Background: Therapeutic plasmapheresis (TP) is an extracorporeal therapy that allows the removal of pathogens from plasma. The role of TP in immuno-mediated diseases and toxic conditions has been of interest for decades. Summary: We reviewed the recent literature on the application and the optimal choice of TP technique ranging from plasma exchange, double filtration plasmapheresis, rheopheresis, immunoadsorptions, plasma adsorption perfusion and lipidoapheresis. In addition, we report our experience in the application of TP for various diseases ranging in different medical specialties, following the American Society for Apheresis (ASFA) recommendations. Key Messages: Overall patients receiving TP showed an improvement in clinical and laboratory parameters. Our review and single-center experience suggest a benefit of the application of TP in multiple clinical disciplines.
The term “Apheresis,” from the Latin “aphaeresis” and the Greek “ἀφαίρεσις,” is commonly used in medicine with the meaning of “separation.” It indicates an extracorporeal therapy that allows both selective collection of one or more blood components (cytapheresis) and removal of pathogenic elements with a high molecular weight (mw) (>150 kDa) such as immunoglobulins, immune complexes, or inflammatory mediators from plasma (plasmapheresis).
Therapeutic plasmapheresis (TP) has been applied for the treatment of autoimmune diseases, some poisonings, and/or all those pathological conditions in which it is necessary to quickly remove toxins from plasma. The effects of TP consist in the immunomodulation resulting from the activation of the reticuloendothelial system and the stimulation of lymphocyte clones subsequent to the removal of circulating pathogenic solutes. At the same time, apheresis allows the replacement of large volumes of plasma without causing an overload for the circulation .
The first step to perform plasmapheresis is the separation of the corpuscular component of the blood from plasma. This can occur by centrifugation or by filtration on semipermeable membranes [2, 3]. After being separated, the plasma can (a) be completely eliminated and replaced in equal volume by replacement solutions, by performing a nonselective technique named therapeutic plasma exchange (TPE); or (b) further be treated by pathogens removal by the use of specific binders. Purified plasma is subsequently reinfused during selective techniques; or (c) additionally treated by removing both the pathogenic substances and part of useful molecules performing non-selective techniques. This is allowed by hollow fiber filters with variable porosity. Treated plasma is then reinfused  (Table 1). Clinical indications to therapeutic apheresis (TA) are enclosed in the McLeod criteria , periodically updated by the American Society for Apheresis (ASFA) and classified according to the grade of evidence  (Table 2).
Ahmadpoor et al. sought to provide guidance on the choice of TP methods and therapeutic protocols based on clinical physiology, plasma volume (PV) estimation, plasma viscosity, size, volume of distribution, and half-life of the pathogens. Based on these criteria, the effectiveness of the procedure is guaranteed by preventing and promptly managing possible complications .
We reviewed all reports between 2019 and 2021, published after the ASFA guidelines, that were focused on different aspects of plasmapheresis: indications to treatment, technical features, and application of different procedures. At support of literature review, we report our single-center experience on TP ranging in different fields: hematology, rheumatology, neurology, and vascular and metabolic disorders. We discuss different modalities of TP, their application in some autoimmune disorders, and its rationale and complications in different fields of medicine.
Databases MEDLINE via PubMed were searched and relevant publications up to 2019 were assessed. We included in our analysis only some reviews articles published after the latest ASFA guidelines.
Plasma Purification Techniques
Therapeutic Plasma Exchange
TPE is the oldest and most widespread apheretic technique due to its simple execution. It is a nonselective technique that indiscriminately eliminates all components of plasma. TPE can be used for the treatment of diseases in which the pathogen and pathogenesis are not known, or in the absence of more selective apheretic methods.
Technically, the whole blood, from the patient’s vascular access, is pumped inside the plasma separator, also named primary or high cutoff filter (pores ranging in size from 0.3 to 0.5 microns). Because of their larger dimensions, white blood cells, red blood cells, and platelets are not able to cross the membrane and run along the deep fiber coming out at the opposite end of the filter, to be returned to the patient after being mixed with the replacement solution. The liquid fraction of the blood and the molecules in solution and in suspension, being smaller than the holes, pass through them, constituting the waste plasma. At the same time as the extraction of the waste plasma, the replacement solution is isovolemic, ensuring hemodynamic stability. Replacement must be carried out using sterile, nonpyrogenic, allergen-free, isosmotic, isotonic solutions. The replacement solutions are crystalloid solution (physiological or electrolytic solution) and colloids (dextran, albumin, fresh frozen plasma). Usually, a replacement 4% albumin solution of 2,000 mL by plasma is infused: it is constituted of 1,600 mL physiological solution plus 400 mL of 20% human albumin. Exchange volumes and number of treatments are variable and subjective based on the underlining disease and patient clinical characteristics. As discussed recently by Redant et al. , coagulation factors often decrease after repeated TPEs using the albumin solution as a replacement fluid. If fibrinogen reaches levels below 100 mg/dL, fresh frozen plasma should be used instead of other replacement solutions.
TPE may have major complications (allergic and infectious disease risk for the colloids replacement) compared to selective and semiselective plasmapheresis methods, which do, usually, not require replacement solutions . Pham et al.  recently proposed an interesting and practical classification of TPE grading the urgency of the procedures and subdividing the ASFA category I and II indications into 3 groups: “emergent,” “urgent,” and “routine” indications for critically ill patients, acute diseases, and scheduled conditions, respectively. In the first group, TPE has been considered a life-threatening procedure performed in the critical care unit and should be initiated within 4–6 h from the request. Urgent nephrological indications are acute conditions like ANCA-associated rapidly glomerulonephritis or antiglomerular basement membrane disease, HELLP syndrome. Finally, routine indications occur in stable patients like neurological disorders or before rituximab administration .
More recently, Wind et al.  addressed the role of TPE during pregnancy and assessed that the procedure can be safely performed in pregnant women with the appropriate preparation and experience of a multidisciplinary team. The main indications of TPE during pregnancy are thrombotic microangiopathies, lipid disorders, and various autoimmune diseases .
Both bleeding and thrombosis were reported as side effects of TPE . Hodulik et al.  described the effects of TPE in patients receiving therapeutic anticoagulation, which has been demonstrated that TPE removes coagulation proteins from the circulation. The latter effect has been associated with a decrease in measured anti-Xa activity levels and an increase in activated partial thrombostin time (aPTT) and International Normalized Ratio (INR) levels .
One of the limitations of TPE is the impossibility of eliminating high PVs, due to the difficulty of finding the high percentage of replacement solutions, especially for multiple sessions, and due to the loss of many constituents necessary for the body, not fully supplied from albumin replacement . Furthermore, TPE, by subtracting at least 60% of the original plasma, alters the pharmacological structure and requires appropriate therapeutic adjustments, especially for antibiotic, immunosuppressive or anticoagulant therapies .
Cascade filtration or double filtration plasmapheresis (DFPP) is less performed than TPE but has almost the same costs of TPE including the costs of replacement solutions. DFPP is a semiselective plasmapheresis technique characterized by the presence of a secondary filter. The secondary deep fiber filter, placed in series behind the plasma separator, allows in relation to its pores size, the separation of large molecules from the rest of the plasma. Only pathogenic macromolecules (immunoglobulins, immune complexes, and others) remain trapped into the filter pores, while the purified plasma returns to the patient avoiding, in most cases, the replacement solutions [4, 15]. During treatment, the cascade filter can saturate, so it can be decompressed by performing a purge of plasma waste, until a total loss of 250 mL of plasma; once this limit is exceeded, it is necessary to proceed with the early return of blood and plasma to the patient. With DFPP, not using the replacement solutions, the risk of allergy and infective complications is reduced. However, the patient’s blood volume often decreases due to the loss of albumin trapped in the secondary filter. In this case, DFPP could be accompanied by a drop in oncotic pressure manifested with a fall in blood pressure. To avoid this negative effect, albumin solutions can be infused. Mineshima introduced a variable blood volume model for albumin transport in infusion supplementation during DFPP .
Low cutoff cascade filters have pores ranging in size from 0.01 to 0.02 microns, depending on the dimension, the mass, and the type of the pathogen to be trapped. Filters with larger pores eliminate IgM, cryoglobulins, or lipid and could be used in several conditions such as Waldenstrom’ macroglobulinemia, cryoglobulinemia, MAG antibody polyneuropathy, panarteritis nodosa, nephrotic syndrome, hypertriglyceridemia, and HCV removal in liver transplants . Filters with smaller pore size reach the maximum removal of IgA and IgG with a consequent increase in albumin loss. Instead, secondary filters with pores middle size present a good compromise between IgG/IgA removal and low albumin content. The latter is recommended for the treatment of ABO-incompatible kidney transplantation, post kidney transplant rejection anti HLA antibodies, IgA/IgG myeloma, vasculitis, glomerulonephritis, focal glomerulosclerosis, and neurological immuno-mediated diseases like multiple sclerosis (MS) and myasthenia gravis [4, 13, 17].
The clinical applications of DFPP have been recently reviewed  and the Japan’s National Health Insurance program included 26 diseases, with new treated conditions such as familial hypercholesterolemia (FH) and lipoprotein (a) (Lp(a)) hyperlipoproteinemia . Grupp et al.  and Chang et al. , respectively, described the use of DFPP in hypertriglyceridemia-associated complications and hypertriglyceridemia associated to acute pancreatitis and its efficacy to rapidly remove triglycerides.
Rheopheresis is one of the semiselective apheresis methods and differs from DFPP for the characteristics only of the secondary filter, which is able to remove fibrinogen, total and LDL cholesterol, triglycerides, lipoproteins, von Willebrand factor, alpha 2 macroglobulin, IgM, and other vascular risk factors (mw > 60 kDa). The technical aspects are the same as those described above for the DFPP. Rheopheresis is suitable for the treatment of microcirculatory diseases characterized by blood hyperviscosity, due to the known effect of improving hemorheology . Rheopheresis has acute and chronic cardiovascular effects . So far, rheopheresis is mainly addressed to the treatment of age-related macular degeneration, sudden deafness, peripheral arterial disease, and diabetic foot [22‒28]. Unfortunately, the literature is sparse and further studies are needed to better clarify the indications of this semiselective technique.
Selective techniques are more expensive than TPE and can be distinguished mainly in plasma adsorption perfusion (PAP), immunoadsorption (IA), lipoprotein apheresis (LA), and fibrinogen apheresis. Selective apheresis techniques remove from plasma specific pathogens (antibodies, immune complexes, or toxic molecules in general) avoiding the loss of large amount of other plasma constituents, such as albumin and coagulation factors. Allowing the treatment of large amount of PV and avoiding the infusion of donor fresh plasma or replacement solutions, since the purified plasma returns to the patient. This selection is permitted by the contact of the plasma with adsorbent substances present in the columns in which it is conveyed the unclean plasma to be purified [4, 14, 29].
The columns consist of a specific ligand attached to an insoluble matrix. More in details, the ligand has the property of an active adsorbent substance with high binding affinity with the molecule to be removed. The interaction between ligand and pathogens could be chemical-physical, immunological, and biological . The chemical-physical ligands are achieved by ion exchange resins, styrene divinyl benzene, and activated carbon used in PAP to adsorb bilirubin [30, 31]; dextran sulfate , polyacrylate , and heparin in low pH  into LA to bind lipoproteins; and pentapeptides in fibrinogen apheresis to link fibrinogen . The immunological ligands are animal or monoclonal antibodies that adsorb IgG, IgM, IgA, IgE, immunocomplexes, or free light chains to realize IA , or LA binding apolipoproteinB (apoB) of LDL cholesterol . The biological ligands, used in IA, are tryptophan, phenylalanine , staphylococcal protein A , coagulation factors VIII and IX , and C1q that joins immunoglobulins and immunocomplexes by hydrophobic bonds . Biological ligands also include oligosaccharides; those remove anti A/B/AB isoagglutinins thanks to an antibody antigen reaction .
An indication of PAP is hyperbilirubinemia and excess bile acids in severe liver failure [30, 31]. IA is indicated for the treatment of various autoimmune diseases, mainly neurological and rheumatological, including myasthenia gravis, Guillain-Barrè syndrome, MS, Fischer’s syndrome, chronic inflammatory demyelinating polyneuropathy, pemphigus, systemic lupus erythematosus, and rheumatoid arthritis [43‒46].
Fuchs et al.  reported their experience of 599 IA treatments performed on 81 patients for several indications (e.g., neurological and cardiological diseases, before and after organ transplantation). They confirmed that in routine clinical practice, IA is safe, well tolerated, and effective in reducing immunoglobulins with clinical improvement in almost 70% of treated patients. The remaining 30% achieved a clinical stability without progression of symptoms. Therefore, IA represents an additional therapeutic option for therapy-refractory immune disorders.
LA removes mainly LDL cholesterol, LDL-oxidized cholesterol, Lp(a), and triglycerides with a variability depending on the chosen technique. Some LA methods selectively treat the plasma, and others are applied to the whole blood.
Despite other LA techniques, H.E.L.P. system can reduce beyond low-density lipoproteins even levels of fibrinogen, C-reactive protein (CRP), and proinflammatory molecules. This objective is reached thanks to the precipitation of these molecules at a very low pH induced by a temporary addition to the plasma of an acetate buffer saturated with heparin. The latter is finally eliminated through the passage on a specific filter for heparin adsorption. Plasma pH is restored through a bicarbonate dialysis [48, 49].
Several experts have tried to define LA guidelines that differ in different countries and are clearly summarized in Thompson’s article . Typically, LA is indicated for homozygous and heterozygous FH unresponsive to conventional drug therapies, especially if homozygous FH with LDL cholesterol levels >500 mg/dL, heterozygous FH with LDL cholesterol levels >300 mg/dL or heterozygous FH with high risk of cardiovascular disease and LDL cholesterol >200 mg/dL or heterozygous FH with cardiovascular disease diabetes and LDL cholesterol >160 mg/dL. Other LA indication is hyperlipoproteinemia (a) with Lp(a) levels >60 mg/dL alone or in progressive cardiovascular disease . The reduction of cardiovascular risk in treated patients is described in the literature [49, 51]. Raina et al.  reported a reduction of adverse cardiovascular events by controlling lipid levels, such as the progression of atherosclerosis, and the coronary artery stenosis improving myocardial perfusion. Recent advances suggest that lipid-lowering drugs might reduce but not abolish the application of LA, especially for children and pregnant women with homozygous FH . LA is also rationally used in microcirculation disorders such as non revascularized diabetic foot, senile degenerative maculopathy, sudden deafness, and ischemic optic neuropathy [53‒56]. Moreover, several studies have shown that the application of LA treatment in nephrotic syndrome in adults may improve proteinuria and lipid levels, preventing the progression of renal disease and sometimes inducing resolution of symptoms . On the other hand, evidence in children is poor .
Different types of vascular access can be used to perform TA. The vascular access must guarantee adequate blood flow into the plasmapheresis device; otherwise, apheresis cannot be performed, or if achieved there will be many disadvantages including longer procedural times and lower efficacy . Since low blood flows (QB) (60–120 mL/min) are required for apheretic practices, it is sufficient that the vascular access has the ability to withstand both high negative pressure without collapsing and high positive pressure without breaking blood vessels. The choice is based on technical (urgency, number duration and frequency of procedures, exchanged PVs) and clinical (vascular anatomy, underlying disease, mental status, hygiene, inpatient or outpatient, or critically ill patient status) requirements . The main vascular access is the peripheral venovenous access in Europe, whereas the central venous access in North, Central, and South America. In Asia, there is a recent shift from the use of peripheral venovenous access to central venous access . Anyhow, in Italy to perform a TA, the peripheral venovenous access through venipuncture of superficial veins of the arms with 17–19 gauge (G) needles in almost 60% of the cases, the central venous access in almost 13% of the cases, and other accesses in a minimal percentage  are used.
The use of anticoagulants is essential to minimize blood coagulation in the extracorporeal circuit and reduce the effectiveness of the method. Both high or low molecular weight heparin and citrate can be used as anticoagulants. Obviously, the dose must be evaluated based on the parameters of coagulation and ionized calcium (the least for citrate), as well as the weight of the patient and the type of plasmapheresis performed .
Complications and adverse events (AEs) can occur during or after TA (Table 3). Data from the World Apheresis Association (WAA) registry (www.waa-registry.org) reported AEs in 7,142 patients out of 50,846 TA performed. AEs were divided into four grades, respectively, mild (if AE is tolerated without medication), moderate (if AE requires medication), severe (if AE requests discontinuation of TA), or death (if AE is responsible for patient death). AEs were mild in 2.4% (linked to vascular access in 54% and to the device in 7% of cases, besides hypotension and tingling), moderate in 3% (tingling, urticarial, hypotension, and nausea), and severe in 0.4% of treatments (hypotension and syncope, urticaria, chills or fever, arrhythmia or asystole, nausea, or vomiting) . AEs may also depend on the type of TA performed, the choice of replacement solutions, and anticoagulant used. An avoidable complication is the anaphylactoid reaction triggered by the intake of ACE inhibitors (ACE-I).
The ACE-I-induced anaphylactoid reaction is characterized by hypotension, flushing, dyspnea, and bradycardia. It is triggered by the combined effect of the increase in bradykinins due to the effect of almost all kind of apheresis and the reduction of their metabolism exerted by ACE-I [59‒61].
Another fundamental aspect to perform TP safely and reduce the appearance of bleeding is the careful evaluation of the patient’s coagulation structure before and after each treatment. Patients’ fibrinogenemia at baseline should not be below 150 mg/dL. If the control fibrinogenemia after TP should be lower than 150 mg/dL, a plasma transfusion could be necessary, obviously considering the patient clinical picture.
Common Aspects of Plasmapheresis Effectiveness
The volume of plasma to be removed and or treated varies based on the patient’s estimated PV. PV is often calculated with the following formula PV = body weight (kg) × 0.065 × (1-hematocrit) . Generally, in a patient of approximately 70 kg and normal hematocrit, the PV is approximately 2.5–2.7 L. Normally the aphaeretic indications foresee the treatment of 1–1.5 PV per plasmapheresis session. The greater the volume of plasma removed, the greater the number of pathogens removed. To eliminate 75% of a harmful substance, 1.4 PV should be exchanged during one procedure; instead to eliminate almost 95% of dangerous substances, it is necessary to exchange almost 3 PV . The clearance of toxic substances is influenced by the basal values, as well as by the size of the particle removed, by its half-life in plasma, by the speed in moving from the extravascular to the intravascular compartment and by its synthesis rate. After TP, there is a rebound in the plasma concentration of the pathogen, due to resynthesis and/or their transfer from the extra- to the intravascular compartment. For all this, plasmapheresis should be repeated several times, commonly 4–5 TP usually every 24– 48 h .
Our Single-Center Experience in the Application of TP
In the following section, we report part of the single-center experience at the Division of Nephrology of the University of Campania Luigi Vanvitelli, Naples, Italy, in the application of TP for a case series of patients with various autoimmune and metabolic diseases, as summarized in Table 4. We treated 5 patients with Waldenstrom’s macroglobulinemia and symptomatic blood hyperviscosity syndrome. Clinical presentation ranged from paresthesia, headache, somnolence, visual disturbances, hypoacusia, anemia, and splenomegaly. Patients performed from 3 to 7 DFPP and infusion of rituximab, and/or dexamethasone and/or cyclophosphamide. DFPP was effective in reducing circulating IgM by about 50%, with a minor effect on other classes of immunoglobulins and other plasma compounds. After IgM plasma level normalization, the hyperviscosity-related manifestations (neurological symptoms, vision, and hearing disorders) significantly improved or disappeared. In our experience, aphaeretic and hematological therapy allowed the control of Waldenstrom’s macroglobulinemia.
An 80-year-old patient suffering from severe and symptomatic HCV-related cryoglobulinemia with multiorgan involvement (acute glomerulonephritis and chronic kidney disease, angina abdominis, diarrhea, and cutaneous purpura) was treated with DFPP. The patient came to our attention in oligoanuria unresponsive to high-dose diuretic therapy and underwent to hemodialysis treatment and endovenous methylprednisone. Six DFPP sessions were sufficient to break down both the cryocrit and HCV RNA levels, allowing the patient to withdraw hemodialysis. At follow-up visits, the patient was asymptomatic and showed a stable renal function, with a stable cryocrit <2%. DFPP was effective to achieve the resolution of this severe case of cryoglobulinemia.
We are performing LA with H.E.L.P. in hyperlipoproteinemia in 3 patients, as secondary cardiovascular prevention, in ischemic heart disease and hyperLp(a), obtaining a 63% reduction of the Lp(a) levels and a 50% decrease of total cholesterol, LDL cholesterol levels, and fibrinogen. Diet and lifestyle had no influence on Lp(a) concentration; instead, drugs had small influence on Lp(a) concentration. We treated two young women affected by Myasthenia gravis. After DFPP, we observed a significant reduction of the levels of immunoglobulins, complement fractions, total protein, albumin, and antiacetylcholinesterase antibodies (decreased by 90% from basal) and anti-titin antibodies . TP reverted the acute neurological symptoms, making the patient responsive to pharmacological therapies without further relapses.
A paraneoplastic cerebellar ataxia due to anti-Yo antibodies and ENA anti-Ro antibodies was treated with DFPP. Patient presented inability to walk autonomously, lack of coordination in the lower and upper limbs, weakness, diplopia, dysarthria, and dysphagia for liquids. The benefit of TP was a reduction of the anti-Yo and ENA anti-Ro autoantibody title and an improvement of neurological manifestations.
Eight women suffering from clinical and instrumental relapse of MS unresponsive to steroid boluses, with significant disabilities and mean Kurtzke Expanded Disability Status Scale (EDSS) score 7.9 ± 1.3, underwent six DFPP sessions (two sessions/week). We observed a clinical improvement at follow-up visits (at 1, 3 and 6 months after DFPP) and a reduction in gadolinium impregnation in magnetic resonance images in all patients.
Finally, two young males affected by malign MS with significant cognitive impairment, reduced motility, and aphasia, with an EDSS score of 9.5 and 9, came to our attention after the failure of steroid therapy and were treated with IA. After treatments, there was a notable improvement in cognitive disorders, with recovery of motility and disappearance of aphasia in both patients. EDSS moved from 9.5 to 9 before IA to 5.5 and 5, respectively. Post-IA magnetic resonance images showed a reduction in the gadoliniumenhancement of the lesions. IA was able to contribute to the resolution of malignant form of MS.
TP, in all its modalities (TPE, DFPP, rheopheresis, IA, LA, PAP), is a versatile and potentially effective extracorporeal plasma purification technique. Unfortunately, not all the clinical indications have yet been fully explored. Although outcomes are difficult to predict, it appears that therapeutic benefits of TP overcome the simple plasma purification and below to a general immunomodulation responsible for remission of symptoms.
Based on current knowledge and clinical experience, TP appears an intriguing and high potential therapy in several specialties of medicine. More studies on the applications of TP are needed to enhance clinicians’ consciousness and patient benefits of these extracorporeal techniques.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
The research received no funding.
Conceptualization: Giovanna Capolongo and Claudia Altobelli; methodology and validation: Claudia Altobelli, Giovanna Capolongo, and Giovambattista Capasso; writing – original draft preparation: Claudia Altobelli, Pietro Anastasio, Alessandro Cerrone, Elisabetta Signoriello, Mariadelina Simeoni, Corrado Pluvio, and Giacomo Lus; writing – review and editing: Claudia Altobelli and Giovanna Capolongo; and supervision: Alessandra F. Perna and Giovambattista Capasso.