clinical applications of therapeutic apheresis. diseases treated with ta guillain-barre syndrome 11%...

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