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19 Polman CH, O’Connor PW, Havrdova E et al. A randomized, placebo-controlled Therapeutic – trial of natalizumab for relapsing . N Engl J Med 2006;354:899–910. 20 Yousry TA, Major EO, Ryschkewitsch C Khaled El-Ghariani MA MRCP(UK) MRCPath, pheresis) with retention of cells. et al. Evaluation of patients treated with Consultant Haematologist, National Blood Centrifugal systems are more versatile, natalizumab for progressive multifocal Service, Sheffield Centre leukoencephalopathy. N Engl J Med 2006; allowing plasmapheresis or selective 354:924–33. David J Unsworth PhD FRCP(UK) FRCPath, removal of cell types (eg - 21 Vincenti F, Kirkman R, Light S et al. Consultant Immunologist, North Bristol NHS phoresis). Blood components (eg HLA- Interleukin-2-receptor blockade with Trust, Bristol matched or daclizumab to prevent acute rejection in derived ‘stem cells’) can be ‘withdrawn’ renal transplantation. Daclizumab Triple Clin Med 2006;6:343–7 Therapy Study Group. N Engl J Med 1998; from healthy volunteers for patient treat- 338:161–5. ment. This article focuses on the removal 22 Beniaminovitz A, Itescu S, Lietz K et al. of pathogenic/abnormal blood con- Prevention of rejection in cardiac trans- Background stituents. plantation by blockade of the interleukin-2- Typically, plasmapheresis is an emer- receptor with a monoclonal . Apheresis is derived from the Greek, gency intervention, effective for only a few NEngl J Med 2000;342:613–9. meaning ‘withdrawal’. Blood compo- days unless parallel treatment for the 23 Vincenti F, Larsen C, Durrbach A et al. nents can be separated by either filtration Costimulation blockade with belatacept in underlying condition is instituted. or centrifugation (Fig 1). Filtration sys- renal transplantation. N Engl J Med 2005; Plasmapheresis buys time whilst immuno- tems allow plasma removal (plasma- 353:770–81. suppression takes effect. Where possible, 24 Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal the patient travels to the treatment centre, antibody against HER2 for metastatic but the staff and machine may need to breast cancer that overexpresses HER2. N Plasma 1.025–1.029 travel to the bedside for sick patients. Engl J Med 2001;344:783–92. 25 Use of a monoclonal antibody directed Platelets 1.040–1.045 against the platelet glycoprotein IIb/IIIa Continuous versus intermittent receptor in high-risk coronary angioplasty. flow apheresis machines The EPIC Investigation. N Engl J Med 1994; 1.050–1.061 330:956–61. Continuous flow separators (Fig 2) 26 Milgrom H, Fick RB Jr, Su JQ et al. retain healthy blood components and Treatment of allergic asthma with mono- separate plasma for disposal. Using a clonal anti-IgE antibody. rhuMAb-E25 double-needle kit, blood enters one limb Study Group. N Engl J Med 1999;341: 1.087–1.092 1966–73. and returns post-centrifugation and 27 Griffiths I, Silman A, Symmons D, Scott plasma removal via another. Continuous DG. BSR Biologics Registry. Rheumatology Erythrocytes 1.078–1.114 maintains isovolaemic (Oxford) 2004;43:1463–4. balance. The extracorporeal circuit Fig 1. Blood components, separated by volume is minimal (<150 mol), but centrifugation according to relative none the less large for babies and small density. infants.

Key Points

Plasma removal (plasmapheresis) directly removes pathogenic and other plasma factors (eg cytokines) to provide temporary therapeutic benefit

Relapse is likely without concurrent and/or other appropriate treatment of the underlying condition (preventing production)

Plasmapheresis is a limited resource, largely limited to regional centres; it requires staff experienced in use of specialist apheresis machines

Alternative treatments should be used first (eg Guillain–Barré syndrome for which intravenous is equally effective)

Commoner side effects relate to central-line insertion, loss of plasma clotting factors and hypocalcaemia caused by citrate anticoagulation

KEY WORDS: autoantibody, immunosuppression, plasmapheresis, vasculitis

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In contrast, intermittent flow genic autoantibodies are IgG isotype) or IgM. Three consecutive daily treatments machines use a single lumen line. Blood specific autoantibody (using specific reduce IgM to 10–20% of pretreatment enters a spinning centrifuge and sepa- as affinity ligand).1 Staphylo- level. Smaller molecules (IgG or rates the plasma. Blood cells are returned coccal A (an accident of nature cytokines) re-equilibrate rapidly (50% of to the patient at intervals by reversing the which selectively binds IgG) columns can IgG is extravascular) so removal is less direction of flow. The extracorporeal be reused about 20 times for a given efficient. Typically, 40–60 mol of volume can be large and unsatisfactory patient, but are expensive. plasma/kg body weight are removed over for cardiovascularly unstable patients. 2–3 hours. Human albumin Kinetics (Fig 3) 4.5% diluted with normal is the Selective affinity columns routine replacement fluid. Three consec- IgM is mainly intravascular and re-equi- utive daily treatments also significantly Separated plasma passed through an librates slowly following plasma removal. reduce clotting factor concentrations. affinity column allows selective removal Processing one plasma volume (3 litre Plasmapheresis within days of diagnostic of immunoglobulin (Ig) G (most patho- for a 70 kg patient) removes 50% of lung or renal biopsy risks into the biopsy. Cross-matched (FFP) (10–15 ml/kg) should be included in the replacement fluid after each daily treatment.

Complications Fatalities are very rare and more likely to be related to the acute underlying con- dition (eg pulmonary haemorrhage in Goodpasture’s syndrome). Other complications are: • central line complications (pneumothorax, and internal bleeding) • hypersensitivity reactions (most likely with FFP) • (including prions) from blood products • citrate anticoagulation; this is used almost universally and can lead to hypocalcaemia. FFP carries a high citrate load. Renal failure patients receiving large amounts of citrate may develop profound metabolic alkalosis. • Loss of normal clotting factors increases haemorrhage risk, and loss of normal Ig (hypogammaglobulinaemia) increases risk.

Indications (Table 1)2 Plasmapheresis has applications in several areas of medicine: • haematology • renal diseases • neurological diseases • immunology Fig 2. Continuous flow apheresis machine. • metabolic disorders.

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Haematology Cytokine lgG IgM Sickle-cell crisis – erythrophoresis 100 Erythrocyte exchange can help in the acute chest syndrome and other life- 75 threatening crises, also for priapism or before surgery. The goal is to achieve sickle-cell concentrations below 30% 50 with a haematocrit of not more than

120% of baseline. % remaining 25 Hyperviscosity due to excess 0 Hyperviscosity may present as a medical 0255075100 emergency with visual disturbance, cere- Plasma volume exchanged (%) brovascular accidents or angina, but the Fig 3. Kinetics for removal of immunoglobulin (Ig) M v IgG. commonest cause is polycythaemia. Venesection, rather than ery- throphoresis, may suffice. Leukophoresis can help excess (chronic cosity. Symptoms can usually be alleviated tion. Normally, a metalloprotease myeloid leukaemia). long enough for myeloma chemotherapy enzyme degrades multimers. This to take effect with 2–3 daily treatments. enzyme can be genetically defective or a blocking autoantibody may develop. Monoclonal and Plasmapheresis can limit renal and/or hyperviscosity syndromes Thrombotic purpura neurological complications. FFP or IgM paraproteins cause the most prob- is preferred as replace- lems on a gram-for-gram basis. IgA and Abnormal von Willebrand factor (vWF) ment fluid and immunosuppression IgG3 paraproteins tend to aggregate and multimers develop, allowing platelet (corticosteroid therapy or other) is also contribute significantly to plasma vis- clumping and microvascular coagula- advised.2–5 Plasma replaces VWF and enzyme and also removes autoantibody. Plasmapheresis with FFP replacement gives better outcomes than FFP infusion Table 1. Indications for plasmapheresis.2 alone, reducing mortality from 85–15%. Evidence base Disease Refs Factor removed

Accepted benefit Cryoglobulinaemia Cryoglobulin Renal diseases Hyperviscosity Paraprotein TTP 3–6 Anti-metalloproteinase Anti-glomerular basement Goodpasture’s disease 7,8 Anti-basement membrane membrane (GBM) antibody disease Pauci-immune 7 ANCA? glomerulonephritis Other factors? Patients with pulmonary haemorrhage or FSGS 9,10 Permeability factor advanced renal failure need urgent GBS 11 Anti-ganglioside? plasmapheresis. Concurrent immunosup- CIDP 12 ? Anti-acetylcholine receptor pression with oral prednisolone 1 mg/kg, Possible benefit Renal allograft rejection 13,14 Anti-ABO slowly reduced over six months, and Anti-HLA 2–3 mg/kg/day is Paraprotein-associated 15,16 Paraprotein required.6 A small pilot study in the mid- neuropathy 1980s pointed to added benefit when Multiple sclerosis 17 Cytokines plasmapheresis is added to immunosup- Hyperlipidaemia 18 LDL pression.7 Daily plasmapheresis treat- Doubtful value SLE 19 Immune complexes Myeloma protein to prevent 20 Paraprotein ments, usually for 10–14 days, is required. renal damage Fluid overload may provoke haemorrhage. Patients treated before serum creatinine ANCA = antineutrophilic cytoplasmic antibody; CIDP = chronic inflammatory demyelinating reaches 500 mmol/l do well,6 but those ; FSGS = focal segmental glomerulosclerosis; GBS = Guillain–Barré syndrome; LDL = low- density lipoprotein; SLE = systemic erythematosus; TTP = thrombotic thrombocytopenia purpura. who are dependent before treat- ment rarely become dialysis independent.

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Antineutrophilic cytoplasmic with clear benefit proven by several well- Myasthenia gravis antibody (ANCA)-associated designed clinical trials.12 Therapeutic Anti-acetylcholine receptor glomerulonephritis benefit is likely in cases treated within play a direct pathogenic role in myas- two weeks of developing symptoms. Wegener’s granulomatosis and micro- thenia gravis and clinical recovery paral- High-dose intravenous immunoglobulin scopic polyarteritis are both associated lels titre reductions. Plasmapheresis (IVIG) is equally effective, logistically with ANCA. Opinion is divided whether helps patients who fail medical treatment easier and with comparable costs. Few the autoantibody ANCA is directly path- and develop respiratory failure or swal- GBS patients now require plasma- ogenic in anti-GBM disease. Some lowing difficulties. It is also used to pre- pheresis.12 One-quarter of cases follow studies have shown benefit when plasma- pare for thymectomy. There is no Campylobacter jejuni infection, a bac- pheresis is added to conventional evidence to support long-term mainte- terium associated with the production immunosuppression.6 With early treat- nance plasmapheresis. Anecdotally, of antiganglioside antibodies. Most cases ment, some patients become dialysis plasmapheresis seems more effective benefit without immunosuppression. independent. than IVIG in this context. GBS may be a self-limiting, post-infec- tious process. There have been trials Focal segmental glomerulosclerosis of affinity columns loaded with ganglio- Multiple sclerosis side. Focal segmental glomerulosclerosis will Some patients (≤70% in open, uncon- recur in around 35% of renal transplants. trolled small studies) with acute relapses Outcome is improved by starting Chronic inflammatory demyelinating unresponsive to steroids show clear ben- plasmapheresis as soon as significant polyneuropathy efit. Early intervention (within one proteinuria is detected post-transplanta- month of relapse) seems necessary.16 The Corticosteroids, IVIG and plasma- tion.8,9 The pathogenesis is not under- factor or factors removed (query pheresis are all effective in chronic stood, but a circulating permeability cytokines) remain elusive. inflammatory demyelinating poly- factor is suspected. Prednisolone reduces neuropathy, suggesting an autoimmune proteinuria in up to 40% of those with type pathogenesis.13 Relapse is common Immunology primary disease. and, in contrast to GBS, parallel Cryoglobulins immunosuppression seems logical to Renal transplants and prevent relapse. Plasmapheresis and Plasmapheresis can be lifesaving in the plasmapheresis IVIG seem equally effective, with benefit exceptional cases where cryoglobulins in around 80% of cases.13 Hyperacute rejection occurs in the oper- are associated with a fulminant acute ating room; it is an antibody-mediated clinical picture. Technically, the proce- rejection process due to either anti-ABO associated dure can be challenging, with cryopre- blood group antibodies or anti-HLA anti- with paraproteinaemia cipitation and blockage in the tubing bodies. In contrast, acute rejection occurs unless return fluids are adequately Small, open trials showed partial benefit weeks to months post-transplantation, warmed. The cause of the cryoglobuli- in some patients with peripheral neu- often in patients who were antibody naemia must be determined and defini- ropathy associated with parapro- cross-match negative pre-transplant but tive therapy (eg cyclophosphamide for teinaemia when plasmapheresis removed who develop allograft reaction post- haematological malignancy) instituted. IgG or IgA (but not IgM) paraproteins.14 transplant. Transplant biopsies showing A case of type II cryoglobulinaemia Predicting those who will benefit is diffi- IgG and complement C4d deposits sug- associated with is shown in cult. It is not surprising that many cases gest that humoral (antibody) rejection Fig 4. Secondary complement C4 con- fail to benefit as monoclonal gam- contributes to the process. Plasmapheresis sumption was a useful indicator of mopathy of uncertain significance is combined with anti-T cell immunosup- relapse. common, especially in the elderly (≤5%). pression has been successfully used either IgM paraproteins should not however pre-transplant (to prevent hyperacute Other autoantibody-based disorders be ignored. Neuronal deposits of IgM rejection) or post-transplant to treat found in some cases on biopsy and IgM vulgaris with erythroderma, acute rejection.10,11 anti-myelin-associated glycoprotein in the primary antiphospholipid syndrome blood tests suggest a role in pathogenesis. (preventing recurrent miscarriage) and Neurological diseases The associated neuropathy is distal, pregnancy complicated by anti-Ro/La Guillain–Barré syndrome demyelinating, sensory and often indo- (fetal heart block) are conditions for lent. Logically, a course of plasmapheresis which anecdotal reports suggest that Plasmapheresis became the gold stan- in this situation should be accompanied directly pathogenic antibody can be dard, first-line treatment for Guillain– by concurrent cytotoxic therapy to switch removed by plasmapheresis, with clinical Barré syndrome (GBS) 15 years ago, off paraprotein production.15 benefit.

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3.5 0.25 body monitoring without splenectomy in cryoglobulin ABO-incompatible . Transplantation 2005;80:1572–7. complement C4 3 14 Ibernon M, Gil-Vernet S, Carrera M et al. 0.2 Therapy with plasmapheresis and intra- venous immunoglobulin for acute humoral 2.5 rejection in kidney transplantation. Transplantation Proc 2005;37:3743–5. 0.15 2 15 Dyck PJ, Low PA, Windebank AJ et al. Plasma exchange in polyneuropathy associ- ated with of

1.5 C4 (g/l) 0.1 undetermined significance. N Engl J Med 1991;325:1482–6. Cryoglobulin (g/l) 1 16 Joint Task Force of EFNS and the PNS. European Federation of Neurological 0.05 Societies/Peripheral Nerve Society Guide- 0.5 line on management of paraproteinemic demyelinating neuropathies. Report of a 0 0 joint task force of the European Federation

0 of Neurological Societies and the Peripheral 31 59 133 190 261 269 305 388 444 500 Nerve Society. J Periph Nerv Syst 2006; Days post-diagnosis 111:9–19. 17 Schilling S, Linker RA, Konig FB et al. Fig 4. Treatment profile for a case of type II cryoglobulinaemia. Plasmapheresis Plasma exchange therapy for steroid-unre- rapidly reduced cryoglobulin levels (C4 consumption acted as an indirect measure of sponsive multiple sclerosis relapses: clinical cryoglobulin). Cyclophosphamide was used to treat the underlying lymphoma. experience with 16 patients. Nervenartz 2006;77:430–8. [in German] 18 Thompson GR, Kitano Y. The role of low density lipoprotein apheresis in the treat- ment of familial . Metabolic disorders dose plasma infusion versus plasma Review. Ther Apher 1997;1:13–6. exchange as early treatment of thrombotic 19 Clark WF, Stewart AK, Rock GA et al. Homozygous familial hypercholestero- thrombocytopenia purpura/hemolytic Plasma exchange when myeloma presents as laemia may respond poorly to drugs and uremic syndrome. Medicine (Baltimore) acute renal failure: a randomized, controlled diet. Plasma exchange can remove the 2003;82:27–38. trial. Ann Intern Med 2005;143:777–84. 6Winters JL, Pineda AA. New directions in 20 Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, low-density lipoproteins. Dextran sul- plasma exchange. Curr Opin Hematol Lachin JM. A controlled trial of plasma- phate/cellulose affinity absorption 2003;10:424–8. pheresis in severe lupus nephritis. The columns are successfully used. 7 Little MA, Pusey CD. Rapidly progressive Lupus Nephritis Collaborative Study Plasmapheresis has also been used in glomerulonephritis: current and evolving Group. N Engl J Med 1992;326:1373–9. Refsum’s disease, acute porphyria and treatment strategies. Review. J Nephrol 2004; 17(Suppl 8):S10–9. thyrotoxic crises, with reported benefit. 8Johnson JP, Moore J Jr, Austin HA 3rd et al. Therapy of anti-glomerular basement References membrane antibody disease: analysis of prognostic significance of clinical, patho- 1Freedman J, Garvey MB. Immuno- logic, and treatment factors. Medicine adsorption of factor VIII inhibitors. Review. (Baltimore) 1985;64:219–27. Curr Opin Hematol 2004;11:327–33. 9Artero ML, Sharma R, Savin VJ, Vincenti F. 2 Smith JW, Weinstein R, for the AABB Plasmapheresis reduces proteinuria and Hemapheresis Committee KL; AABB serum capacity to injure glomeruli in Hemapheresis Committee; American Society patients with recurrent focal glomerulo- for Apheresis. Therapeutic apheresis: a sum- sclerosis. Am J Kidney Dis 1994;23:574–81. mary of current indication categories 10 Pradhan M, Petro J, Palmer J, Meyers K, endorsed by the AABB and the American Baluarte HJ. Early use of plasmapheresis for Society for Apheresis. Transfusion 2003;43: recurrent post-transplant FSGS. Pediatr 820–2. Nephrol 2003;18:934–8. 3Cataland SR, Wu HM. Immunotherapy for 11 Hughes RA, Cornblath DR. Guillain-Barré thrombotic thrombocytopenic purpura. syndrome. Review. Lancet 2005;366: Curr Opin Hematol 2005;12:359–63. 1653–66. 4Rock GA, Shumak KH, Buskard NA et al. 12 Koller HK, Kieseier BC, Jander S, Hartung Comparison of plasma exchange with HP. Chronic inflammatory demyelinating plasma infusion in the treatment of throm- polyneuropathy. Review. N Engl J Med botic thrombocytopenic purpura. Canadian 2005;352:1343–56. Apheresis Study Group. N Engl J Med 13 Gloor JM, Lager DJ, Fidler ME et al. A com- 1991;325:393–7. parison of splenectomy versus intensive 5Coppo P, Bussel A, Charrier S et al. High- posttransplant antidonor blood group anti-

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