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Therapeutic apheresis in neurological, nephrological and gastrointestinal diseases
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Therapeutic apheresis in neurological, nephrological and gastrointestinal diseases ⁎
Azita Cheginia, , Sanaz Ahmadi Karvighb, Maryam Rahbarb, AliReza Sharifi Rayenib a b
Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine,Tehran, Iran Sina hospital, Tehran university of medical science, Tehran, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Blood component removal Plasma Exchange Plasmapheresis Autoimmune diseases of the nervous system Kidney diseases Gastrointestinal diseases
Therapeutic plasma exchange (TPE) is a process in which plasma containing antibodies, immune complexes, inflammatory moderators, paraproteins and other toxins which are believed to be the cause of disease is removed from a patient. TPE is the first-line treatment (category I, level 1A) in all forms of Acute inflammatory demyelinating polyradiculoneuropathy disease (axonal, demyelinating and miller-fisher variant) as well as in acute myasthenic crisis, chronic inflammatory demyelinating polyradiculoneuropathy and Paraproteinemic neuropathies (category I, level 1B). Moreover, TPE in kidney diseases, for instance: desensitization in renal transplantation(ABO compatible) (living donor)and desensitization in deceased donor, desensitization in renal transplantation(ABO incompatible) (living donor), thrombotic microangiopathy complement Mediated (Factor H autoantibodies), Focal segmental glomerulosclerosis(recurrent in transplanted kidney), ANCA-associated rapidly progressive glomerulonephritis(Dialysis dependence, DAH), Anti-Glomerular basement membrane disease Goodpasture’s syndrome)(DAH,Dialysis-independence,) has been utilized as an initial treatment. (category I) TPE has been used as the key therapeutic modality to reduce anti-A or anti-B antibody titers in the liver peritransplant period with the goal of preventing rejection and facilitating graft survival. Also, plasma exchange is the first-line therapy in Wilson’s disease (category I, level1C).
1. Historical background Apheresis is a word with a Greek root meaning ‘to take away’ [1]. There is information of therapeutic apheresis from India, Egypt and Greece. Abel et al removed plasma in uremic dogs and used the terms Apheresis and Plasmapheresis in 1914, but because of inadequate devices they could not use the procedures in clinical practice [2]. From the 20th century the other investigators have had the idea of apheresis for treating diseases [3]. In 1940 professor E.J Cohn thought of a centrifugal method for blood which resembled the centrifugal instrument for milk separation (De Laval). [4]. Incipiently, Adams WS et al used plasma exchange in treating multiple myeloma and hyperviscosity patients. [5] Freireich et al made a centrifugal machine for removing white blood cells in an acute leukemia patient in 1965 [6]. Apheresis describes a procedure to remove or exchange a part of the blood that contains cells or plasma [7]. Sometimes two terms therapeutic plasmapheresis and therapeutic plasma exchange are used interchangeably. Blood extracted from a patient flows into an extracorporeal separation machine, then after a cellular component or
plasma are removed the remaining blood components return to the patient. Cytapheresis is the technique in which the cellular elements of the bloodie platelets, leucocytes, lymphocytes and red blood cells (RBCs) are selectively separated from the blood. Therapeutic plasma exchange is a process in which the plasma containing antibodies, immune complexes, inflammatory moderator, paraproteins and other excess toxins which are believed to be the root cause of disease is removed from a patient [8]. Apheresis procedures have different technical modalities such as centrifugal, filtration (membranous) and a centrifuge –filter combination. Centrifugal apheresis separates the plasma from cellular components based on specific gravity or density; the principle of membrane apheresis is basedon basis of molecular size [9]. The American Society for Apheresis has separated therapeutic apheresis indications into 4 categories in line with evidence-based literature reviews. These are: Category I: Therapeutic apheresis is initial treatment and standard adjunct therapy. Category II: Therapeutic apheresis is usually confirmed to be
⁎ Corresponding author at: Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. P.O.Box: 146651157. E-mail address: [email protected] (A. Chegini).
https://doi.org/10.1016/j.transci.2019.04.011
1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Azita Chegini, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.04.011
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Repeated TPE can be used (category III, 2C) but many patients need a nerve block [17]. Myasthenia gravis is usually associated with thymoma and autoantibodies are directed against the postsynaptic acethylcholine receptor or, less often, MUSK. As a result, neuromuscular transmission is interrupted and fatigability, diplopia and eyelid ptosis are common. In generalized cases, respiratory and bulbar muscles are involved and a severe crisis can be mortal. TPE and IVIG are the first-line therapy in acute mysthenic crisis (category I, level 1B) [18]. Certain conditions (infections, drugs and surgery) can predispose patients to crisis therefore prophylactic TPE is often recommended before thymectomy (category I, level 1c) [11]. Long-term treatment is with steroids and cytotoxic drugs, however, certain refractory types may benefit from chronic TPE [18]. Lambert-Eaton myasthenic syndrome is another neuromuscular junction disorder in which antibodies are directed to presynaptic calcium channels. The disorder is more often associated with lung cancer and patients present with proximal and respiratory muscle weakness and autonomic dysfunction. TPE can be useful especially in exacerbations (category II, level 2C) [11,19].
supportive or adjunctive treatment. Category III: Randomized controlled studies have substantiated benefits of this treatment although there is lack of enough grounding to establish the validity of therapeutic apheresis. Different controlled trials have shown conflicting outcomes resulting from insufficient samples available. Category IV: Controlled trials are devoid of illustrated benefits or reliable reports. Therapeutic apheresis is an extracorporeal treatment in several disease categories such as neurology, nephrology, hematologic, oncologic, rheumatology, and gastroenterology [10] some of which will later be explained in depth. 2. TPE in neurological diseases Therapeutic plasmapheresis (TPE) has been used widely in immune–mediated inflammatory neurologic disorders since the 80 s. In fact, these disorders are the first or second most common indication for TPE in most hospitals [11,12]. The underlying pathology may be paraneoplastic or autoimmune reactions. As expected, when the humoral immune system (B-cells, antibodies, complement and cytokines) is the main mechanism instead of cellular immunity, TPE can be most effective [13]. Nonetheless, there are some compromising factors regarding the efficacy of TPE in neurologic disorders. The central nervous system (CNS) is protected and somewhat inaccessible because of the Blood-Brain-Barrier and therefore the autoantibodies accumulated and often produced in the CSF can be out of reach for TPE. In the following diseases, TPE is used as the first or second-line therapy with the usual regimen of 50 mL/kg plasma volume exchange for five sessions, every other day [11].
2.2. Diseases of the central nervous system Multiple sclerosis is an inflammatory-degenerative disease of the CNS with heterogeneous pathophysiology that includes perivascular Tcell mediated inflammation and demyelination and intrathecal production of immunoglobolins (CSF Oligocolonal bands). Acute CNS inflammatory demyelination presents clinically as attacks of focal neurologic deficits. In severe attacks of relapsing MS that are refractory to high-dose methylprednisolone, TPE is shown to be effective (category II, level 1B) [11,20]. However, in progressive MS the degenerative process predominates and the use of chronic TPE is not helpful (category IV 1 A) [20]. Natalizumab is a disease modifying treatment for MS. Unfortunately, despite high efficacy, it can result in JC–virus reactivation in the CNS as a progressive multifocal leukoencephalopathy (PML) associated with natalizumab. This potentially lethal condition is treated by rapidly extracting the drug from the plasma by TPE (category I, level 1C) which can otherwise take up to 90 days to happen spontaneously [11]. TPE has also been shown to accelerate the desaturation of the targeted alpha-4-integrin receptor, and restore leukocyte transmigration and reverse the immune system [21]. However, this method often results in an immune reconstitution inflammatory syndrome (IRIS) requiring high-dose steroids [21]. Neuromyelitis optica spectrum disorder is signified by the presence of an IgG autoantibody directed towards the aquaporin-4 water channel on the surface of astrocytes, which causes demyelination and neuronal loss. Patients present with optic neuritis or longitudinally extensive transverse myelitis (LETM). The B-cell mediated immune response is very prominent in this disorder and TPE can be helpful for treating the acute attacks (category II, level 1B) as a first-line or after steroids [22]. Also, TPE can be used as maintenance therapy (category III,level 2C) when rituximab and immunosuppressants fail [11,22]. Plasma volume exchange of 1.5 lit for five sessions over 10 days is recommended [11,22]. Acute disseminated encephalomyelitis (ADEM) is a monophasic post-infectious inflammatory reaction in CND presenting with fever, encephalopathy, seizure and focal neurological deficits. Immune responses which are mostly T-cell mediated and patchy demyelination is associated with a transient autoimmune response against myelin oligodendrocyte glycoprotein or other autoantigens. After high-dose steroids, IVIG and TPE (category II, level 2C) can be used in severe cases [11]. Autoimmune encephalitis is a large group of diseases that have been under the spotlight in the past decade. Every day, new autoantibodies with specific clinical presentations are found. These disorders can affect
2.1. Diseases of the peripheral nervous system Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or Guillain-Barre syndrome is an inflammatory, usually post-infectious disease that can cause demylination or axonal loss in the peripheral nerves. Auto-Antibodies against GM1, GD1a, GQ1b and LOS are present in the serum and CSF. Patients present with distal ascending weakness and paresthesis that, in severe cases, can cause respiratory and autonomic failure resulting in death. TPE and IVIG are the first-line treatments (category I, level 1 A) in all forms of the disease (axonal, demyelinating and Miller-Fisher variant) and seem to be equally effective [14]. But in some cases that have not initially responded to IVIG, delayed TPE can also be tried (category III, level 2C) [11]. Even in milder ambulatory cases, TPE can provide faster recovery and less long-term disability (Level B) [14]. In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) the demyelinating process lasts more than 2 months and the disease is characterized by ongoing distal weakness with occasional relapses. The treatment strategy consists of chronic use of corticosteroids, IVIG, TPE (category I, level 1B) and long-term immunosuppression [12]. Paraproteinemic neuropathies are a varied group of conditions, where monoclonal overproduction of immunoglobulins causes axonal or demyelinating damage to peripheral nerves. They can be associated with hematologic malignancies or monoclonal gammopathy of undetermined significance (MGUS). TPE seems to be more effective in certain subtypes with demyelination like IgG/IgA(category I, level 1B) [12] rather than those with IgM (category I, level 1C) [15]. TPE is also used in subtypes of Anti-MAG neuropathy (category III, level 1C) and multiple myeloma (category III, level 2C), but is not effective in multifocal motor neuropathy(IV 1C) or POEMS syndrome (IV) [16]. Complex regional pain syndrome is recognized by inflammation after an injury to peripheral nerves. Anti-muscarinic and anti-adrenergic autoantibodies are detected to be targeting the autonomic peripheral nerves. Severe chronic pain in the limb is characteristic. 2
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In TTP, there may be genetic deficiency of the Von Willebrand Factor- cleaving protease (ADAMTS13) or autoantibodies made against it. Therapeutic plasma exchange will replace normal plasma components, regardless of etiology and will remove autoantibodies when they exist. [31,32] In 1991, the Canadian Apheresis Group published a definitive, randomized controlled trial demonstrating the superiority of plasma exchange over plasma infusion for treating TTP patients. [32] In diarrhea negative (D-) HUS (atypical HUS) there are no controlled trials but there are several reports of the benefit of plasma exchange for FFP in severely affected patients. [32] Diarrhea positive (D+) HUS in children is usually a self-limiting disease but there are recent reports of the benefit of therapeutic plasmapheresis in adults with acute D + HUS. [33] Recently, Eculizumab (a monoclonal antibody against C5 that inhibits the formation of the membrane attack complex of complement) has been used to treat (D-) HUS and the results have been very encouraging. [32]
a restricted focus in the CNS, like limbic encephalitis due to VGKC antibody, or have diffuse involvement like diffuse encephalomyelitis due to an anti-NMDA receptor antibody. The clinical presentation varies but encephalopathy, psychiatric disorders, seizures, abnormal movement and focal neurologic deficits are common. Two categories of neuronal autoantigens are recognized; first intracellular antigens (Hu, Yo, Ri, Ma2, Cv2/CRMP5, amphiphysin, and Sox1/2, GAD65) that involve T-cell mediated immunity and are often paraneoplastic and respond poorly to immunomodulatory treatments. In these cases, steroids and cytotoxic drugs are preferred to TPE [23]. The other is the neural specific surface/synaptic antigens (VGKC complex of LGI1-CASPR2, NMDA-R, AMPA-R, GluR5 and GABA-B-R) that involve B-cell mediated immunity producing pathogenic auto-antibodies. They can be paraneoplastic or not and usually respond better to immune therapy [23]. The general therapeutic approach is to use steroids, IVIG or TPE as the first or second-line of therapy and even repeat them for maintenance for a few months [13,24,25]. In refractory cases, treatment can be escalated to IV immunosuppressors and rituximab [13]. Good evidence supporting TPE is only available for a few of these syndromes such as NMDA-R encephalomyelitis (category I, level 1C), limbic encephalitis with voltage-gated potassium channel antibodies (category II, level 2C), Rasmussen Encephalitis with anti GLU-R3 Ab (category III, level 2C) and Hashimoto encephalitis with Anti TPO Ab(category II, level 2C) [11,12]. In other similar conditions like Gluten-sensitive cerebellar ataxia with anti-endomysial, anti gliadin Ab, Pediatric Bickerstaff brainstem encephalitis with anti GQ1b Ab or New-Onset Refractory Status Epilepticus (NORSE) [26], TPE is used with little evidence [11,13,27]. Stiff-person syndrome, which can be an autoimmune disorder associated with anti GAD-65 Ab or a paraneoplastic disorder with anti-amphiphysin presents with stimulus-sensitive disabling muscle spasms and fluctuating truncal rigidity, has long been known to respond well to TPE (category III, level 2C) [11]. A group of post-infectious inflammatory disorders can involve CNS after streptococcal infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) that present with tic or obsessive compulsive disorders are treated with TPE (category II, level 1B), IVIG and steroids [28]. Also, Sydenham’s chorea (cateogoryIII, level 2B) is included in is group [29] (Tables 1–4).
3.3. Cryoglobulinemia Therapeutic plasma exchange has been used for the treatment of cryoglobulinemia for over 20 years and there are a lot of antibodies and complement that precipitate when exposed to cold temperature. There are no controlled trials, but there are multiple reports establishing the efficacy of plasma exchange in patients with acute vasculitis and renal involvement. [32] 3.4. Anti GBM disease (Good pastures) There is evidence of the pathogenicity of anti GBM antibodies which are confirmed to be rapidly fatal when not treated in time. In the largest long term study using plasmapheresis together with immunosuppression, virtually all patients with a creatinine < 200 mol/ L (5.7 mg/dl) recovered renal function. [34] 3.5. Recurrent focal segmental glomerulosclerosis (FSGS) Recurrent FSGS in renal transplantation appears to be mediated, in some cases, by a circulating factor that increases glomerular permeability. FSGS can recur promptly following renal transplantation (15%–55) In some patients using therapeutic plasmapheresis is frequently reported to be of benefit but FSGS in the native kidney has variable results. [35,36]
3. TPE in nephrology diseases 3.1. Anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis These patients have a small vessel vasculitis often affecting the kidney, with pauci-immune precipitation. This group of diseases includes granulomatosis with polyangitis (previously Wegner Granulomatosis) microscopic polyangitis and eosinophilic granulomatosis with polyangitis (previously Churg – Strauss syndrome). In 1977, Lock wood et al. published the first report demonstrating the use of therapeutic plasmapheresis in 9 patients with crescentic glomerulonephritis (GN) from which 5 rapidly recovered from kidney failure. [30] Then, in 1991, Pusy et al (ref) published a randomized control trial (RCY) that showed a benefit of therapeutic plasmapheresis together with immunosuppressive drugs in ANCA associated vasculitis often requiring dialysis. A large European multicenter study (MEPEX) confirmed this finding which demonstrated a better recovery of renal function in patients with a creatinine of > 500 mcmol/L (5.7 mg/dl) treated with therapeutic plasmapheresis compared to those treated with pulse methylprednisolone. [30]
3.6. Renal transplantation Therapeutic plasmapheresis has been used for over 20 years for treating antibody mediated rejection and recently, this has been used in a desensitization protocol for ABO incompatible or highly sensitized patients. [32] These were six disorders which have TPE indicated as for first line or second line therapy in the ASFA categories. There are several mechanisms by which TPE has beneficial effects for renal diseases including immunomodulatory actions and therapeutic actions. [37] 4. TPE in Gastroenterology and hepatobiliary diseases 4.1. Acute liver failure
3.2. Thrombotic thrombocytopenic Purpura (TTP) and hemolytic uremic syndrome (HUS)
Standard treatment for acute liver failure (ALF) with low likelihood of spontaneous recovery, is supportive care as a bridge to liver transplantation (LT). Therapeutic plasma exchange (TPE) can remove albumin bound and unbound toxins and restore hemostasis.
Both TTP and HUS lead to thrombotic microangiopathy, in particular, HUS affects the kidney and TTP-afflicted patients often have their central nervous system impaired. 3
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Table 1 Neurology diseases and their treatments. Disease
Form of diseases
Treatment
Diseases of the Peripheral Nervous System Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or Guillain-Barre syndrome
Axonal, demyelinating and miller-fisher variant
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Mainly demyelinating
Paraproteinemic neuropathies
Complex regional pain syndrome
axonal or demyelinating damage to peripheral nerves IgG/IgA demyelination IgM demyelination Anti-MAG neuropathy Multiple myeloma Multifocal Motor Neuropathy inflammation after an injury to peripheral nerves
TPE and IVIG No initially response to IVIG delayed TPE chronic use of corticosteroids IVIG TPE long-term immunosuppression TPE TPE TPE TPE TPE TPE TPE nerve block
Neuromuscular junction disorders Myasthenia gravis
associated with thymoma and autoantibodies acute mysthenic crisis severe crisis(respiratory) refractory types
Lambert-Eaton myasthenic syndrome Diseases of the Central Nervous System Multiple sclerosis (Acute CNS inflammatory demyelination)
Neuromyelitis optica
Acute disseminated encephalomyelitis (ADEM)
Autoimmune Encephalitis
Autoimmune or paraneoplastic associated with VGCC
prophylactic TPE before thymectomy TPE TPE and IVIG steroids cytotoxic drugs TPE TPE
severe attacks relapsing refractory MS progressive MS (the degenerative process) Progressive multifocal leukoenchephalopathy (PML) associated with natalizumab
high-dose methylprednisolone TPE
acute attacks
Steroids TPE TPE (maintenance therapy
Failing rituximab and other Immunosuppressants monophasic post-infectious inflammatory reaction in CND Sever cases paraneoplastic or autoimmune refractory cases NMDA-R encephalomyelitis limbic encephalitis with voltage-gated potassium channel antibodies Rasmussen Encephalitis with anti GLU-R3 Ab Hashimoto encephalitis with Anti TPO Ab anti-amphiphysin
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) Sydenham’s chorea
TPE TPE extracting the drug from the plasma
After high-dose steroids IVIG TPE First line treatment: steroids, IVIG or TPE IV immunosuppressors and rituximab TPE TPE TPE TPE TPE TPE IVIG and steroids TPE
and eliminated the need for LT. [11]
A controlled trial by Yue-Meng showed significant survival benefit in patients who received TPE for patients with entecavir-treated hepatitis B and acute-on-chronic liver failure. The cumulative survival rates were 37% (TPE) and 18% (non TPE) at week 4 and 29% (TPE) and 14% (non TPE) at week 12 (P < 0.001). [38] A recent RCT performed in 183 patients demonstrated statistically significant overall survival benefit: 58.7% with TPE-high volume (TPEHV) + standard care versus 47.8% standard care (P < 0.001). [39]
4.3. Liver transplantation There has been significant progress in the use of TPE perioperatively in ABO incompatible (ABOi) deceased donor liver transplantion (DDLT) and for preconditioning/ antibody mediated rejection (AMR) treatment in ABOi live donor liver transplant (LDLT). [11] Because hyperacute rejection, and acute AMR are definitive risks in ABOi liver transplants, TPE has been used as the key therapeutic modality to reduce anti-A or anti-B antibody titers in the peri-transplant period with the goal of preventing rejection and facilitating graft survival. [11] In the DDLT setting, TPE is typically instituted immediately before and sometimes both before and after transplantation in an attempt to prevent hyperacute rejection and acute AMR. ABOi LDLT has been increasingly used in East Asia with patients being treated with rituximab,
4.2. Wilson’s disease TPE can be beneficial as it rapidly removes significant amounts of copper from the circulation (average 20 mg per TPE). Decreased serum copper may decrease hemolysis, prevent progression of renal failure, and provide clinical stabilization. TPE can also remove large molecular weight toxins which may be responsible for hepatic coma. Recent reports showed that TPE combined with chelating agents improved ALF 4
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Table 2 TPE indications in Renal and Gastrointestinal hepatobiliary diseases. Renal diseases
Gastrointestinal diseases
Renal transplantation (ABO compatible)[Desensitization, living donor,Desensitization, deceased donor,Antibody mediated rejection]
Liver Transplantation (Desensitization, ABOi living donor,Desensitization, ABOi deceased donor,Antibody mediated rejection) Acute liver failure
Renal transplantation(ABO incompatible)[ Desensitization, living donor,Antibody mediated rejection,A2/A2B into B, deceased donor] Thrombotic microangiopathy, coagulation mediated Thrombotic microangiopathy,complement mediated(Complement factor gene mutations ,Factor H autoantibodies ,MCP mutations) Thrombotic microangiopathy,Shiga toxin mediated(Severe neurological symptoms,pHUS) Focal segmental glomerulosclerosis(Recurrent in transplanted kidney,Steroid resistant in native kidney) ANCA-associated rapidly progressive glomerulonephritis (Granulomatosis with polyangiitis and microscopic polyangiitis)[Dialysis dependence,DAH I,Dialysis independence] Anti-Glomerular basement membrane disease Goodpasture’s syndrome)Dialysis-dependencea, no DAH (diffuse alveolar hemorrhage) ,DAH ,Dialysis-independence Immunoglobulin a nephropathy(Crescentic ,Chronic progressive) Myeloma cast nephropathy Nephrogenic systemic fibrosis Cryoglobulinemia Symptomatic/severe
Modality
Renal transplantation (ABO compatible) Desensitization, living donor Desensitization, deceased donor Antibody mediated rejection Renal transplantation(ABO incompatible) Desensitization, living donor Antibody mediated rejection A2/A2B into B, deceased donor Thrombotic microangiopathy, coagulation mediated Thrombotic microangiopathy,complement Mediated Complement factor gene mutations Factor H autoantibodies MCP mutations Thrombotic microangiopathy,Shiga toxin mediated Severe neurological symptoms pHUS Absense of severe neurologic symptoms Focal segmental glomerulosclerosis Recurrent in transplanted kidney Steroid resistant in native kidney ANCA-associated rapidly progressive glomerulonephritis (Granulomatosis with polyangiitis and microscopic polyangiitis) Dialysis dependence DAH I Dialysis independencea Anti-Glomerular basement membrane disease Goodpasture’s syndrome) Dialysis-dependencea, no DAH (diffuse alveolar hemorrhage) DAH Dialysis-independence Immunoglobulin a nephropathy Crescentic Chronic progressive Myeloma cast nephropathy Nephrogenic systemic fibrosis Cryoglobulinemia Symptomatic/severe
TPE
• • • • • • • • •
• • • • • • • •
Recommendation
TPE
Inflammatory bowel disease
4.4. Pruritus due to hepatobiliary diseases I I III
Grade1B Grade 1B Grade 2C
I II IV III
Grade Grade Grade Grade
For patients unresponsive to medications, TPE may remove the potential pruritogens from the systemic circulation. In patients with chronic pruritus due to hepatobiliary disorders, 10 of 13 (77%) responded to TPE. Patients may experience decreased pruritus after the 2nd TPE. For some patients, the effects may last many months, while for others, chronic maintenance TPE is needed. [11]
TPE 1B 1B 1B 2C
4.5. Hypertriglyceridemic pancreatitis
TPE
III I III
Grade 2C Grade 2C Grade 1C
III III IV
Grade 2C Grade 2C Grade 1C
I III
Grade 1B Grade 2C
I I III
Grade 1A Grade 1C Grade 2C
III
Grade 2B
I I
Grade 1C Grade 1B
III III II III II
Grade Grade Grade Grade Grade
TPE can significantly decrease triglyceride (TG) levels, reduce inflammatory cytokines, and potentially replace deficient lipoprotein lipase or apolipoproteins when plasma is used as the replacement fluid. Reductions in TG levels of 49–80% have been reported following a single TPE procedure. While TPE can rapidly decrease the TG level, its effect is transient; adequate lipid lowering treatment is essential to achieve a persistent effect. TPE has also been successfully used as a treatment strategy during pregnancy [40] There was no difference in mortality between early (< 36 h after onset of pain) and late initiation of TPE. Several series have been reported on the use of maintenance TPE to maintain TG levels < 150 mg/ dL to prevent further episodes of pancreatitis. [41]
TPE
• • • • •
Category
Hypertriglyceridemic pancreatitis Hereditary hemochromatosis
TPE, and hepatic infusion with prostaglandin E1 and methylprednisolone with good survival statistics. TPE has also been used in the setting of AMR in liver allograft to decease the levels of both ABO and HLA antibodies. [11]
Table 3 Therapeutic Apheresis in nephrological diseases according to the ASFA guidelines-2016. Disease
Wilson’s disease Pruritus due to hepatobiliary diseases
TPE
TPE
4.6. Hereditary hemochromatosis A RCT compared biweekly erythrocytapheresis with weekly phlebotomy among 38 patients with newly diagnosed hereditary hemochromatosis (HH). The mean number of procedures and treatment duration to achieve a ferritin of < 50 ng/mL were 9 and 20 weeks for the erythrocytapheresis group versus 27 and 34 weeks (p < 0.001 and p < 0.002), respectively, for the phlebotomy group. [42]
TPE
TPE
TPE TPE TPE
2B 2C 2B 2C 2A
4.7. Inflammatory bowel disease Selective apheresis is a potentially useful adjunct for the management of inflammatory bowel disease (IBD) with the goal of removing the activated leukocytes or moderating their proinflamatory nature toward an immune modulatory phenotype. 5
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Table 4 Therapeutic Apheresis in Gastroenterology and hepatobiliary diseases according to the ASFA guideline-2016. Disease
Modality
Category
Recommendation
Acute liver failure Wilson’s disease Liver transplantation Desensitization, ABOi living donor Desensitization, ABOi deceased donor Antibody mediated rejection Pruritus due to hepatobiliary diseases Hypertriglyceridemic pancreatitis Hereditary hemochromatosis Inflammatory bowel disease
TPE TPE
III I
Grade 2B Grade 1C
TPE TPE TPE TPE TPE Erythrocytapheresis Adsorptive cytapheresis
I III III III III I III
Grade Grade Grade Grade Grade Grade Grade
• • •
A recent meta-analysis showed granulocytapheresis was effective for achieving a clinical response in patients with active ulcerative colitis (UC) when compared to corticosteroids [43]. Evidence supporting the use of adsorptive cytapheresis to treat Crohn’s disease (CD) is more limited. Although a few uncontrolled studies have demonstrated efficacy in the treatment of active CD, a recently published large RCT did not demonstrate any difference in remission rates when compared to sham treatment in patients with moderate to severe CD [44].
1C 2C 2C 1C 2C 1B 1B
the seventh special issue. J Clin Apher 2016;31(June (3)):149–62. [12] Codron P, Cousin M, Subra JF, Pautot V, Letournel F, Verny C, et al. Therapeutic plasma exchange in chronic dysimmune peripheral neuropathies: A 10-year retrospective study. J Clin Apher 2017;32(December (6)):413–22. [13] Shin YW, Lee ST, Park KI, Jung KH, Jung KY, Lee SK, et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord 2017;11(August (16)):17. [14] Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev 2017;2(February (27)):CD001798. [15] Lunn MP, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev 2016;10(October (4)):CD002827. [16] Ipe TS, Pham HP, Williams 3rd LA. Critical updates in the 7(th) edition of the American Society for Apheresis guidelines. J Clin Apher 2018;33(February (1)):78–94. [17] Aradillas E, Schwartzman RJ, Grothusen JR, Goebel A, Alexander GM. Plasma exchange therapy in patients with complex regional pain syndrome. Pain Physician 2015;18(July–August (4)):383–94. [18] Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology 2016;87(4):419–25. [19] Schoser B, Eymard B, Datt J, Mantegazza R. Lambert-Eaton myasthenic syndrome (LEMS): a rare autoimmune presynaptic disorder often associated with cancer. J Neurol 2017;264(September (9)):1854–63. [20] Markowitz CE. Multiple sclerosis update. Am J Manag Care 2013;19(November (16 Suppl.)):s294–300. [21] Tyler KL, Vollmer TL. To PLEX or not to PLEX in natalizumab-associated PML. Neurology 2017;88(March (12)):1108–9. [22] Kleiter I, Gold R. Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders. Neurotherapeutics 2016;13(January (1)):70–83. [23] Hermetter C, Fazekas F, Hochmeister S. Systematic review: syndromes, early diagnosis, and treatment in autoimmune encephalitis. Front Neurol 2018;9(September (5)):706. [24] Fassbender C, Klingel R, Köhler W. Immunoadsorption for autoimmune encephalitis. Atheroscler Suppl 2017;30(November):257–63. [25] Bhatia S, Schmitt SE. Treating immune-related epilepsy. Curr Neurol Neurosci Rep 2018;18(February (3)):10. [26] Zeiler FA, Matuszczak M, Teitelbaum J, Kazina CJ, Gillman LM. Plasmapheresis for refractory status epilepticus Part II: a scoping systematic review of the pediatric literature. Seizure 2016;43(December):61–8. [27] Mahdi-Rogers M, Brassington R, Gunn AA, van Doorn PA, Hughes RA. Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2017;5(May (8)):CD003280. [28] Eyre M, Hacohen Y, Barton C, Hemingway C, Lim M. Therapeutic plasma exchange in paediatric neurology: a critical review and proposed treatment algorithm. Dev Med Child Neurol 2018;60(August (8)):765–79. [29] Dean SL, Singer HS. Treatment of Sydenham’s chorea: a review of the current evidence. Tremor Other Hyperkinet Mov (N Y) 2017;7(June (1)):456. [30] Reeves Hollie M, Jeffrey LWinters. The mechanisms of action of plasma exchange. British J of hematology 2013;16413:342–51. [31] Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. ASH Education Program Book. 2004;2004(January (1)):407–23. [32] Clark WF, Huang SH, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int 2016;90(November (5)):97484. https://doi.org/10.1016/j.kint.2016.06.009. [33] Colic E, Dieperink H, Titlestad K, Tepel M. Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study. Lancet 2011;378(September (9796)):1089–93. [34] Levy JB, Turner AN, Rees AJ, Pusey CD. long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immuno suppressive Ann Intern Med 2001;134:1033–42. [35] Montagnino G, Tarantino A, Banfi G, Maccario M, Costamagna L, et al. Double recurrence of FSGS after two renal transplants with complete regression after plasmapheresis and ACE inhibitors. Transpl Int 2000;13(March (2)):166–8. [36] Wol f J. Predictors for success of plasmapheresis on the long-term outcome of renal
5. Summary Therapeutic apheresis is a process used for patients with numerous disorders. Publications of evidence-based guidelines of the American Society for Apheresis (ASFA) include indications, rate, and duration of apheresis treatment (last updated in 2016). TPE is the first-line treatment (category I, level 1A) in all forms of the acute inflammatory demyelinating polyradiculoneuropathy disease (axonal, demyelinating and Miller-Fisher variant) as well as in acute myasthenic crisis, chronic inflammatory demyelinating polyradiculoneuropathy and paraproteinemic neuropathies(category I, level 1B), desensitization in renal transplantation(ABO compatible) (living donor)and desensitization in deceased donor, desensitization in renal transplantation(ABO incompatible) (living donor), Thrombotic microangiopathy complement mediated (Factor H autoantibodies), focal segmental glomerulosclerosis (recurrent in a transplanted kidney), ANCA-associated rapidly progressive glomerulonephritis (dialysis dependence, DAH), AntiGlomerular basement membrane disease.(Goodpasture’s syndrome) (DAH,dialysis-independent), for reduction of anti-A or anti-B antibody titers in the liver peri-transplant period and Wilson’s disease. References [1] Gilcher R. Simon T, Synder E, Stowell C, Strauss R, Solheim B, Petrides M, editors. Rossi’s principles of transfusion medicine. 4th ed.West Sussex: Blackwell Publishing Ltd; 2009. p. 617–28. [2] Abel JJ, Rowntree LG, Turner BB. Plasma removal with return of corpuscles JPharmacol Exp Ther 1914;5:625–41. [3] Shumak KH, Rock GA. Therapeutic plasma exchange. N Engl J Med 1984;310:762–71. [4] Millward BL, Hoeltge GA. The historical development of automated hemapheresis. J Clin Apher 1982;1:25–32. [5] Adams WS, Blahd WH, Bassett SH. A method of human plasmapheresis. Proc Soc Exp Biol Med 1952;80:377–9. [6] Freireich EJ, Judson G, Levin RH. Separation and collection of leukocytes. Cancer Res 1965;25:1516–20. [7] Ward DM. Conventional apheresis therapies: a review. J Clin Apher 2011;26(5):230–8. [8] Bose N, Kanzariya H. Role of therapeutic apheresis and phlebotomy techniques in anaesthesia and critical care. Indian J Anaesth 2014;58:672–8. [9] Williams ME, Balogun RA. Principles of separation: indications and therapeutic targets for plasma exchange. Clin J Am Soc Nephrol 2014;9(January (1)):181–90. [10] McLeod BC. Therapeutic apheresis: history, clinical application, and lingering uncertainties. Transfusion 2010;50(July (7)):1413–26. [11] Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidenceBased approach from the writing committee of the american society for apheresis:
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[41] Gubensek J, Buturovic-Ponikvar J, Romozi K, Ponikvar R. Factors affecting outcome in acute hypertriglyceridemic pancreatitis treated with plasma exchange: an observational cohort study. PLoS One 2014;9:e102748. [42] Rombout-Sestrienkova E, Nieman FH, Essers BA, van Noord PA, Janssen MC, et al. Erythrocytapheresis versus phlebotomy in the initial treatment of HFE hemochromatosis patients: results from a randomized trial. Transfusion 2012;52:470–7. [43] Yoshino T, Nakase H, Minami N, Yamada S, Matsuura M, Yazumi S, et al. Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: a meta-analysis. Dig Liver Dis 2014;46:219–26. [44] Sands BE, Katz S, Wolf DC, Feagan BG, Wang T, Gustofson LM, et al. A randomised, double-blind, sham-controlled study of granulocyte/monocyte apheresis for moderate to severe Crohn’s disease. Gut 2013;62:1288–94.
transplant patients with recurrent FSGS. J Am Soc Nephrol 2014;9:181–9. [37] W.M. Szpirt. plasma exchange in antineutrophil cytoplasmic antibody ? associated vasculitis- a 25 ? year perspective Nephrol Dial Ttransplant 2015; 30: il46-il49. [38] Yue-Meng W, Yang LH, Yang JH, Xu Y, Yang J, et al. The effect of plasma exchange on entecavir-treated chronic hepatitis B patients with hepatic de-compensation and acute-on-chronic liver failure. Hepatol Int 2016;10(May (3)):462–9. [39] Larsen FS, Schmidt LE, Bernsmeier C, Rasmussen A, Isoniemi H, Patel VC, et al. Highvolume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J. Hepatol 2016;64:69–78. [40] Basar R, Uzum AK, Canbaz B, Dogansen SC, Kalayoglu-Besisik S, et al. Therapeutic apheresis for severe hypertriglyceridemia in pregnancy. Arch Gynecol Obstet 2013;287:839–43.
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Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Therapeutic apheresis in neurological, nephrological and gastrointestinal diseases ⁎
Azita Cheginia, , Sanaz Ahmadi Karvighb, Maryam Rahbarb, AliReza Sharifi Rayenib a b
Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine,Tehran, Iran Sina hospital, Tehran university of medical science, Tehran, Iran
A R T I C LE I N FO
A B S T R A C T
Keywords: Blood component removal Plasma Exchange Plasmapheresis Autoimmune diseases of the nervous system Kidney diseases Gastrointestinal diseases
Therapeutic plasma exchange (TPE) is a process in which plasma containing antibodies, immune complexes, inflammatory moderators, paraproteins and other toxins which are believed to be the cause of disease is removed from a patient. TPE is the first-line treatment (category I, level 1A) in all forms of Acute inflammatory demyelinating polyradiculoneuropathy disease (axonal, demyelinating and miller-fisher variant) as well as in acute myasthenic crisis, chronic inflammatory demyelinating polyradiculoneuropathy and Paraproteinemic neuropathies (category I, level 1B). Moreover, TPE in kidney diseases, for instance: desensitization in renal transplantation(ABO compatible) (living donor)and desensitization in deceased donor, desensitization in renal transplantation(ABO incompatible) (living donor), thrombotic microangiopathy complement Mediated (Factor H autoantibodies), Focal segmental glomerulosclerosis(recurrent in transplanted kidney), ANCA-associated rapidly progressive glomerulonephritis(Dialysis dependence, DAH), Anti-Glomerular basement membrane disease Goodpasture’s syndrome)(DAH,Dialysis-independence,) has been utilized as an initial treatment. (category I) TPE has been used as the key therapeutic modality to reduce anti-A or anti-B antibody titers in the liver peritransplant period with the goal of preventing rejection and facilitating graft survival. Also, plasma exchange is the first-line therapy in Wilson’s disease (category I, level1C).
1. Historical background Apheresis is a word with a Greek root meaning ‘to take away’ [1]. There is information of therapeutic apheresis from India, Egypt and Greece. Abel et al removed plasma in uremic dogs and used the terms Apheresis and Plasmapheresis in 1914, but because of inadequate devices they could not use the procedures in clinical practice [2]. From the 20th century the other investigators have had the idea of apheresis for treating diseases [3]. In 1940 professor E.J Cohn thought of a centrifugal method for blood which resembled the centrifugal instrument for milk separation (De Laval). [4]. Incipiently, Adams WS et al used plasma exchange in treating multiple myeloma and hyperviscosity patients. [5] Freireich et al made a centrifugal machine for removing white blood cells in an acute leukemia patient in 1965 [6]. Apheresis describes a procedure to remove or exchange a part of the blood that contains cells or plasma [7]. Sometimes two terms therapeutic plasmapheresis and therapeutic plasma exchange are used interchangeably. Blood extracted from a patient flows into an extracorporeal separation machine, then after a cellular component or
plasma are removed the remaining blood components return to the patient. Cytapheresis is the technique in which the cellular elements of the bloodie platelets, leucocytes, lymphocytes and red blood cells (RBCs) are selectively separated from the blood. Therapeutic plasma exchange is a process in which the plasma containing antibodies, immune complexes, inflammatory moderator, paraproteins and other excess toxins which are believed to be the root cause of disease is removed from a patient [8]. Apheresis procedures have different technical modalities such as centrifugal, filtration (membranous) and a centrifuge –filter combination. Centrifugal apheresis separates the plasma from cellular components based on specific gravity or density; the principle of membrane apheresis is basedon basis of molecular size [9]. The American Society for Apheresis has separated therapeutic apheresis indications into 4 categories in line with evidence-based literature reviews. These are: Category I: Therapeutic apheresis is initial treatment and standard adjunct therapy. Category II: Therapeutic apheresis is usually confirmed to be
⁎ Corresponding author at: Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. P.O.Box: 146651157. E-mail address: [email protected] (A. Chegini).
https://doi.org/10.1016/j.transci.2019.04.011
1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Azita Chegini, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.04.011
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Repeated TPE can be used (category III, 2C) but many patients need a nerve block [17]. Myasthenia gravis is usually associated with thymoma and autoantibodies are directed against the postsynaptic acethylcholine receptor or, less often, MUSK. As a result, neuromuscular transmission is interrupted and fatigability, diplopia and eyelid ptosis are common. In generalized cases, respiratory and bulbar muscles are involved and a severe crisis can be mortal. TPE and IVIG are the first-line therapy in acute mysthenic crisis (category I, level 1B) [18]. Certain conditions (infections, drugs and surgery) can predispose patients to crisis therefore prophylactic TPE is often recommended before thymectomy (category I, level 1c) [11]. Long-term treatment is with steroids and cytotoxic drugs, however, certain refractory types may benefit from chronic TPE [18]. Lambert-Eaton myasthenic syndrome is another neuromuscular junction disorder in which antibodies are directed to presynaptic calcium channels. The disorder is more often associated with lung cancer and patients present with proximal and respiratory muscle weakness and autonomic dysfunction. TPE can be useful especially in exacerbations (category II, level 2C) [11,19].
supportive or adjunctive treatment. Category III: Randomized controlled studies have substantiated benefits of this treatment although there is lack of enough grounding to establish the validity of therapeutic apheresis. Different controlled trials have shown conflicting outcomes resulting from insufficient samples available. Category IV: Controlled trials are devoid of illustrated benefits or reliable reports. Therapeutic apheresis is an extracorporeal treatment in several disease categories such as neurology, nephrology, hematologic, oncologic, rheumatology, and gastroenterology [10] some of which will later be explained in depth. 2. TPE in neurological diseases Therapeutic plasmapheresis (TPE) has been used widely in immune–mediated inflammatory neurologic disorders since the 80 s. In fact, these disorders are the first or second most common indication for TPE in most hospitals [11,12]. The underlying pathology may be paraneoplastic or autoimmune reactions. As expected, when the humoral immune system (B-cells, antibodies, complement and cytokines) is the main mechanism instead of cellular immunity, TPE can be most effective [13]. Nonetheless, there are some compromising factors regarding the efficacy of TPE in neurologic disorders. The central nervous system (CNS) is protected and somewhat inaccessible because of the Blood-Brain-Barrier and therefore the autoantibodies accumulated and often produced in the CSF can be out of reach for TPE. In the following diseases, TPE is used as the first or second-line therapy with the usual regimen of 50 mL/kg plasma volume exchange for five sessions, every other day [11].
2.2. Diseases of the central nervous system Multiple sclerosis is an inflammatory-degenerative disease of the CNS with heterogeneous pathophysiology that includes perivascular Tcell mediated inflammation and demyelination and intrathecal production of immunoglobolins (CSF Oligocolonal bands). Acute CNS inflammatory demyelination presents clinically as attacks of focal neurologic deficits. In severe attacks of relapsing MS that are refractory to high-dose methylprednisolone, TPE is shown to be effective (category II, level 1B) [11,20]. However, in progressive MS the degenerative process predominates and the use of chronic TPE is not helpful (category IV 1 A) [20]. Natalizumab is a disease modifying treatment for MS. Unfortunately, despite high efficacy, it can result in JC–virus reactivation in the CNS as a progressive multifocal leukoencephalopathy (PML) associated with natalizumab. This potentially lethal condition is treated by rapidly extracting the drug from the plasma by TPE (category I, level 1C) which can otherwise take up to 90 days to happen spontaneously [11]. TPE has also been shown to accelerate the desaturation of the targeted alpha-4-integrin receptor, and restore leukocyte transmigration and reverse the immune system [21]. However, this method often results in an immune reconstitution inflammatory syndrome (IRIS) requiring high-dose steroids [21]. Neuromyelitis optica spectrum disorder is signified by the presence of an IgG autoantibody directed towards the aquaporin-4 water channel on the surface of astrocytes, which causes demyelination and neuronal loss. Patients present with optic neuritis or longitudinally extensive transverse myelitis (LETM). The B-cell mediated immune response is very prominent in this disorder and TPE can be helpful for treating the acute attacks (category II, level 1B) as a first-line or after steroids [22]. Also, TPE can be used as maintenance therapy (category III,level 2C) when rituximab and immunosuppressants fail [11,22]. Plasma volume exchange of 1.5 lit for five sessions over 10 days is recommended [11,22]. Acute disseminated encephalomyelitis (ADEM) is a monophasic post-infectious inflammatory reaction in CND presenting with fever, encephalopathy, seizure and focal neurological deficits. Immune responses which are mostly T-cell mediated and patchy demyelination is associated with a transient autoimmune response against myelin oligodendrocyte glycoprotein or other autoantigens. After high-dose steroids, IVIG and TPE (category II, level 2C) can be used in severe cases [11]. Autoimmune encephalitis is a large group of diseases that have been under the spotlight in the past decade. Every day, new autoantibodies with specific clinical presentations are found. These disorders can affect
2.1. Diseases of the peripheral nervous system Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or Guillain-Barre syndrome is an inflammatory, usually post-infectious disease that can cause demylination or axonal loss in the peripheral nerves. Auto-Antibodies against GM1, GD1a, GQ1b and LOS are present in the serum and CSF. Patients present with distal ascending weakness and paresthesis that, in severe cases, can cause respiratory and autonomic failure resulting in death. TPE and IVIG are the first-line treatments (category I, level 1 A) in all forms of the disease (axonal, demyelinating and Miller-Fisher variant) and seem to be equally effective [14]. But in some cases that have not initially responded to IVIG, delayed TPE can also be tried (category III, level 2C) [11]. Even in milder ambulatory cases, TPE can provide faster recovery and less long-term disability (Level B) [14]. In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) the demyelinating process lasts more than 2 months and the disease is characterized by ongoing distal weakness with occasional relapses. The treatment strategy consists of chronic use of corticosteroids, IVIG, TPE (category I, level 1B) and long-term immunosuppression [12]. Paraproteinemic neuropathies are a varied group of conditions, where monoclonal overproduction of immunoglobulins causes axonal or demyelinating damage to peripheral nerves. They can be associated with hematologic malignancies or monoclonal gammopathy of undetermined significance (MGUS). TPE seems to be more effective in certain subtypes with demyelination like IgG/IgA(category I, level 1B) [12] rather than those with IgM (category I, level 1C) [15]. TPE is also used in subtypes of Anti-MAG neuropathy (category III, level 1C) and multiple myeloma (category III, level 2C), but is not effective in multifocal motor neuropathy(IV 1C) or POEMS syndrome (IV) [16]. Complex regional pain syndrome is recognized by inflammation after an injury to peripheral nerves. Anti-muscarinic and anti-adrenergic autoantibodies are detected to be targeting the autonomic peripheral nerves. Severe chronic pain in the limb is characteristic. 2
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In TTP, there may be genetic deficiency of the Von Willebrand Factor- cleaving protease (ADAMTS13) or autoantibodies made against it. Therapeutic plasma exchange will replace normal plasma components, regardless of etiology and will remove autoantibodies when they exist. [31,32] In 1991, the Canadian Apheresis Group published a definitive, randomized controlled trial demonstrating the superiority of plasma exchange over plasma infusion for treating TTP patients. [32] In diarrhea negative (D-) HUS (atypical HUS) there are no controlled trials but there are several reports of the benefit of plasma exchange for FFP in severely affected patients. [32] Diarrhea positive (D+) HUS in children is usually a self-limiting disease but there are recent reports of the benefit of therapeutic plasmapheresis in adults with acute D + HUS. [33] Recently, Eculizumab (a monoclonal antibody against C5 that inhibits the formation of the membrane attack complex of complement) has been used to treat (D-) HUS and the results have been very encouraging. [32]
a restricted focus in the CNS, like limbic encephalitis due to VGKC antibody, or have diffuse involvement like diffuse encephalomyelitis due to an anti-NMDA receptor antibody. The clinical presentation varies but encephalopathy, psychiatric disorders, seizures, abnormal movement and focal neurologic deficits are common. Two categories of neuronal autoantigens are recognized; first intracellular antigens (Hu, Yo, Ri, Ma2, Cv2/CRMP5, amphiphysin, and Sox1/2, GAD65) that involve T-cell mediated immunity and are often paraneoplastic and respond poorly to immunomodulatory treatments. In these cases, steroids and cytotoxic drugs are preferred to TPE [23]. The other is the neural specific surface/synaptic antigens (VGKC complex of LGI1-CASPR2, NMDA-R, AMPA-R, GluR5 and GABA-B-R) that involve B-cell mediated immunity producing pathogenic auto-antibodies. They can be paraneoplastic or not and usually respond better to immune therapy [23]. The general therapeutic approach is to use steroids, IVIG or TPE as the first or second-line of therapy and even repeat them for maintenance for a few months [13,24,25]. In refractory cases, treatment can be escalated to IV immunosuppressors and rituximab [13]. Good evidence supporting TPE is only available for a few of these syndromes such as NMDA-R encephalomyelitis (category I, level 1C), limbic encephalitis with voltage-gated potassium channel antibodies (category II, level 2C), Rasmussen Encephalitis with anti GLU-R3 Ab (category III, level 2C) and Hashimoto encephalitis with Anti TPO Ab(category II, level 2C) [11,12]. In other similar conditions like Gluten-sensitive cerebellar ataxia with anti-endomysial, anti gliadin Ab, Pediatric Bickerstaff brainstem encephalitis with anti GQ1b Ab or New-Onset Refractory Status Epilepticus (NORSE) [26], TPE is used with little evidence [11,13,27]. Stiff-person syndrome, which can be an autoimmune disorder associated with anti GAD-65 Ab or a paraneoplastic disorder with anti-amphiphysin presents with stimulus-sensitive disabling muscle spasms and fluctuating truncal rigidity, has long been known to respond well to TPE (category III, level 2C) [11]. A group of post-infectious inflammatory disorders can involve CNS after streptococcal infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) that present with tic or obsessive compulsive disorders are treated with TPE (category II, level 1B), IVIG and steroids [28]. Also, Sydenham’s chorea (cateogoryIII, level 2B) is included in is group [29] (Tables 1–4).
3.3. Cryoglobulinemia Therapeutic plasma exchange has been used for the treatment of cryoglobulinemia for over 20 years and there are a lot of antibodies and complement that precipitate when exposed to cold temperature. There are no controlled trials, but there are multiple reports establishing the efficacy of plasma exchange in patients with acute vasculitis and renal involvement. [32] 3.4. Anti GBM disease (Good pastures) There is evidence of the pathogenicity of anti GBM antibodies which are confirmed to be rapidly fatal when not treated in time. In the largest long term study using plasmapheresis together with immunosuppression, virtually all patients with a creatinine < 200 mol/ L (5.7 mg/dl) recovered renal function. [34] 3.5. Recurrent focal segmental glomerulosclerosis (FSGS) Recurrent FSGS in renal transplantation appears to be mediated, in some cases, by a circulating factor that increases glomerular permeability. FSGS can recur promptly following renal transplantation (15%–55) In some patients using therapeutic plasmapheresis is frequently reported to be of benefit but FSGS in the native kidney has variable results. [35,36]
3. TPE in nephrology diseases 3.1. Anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis These patients have a small vessel vasculitis often affecting the kidney, with pauci-immune precipitation. This group of diseases includes granulomatosis with polyangitis (previously Wegner Granulomatosis) microscopic polyangitis and eosinophilic granulomatosis with polyangitis (previously Churg – Strauss syndrome). In 1977, Lock wood et al. published the first report demonstrating the use of therapeutic plasmapheresis in 9 patients with crescentic glomerulonephritis (GN) from which 5 rapidly recovered from kidney failure. [30] Then, in 1991, Pusy et al (ref) published a randomized control trial (RCY) that showed a benefit of therapeutic plasmapheresis together with immunosuppressive drugs in ANCA associated vasculitis often requiring dialysis. A large European multicenter study (MEPEX) confirmed this finding which demonstrated a better recovery of renal function in patients with a creatinine of > 500 mcmol/L (5.7 mg/dl) treated with therapeutic plasmapheresis compared to those treated with pulse methylprednisolone. [30]
3.6. Renal transplantation Therapeutic plasmapheresis has been used for over 20 years for treating antibody mediated rejection and recently, this has been used in a desensitization protocol for ABO incompatible or highly sensitized patients. [32] These were six disorders which have TPE indicated as for first line or second line therapy in the ASFA categories. There are several mechanisms by which TPE has beneficial effects for renal diseases including immunomodulatory actions and therapeutic actions. [37] 4. TPE in Gastroenterology and hepatobiliary diseases 4.1. Acute liver failure
3.2. Thrombotic thrombocytopenic Purpura (TTP) and hemolytic uremic syndrome (HUS)
Standard treatment for acute liver failure (ALF) with low likelihood of spontaneous recovery, is supportive care as a bridge to liver transplantation (LT). Therapeutic plasma exchange (TPE) can remove albumin bound and unbound toxins and restore hemostasis.
Both TTP and HUS lead to thrombotic microangiopathy, in particular, HUS affects the kidney and TTP-afflicted patients often have their central nervous system impaired. 3
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Table 1 Neurology diseases and their treatments. Disease
Form of diseases
Treatment
Diseases of the Peripheral Nervous System Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or Guillain-Barre syndrome
Axonal, demyelinating and miller-fisher variant
chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Mainly demyelinating
Paraproteinemic neuropathies
Complex regional pain syndrome
axonal or demyelinating damage to peripheral nerves IgG/IgA demyelination IgM demyelination Anti-MAG neuropathy Multiple myeloma Multifocal Motor Neuropathy inflammation after an injury to peripheral nerves
TPE and IVIG No initially response to IVIG delayed TPE chronic use of corticosteroids IVIG TPE long-term immunosuppression TPE TPE TPE TPE TPE TPE TPE nerve block
Neuromuscular junction disorders Myasthenia gravis
associated with thymoma and autoantibodies acute mysthenic crisis severe crisis(respiratory) refractory types
Lambert-Eaton myasthenic syndrome Diseases of the Central Nervous System Multiple sclerosis (Acute CNS inflammatory demyelination)
Neuromyelitis optica
Acute disseminated encephalomyelitis (ADEM)
Autoimmune Encephalitis
Autoimmune or paraneoplastic associated with VGCC
prophylactic TPE before thymectomy TPE TPE and IVIG steroids cytotoxic drugs TPE TPE
severe attacks relapsing refractory MS progressive MS (the degenerative process) Progressive multifocal leukoenchephalopathy (PML) associated with natalizumab
high-dose methylprednisolone TPE
acute attacks
Steroids TPE TPE (maintenance therapy
Failing rituximab and other Immunosuppressants monophasic post-infectious inflammatory reaction in CND Sever cases paraneoplastic or autoimmune refractory cases NMDA-R encephalomyelitis limbic encephalitis with voltage-gated potassium channel antibodies Rasmussen Encephalitis with anti GLU-R3 Ab Hashimoto encephalitis with Anti TPO Ab anti-amphiphysin
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) Sydenham’s chorea
TPE TPE extracting the drug from the plasma
After high-dose steroids IVIG TPE First line treatment: steroids, IVIG or TPE IV immunosuppressors and rituximab TPE TPE TPE TPE TPE TPE IVIG and steroids TPE
and eliminated the need for LT. [11]
A controlled trial by Yue-Meng showed significant survival benefit in patients who received TPE for patients with entecavir-treated hepatitis B and acute-on-chronic liver failure. The cumulative survival rates were 37% (TPE) and 18% (non TPE) at week 4 and 29% (TPE) and 14% (non TPE) at week 12 (P < 0.001). [38] A recent RCT performed in 183 patients demonstrated statistically significant overall survival benefit: 58.7% with TPE-high volume (TPEHV) + standard care versus 47.8% standard care (P < 0.001). [39]
4.3. Liver transplantation There has been significant progress in the use of TPE perioperatively in ABO incompatible (ABOi) deceased donor liver transplantion (DDLT) and for preconditioning/ antibody mediated rejection (AMR) treatment in ABOi live donor liver transplant (LDLT). [11] Because hyperacute rejection, and acute AMR are definitive risks in ABOi liver transplants, TPE has been used as the key therapeutic modality to reduce anti-A or anti-B antibody titers in the peri-transplant period with the goal of preventing rejection and facilitating graft survival. [11] In the DDLT setting, TPE is typically instituted immediately before and sometimes both before and after transplantation in an attempt to prevent hyperacute rejection and acute AMR. ABOi LDLT has been increasingly used in East Asia with patients being treated with rituximab,
4.2. Wilson’s disease TPE can be beneficial as it rapidly removes significant amounts of copper from the circulation (average 20 mg per TPE). Decreased serum copper may decrease hemolysis, prevent progression of renal failure, and provide clinical stabilization. TPE can also remove large molecular weight toxins which may be responsible for hepatic coma. Recent reports showed that TPE combined with chelating agents improved ALF 4
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Table 2 TPE indications in Renal and Gastrointestinal hepatobiliary diseases. Renal diseases
Gastrointestinal diseases
Renal transplantation (ABO compatible)[Desensitization, living donor,Desensitization, deceased donor,Antibody mediated rejection]
Liver Transplantation (Desensitization, ABOi living donor,Desensitization, ABOi deceased donor,Antibody mediated rejection) Acute liver failure
Renal transplantation(ABO incompatible)[ Desensitization, living donor,Antibody mediated rejection,A2/A2B into B, deceased donor] Thrombotic microangiopathy, coagulation mediated Thrombotic microangiopathy,complement mediated(Complement factor gene mutations ,Factor H autoantibodies ,MCP mutations) Thrombotic microangiopathy,Shiga toxin mediated(Severe neurological symptoms,pHUS) Focal segmental glomerulosclerosis(Recurrent in transplanted kidney,Steroid resistant in native kidney) ANCA-associated rapidly progressive glomerulonephritis (Granulomatosis with polyangiitis and microscopic polyangiitis)[Dialysis dependence,DAH I,Dialysis independence] Anti-Glomerular basement membrane disease Goodpasture’s syndrome)Dialysis-dependencea, no DAH (diffuse alveolar hemorrhage) ,DAH ,Dialysis-independence Immunoglobulin a nephropathy(Crescentic ,Chronic progressive) Myeloma cast nephropathy Nephrogenic systemic fibrosis Cryoglobulinemia Symptomatic/severe
Modality
Renal transplantation (ABO compatible) Desensitization, living donor Desensitization, deceased donor Antibody mediated rejection Renal transplantation(ABO incompatible) Desensitization, living donor Antibody mediated rejection A2/A2B into B, deceased donor Thrombotic microangiopathy, coagulation mediated Thrombotic microangiopathy,complement Mediated Complement factor gene mutations Factor H autoantibodies MCP mutations Thrombotic microangiopathy,Shiga toxin mediated Severe neurological symptoms pHUS Absense of severe neurologic symptoms Focal segmental glomerulosclerosis Recurrent in transplanted kidney Steroid resistant in native kidney ANCA-associated rapidly progressive glomerulonephritis (Granulomatosis with polyangiitis and microscopic polyangiitis) Dialysis dependence DAH I Dialysis independencea Anti-Glomerular basement membrane disease Goodpasture’s syndrome) Dialysis-dependencea, no DAH (diffuse alveolar hemorrhage) DAH Dialysis-independence Immunoglobulin a nephropathy Crescentic Chronic progressive Myeloma cast nephropathy Nephrogenic systemic fibrosis Cryoglobulinemia Symptomatic/severe
TPE
• • • • • • • • •
• • • • • • • •
Recommendation
TPE
Inflammatory bowel disease
4.4. Pruritus due to hepatobiliary diseases I I III
Grade1B Grade 1B Grade 2C
I II IV III
Grade Grade Grade Grade
For patients unresponsive to medications, TPE may remove the potential pruritogens from the systemic circulation. In patients with chronic pruritus due to hepatobiliary disorders, 10 of 13 (77%) responded to TPE. Patients may experience decreased pruritus after the 2nd TPE. For some patients, the effects may last many months, while for others, chronic maintenance TPE is needed. [11]
TPE 1B 1B 1B 2C
4.5. Hypertriglyceridemic pancreatitis
TPE
III I III
Grade 2C Grade 2C Grade 1C
III III IV
Grade 2C Grade 2C Grade 1C
I III
Grade 1B Grade 2C
I I III
Grade 1A Grade 1C Grade 2C
III
Grade 2B
I I
Grade 1C Grade 1B
III III II III II
Grade Grade Grade Grade Grade
TPE can significantly decrease triglyceride (TG) levels, reduce inflammatory cytokines, and potentially replace deficient lipoprotein lipase or apolipoproteins when plasma is used as the replacement fluid. Reductions in TG levels of 49–80% have been reported following a single TPE procedure. While TPE can rapidly decrease the TG level, its effect is transient; adequate lipid lowering treatment is essential to achieve a persistent effect. TPE has also been successfully used as a treatment strategy during pregnancy [40] There was no difference in mortality between early (< 36 h after onset of pain) and late initiation of TPE. Several series have been reported on the use of maintenance TPE to maintain TG levels < 150 mg/ dL to prevent further episodes of pancreatitis. [41]
TPE
• • • • •
Category
Hypertriglyceridemic pancreatitis Hereditary hemochromatosis
TPE, and hepatic infusion with prostaglandin E1 and methylprednisolone with good survival statistics. TPE has also been used in the setting of AMR in liver allograft to decease the levels of both ABO and HLA antibodies. [11]
Table 3 Therapeutic Apheresis in nephrological diseases according to the ASFA guidelines-2016. Disease
Wilson’s disease Pruritus due to hepatobiliary diseases
TPE
TPE
4.6. Hereditary hemochromatosis A RCT compared biweekly erythrocytapheresis with weekly phlebotomy among 38 patients with newly diagnosed hereditary hemochromatosis (HH). The mean number of procedures and treatment duration to achieve a ferritin of < 50 ng/mL were 9 and 20 weeks for the erythrocytapheresis group versus 27 and 34 weeks (p < 0.001 and p < 0.002), respectively, for the phlebotomy group. [42]
TPE
TPE
TPE TPE TPE
2B 2C 2B 2C 2A
4.7. Inflammatory bowel disease Selective apheresis is a potentially useful adjunct for the management of inflammatory bowel disease (IBD) with the goal of removing the activated leukocytes or moderating their proinflamatory nature toward an immune modulatory phenotype. 5
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Table 4 Therapeutic Apheresis in Gastroenterology and hepatobiliary diseases according to the ASFA guideline-2016. Disease
Modality
Category
Recommendation
Acute liver failure Wilson’s disease Liver transplantation Desensitization, ABOi living donor Desensitization, ABOi deceased donor Antibody mediated rejection Pruritus due to hepatobiliary diseases Hypertriglyceridemic pancreatitis Hereditary hemochromatosis Inflammatory bowel disease
TPE TPE
III I
Grade 2B Grade 1C
TPE TPE TPE TPE TPE Erythrocytapheresis Adsorptive cytapheresis
I III III III III I III
Grade Grade Grade Grade Grade Grade Grade
• • •
A recent meta-analysis showed granulocytapheresis was effective for achieving a clinical response in patients with active ulcerative colitis (UC) when compared to corticosteroids [43]. Evidence supporting the use of adsorptive cytapheresis to treat Crohn’s disease (CD) is more limited. Although a few uncontrolled studies have demonstrated efficacy in the treatment of active CD, a recently published large RCT did not demonstrate any difference in remission rates when compared to sham treatment in patients with moderate to severe CD [44].
1C 2C 2C 1C 2C 1B 1B
the seventh special issue. J Clin Apher 2016;31(June (3)):149–62. [12] Codron P, Cousin M, Subra JF, Pautot V, Letournel F, Verny C, et al. Therapeutic plasma exchange in chronic dysimmune peripheral neuropathies: A 10-year retrospective study. J Clin Apher 2017;32(December (6)):413–22. [13] Shin YW, Lee ST, Park KI, Jung KH, Jung KY, Lee SK, et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord 2017;11(August (16)):17. [14] Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev 2017;2(February (27)):CD001798. [15] Lunn MP, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathies. Cochrane Database Syst Rev 2016;10(October (4)):CD002827. [16] Ipe TS, Pham HP, Williams 3rd LA. Critical updates in the 7(th) edition of the American Society for Apheresis guidelines. J Clin Apher 2018;33(February (1)):78–94. [17] Aradillas E, Schwartzman RJ, Grothusen JR, Goebel A, Alexander GM. Plasma exchange therapy in patients with complex regional pain syndrome. Pain Physician 2015;18(July–August (4)):383–94. [18] Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology 2016;87(4):419–25. [19] Schoser B, Eymard B, Datt J, Mantegazza R. Lambert-Eaton myasthenic syndrome (LEMS): a rare autoimmune presynaptic disorder often associated with cancer. J Neurol 2017;264(September (9)):1854–63. [20] Markowitz CE. Multiple sclerosis update. Am J Manag Care 2013;19(November (16 Suppl.)):s294–300. [21] Tyler KL, Vollmer TL. To PLEX or not to PLEX in natalizumab-associated PML. Neurology 2017;88(March (12)):1108–9. [22] Kleiter I, Gold R. Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders. Neurotherapeutics 2016;13(January (1)):70–83. [23] Hermetter C, Fazekas F, Hochmeister S. Systematic review: syndromes, early diagnosis, and treatment in autoimmune encephalitis. Front Neurol 2018;9(September (5)):706. [24] Fassbender C, Klingel R, Köhler W. Immunoadsorption for autoimmune encephalitis. Atheroscler Suppl 2017;30(November):257–63. [25] Bhatia S, Schmitt SE. Treating immune-related epilepsy. Curr Neurol Neurosci Rep 2018;18(February (3)):10. [26] Zeiler FA, Matuszczak M, Teitelbaum J, Kazina CJ, Gillman LM. Plasmapheresis for refractory status epilepticus Part II: a scoping systematic review of the pediatric literature. Seizure 2016;43(December):61–8. [27] Mahdi-Rogers M, Brassington R, Gunn AA, van Doorn PA, Hughes RA. Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2017;5(May (8)):CD003280. [28] Eyre M, Hacohen Y, Barton C, Hemingway C, Lim M. Therapeutic plasma exchange in paediatric neurology: a critical review and proposed treatment algorithm. Dev Med Child Neurol 2018;60(August (8)):765–79. [29] Dean SL, Singer HS. Treatment of Sydenham’s chorea: a review of the current evidence. Tremor Other Hyperkinet Mov (N Y) 2017;7(June (1)):456. [30] Reeves Hollie M, Jeffrey LWinters. The mechanisms of action of plasma exchange. British J of hematology 2013;16413:342–51. [31] Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. ASH Education Program Book. 2004;2004(January (1)):407–23. [32] Clark WF, Huang SH, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int 2016;90(November (5)):97484. https://doi.org/10.1016/j.kint.2016.06.009. [33] Colic E, Dieperink H, Titlestad K, Tepel M. Management of an acute outbreak of diarrhoea-associated haemolytic uraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study. Lancet 2011;378(September (9796)):1089–93. [34] Levy JB, Turner AN, Rees AJ, Pusey CD. long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immuno suppressive Ann Intern Med 2001;134:1033–42. [35] Montagnino G, Tarantino A, Banfi G, Maccario M, Costamagna L, et al. Double recurrence of FSGS after two renal transplants with complete regression after plasmapheresis and ACE inhibitors. Transpl Int 2000;13(March (2)):166–8. [36] Wol f J. Predictors for success of plasmapheresis on the long-term outcome of renal
5. Summary Therapeutic apheresis is a process used for patients with numerous disorders. Publications of evidence-based guidelines of the American Society for Apheresis (ASFA) include indications, rate, and duration of apheresis treatment (last updated in 2016). TPE is the first-line treatment (category I, level 1A) in all forms of the acute inflammatory demyelinating polyradiculoneuropathy disease (axonal, demyelinating and Miller-Fisher variant) as well as in acute myasthenic crisis, chronic inflammatory demyelinating polyradiculoneuropathy and paraproteinemic neuropathies(category I, level 1B), desensitization in renal transplantation(ABO compatible) (living donor)and desensitization in deceased donor, desensitization in renal transplantation(ABO incompatible) (living donor), Thrombotic microangiopathy complement mediated (Factor H autoantibodies), focal segmental glomerulosclerosis (recurrent in a transplanted kidney), ANCA-associated rapidly progressive glomerulonephritis (dialysis dependence, DAH), AntiGlomerular basement membrane disease.(Goodpasture’s syndrome) (DAH,dialysis-independent), for reduction of anti-A or anti-B antibody titers in the liver peri-transplant period and Wilson’s disease. References [1] Gilcher R. Simon T, Synder E, Stowell C, Strauss R, Solheim B, Petrides M, editors. Rossi’s principles of transfusion medicine. 4th ed.West Sussex: Blackwell Publishing Ltd; 2009. p. 617–28. [2] Abel JJ, Rowntree LG, Turner BB. Plasma removal with return of corpuscles JPharmacol Exp Ther 1914;5:625–41. [3] Shumak KH, Rock GA. Therapeutic plasma exchange. N Engl J Med 1984;310:762–71. [4] Millward BL, Hoeltge GA. The historical development of automated hemapheresis. J Clin Apher 1982;1:25–32. [5] Adams WS, Blahd WH, Bassett SH. A method of human plasmapheresis. Proc Soc Exp Biol Med 1952;80:377–9. [6] Freireich EJ, Judson G, Levin RH. Separation and collection of leukocytes. Cancer Res 1965;25:1516–20. [7] Ward DM. Conventional apheresis therapies: a review. J Clin Apher 2011;26(5):230–8. [8] Bose N, Kanzariya H. Role of therapeutic apheresis and phlebotomy techniques in anaesthesia and critical care. Indian J Anaesth 2014;58:672–8. [9] Williams ME, Balogun RA. Principles of separation: indications and therapeutic targets for plasma exchange. Clin J Am Soc Nephrol 2014;9(January (1)):181–90. [10] McLeod BC. Therapeutic apheresis: history, clinical application, and lingering uncertainties. Transfusion 2010;50(July (7)):1413–26. [11] Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidenceBased approach from the writing committee of the american society for apheresis:
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[41] Gubensek J, Buturovic-Ponikvar J, Romozi K, Ponikvar R. Factors affecting outcome in acute hypertriglyceridemic pancreatitis treated with plasma exchange: an observational cohort study. PLoS One 2014;9:e102748. [42] Rombout-Sestrienkova E, Nieman FH, Essers BA, van Noord PA, Janssen MC, et al. Erythrocytapheresis versus phlebotomy in the initial treatment of HFE hemochromatosis patients: results from a randomized trial. Transfusion 2012;52:470–7. [43] Yoshino T, Nakase H, Minami N, Yamada S, Matsuura M, Yazumi S, et al. Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: a meta-analysis. Dig Liver Dis 2014;46:219–26. [44] Sands BE, Katz S, Wolf DC, Feagan BG, Wang T, Gustofson LM, et al. A randomised, double-blind, sham-controlled study of granulocyte/monocyte apheresis for moderate to severe Crohn’s disease. Gut 2013;62:1288–94.
transplant patients with recurrent FSGS. J Am Soc Nephrol 2014;9:181–9. [37] W.M. Szpirt. plasma exchange in antineutrophil cytoplasmic antibody ? associated vasculitis- a 25 ? year perspective Nephrol Dial Ttransplant 2015; 30: il46-il49. [38] Yue-Meng W, Yang LH, Yang JH, Xu Y, Yang J, et al. The effect of plasma exchange on entecavir-treated chronic hepatitis B patients with hepatic de-compensation and acute-on-chronic liver failure. Hepatol Int 2016;10(May (3)):462–9. [39] Larsen FS, Schmidt LE, Bernsmeier C, Rasmussen A, Isoniemi H, Patel VC, et al. Highvolume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J. Hepatol 2016;64:69–78. [40] Basar R, Uzum AK, Canbaz B, Dogansen SC, Kalayoglu-Besisik S, et al. Therapeutic apheresis for severe hypertriglyceridemia in pregnancy. Arch Gynecol Obstet 2013;287:839–43.
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