The kinetics of removing largeThe kinetics of removing largemolecules: implications for themolecules: implications for therational prescription of plasmarational prescription of plasma
exchangeexchange
Andre A. Kaplan, MD, FACP, FASNAndre A. Kaplan, MD, FACP, FASNUniversity of Connecticut Health CenterUniversity of Connecticut Health Center
Farmington, CTFarmington, CT
General Guidelines inGeneral Guidelines inPrescribing PlasmapheresisPrescribing Plasmapheresis
Kinetics of Immunoglobulin RemovalKinetics of Immunoglobulin Removal
Calculation of Estimated PlasmaVolume (EPV)
EPV = 0.065 x TBW x [1-Hct]
Kaplan: Trans ASAIO 36:M597, 1990
Anti-Anti-PhospholipidPhospholipid Antibody Syndrome Antibody Syndrome
Lupus anticoagulant and Lupus anticoagulant and anticardiolipinanticardiolipinantibody associated with arterial andantibody associated with arterial andvenous thrombosis, recurrent fetal loss andvenous thrombosis, recurrent fetal loss andrenal disease.renal disease.
Plasmapheresis has resulted in successfulPlasmapheresis has resulted in successfulpregnancy and reversal of renal disease.pregnancy and reversal of renal disease.Frampton et al. Lancet ii:1023, 1987, Frampton et al. Lancet ii:1023, 1987, FulcherFulcheret al. Lancet ii:171, 1989, Kincaid-Smith et al.et al. Lancet ii:171, 1989, Kincaid-Smith et al.Quart J Med 258:795, 1988Quart J Med 258:795, 1988
Are anti-phospholipid antibodiespathogenic?
Anti-ß2-glycoprotein-I antibodies ß2-GP-I (apolipoprotein H) binds to negatively
charged phospholipids and inhibits both contactactivation of the clotting cascade and theconversion of prothrombin to thrombin.
The properties of this protein as a clotting inhibitormay explain why neutralizing antibodies canpromote thrombosis.
Schousboue I: Blood 1985, 66:1086Nimpf J et al: Biochim Biophys Acta, 1986, 884:142
Are anti-phospholipid antibodiespathogenic?
“Antiphosphospholipid antibodies (aPL) havebeen demonstrated to have procoagulant actionsupon protein C, annexin V, platelets, serumproteases, toll-like receptors, tissue factor, andvia impaired fibrinolysis.
Aside from increasing the risk of vascularthrombosis, aPL increase vascular tone, therebyincreasing the susceptibility to atherosclerosis,fetal loss and neurological damage.”
BL Bermas, PH Schur, UpToDate, 2010
Catastrophic Catastrophic AntiphospholipidAntiphospholipid Antibody AntibodySyndrome (CAPS)Syndrome (CAPS)
CAPS is a rare life-threatening form ofCAPS is a rare life-threatening form ofantiphospholipidantiphospholipid antibody syndrome antibody syndrome(APS) with (APS) with multiorganmultiorgan involvement involvement
Associated mortality rate is >50%.Associated mortality rate is >50%.
Treatment consists of IV heparin, IVTreatment consists of IV heparin, IVsteroids, IVIG and/or TPEsteroids, IVIG and/or TPE..
Catastrophic Catastrophic AntiphospholipidAntiphospholipid Antibody AntibodySyndrome: Case ReportSyndrome: Case Report
33 year old female with history of primary APS with multiple33 year old female with history of primary APS with multiplemiscarriages and deep venous thrombosismiscarriages and deep venous thrombosis
Presented with headaches and visual field defects.Presented with headaches and visual field defects. Non-compliance with Non-compliance with coumadincoumadin. INR was 1.3.. INR was 1.3.
Patient presents with AKI and myocardial infarction. SerumPatient presents with AKI and myocardial infarction. Serumcreatininecreatinine ( (S.CrS.Cr) peaked at 2.8 mg/dl by the third day.) peaked at 2.8 mg/dl by the third day.
Transferred to ICU and started on IV heparin.Transferred to ICU and started on IV heparin.
Within 24 hours of admission, her mental status deteriorated andWithin 24 hours of admission, her mental status deteriorated andshe developed seizures and left sided she developed seizures and left sided hemiplegiahemiplegia. She. Shesubsequently developed malignant hypertension (BP 225/130subsequently developed malignant hypertension (BP 225/130mmHg), flash pulmonary edema and required intubationmmHg), flash pulmonary edema and required intubation
Anticardiolipin antibody removal by TPE
0
10
20
30
40
50
60
70
TPE treatments
Imm
unoglo
bulin
Concentr
ation (
mg/d
l)
IgM aCL AB IgG aCL AB Zar & Kaplan: Clin Nephrol, 70:77, 2008
Observed and predicted decline in IgG anticardiolipinantibody.
DayaCL IgG (u/ml) Ve
(ml)EPV Ve/EPV
(ml)% decline in aCLIgG
Pre Post Expected Achieved
#1 56 27 4000 3682 1.08 66 51.7
25 11 4000 3574 1.11 67 56.0
#2 19 6 4000 3549 1.07 66 68.4
#3 13 5 4000 3603 1.11 67 61.5
#4 10 4 4000 3648 1.09 66 60.0
#5 9 3 4000 3648 1.09 66 66.6
T. Zar & A. Kaplan. Clin Nephrol, 70:77, 2008
Observed and predicted decline in IgM anticardiolipin
DayaCL IgM(u/ml)
Ve(ml)
EPV(ml)
Ve/EPV % decline in aCLIgM
Pre Post Expected Achieved
#1 59 23 4000 3682 1.08 66 61.0
23 11 4000 3574 1.11 67 52.1
#2 17 8 4000 3549 1.07 66 52.9
#3 9 4 4000 3603 1.11 67 55.5
#4 9 4 4000 3648 1.09 66 55.5
#5 8 3 4000 3648 1.09 66 62.5
T. Zar & A. Kaplan. Clin Nephrol, 70:77, 2008
TPE for CAPS
CAPS has never been investigated in aprospective, randomized trial but a review ofthe first 250 patients entered into the CAPSRegistry demonstrated that the combination ofTPE, anticoagulants and steroids wasassociated with an overall 78% survivalleading the authors to conclude that thistreatment combination should be the first lineof therapy for patients with CAPS
Bucciarelli S. et al. Arthritis Rheum 2006;54:2568
ApheresisApheresis for Renal Disease for Renal Disease
Primary Renal DiseasePrimary Renal Disease GoodpastureGoodpasture’’ss disease disease
IgAIgA nephritis/HSP nephritis/HSP
PauciPauci-immune RPGN-immune RPGN
Focal segmentalFocal segmentalglomerulosclerosisglomerulosclerosis
Secondary Renal DiseaseSecondary Renal Disease SLESLE
APA syndromeAPA syndrome
CryoglobulinemiaCryoglobulinemia
Multiple MyelomaMultiple Myeloma
TTP/HUSTTP/HUS
TransplantationTransplantation
Rapidly Progressive Rapidly Progressive GlomerulonephritisGlomerulonephritis
Anti-GBM
Post-StrepS.B.E.Lupus
IgACryoglobulines
Membrano-Proliferative
Immune-Complex
Wegener'sPANIdiopathic
Pauci-Immune
RPGN
Anti-GBM Antibody andAnti-GBM Antibody andGoodpastureGoodpasture’’ss Syndrome Syndrome
Pathogenic antibody capable of causingPathogenic antibody capable of causingalveolar hemorrhage and rapidlyalveolar hemorrhage and rapidlyprogressive progressive glomerulonephritisglomerulonephritis
Only one randomized, controlled trial:Only one randomized, controlled trial:Johnson et al. Medicine 64:219, 1985Johnson et al. Medicine 64:219, 1985
Plasmapheresis results in rapid lowering ofPlasmapheresis results in rapid lowering ofanti-GBM antibody, lower post RXanti-GBM antibody, lower post RXcreatininecreatinine and reduced incidence of ESRD and reduced incidence of ESRD
Rapidly Progressive Rapidly Progressive GlomerulonephritisGlomerulonephritis
Anti-GBM
Post-StrepS.B.E.Lupus
IgACryoglobulines
Membrano-Proliferative
Immune-Complex
Wegener'sPANIdiopathic
Pauci-Immune
RPGN
CryoglobulinemiaCryoglobulinemia
Despite lack of randomized, controlledDespite lack of randomized, controlledtrials, there is a general consensus thattrials, there is a general consensus thatplasmapheresis is useful for rapid removalplasmapheresis is useful for rapid removalof of cryoglobulinscryoglobulins..
ConcomittantConcomittant hepatitis C infection may hepatitis C infection mayrender chemotherapy problematic.render chemotherapy problematic.
Some patients may respond toSome patients may respond toplasmapheresis alone. plasmapheresis alone. FerriFerri et al. et al. NephronNephron43, 246, 198643, 246, 1986
Cryoglobulin Removal with TherapeuticPlasma Exchange (TPE)
DATE IgM
mg/dL
Crycrit %
Day 1 pre TPE
post TPE
294
97
8%
Day 2 pre TPE
post TPE
119
61 trace
Hepatitis C associated cryoglobulinemiapresenting with RPGN eight months aftersuccessful suppression of viral load withinterferon
Creat
mg/dL
WaldenstromWaldenstrom’’ssMacroglobulinemiaMacroglobulinemia
FunduscopicFunduscopic abnormalities abnormalitiesin in hyperviscosityhyperviscositysyndrome include dilatedsyndrome include dilatedand tortuous retinal veins,and tortuous retinal veins,giving a "sausage link"giving a "sausage link"appearance(8)appearance(8)
Other retinal lesionsOther retinal lesionsinclude hemorrhages,include hemorrhages,exudates and exudates and papilledemapapilledema
Clinical Manifestations of Clinical Manifestations of WaldenstromWaldenstrom’’ss MacroglobulinemiaMacroglobulinemiaGarcia-Garcia-SanzSanz R et al. Br J R et al. Br J HaematolHaematol 2001 Dec;115(3):575-82 2001 Dec;115(3):575-82
Anemia/fatigue 80%Anemia/fatigue 80%
Bleeding 23%Bleeding 23%
Fevers, Night sweats, Weight loss: 23%Fevers, Night sweats, Weight loss: 23%
Neurologic symptoms 27%Neurologic symptoms 27%
Distal, symmetric, and slowly progressive Distal, symmetric, and slowly progressive sensorimotorsensorimotor peripheral peripheralneuropathy causing neuropathy causing paresthesiasparesthesias and weakness and weakness
LymphadenopathyLymphadenopathy 40%, 40%, hepatomegalyhepatomegaly or splenomegaly30%, and or splenomegaly30%, andhepatosplenomegaly(25%)hepatosplenomegaly(25%)
HyperviscosityHyperviscosity related symptoms due to increased levels of related symptoms due to increased levels ofIgMIgM (31%) (31%)
Loss or blurring of vision, Loss or blurring of vision, nystagmusnystagmus, ataxia, tinnitus,, ataxia, tinnitus,sudden deafness, sudden deafness, diplopiadiplopia, vertigo, headache, dizziness, vertigo, headache, dizziness
DateDate IgMIgM
Mg/dlMg/dlViscosity (1.1-Viscosity (1.1-1.8 1.8 centipoisecentipoise))
Day 1Day 1
TpeTpe 1 158875887
314131414.224.22
2.22.2
Day 2Day 2
TpeTpe 2/ 2/RituxmabRituxmab
38933893
164416442.172.17
1.521.52
Day 3Day 3 26902690 1.61.6
Day 5Day 5
TpeTpe 3 340744074
174817482.712.71
1.411.41
Day 6Day 6
TpeTpe 4 423782378
120412041.651.65
1.131.13
Day 7Day 7 19941994 1.361.36
Single plasma volume exchange in Primary Biliary Cirrhosis
0
50
100
150
200
250
300
350
AST ALT TRIGLYC T. CHOL T.BILI D. BILI
pre treatment post treatment(values x 10)
TPE treated patients survived a mean 5.5 years longer than untreated siblings
Thompson et al. Br Med J, 291:1671-1672, 1985
Case report: Familial homozygotichypercholesterolemia
s/p orthotopic heart transplant x 1 year
meds: cyclosporine, prednisone, imuran,lasix, quinine, bactrim, nystatin, digoxin,calcium, lipitor, didronel, premarin,provera
61 year old female
Cholesterol 489 mg/dL
Pt#2 pre and post Cholesterol
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
1/
28
/1
99
7
2/
11
/1
99
7
2/
25
/1
99
7
3/
11
/1
99
7
3/
25
/1
99
7
4/
8/
19
97
4/
22
/1
99
7
5/
6/
19
97
5/
20
/1
99
7
6/
3/
19
97
Chol (mg/dL)
Haider & Kaplan
050100150200250300350400
7/1/2003
9/1/2003
11/1/2003
1/1/2004
3/1/2004
5/1/2004
7/1/2004
LDL(md/dL)
Pt#1 Pre and Post LDL (mg/dL)
Haider & Kaplan
In Summary:
Removal of large molecules from the intravascularspace follows first order kinetics analogous to theKT/V prescription for urea
In general, a single plasma volume exchange lowersintravascular levels by 65%
After a single treatment, there is a slow equilibrationfrom the extravascular to intravascular space
Scheduling of treatments should account for the halflife of the target and the acuity of its toxicity