Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology

INTRODUCTION — Therapeutic apheresis (TA) is an extracorporeal treatment that selectively removes abnormal cells or substances in the blood that are associated with or cause certain disease states. It can also be used to administer cells or plasma constituents that are present in subtherapeutic concentrations.

An overview of indications for which TA is used and practical information for performing apheresis are presented here. Many indications for TA are presented in separate reviews about specific clinical conditions treated with TA.

Complications of TA are discussed separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

TERMINOLOGY — The following terminology is used to describe procedures related to apheresis and TA:

●Apheresis – A general term for "taking away" a targeted cell type or substance from blood. Apheresis includes plasmapheresis (plasma) and cytapheresis (blood cells).

●Plasmapheresis – A general term to denote selective removal of plasma. Plasma can be separated from blood with centrifugation or filtration. Plasmapheresis is mostly used to collect plasma from a healthy blood donor for transfusion (ie, plasma donation). (See "Clinical use of plasma components", section on 'Plasma products'.)

●Therapeutic apheresis (TA) – A general phrase that denotes replacement of plasma with another fluid such as colloid, crystalloid, or allogeneic plasma; or removal or replacement of abnormal or excessive cells for the purpose of achieving a clinical benefit.

●Therapeutic plasma exchange (TPE) – This phrase was historically used synonymously with "therapeutic apheresis" because generally only plasma was used as replacement fluid. However, TPE is now applied specifically to procedures that involve replacement solely with plasma. TPE is also referred to as plasma exchange or therapeutic plasmapheresis and involves removal of patient plasma and replacement with allogeneic or autologous plasma. Plasma removed during plasma exchange must not be used for transfusion to another individual, according to regulations from the US Food and Drug Administration (FDA).

●Therapeutic cytapheresis (hemapheresis) – A term used to denote selective removal of abnormal blood cells (eg, sickled cells [erythrocytapheresis, red blood cell exchange]) or excessive numbers of cells (eg, platelets [thrombocytapheresis], white blood cells [leukocytapheresis]).

●Dialysis – A diffusion-based treatment best suited for the removal of fluid or small molecules (eg, uremic toxins, some drugs) from the blood using a filter. Fluid is removed by filtration (convection); solutes are removed by diffusion.

●Plasma filtration – A technique that separates plasma from cellular components with a highly permeable filter (plasma filter) using a dialysis or hemofiltration machine. (See "Therapeutic plasma exchange (plasmapheresis) with hemodialysis equipment".)

OVERVIEW OF INDICATIONS

Rationale and benefits of therapeutic apheresis — The basic premise of TA is that by removing or decreasing levels of certain pathologic substances from the plasma, prevention of further damage or reversal of a pathologic process can occur (table 1). The pathologic substance may be an autoantibody, immune complex, cryoglobulin, myeloma light chains, endotoxin, cholesterol-containing lipoprotein, or other substances.

TA involves the passing of venous blood through an extracorporeal device that separates blood into its components, cells and plasma, shunts much of the targeted pathologic cells or plasma into a discard container and returns most of the remaining blood to the patient along with replacement fluid and normal cells and a short-acting anticoagulant, usually citrate.

Potential replacement fluids include the patient's own plasma from which an unwanted substance has been removed, or allogeneic (donor) plasma, colloid, or crystalloid. In some cases, use of allogeneic plasma is preferred because it provides needed proteins, immunoglobulins, clotting factors, or other substances. However, allogeneic plasma should only be used as replacement fluid for specific indications such as thrombotic thrombocytopenic purpura (TTP) that is associated with ADAMTS13 deficiency. In other clinical situations, use of appropriate non-plasma replacement fluid eliminates unnecessary exposure to allogeneic plasma.

At least one of the following conditions must be present for therapeutic plasma exchange (TPE) to be considered as a rational therapeutic choice:

●The substance targeted for removal must have a sufficiently long half-life so that extracorporeal removal is more rapid than endogenous clearance pathways.

●The substance to be removed must be acutely toxic and/or resistant to conventional therapy so that rapid elimination from the extracellular fluid by TA is indicated.

●The substance to be removed should be large, with a molecular weight >15,000 daltons, so that it cannot be easily removed by less expensive purification techniques such as hemofiltration or high-flux hemodialysis.

TA is highly effective for the removal of pathologic autoantibodies. Immunoglobulin G (IgG) has an average molecular weight >150,000 daltons and a half-life of approximately 21 days [1]. Thus, even if immunosuppressive therapy could immediately inhibit new antibody production, the plasma concentration would decrease by only approximately 50 percent within 21 days. Such a delay may not be acceptable with an aggressive autoantibody such as that seen in anti-glomerular basement membrane (anti-GBM) antibody disease. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)

TA has other potential benefits, including unloading of the reticuloendothelial system, which can enhance endogenous removal of circulating toxins; stimulation of lymphocyte clones to enhance cytotoxic therapy; and the possibility of reinfusing plasma volumes in such a way that the risk of intravascular volume overload can be decreased [2,3].

The infusion of allogeneic plasma is particularly important in immune or congenital TTP. For immune TTP, TPE using plasma as replacement fluid may be lifesaving. TPE works in TTP both by removing very high molecular weight von Willebrand factor (VWF) multimers and autoantibodies against ADAMTS13 (the VWF multimer-cleaving protease), as well as by providing ADAMTS13. (See "Immune TTP: Initial treatment".)

For some indications, TA is considered first-line therapy (eg, TTP, acute Guillain-Barré syndrome), whereas for others such as light chain cast nephropathy in multiple myeloma, apheresis may need to be used in combination with other established treatments such as chemotherapy to inhibit antibody production. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis", section on 'Extracorporeal methods for light chain removal'.)

Common uses of therapeutic apheresis — In the United States, most TA procedures are performed for neurologic, immunologic, or hematologic diseases (table 2). A collaborative survey by the Association for the Advancement of Blood & Biotherapies (AABB) and the American Society for Apheresis (ASFA) showed that more than one-half of all procedures were performed for neurologic conditions such as Guillain-Barré syndrome or myasthenia gravis [4,5].

The Canadian Apheresis Group has reported a growing use of TA for hematologic disorders, which constituted 55 percent of all TA procedures in 2003; use of TA for neurologic conditions had decreased from 50 percent in 1988 to 40 percent in 2003 [6,7]. This change reflects the growing use of evidence-based practice and advances in pharmacologic treatments that in some instances replace apheresis as standard treatment for some conditions.

The more common indications for TA are discussed in separate topic reviews. Examples include the following:

●Immune thrombotic thrombocytopenic purpura (TTP) – (See "Immune TTP: Initial treatment" and "Thrombotic microangiopathy after kidney transplantation".)

●Renal diseases – (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)

●Hyperviscosity – (See "Treatment and prognosis of Waldenström macroglobulinemia" and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

●Neurologic syndromes – (See "Guillain-Barré syndrome in adults: Treatment and prognosis" and "Overview of the treatment of myasthenia gravis" and "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)

Previously, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis were treated with TA, but this practice often was not based on data from controlled studies. Use of this complex and expensive treatment in the absence of supporting data prompted the development of evidence-based guidelines rather than reliance on anecdotal reports or data from small series or uncontrolled trials (table 2). (See 'ASFA therapeutic categories' below.)

Common uses of therapeutic cytapheresis — In contrast to routine TA, therapeutic cytapheresis is used to lower abnormally high cell counts and to remove abnormal cells such as in sickle cell disease, in which sickle hemoglobin (Hb S)-containing cells can be removed and simultaneously replaced with blood cells (RBC) from blood donors who lack the Hb S variant.

In most conditions, a complete blood count (CBC) will demonstrate whether cell counts have been lowered.

●For hyperleukocytosis, the post-procedure target white blood cell count (WBC) is <100,000/microL.

●For thrombocytosis, the target platelet count is <1,000,000/microL [8].

For RBC exchange in sickle cell disease, the total Hb and percent of Hb S are measured to determine the efficacy of apheresis. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Simple versus exchange transfusion'.)

ASFA therapeutic categories — A comprehensive review of indications for TA based on literature reviews is published approximately every two to three years by the American Society for Apheresis (ASFA) [9-13]. Conditions are assigned to one of four categories based on evidence of clinical efficacy as determined by evaluation of peer-reviewed literature. These guidelines are not intended to mandate TA for conditions in which it is clearly not effective, nor are they intended to deny or exclude patients from receiving TA when a benefit may be potentially achievable. Given the complexity and expense of the procedure, however, the guidelines provide a framework for clinical decision-making.

ASFA categorizations are summarized in the 2023 guidelines (9^th edition) (table 2) [13].

The categories are defined as follows:

●Category I – Disorders for which apheresis is accepted "as first-line therapy, either as primary stand-alone treatment or in conjunction with other modes of treatment." Examples include TA in Guillain-Barré syndrome or immune TTP, and erythrocytapheresis in sickle cell disease with certain complications such as stroke. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.)

●Category II – Disorders for which apheresis is accepted "as second-line therapy," either as a stand-alone treatment or in conjunction with other treatments. Examples include TA for life-threatening hemolytic anemia for cold agglutinin disease or Lambert-Eaton myasthenic syndrome. (See "Lambert-Eaton myasthenic syndrome: Treatment and prognosis", section on 'Plasma exchange'.)

●Category III – Disorders for which the "optimum role of apheresis therapy is not established." Decision-making should be individualized. Examples include TPE for hypertriglyceridemic pancreatitis or extracorporeal photopheresis for nephrogenic systemic fibrosis. (See "Hypertriglyceridemia-induced acute pancreatitis", section on 'Plasmapheresis' and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease", section on 'Treatment'.)

●Category IV – Disorders for which "published evidence demonstrates or suggests apheresis may be ineffective or harmful." Examples include TPE for active rheumatoid arthritis.

The efficacy of TPE in some conditions and intoxications that are not addressed in the ASFA guidelines are available in a separate publication [14].

Opinions and small studies regarding TA for treating coronavirus disease 2019 (COVID-19) or COVID-19 syndromes such as cytokine release syndrome (CRS) or hyperviscosity have been published, but standards-of-practice guidelines have not been determined. A 2021 International Society of Blood Transfusion (ISBT) Working Group preliminarily suggested a role for TA in treating COVID-19-associated syndromes, particularly CRS, applying ASFA guidelines for multiple organ dysfunction to assign a category III, 2B classification to COVID-19-associated CRS; however, the authors cited lack of high-quality evidence for TA [15].

The value of the ASFA guidelines lies not only on the comprehensive nature of the literature reviews but also the concise format for each listed disease state or condition. Categories and recommendation ratings are provided for each condition, as well as a succinct literature synopsis, evidence grading, and recommendations for the treatment schedule, replacement fluids, exchange volumes, and procedure frequency.

TECHNOLOGY — Therapeutic plasma exchange (TPE) is most commonly performed with centrifugation devices referred to as apheresis instruments, also used for blood component collection in healthy donors. These instruments offer the additional advantage of allowing selective cell removal (cytapheresis).

The use of a highly permeable filter with standard hemodialysis equipment is discussed separately. (See "Therapeutic plasma exchange (plasmapheresis) with hemodialysis equipment".)

Venous access — Successful TA requires reliable vascular access, which may consist of two large, durable peripheral veins or a central dual-lumen catheter that is adequately rigid to withstand significant flow pressures; appropriate lines are apheresis/dialysis catheters.

Radiographic confirmation of catheter placement is critical to prevent perforation of adjacent tissues or organs and also because cardiac arrhythmias may result if citrate anticoagulant, which binds ionized calcium, is infused in close proximity to the sinoatrial node.

Use of peripheral veins may avoid complications associated with central venous catheters but is associated with slower blood flow and longer procedures that may eventually render peripheral veins ineffective or create patient discomfort. It may be more practical to insert a central catheter to manage conditions that warrant several procedures over a longer period of time.

Exchange volumes — For most conditions, it has become standard practice to perform 1 to 1.5 plasma volume exchanges per procedure. Exchange of the first 1 to 1.5 plasma volumes removes the greatest concentration of the targeted substance, with diminishing amounts removed in each subsequent exchange procedure. A single plasma volume exchange in an average-sized adult uses approximately 3 liters of replacement fluid.

In general, large molecular weight compounds equilibrate slowly between the vascular space and the interstitium. Thus, calculations of the rate of removal by TA can be simplified to first-order kinetics. A single plasma volume exchange will lower plasma macromolecule levels by 60 percent, and an exchange equal to 1.4 times the plasma volume will lower plasma levels by 75 percent [16,17].

The following formula can be used to estimate the plasma volume in most adults [18]:

The app of the American Red Cross Compendium of Transfusion Practice Guidelines, 4^th edition, offers a function for calculating total blood, red cell, and plasma volumes [19].

Exchanging more than 1 to 1.5 plasma volumes in a single treatment increases procedure time, challenges patient tolerance, and increases cost. As an example, cell separators can perform one complete volume exchange in 1.5 to 2 hours; two to three plasma exchanges will double or triple the time required to perform the procedure.

Replacement fluids — The patient's fluid volume removed by apheresis must be replaced to prevent marked volume depletion. Albumin (5 percent), normal saline, or a combination of albumin and normal saline are the replacement fluids of choice for most conditions.

The optimal choice often varies with the clinical setting. Albumin is used for most conditions; normal saline for hyperviscosity; and some combination of albumin and normal saline if cost is a consideration.

We prefer 5 percent albumin or a crystalloid-colloid (albumin-normal saline) combination as the replacement fluid, rather than normal saline alone. It is generally recommended that plasma only be used as the replacement fluid for conditions in which constituents of plasma are necessary, such as in thrombotic thrombocytopenic purpura (TTP). Albumin 25 percent should not be used unless it is diluted to 5 percent concentration by the hospital pharmacy.

●Five percent albumin – The advantages of 5 percent albumin are the markedly lowered risks of pathogen transmission and anaphylactic reactions [20]. However, a post-apheresis dilutional coagulopathy due to coagulation factor depletion and a net loss of immunoglobulins can occur.

●Albumin-saline combination – When colloid and crystalloid solutions are used in combination, the amount of colloid should not be less than 50 percent of the total infused. An appropriate replacement solution would consist of 1:1 ratio of 5 percent albumin to whole blood and a 2:1 ratio of saline to whole blood for the remainder. For example, if a 3000 mL exchange is performed and 1500 mL of 5 percent albumin is used, 3000 mL of saline solution should be used to replace the other 1500 mL of patient fluid [8,21].

●Saline – Normal saline alone provides insufficient oncotic pressure and tends to lead to significant edema and/or hypotension. Thus, we prefer 5 percent albumin or an albumin-normal saline combination. However, there may be medically compelling reasons for the use of normal saline in some cases, for example, if albumin is not available or for complications such as allergies occurring with albumin or plasma.

●Plasma – Plasma can be provided in the form of Fresh Frozen Plasma (FFP), Plasma Frozen Within 24 hours After Phlebotomy (PF24), Thawed Plasma, or other products. (See "Clinical use of plasma components", section on 'Plasma products'.)

Plasma replaces proteins removed by apheresis so that significant depletion of coagulation factors or immunoglobulins does not occur with multiple or consecutive daily procedures. However, other complications are more common with plasma than with albumin. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'Donor plasma or red blood cell exposure'.)

Additional information about replacement fluids, apheresis schedules, and other technical information have also been published for each listed condition by the American Society for Apheresis (ASFA) [13].

Apheresis schedule — The TA schedule should be based on the nature of the targeted pathologic substance and by the desired endpoint, (eg, clinical improvement or reduction in the level of the pathologic entity). In immunologically mediated, paraproteinemic, or hyperviscosity conditions, immunoglobulin compartmental shifts, especially of IgG and IgM, must be considered [8]. In many of these cases, TA only serves an adjunct role, as the patients are receiving concomitant chemotherapy or immunosuppressive therapy.

●IgM – Approximately 75 percent of IgM is intravascular. As a result, only one or two procedures are usually required to rapidly reduce IgM levels.

●IgG – Only 45 percent of IgG is intravascular, and within 48 hours, plasma IgG returns to approximately 60 percent of the pre-apheresis level [14,17]. IgG production is also characterized by a "rebound" phenomenon, especially if the patient is not on immunosuppressive therapy. Consequently, a more rigorous regimen involving several TA procedures and the institution of immunosuppressive therapy are important to significantly reduce IgG levels [22].

If, as a result of concurrent immunosuppressive therapy, one assumes a negligible production rate of immunoglobulin, and the rate of extravascular to intravascular equilibration to be approximately 1 to 2 percent per hour, then five separate procedures over 7 to 10 days are required to remove 90 percent of the total initial body immunoglobulin burden [23]. Additional treatments may be required if new antibody production occurs.

The AABB general recommendation for conditions requiring TA is that one exchange be performed every second or third day, each exchange consisting of 1 to 1.5 plasma volumes for, in most cases, a total of three to five procedures. Exceptions include the following:

●In immune TTP, TPE is usually performed daily. (See "Immune TTP: Initial treatment".)

●Treatment for Goodpasture's syndrome (anti-GBM mediated disease) is generally also performed on a daily or every-other-day basis. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)

Laboratory evaluation — Laboratory assessment is based on the desired endpoint of therapy, the number of planned procedures, and the type of replacement fluid.

For TA performed without plasma, a baseline complete blood count (CBC), immunoglobulin levels, and coagulation and electrolyte studies should be obtained. If serial or several closely spaced procedures are planned, more frequent subsequent laboratory evaluation may be warranted.

For therapeutic cytapheresis, the appropriate cell count determines adequacy of response. (See 'Common uses of therapeutic cytapheresis' above.)

SUMMARY AND RECOMMENDATIONS

●Definitions – Therapeutic apheresis (TA; plasma exchange or cytapheresis) is an extracorporeal technique for the removal of large molecular weight substances or cells from the blood or plasma, respectively. (See 'Terminology' above.)

●Indications (general principles) – For apheresis to be an appropriate therapeutic choice, the substance to be removed should be sufficiently large so that it cannot be easily removed by hemofiltration or high-flux hemodialysis, must have a sufficiently long half-life, or must be acutely toxic and/or resistant to conventional therapy. Examples include pathogenic autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxin, cholesterol-containing lipoproteins. (See 'Rationale and benefits of therapeutic apheresis' above.)

●Indications (cytapheresis) – Therapeutic cytapheresis (ie, removal of white blood cells, platelets, or red blood cells) can be performed to reduce excessive numbers of cells or pathologically abnormal cells; this may be used for hyperleukocytosis, marked thrombocytosis, or red blood cell exchange transfusion. (See 'Common uses of therapeutic cytapheresis' above.)

●ASFA categories – The American Society for Apheresis (ASFA) guidelines for TA are based on literature reviews of multiple disease states. Conditions are assigned to one of four categories based on evidence of clinical efficacy (table 2). (See 'ASFA therapeutic categories' above.)

●Venous access – Successful TA requires reliable vascular access with either two large, durable peripheral veins or a central dual lumen catheter that is rigid enough to withstand significant flow pressures. (See 'Venous access' above.)

●Choice of replacement fluid – The intravascular volume removed by TA must be replaced to prevent marked volume depletion. Albumin, normal saline, or a combination of albumin and normal saline are the replacement fluids of choice for most conditions. Plasma is appropriate in some conditions that require replacement of a plasma protein or substance with low or absent levels (eg, ADAMTS13 in immune thrombotic thrombocytopenic purpura [TTP]). For most conditions, it should be adequate to perform 1 to 1.5 plasma volume exchanges per procedure. A single plasma volume exchange in an average-sized adult uses approximately 3 liters of replacement fluid. (See 'Replacement fluids' above.)

●Frequency – The apheresis schedule should be determined by the patient's condition, the pathologic substance targeted for removal, and the desired clinical and/or laboratory endpoint. Only one or two procedures may be required to rapidly reduce IgM levels; a more rigorous regimen involving several apheresis procedures may be warranted to significantly reduce IgG levels. Adjunctive use of immunosuppressive therapy may be required, depending on the patient's diagnosis. (See 'Apheresis schedule' above.)

●Complications – Complications of TA are discussed separately, including hypocalcemia; depletion of coagulation factors, immunoglobulins, or medications; angiotensin-converting enzyme (ACE) inhibitor-related symptoms; and adverse reactions to donor plasma such as anaphylaxis, transfusion-related acute lung injury (TRALI), and exposure to infectious pathogens. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications" and "Approach to the patient with a suspected acute transfusion reaction".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Arthur J Silvergleid, MD to earlier versions of this and many other topic reviews.