The kinetics of removing large The kinetics of removing large molecules: implications for the molecules: implications for the rational prescription of plasma rational prescription of plasma exchange exchange Andre A. Kaplan, MD, FACP, FASN Andre A. Kaplan, MD, FACP, FASN University of Connecticut Health Center University of Connecticut Health Center Farmington, CT Farmington, CT
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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
Kaplan: A Practical Guide to Therapeutic Plasma Exchange, Blackwell Science, 1999
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.
“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.”
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
MRI inpatient withCAPS
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
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
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
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