Clinical Applications of Therapeutic Apheresis
Diseases Treated with TA
Guillain-Barre Syndrome 11%Myasthenia Gravis 12%
CIDP 8%
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%
Cryoglobulinemia 30%Anti-GBM Disease 30%
Pauci-immune RPGN 13%SLE nephropathy 10%Myeloma kidney 7%Recurrent FSG 5%
Renal transplantation 5%
TTP – hyaline thrombi in glomerolus
TTP – Mortality Rate
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Before Plasma Exchange After Plasma Exchange
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
Plasma Exchange in TTPFFP as exchange fluid
Removal of auto-antibodies to vWF multimers cleaving enzyme
Infusion of vWF multimers cleaving enzyme
Endothelial CellEndothelial Cell
Pathophysiology of TTP
Cleaved von Willebrand Factormultimers
vWF-CleavingEnzyme
Platelet aggregate
Auto-antibody tovWF-Cleaving Enzyme
Uncleaved unusually large vWF multimers
Normal TTP
DiagnosisFrom Pentad to Triad Thrombocytopenia MAHA CNS symptoms Renal insufficiency Fever
Thrombocytopenia MAHA LDH elevation
Conditions Associated with TTP
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
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
Treatment of persistent TTP
Plasma exchange Corticosteroids Vincristine Rituximab Splenectomy
Treatment of relapsing TTP
Plasma exchange Treat beyond improvement Consider adding medications Splenectomy Look for other disease association
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
Rapidly Progressive Glomerulonephritis (RPGN); Crescentic Glomerulonephritis
Subacute deterioration of renal function Crescents in glomeruli Various etiologies
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
Goodpasture’s syndrome
Anti-GBM antibodies crossrective with alveolar basement membrane
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
Pauci immune GN
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.
Vasculitis
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
Immune Complex RPGN (MPGN)
Immune Complex RPGN
Clinical presentation RPGN Membranoproliferative GN (MPGN)
Associations Hepatitis C Cryoglobulinemia
Treatment Antiviral drugs Corticosteroids Plasmapheresis (ASFA Category II)
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
‘
Anti-myelin Antibodies
GBS Clinical Course
GBS course
Time
Sym
ptom
sev
erit
y
Myasthenia Gravis
Nerve
Anti-AchR Ab
Muscle
Acetylcholine (Ach)
AchR
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
Myasthenia Gravis
Plasmapheresis Acute myasthenic crisis Respiratory insufficiency Failure to respond to medications Side effects of medications (prednisone) Before and after surgery (thymectomy)
Myasthenia Gravis Myasthenia Gravis
Before plasmapheresisBefore plasmapheresis After PlasmapheresisAfter Plasmapheresis
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
Infectious agent
APC
T-cell B-cellPlasma cell
IL-4 , IL-6
Antibodies
V
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)
SLE
Red Cell Exchange
Sickle Cell Disease Malaria Babesiosis
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
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)
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
Plateletpheresis Thrombocytosis (>1,000 x 10 /L)
Essential Polycytemia vera
Clinical picture Microvascular occlusion
CNS symptoms Hemorrhage Pulmonary insufficiency
Treatment Chemotherapy Plateletpheresis (ASFA Category I)
9
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)
Protein A binds IgG
Protocols for Reducing anti-HLA antibodies in positive CXM and AMR
IVIG alone Plasmapheresis and IVIG Plasmapheresis, IVIG and anti-CD20
antibody (splenectomy)
AmJTransplant 4(7):1033-1041, 2004AmJTransplant 4(7):1033-1041, 2004
Protocols for Reducing anti-HLA antibodies in positive CXM and AMR
AmJTransplant 4(7):1033-1041, 2004AmJTransplant 4(7):1033-1041, 2004
IVIG 42 patients
30% rejection episodes
89% graft survival at 2 years
Plasmapheresis and IVIG
62 patients 94.2% graft survival at 3 years
