Clinical Applications of Therapeutic Apheresis

1. Clinical Applications of Therapeutic Apheresis Dobri Kiprov, MD, HP Chief, Division of Immunotherapy California Pacific Medical Center Medical Director, Apheresis Care Group Fresenius

2. TA Technologies • Prisma Gambro BCT • Asahi Plasma Flow • Cascade apheresis for selective plasma component removal • Specialized devices Membrane Centrifugation

3. Apheresis in Clinical Practice Sickle Cell Dis. Malaria Thrombocytosis RBC WBC PLT Plasma Leukemias Cell Therapies TTP Guillain Barre Syn. Myasthenia Gravis Goodpasture’s Syn. Waldenstrom’s

4. Bloodletting and Plasmapheresis

5. “When it comes to bloodletting three questions must be answered” • Who? • When? • How much? Which Replacement fluids

6. How much? • Volume of exchange • 1-1.5 plasma volume • Calculation depends on numerous factors • Frequency of procedures • Duration of therapy

7. Efficiency of Plasmapheresis • What is being removed? • IgG - mainly extravascular • IgM – mainly intravascular

8. Exchange Fluids • 5% Albumin • Best choice • Dilute only with saline • Combination of saline and albumin • FFP • Cryopoor plasma

9. Diseases Treated with TA Guillain-Barre Syndrome 11% Myasthenia Gravis 12% CIDP 8% Cryoglobulinemia 30% Anti-GBM Disease 30% Pauci-immune RPGN 13% SLE nephropathy 10% Myeloma kidney 7% Recurrent FSG 5% Renal transplantation 5%

10. TTP – A Thrombotic Microangiopathy • Microvascular Occlusive Disorder • Platelet thrombi • Thrombocytopenia • Mechanical damage to erythrocytes • 70% of patients are women

11. TTP – hyaline thrombi in glomerolus

12. TTP – Mortality Rate Before Plasma Exchange AfterPlasma Exchange

13. 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

14. Plasma Exchange in TTPFFP as exchange fluid • Removal of auto-antibodies to vWF multimers cleaving enzyme • Infusion of vWF multimers cleaving enzyme

15. Pathophysiology of TTP Normal TTP Cleaved von Willebrand Factor multimers Platelet aggregate vWF-Cleaving Enzyme Auto-antibody to vWF-Cleaving Enzyme Uncleaved unusually large vWF multimers Endothelial Cell Endothelial Cell

16. Thrombocytopenia MAHA CNS symptoms Renal insufficiency Fever Thrombocytopenia MAHA LDH elevation DiagnosisFrom Pentad to Triad

17. Primary (idiopathic) Secondary Systemic autoimmune disorders SLE Rheumatoid arthritis Scleroderma Polyarteritis nodosa Infectious diseases HIV infection Bacterial endocarditis Drugs Ticlopidine Clopidrogel Cyclosporine A Tacrolimus Quinine Neoplastic diseases Surgeries Cardiovascular Intestinal PBSC transplantation Pregnancy Conditions Associated with TTP

18. 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

19. Treatment of persistent TTP • Plasma exchange • Corticosteroids • Vincristine • Rituximab • Splenectomy

20. Treatment of relapsing TTP • Plasma exchange • Treat beyond improvement • Consider adding medications • Splenectomy • Look for other disease association

21. 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

22. Rapidly Progressive Glomerulonephritis (RPGN); Crescentic Glomerulonephritis • Subacute deterioration of renal function • Crescents in glomeruli • Various etiologies

24. 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

25. Goodpasture’s syndrome • Anti-GBM antibodies crossrective with alveolar basement membrane

26. 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

27. Pauci immune GN

28. 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.

29. Vasculitis

30. ANCA positive Pauci Immune 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

31. Immune Complex RPGN (MPGN)

32. Immune Complex RPGN • Clinical presentation • RPGN • Membranoproliferative GN (MPGN) • Associations • Hepatitis C • Cryoglobulinemia • Treatment • Antiviral drugs • Corticosteroids • Plasmapheresis (ASFA Category II)

33. 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

34. Anti-myelin Antibodies

35. GBS Clinical Course

36. Myasthenia Gravis Nerve Acetylcholine (Ach) Anti-AchRAb AchR Muscle

37. 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

38. Myasthenia Gravis • Plasmapheresis • Acute myasthenic crisis • Respiratory insufficiency • Failure to respond to medications • Side effects of medications (prednisone) • Before and after surgery (thymectomy)

39. Myasthenia Gravis Before plasmapheresis After Plasmapheresis

40. 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

41. Infectious agent V APC IL-4 , IL-6 Antibodies B-cell T-cell Plasma cell

43. 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)

44. SLE

45. Red Cell Exchange • Sickle Cell Disease • Malaria • Babesiosis

46. 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

47. 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)

48. White Cell DepletionLeukapheresis • 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

49. Plateletpheresis 9 • Thrombocytosis (>1,000 x 10 /L) • Essential • Polycytemia vera • Clinical picture • Microvascular occlusion • CNS symptoms • Hemorrhage • Pulmonary insufficiency • Treatment • Chemotherapy • Plateletpheresis (ASFA Category I)

50. 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)