Clinical Applications of Therapeutic Apheresisalzahra.mui.ac.ir/oldsite/images/stories/Education/paraclinic/... · Malaria n Cause • Plasmodium falciparum,m,vivax, ovale, malariae

Clinical Applications of Clinical Applications of Therapeutic ApheresisTherapeutic Apheresis

Presentation:Presentation:Prof. A.Prof. A. PourazarPourazar

TA TechnologiesTA Technologies

nn Prisma Gambro BCTPrisma Gambro BCTnn Asahi Plasma FlowAsahi Plasma Flow

nn Cascade apheresis for Cascade apheresis for selective plasma selective plasma component removalcomponent removal

nn Specialized devicesSpecialized devices

MembraneMembrane CentrifugationCentrifugation

Apheresis in Clinical PracticeApheresis in Clinical Practice

RBC PlasmaWBC PLT

Sickle Cell Dis.Malaria

LeukemiasCell Therapies

Thrombocytosis

TTPGuillain Barre Syn.Myasthenia GravisGoodpasture’s Syn.Waldenstrom’s

Bloodletting and Plasmapheresis

““When it comes to bloodletting three When it comes to bloodletting three questions must be answered”questions must be answered”

nn Who?Who?nn When?When?nn How much?How much?

Which Replacement fluidsWhich Replacement fluids

How much?How much?

nn Volume of exchangeVolume of exchange•• 11--11..5 5 plasma volume plasma volume

nn Calculation depends on numerous factorsCalculation depends on numerous factors

•• Frequency of proceduresFrequency of procedures•• Duration of therapyDuration of therapy

Efficiency of PlasmapheresisEfficiency of Plasmapheresisnn What is being What is being

removed?removed?•• IgG IgG -- mainly mainly

extravascularextravascular•• IgM IgM –– mainly mainly

intravascular intravascular 0

10203040506070

Percent

Efficiency of Plasmapheresis

1 plasma vol1.5 plasma vol2 plasma vol

Exchange FluidsExchange Fluids

nn 55% % AlbuminAlbumin•• Best choiceBest choice•• Dilute only with salineDilute only with saline

nn Combination of saline and albuminCombination of saline and albuminnn FFPFFPnn Cryopoor plasmaCryopoor plasma

Diseases Treated with TADiseases 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%

TTP TTP –– A Thrombotic MicroangiopathyA Thrombotic Microangiopathy

nn Microvascular Occlusive DisorderMicrovascular Occlusive Disordernn Platelet thrombiPlatelet thrombinn ThrombocytopeniaThrombocytopeniann Mechanical damage to erythrocytes Mechanical damage to erythrocytes nn 7070% % of patients are womenof patients are women

TTP TTP –– hyaline thrombi in hyaline thrombi in glomerolusglomerolus

TTP TTP –– Mortality RateMortality Rate

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Before Plasma Exchange After Plasma Exchange

Pathophysiology of TTPPathophysiology of TTP

nn Presence of Unusually Large von Presence of Unusually Large von Willebrand Factor Multimers Willebrand Factor Multimers (ULvWFM)(ULvWFM)

nn Absence or low levels of ADAMTSAbsence or low levels of ADAMTS13 13 (vWF cleaving metalloprotease)(vWF cleaving metalloprotease)

nn Presence of autoPresence of auto--antibodies to antibodies to ADAMTSADAMTS1313

Plasma Exchange in TTPPlasma Exchange in TTPFFP as exchange fluidFFP as exchange fluid

nn Removal of autoRemoval of auto--antibodies to vWF antibodies to vWF multimers cleaving enzymemultimers cleaving enzyme

nn Infusion of vWF multimers cleaving Infusion of vWF multimers cleaving enzymeenzyme

Endothelial CellEndothelial Cell

Pathophysiology of TTPPathophysiology of TTP

Cleaved von Willebrand Factormultimers

vWF-CleavingEnzyme

Platelet aggregate

Auto-antibody tovWF-Cleaving Enzyme

Uncleaved unusuallylarge vWF multimers

Normal TTP

DiagnosisDiagnosisFrom Pentad to TriadFrom Pentad to Triad

nn ThrombocytopeniaThrombocytopeniann MAHAMAHAnn CNS symptomsCNS symptomsnn Renal insufficiencyRenal insufficiencynn FeverFever

nn ThrombocytopeniaThrombocytopeniann MAHAMAHAnn LDH elevationLDH elevation

Conditions Associated with TTPConditions Associated with TTP

nn Primary (idiopathic)Primary (idiopathic)nn SecondarySecondary

•• Systemic autoimmune Systemic autoimmune disordersdisordersnn SLESLEnn Rheumatoid arthritisRheumatoid arthritisnn SclerodermaSclerodermann Polyarteritis nodosaPolyarteritis nodosa

•• Infectious diseasesInfectious diseasesnn HIV infectionHIV infectionnn Bacterial endocarditisBacterial endocarditis

•• DrugsDrugsnn TiclopidineTiclopidinenn ClopidrogelClopidrogelnn Cyclosporine ACyclosporine Ann TacrolimusTacrolimusnn QuinineQuinine

•• Neoplastic diseasesNeoplastic diseases•• SurgeriesSurgeries

nn CardiovascularCardiovascularnn IntestinalIntestinal

•• PBSC transplantationPBSC transplantation•• PregnancyPregnancy

Treatment of TTPTreatment of TTP

nn Daily plasma exchangeDaily plasma exchangenn Exchange fluidsExchange fluids

•• FFPFFP•• Cryopoor plasmaCryopoor plasma•• Detergent treated plasmaDetergent treated plasma

nn Treat until clinical symptoms improve and Treat until clinical symptoms improve and laboratory values normalizelaboratory values normalize

nn Avoid platelet transfusionsAvoid platelet transfusions

Treatment of persistent TTPTreatment of persistent TTP

nn Plasma exchangePlasma exchangenn CorticosteroidsCorticosteroidsnn VincristineVincristinenn RituximabRituximabnn SplenectomySplenectomy

Treatment of relapsing TTPTreatment of relapsing TTP

nn Plasma exchange Plasma exchange nn Treat beyond improvementTreat beyond improvementnn Consider adding medicationsConsider adding medicationsnn SplenectomySplenectomynn Look for other disease associationLook for other disease association

TTP/HUS (Hemolytic Uremic TTP/HUS (Hemolytic Uremic Syndrome)Syndrome)

nn HUSHUS•• MAHAMAHA•• Renal failureRenal failure

nn Classic HUSClassic HUS•• Childhood, Childhood, Escherichia coli Escherichia coli 01570157::HH7 7 associationassociation

nn Adult HUSAdult HUS•• Renal disease is more severeRenal disease is more severe•• Difficult to differentiate from TTPDifficult to differentiate from TTP

nn Platelet Platelet –– fibrin thrombifibrin thrombinn Normal ADAMTS Normal ADAMTS 13 13 (vWF cleaving enzyme) levels(vWF cleaving enzyme) levelsnn No autoNo auto--antibody to ADAMTSantibody to ADAMTSnn Response to plasma exchange Response to plasma exchange –– equivocal resultsequivocal results

Rapidly Progressive Glomerulonephritis Rapidly Progressive Glomerulonephritis (RPGN); Crescentic Glomerulonephritis(RPGN); Crescentic Glomerulonephritis

nn Subacute deterioration of renal Subacute deterioration of renal functionfunction

nn Crescents in glomeruliCrescents in glomerulinn Various etiologiesVarious etiologies

Rapidly Progressive Glomerulonephritis Rapidly Progressive Glomerulonephritis (RPGN); Crescentic Glomerulonephritis(RPGN); Crescentic Glomerulonephritis

nn Goodpasture’s syndrome (AntiGoodpasture’s syndrome (Anti--Glomerular Glomerular Basement Membrane Disease or AntiBasement Membrane Disease or Anti--GBM GBM Disease)Disease)

nn Pauci immune RPGN (Wegener’s Pauci immune RPGN (Wegener’s Granulomatosis or microscopic Granulomatosis or microscopic polyarteritis with antineutrophil polyarteritis with antineutrophil cytoplasmic antibodies (ANCA)cytoplasmic antibodies (ANCA)

nn RPGN with granular immune complex RPGN with granular immune complex deposits sometimes associated with deposits sometimes associated with systemic vasculitissystemic vasculitis

Goodpasture’s syndromeGoodpasture’s syndrome

nn AntiAnti--GBM antibodies crossrective GBM antibodies crossrective with alveolar basement membranewith alveolar basement membrane

Goodpasture’s SyndromeGoodpasture’s Syndromenn Clinical presentationClinical presentation

•• RPGNRPGN•• Pulmonary hemorrhagePulmonary hemorrhage•• AntiAnti--GBM antibodiesGBM antibodies

nn TreatmentTreatment•• Immunosuppressive drugsImmunosuppressive drugs

nn CyclophosphamideCyclophosphamidenn CorticosteroidsCorticosteroidsnn AzathioprineAzathioprine

•• Plasmapheresis (ASFA Category I)Plasmapheresis (ASFA Category I)nn Daily pheresis for Daily pheresis for 14 14 days with days with 55% % albumin, albumin, 11--1 1 ½ plasma ½ plasma

volumevolumenn Finish procedure with Finish procedure with 1 1 liter of FFP in cases with pulmonary liter of FFP in cases with pulmonary

hemorrhage and /or renal biopsy hemorrhage and /or renal biopsy

Pauci immune GNPauci immune GN

Antineutrophil Cytoplasmic Antineutrophil Cytoplasmic AntibodiesAntibodies

•• ANCA by immunofluorescence ANCA by immunofluorescence methodsmethods•• cc--ANCA =ANCA = Wegener’s Wegener’s

disease (disease (6060% % to to 9090%)%)•• pp--ANCA =ANCA = microscopic microscopic

polyangiitis (MPA) polyangiitis (MPA) ((5050% % to to 8080%), %), UC (UC (4040% % to to 8080%%), Crohn’s ), Crohn’s ((1010% % to to 4040%)%)

Hoffman GS. Arth Rheum. 1998;41(a):1521–1537.

VasculitisVasculitis

ANCA positive Pauci Immune ANCA positive Pauci Immune RPGNRPGN

nn Clinical presentationClinical presentation•• RPGN with or without pulmonary hemorrhageRPGN with or without pulmonary hemorrhage•• Perinuclear (pPerinuclear (p--ANCA)ANCA)--systemic microvasculitissystemic microvasculitis•• Internuclear (cInternuclear (c--ANCA)ANCA)--Wegener’s Wegener’s

granulomatosisgranulomatosis

nn TreatmentTreatment•• Immunosuppressive drugsImmunosuppressive drugs•• Plasmapheresis (ASFA Category II) may Plasmapheresis (ASFA Category II) may

benefit patients with severe renal disease (Cr benefit patients with severe renal disease (Cr 99) and dialysis dependent patients) and dialysis dependent patients

Immune Complex RPGN (MPGN)Immune Complex RPGN (MPGN)

Immune Complex RPGNImmune Complex RPGNnn Clinical presentationClinical presentation

•• RPGNRPGN•• Membranoproliferative GN (MPGN)Membranoproliferative GN (MPGN)

nn AssociationsAssociations•• Hepatitis CHepatitis C•• CryoglobulinemiaCryoglobulinemia

nn TreatmentTreatment•• Antiviral drugsAntiviral drugs•• CorticosteroidsCorticosteroids•• Plasmapheresis (ASFA Category II)Plasmapheresis (ASFA Category II)

Acute Inflammatory Demyelinating Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)Polyradiculoneuropathy (AIDP)GuillainGuillain--Barre Syndrome (GBS)Barre Syndrome (GBS)

nn PathogenesisPathogenesis•• AntiAnti--myelin (gangliosides)myelin (gangliosides) antibodies GMantibodies GM11, GM, GM11b, GDb, GD11aa

nn Clinical presentationClinical presentation•• Ascending paralysisAscending paralysis•• ““albuminocytologic dissociation”albuminocytologic dissociation”

nn High CSF proteinHigh CSF proteinnn No CSF pleocytosisNo CSF pleocytosis

•• 1010--2323% % require assisted ventilationrequire assisted ventilation•• Nerve conduction studies show demyelinationNerve conduction studies show demyelination•• dysautonomiadysautonomia

nn TreatmentTreatment•• Supportive careSupportive care•• IVIG IVIG 400400mg/kg x mg/kg x 5 5 daysdays•• Plasmapheresis (ASFA Category I)Plasmapheresis (ASFA Category I)

nn Start within Start within 14 14 days of onsetdays of onsetnn 55--6 6 Q.O.D.Q.O.D. procedures, procedures, 11--1 11 1//2 2 plasma volume exchange with plasma volume exchange with 55% % albuminalbumin

‘

AntiAnti--myelin Antibodiesmyelin Antibodies

GBS Clinical CourseGBS Clinical Course

GBS course

Time

Sym

ptom

seve

rity

Myasthenia GravisMyasthenia Gravis

Nerve

Anti-AchR Ab

Muscle

Acetylcholine (Ach)

AchR

Myasthenia GravisMyasthenia Gravisnn Clinical pictureClinical picture

•• Variable degrees of weakness; improved by Variable degrees of weakness; improved by rest rest

•• Thymoma in Thymoma in 1515% % of patientsof patients

nn TreatmentTreatment•• MestinonMestinon•• PrednisonePrednisone•• Imuran or other immunomodulatory medsImuran or other immunomodulatory meds•• Plasmapheresis (ASFA Category I)Plasmapheresis (ASFA Category I)•• IVIG IVIG 400 400 mg/kg x mg/kg x 5 5 daysdays•• Thymectomy Thymectomy

Myasthenia GravisMyasthenia Gravis

nn PlasmapheresisPlasmapheresis•• Acute myasthenic crisisAcute myasthenic crisis•• Respiratory insufficiencyRespiratory insufficiency•• Failure to respond to medicationsFailure to respond to medications•• Side effects of medications (prednisone)Side effects of medications (prednisone)•• Before and after surgery (thymectomy)Before and after surgery (thymectomy)

Myasthenia Gravis Myasthenia Gravis

Before plasmapheresisBefore plasmapheresis After PlasmapheresisAfter Plasmapheresis

Hyperviscosity SyndromeHyperviscosity Syndromenn CausesCauses

•• Wadenstrom’s macroglobulinemia Wadenstrom’s macroglobulinemia 5050%%•• Multiple myeloma Multiple myeloma 55%%

nn Clinical presentationClinical presentation•• Neurologic symptomsNeurologic symptoms•• Bleeding diathesisBleeding diathesis•• Retinal hemorrhage and papilledemaRetinal hemorrhage and papilledema•• HypervolemiaHypervolemia•• Congestive heart failureCongestive heart failure

nn TreatmentTreatment•• Plasmapheresis (ASFA Category II)Plasmapheresis (ASFA Category II)•• Chemotherapy Chemotherapy

Infectious agent

APC

T-cell B-cellPlasma cell

IL-4 , IL-6

Antibodies

V

Systemic Lupus ErythematosusSystemic Lupus Erythematosus((SLE)SLE)

nn Systemic autoimmune disease with the Systemic autoimmune disease with the presence of autoantibodies and immune presence of autoantibodies and immune complexes (anticomplexes (anti--DNA, antiDNA, anti--DSDS--DNA)DNA)

nn Multiple organ involvement including the Multiple organ involvement including the kidneyskidneys

nn Controlled clinical trials failed to show Controlled clinical trials failed to show benefit from plasmapheresis in lupus benefit from plasmapheresis in lupus nephropathynephropathy

nn Plasmapheresis (ASFA Category III)Plasmapheresis (ASFA Category III)

SLESLE

Red Cell ExchangeRed Cell Exchange

nn Sickle Cell DiseaseSickle Cell Diseasenn MalariaMalariann BabesiosisBabesiosis

Sickle Cell DiseaseSickle Cell Diseasenn Clinical pictureClinical picture

•• Chronic genetic anemiaChronic genetic anemia•• Hgb S instead of Hgb A alters the erythrocytes and their Hgb S instead of Hgb A alters the erythrocytes and their

membranes (sickle red cells)membranes (sickle red cells)•• Increased blood viscosityIncreased blood viscosity•• Microvascular occlusionMicrovascular occlusion

nn Infarcts in brain, lungs, retinaInfarcts in brain, lungs, retinann Pain crisisPain crisisnn PriapismPriapismnn Acute chest syndromeAcute chest syndromenn StrokeStroke

•• TreatmentTreatmentnn Red cell transfusionsRed cell transfusionsnn HydroxyureaHydroxyureann Red cell exchange (ASFA Category I)Red cell exchange (ASFA Category I)

•• Aims to maintain Hgb S <Aims to maintain Hgb S <3030

MalariaMalariann CauseCause

•• Plasmodium falciparum,Plasmodium falciparum, vivax, ovale, malariaevivax, ovale, malariae•• Transmitted by female anopheline mosqitoTransmitted by female anopheline mosqito•• Infected RBC adhere to endothelial cells of capillaries and Infected RBC adhere to endothelial cells of capillaries and

postcapillary venules via surface knobspostcapillary venules via surface knobs•• Microvascular obstruction of brain, kidneys,lungsMicrovascular obstruction of brain, kidneys,lungs

nn Clinical pictureClinical picture•• Fever, malaise,Fever, malaise, headacheheadache•• Neurologic impairmentNeurologic impairment•• Renal failureRenal failure•• ARDSARDS

nn TraetmentTraetment•• Chloroquine, quinine,Chloroquine, quinine, quinidinequinidine•• Red cell exchange (ASFA Category III)Red cell exchange (ASFA Category III)•• Plasmapheresis for removal of cytokines to prevent or treat Plasmapheresis for removal of cytokines to prevent or treat

lactic acidosis, hypoglycemia (NR)lactic acidosis, hypoglycemia (NR)

White Cell DepletionWhite Cell DepletionLeukapheresis Leukapheresis

nn LeukocytosisLeukocytosis•• Acute Myelogenous Leukemia (AML)Acute Myelogenous Leukemia (AML)•• Chronic Myelogenous Leukemia (CML)Chronic Myelogenous Leukemia (CML)•• Acute Lymphocytic Leukemia (ALL)Acute Lymphocytic Leukemia (ALL)•• Chronic Lymphocytic Leukemia (CLL)Chronic Lymphocytic Leukemia (CLL)

nn Clinical pictureClinical picture•• Hyperviscosity with microvascular occlusionHyperviscosity with microvascular occlusion

nn CNS symptomsCNS symptomsnn HemorrhageHemorrhagenn Pulmonary insufficiencyPulmonary insufficiency

nn TreatmentTreatment•• Combination chemotherapy (tumor cell lysis leads to metabolic Combination chemotherapy (tumor cell lysis leads to metabolic

imbalance and ARDS)imbalance and ARDS)•• Leukapheresis (ASFA Category I)Leukapheresis (ASFA Category I)

nn Ptreatment of leukocytosisPtreatment of leukocytosisnn Prevention of tumor cell lysis syndromePrevention of tumor cell lysis syndrome

PlateletpheresisPlateletpheresisnn Thrombocytosis (>Thrombocytosis (>11,,000 000 x x 10 10 /L)/L)

•• EssentialEssential•• Polycytemia veraPolycytemia vera

nn Clinical pictureClinical picture•• Microvascular occlusionMicrovascular occlusion

nn CNS symptomsCNS symptomsnn HemorrhageHemorrhagenn Pulmonary insufficiencyPulmonary insufficiency

nn TreatmentTreatment•• ChemotherapyChemotherapy•• Plateletpheresis (ASFA Category I)Plateletpheresis (ASFA Category I)

9

Rheumatoid ArthritisRheumatoid Arthritisnn Chronic inflammatory autoimmune diseaseChronic inflammatory autoimmune disease

•• ArthritisArthritis•• Rheumatoid nodulesRheumatoid nodules•• Serum rheumatoid factorSerum rheumatoid factor

nn TreatmentTreatment•• DMARD (Disease Modifying Anti Rheumatic DMARD (Disease Modifying Anti Rheumatic

Drugs)Drugs)•• AntiAnti--TNF alpha monoclonal antibodiesTNF alpha monoclonal antibodies•• ApheresisApheresis

nn Plasmapheresis (ASFA Category IV)Plasmapheresis (ASFA Category IV)nn Lymphoplasmapheresis (ASFA Category II)Lymphoplasmapheresis (ASFA Category II)nn Prosorba column (ASFA Category II)Prosorba column (ASFA Category II)

Protein A binds IgGProtein A binds IgG

Protocols for Reducing antiProtocols for Reducing anti--HLA HLA antibodies in positive CXM and antibodies in positive CXM and

AMRAMR

nn IVIG aloneIVIG alonenn Plasmapheresis and IVIGPlasmapheresis and IVIGnn Plasmapheresis, IVIG and antiPlasmapheresis, IVIG and anti--CDCD20 20

antibody (splenectomy)antibody (splenectomy)

AmJTransplant AmJTransplant 44((77):):10331033--10411041, , 20042004

Protocols for Reducing antiProtocols for Reducing anti--HLA HLA antibodies in positive CXM and AMRantibodies in positive CXM and AMR

AmJTransplant AmJTransplant 44((77):):10331033--10411041, , 20042004

IVIGIVIG 42 42 patientspatients3030% % rejection rejection episodesepisodes8989% % graft graft survival at survival at 2 2 yearsyears

PlasmapheresPlasmapheresis and IVIGis and IVIG

62 62 patientspatients 9494..22% % graft graft survival at survival at 3 3 yearsyears

ReferencesReferences

nn Journal of Clinical Apheresis, Vol.Journal of Clinical Apheresis, Vol.1515, , No.No.11//22, , 20002000, Special Issue, Clinical , Special Issue, Clinical Applications of Therapeutic ApheresisApplications of Therapeutic Apheresis

nn Journal of Clinical Apheresis Journal of Clinical Apheresis 20002000--20062006

nn APHERESIS, Principles and Practice, APHERESIS, Principles and Practice, 22ndnd Edition,Edition, Bruce McLeod Editor, Bruce McLeod Editor, AABB Press AABB Press 20032003