate as always.
- 32. Use of Magnesium IV Magnesium as per an article from FDA, NIH, Walter Reed ARMY Institute of Research (Salim Haddad et al: Transfusion June 2005; 45: 934-944).
- 33. Metabolic Alkalosis dueto TPE It’s common in patients with decreased renal function. Secondary to large sodium citrate load given during the procedure. Can be prevented when using 3% albumin and cryoprecipitate rather than FFP’s Pearl RG, Rosenthal MH: American Journal of Medicine 1985 Sep; 79(3): 391-393.
- 34. Blood Component Collectionby Apheresis Began in the 1970’s. Platelet donors are limited to 24 collections during a rolling 12-month period. RBC’s donors are limited to donate 2 units every 16 weeks. Single whole blood or one PRBC’s unit donor every 8 weeks.
- 35. Use in HematopoieticStem Cell Transplatation as Mobilization & Collection of PBHPC’s Last Standards & Rules by FDA on 11/24/2004 and effective on 05/25/2005. Goal: To achieve the Product CD34+ cell counts appropriate for infusion to the recipient.
- 36. TTP – AThrombotic Microangiopathy Microvascular Occlusive Disorder Platelet thrombi Thrombocytopenia Mechanical damage to erythrocytes 70% of patients are women
- 37. TTP – hyalinethrombi in glomerolus
- 38. TTP – MortalityRate 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Before Plasma Exchange After Plasma Exchange
- 39. Pathophysiology of TTP Presence of Unusually Large von Willebrand Factor Multimers (ULvWFM) Absence or low levels of ADAMTS13 (vWF cleaving metalloprotease) Presence of auto-antibodies to ADAMTS13
- 40. Plasma Exchange inTTP FFP as exchange fluid Removal of auto-antibodies to vWF multimers cleaving enzyme Infusion of vWF multimers cleaving enzyme
- 41. Pathophysiology of TTP Normal TTP Cleaved von Willebrand Factor multimers Platelet aggregate vWF-Cleaving Enzyme Auto-antibody to vWF-Cleaving Uncleaved unusually Enzyme large vWF multimers Endothelial Cell Endothelial Cell
- 42. Diagnosis From Pentad to Triad Thrombocytopenia Thrombocytopenia MAHA MAHA CNS symptoms LDH elevation Renal insufficiency Fever
- 43. Conditions Associated withTTP Primary (idiopathic) Secondary • Systemic autoimmune • Drugs disorders Ticlopidine SLE Clopidrogel Rheumatoid arthritis Cyclosporine A Scleroderma Tacrolimus Polyarteritis nodosa Quinine • Infectious diseases • Neoplastic diseases HIV infection • Surgeries Bacterial endocarditis Cardiovascular Intestinal • PBSC transplantation • Pregnancy
- 44. Treatment of TTP Daily plasma exchange Exchange fluids • FFP • Cryopoor plasma • Detergent treated plasma Treat until clinical symptoms improve and laboratory values normalize Avoid platelet transfusions
- 45. Treatment of persistentTTP Plasma exchange Corticosteroids Vincristine Rituximab Splenectomy
- 46. Treatment of relapsingTTP Plasma exchange Treat beyond improvement Consider adding medications Splenectomy Look for other disease association
- 47. TTP/HUS (Hemolytic Uremic Syndrome) HUS • MAHA • Renal failure Classic HUS • Childhood, Escherichia coli 0157:H7 association Adult HUS • Renal disease is more severe • Difficult to differentiate from TTP Platelet – fibrin thrombi Normal ADAMTS 13 (vWF cleaving enzyme) levels No auto-antibody to ADAMTS Response to plasma exchange – equivocal results
- 48. Rapidly Progressive Glomerulonephritis (RPGN); Crescentic Glomerulonephritis Subacute deterioration of renal function Crescents in glomeruli Various etiologies
- 50. Rapidly Progressive Glomerulonephritis (RPGN); Crescentic Glomerulonephritis Goodpasture’s syndrome (Anti-Glomerular Basement Membrane Disease or Anti-GBM Disease) Pauci immune RPGN (Wegener’s Granulomatosis or microscopic polyarteritis with antineutrophil cytoplasmic antibodies (ANCA) RPGN with granular immune complex deposits sometimes associated with systemic vasculitis
- 51. Goodpasture’s syndrome Anti-GBM antibodies crossrective with alveolar basement membrane
- 52. Goodpasture’s Syndrome Clinical presentation • RPGN • Pulmonary hemorrhage • Anti-GBM antibodies Treatment • Immunosuppressive drugs Cyclophosphamide Corticosteroids Azathioprine • Plasmapheresis (ASFA Category I) Daily pheresis for 14 days with 5% albumin, 1-1 ½ plasma volume Finish procedure with 1 liter of FFP in cases with pulmonary hemorrhage and /or renal biopsy
- 53. Antineutrophil Cytoplasmic Antibodies • ANCA by immunofluorescence methods • c-ANCA = Wegener’s disease (60% to 90%) • p-ANCA = microscopic polyangiitis (MPA) (50% to 80%), UC (40% to 80%), Crohn’s (10% to 40%) Hoffman GS. Arth Rheum. 1998;41(a):1521–1537.
- 54.
- 55. ANCA positive PauciImmune RPGN Clinical presentation • RPGN with or without pulmonary hemorrhage • Perinuclear (p-ANCA)-systemic microvasculitis • Internuclear (c-ANCA)-Wegener’s granulomatosis Treatment • Immunosuppressive drugs • Plasmapheresis (ASFA Category II) may benefit patients with severe renal disease (Cr 9) and dialysis dependent patients
- 56. Immune Complex RPGN(MPGN)
- 57. Immune Complex RPGN Clinical presentation • RPGN • Membranoproliferative GN (MPGN) Associations • Hepatitis C • Cryoglobulinemia Treatment • Antiviral drugs • Corticosteroids • Plasmapheresis (ASFA Category II)
- 58. Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) ‘ Guillain-Barre Syndrome (GBS) Pathogenesis • Anti-myelin (gangliosides) antibodies GM1, GM1b, GD1a Clinical presentation • Ascending paralysis • “albuminocytologic dissociation” High CSF protein No CSF pleocytosis • 10-23% require assisted ventilation • Nerve conduction studies show demyelination • dysautonomia Treatment • Supportive care • IVIG 400mg/kg x 5 days • Plasmapheresis (ASFA Category I) Start within 14 days of onset 5-6 Q.O.D. procedures, 1-1 1/2 plasma volume exchange with 5% albumin
- 59.
- 60. GBS Clinical Course GBS course Symptom severity Time
- 61. Myasthenia Gravis Nerve Acetylcholine (Ach) AchR Anti-AchR Ab Muscle
- 62. Myasthenia Gravis Clinical picture • Variable degrees of weakness; improved by rest • Thymoma in 15% of patients Treatment • Mestinon • Prednisone • Imuran or other immunomodulatory meds • Plasmapheresis (ASFA Category I) • IVIG 400 mg/kg x 5 days • Thymectomy
- 63. Myasthenia Gravis Plasmapheresis • Acute myasthenic crisis • Respiratory insufficiency • Failure to respond to medications • Side effects of medications (prednisone) • Before and after surgery (thymectomy)
- 64. Myasthenia Gravis Before plasmapheresis After Plasmapheresis
- 65. Hyperviscosity Syndrome Causes • Wadenstrom’s macroglobulinemia 50% • Multiple myeloma 5% Clinical presentation • Neurologic symptoms • Bleeding diathesis • Retinal hemorrhage and papilledema • Hypervolemia • Congestive heart failure Treatment • Plasmapheresis (ASFA Category II) • Chemotherapy
- 67. Systemic Lupus Erythematosus (SLE) Systemic autoimmune disease with the presence of autoantibodies and immune complexes (anti-DNA, anti-DS-DNA) Multiple organ involvement including the kidneys Controlled clinical trials failed to show benefit from plasmapheresis in lupus nephropathy Plasmapheresis (ASFA Category III)
- 68. Red Cell Exchange Sickle Cell Disease Malaria Babesiosis
- 69. Sickle Cell Disease Clinical picture • Chronic genetic anemia • Hgb S instead of Hgb A alters the erythrocytes and their membranes (sickle red cells) • Increased blood viscosity • Microvascular occlusion Infarcts in brain, lungs, retina Pain crisis Priapism Acute chest syndrome Stroke • Treatment Red cell transfusions Hydroxyurea Red cell exchange (ASFA Category I) • Aims to maintain Hgb S <30
- 70. Malaria Cause • Plasmodium falciparum, vivax, ovale, malariae • Transmitted by female anopheline mosqito • Infected RBC adhere to endothelial cells of capillaries and postcapillary venules via surface knobs • Microvascular obstruction of brain, kidneys,lungs Clinical picture • Fever, malaise, headache • Neurologic impairment • Renal failure • ARDS Traetment • Chloroquine, quinine, quinidine • Red cell exchange (ASFA Category III) • Plasmapheresis for removal of cytokines to prevent or treat lactic acidosis, hypoglycemia (NR)
- 71. White Cell Depletion Leukapheresis Leukocytosis • Acute Myelogenous Leukemia (AML) • Chronic Myelogenous Leukemia (CML) • Acute Lymphocytic Leukemia (ALL) • Chronic Lymphocytic Leukemia (CLL) Clinical picture • Hyperviscosity with microvascular occlusion CNS symptoms Hemorrhage Pulmonary insufficiency Treatment • Combination chemotherapy (tumor cell lysis leads to metabolic imbalance and ARDS) • Leukapheresis (ASFA Category I) Ptreatment of leukocytosis Prevention of tumor cell lysis syndrome
- 72. Plateletpheresis Thrombocytosis (>1,000 x 10 /L) 9 • Essential • Polycytemia vera Clinical picture • Microvascular occlusion CNS symptoms Hemorrhage Pulmonary insufficiency Treatment • Chemotherapy • Plateletpheresis (ASFA Category I)
- 73. Rheumatoid Arthritis Chronic inflammatory autoimmune disease • Arthritis • Rheumatoid nodules • Serum rheumatoid factor Treatment • DMARD (Disease Modifying Anti Rheumatic Drugs) • Anti-TNF alpha monoclonal antibodies • Apheresis Plasmapheresis (ASFA Category IV) Lymphoplasmapheresis (ASFA Category II) Prosorba column (ASFA Category II)
- 74.
- 75. Protocols for Reducinganti-HLA antibodies in positive CXM and AMR IVIG alone Plasmapheresis and IVIG Plasmapheresis, IVIG and anti-CD20 antibody (splenectomy) AmJTransplant 4(7):1033-1041, 2004
- 76. Protocols for Reducinganti-HLA antibodies in positive CXM and AMR 30% rejection IVIG 42 patients episodes 89% graft survival at 2 years Plasmapheres 62 patients 94.2% graft is and IVIG survival at 3 years AmJTransplant 4(7):1033-1041, 2004
- 77. LDL Apheresis Using Liposorber or HELP system For LDL > 300 mg/dl or LDL > 200 mg/dl plus CAD Can be used in severe hypertriglyceridemia.
- 78. Extracorporeal photopheresis Immunomodulatory effect Cellex or TheraKos Using 8MSO 0.6 mg/kg For: • CTCL • Graft vs. Host Disease • Solid organ transplant rejection • Crohn’s Disease • Scleroderma
- 79. Quality & AuditManagement cGMP, cGTP, SOP’s, CFR FDA requirements & AABB standards OSHA, CMS, Joint Commission CAP CLIA Foundation for the Accreditation of Cellular Therapy (FACT)
- 80. Summary Therapeutic Apheresis is an outpatient or inpatient procedure that usually takes two to three hours and the blood components causing illness are removed from circulation saving lifes. The risks or side effects are manageable or preventable. Its under used. Future review of the guidelines is recommended & encouraged.
- 81. References Journal of Clinical Apheresis, Vol.15, No.1/2, 2000, Special Issue, Clinical Applications of Therapeutic Apheresis Journal of Clinical Apheresis 2000-2006 APHERESIS, Principles and Practice, 2nd & 3rd Editions from 2003 & 2010 respectively, Bruce C. McLeod Editor, AABB Press
- 82. Cont. References R Bambauer, R Latza, R Schiel: Therapeutic Apheresis in the Treatment of Hemolytic Uremic Syndrome in View of Pathophysiological Aspects. Ther Apher Dial 15(1): 10-19, 2011. ZM Szczepiorkowski 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. Jounal of Clinical Apheresis 25: 83-177, 2010. SG Shelat: Practical Considerations for Planning a Therapeutic Apheresis Procedure. The American Journal of Medicine 123(9): 777-784, 2010. Lamont Williams (AABBR Staff Writer): Plasma exchange in Organ Transplantation. AABB News, 8-19, April 2010. K. El-Gharini & DJ. Unsworth: Therapeutic apheresis – pasmapheresis. Clinical Medicine, 6(4): 343-347, July/August 2006. RB Striker, RG Miller & DD Kiprov: Role of plasmapheresis in acute disseminated (postinfectious) encephalitis. J Clin Apher 7(4):173-179, 1992.
- 83. Dr. Raúl H.Morales Borges Hematólogo/Oncólogo Cruz Roja Ashford Medical Americana de PR Center • Servicios de Sangre • Suite # 107 • Ubicados en el • Condado, San Juan Centro Medico de • Tel. 787-722-0412 PR • Fax 787-723-0554 • Tel. 787-759-8100 • Cel. 787-354-0758 • Ext. 3873 • [email protected] • Dir. 787-993-3873 • www.ihoapr.com • Cel. 787-505-5814 • [email protected]
- 84.
Editor's Notes
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