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.

This article provides an overview of indications and practical information about TA. Physicians who do not have day-to-day experience with TA are urged to seek the expertise of specialists and to familiarize themselves with literature offered in this article and other resources if they are considering TA as a treatment option.

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

TERMINOLOGY — 

Terminology for apheresis and TA may seem confusing because some phrases have been used interchangeably for clinical indications and allogeneic blood component collection. Currently accepted definitions, used herein, are as follows:

●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 from blood. Separation is generally performed with centrifugation or filtration devices. Not uncommonly, "plasmapheresis" is used interchangeably with removal of plasma from a patient for clinical reasons and also in the setting of blood and blood component collection in which plasma intended for transfusion is obtained from a qualified donor. (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.

●Therapeutic plasma exchange (TPE) – Historically, this phrase was used synonymously with and understood to mean "therapeutic apheresis" because usually only plasma was used as replacement fluid. However, TPE is now applied specifically to procedures that involve replacement with plasma only. It involves removal of patient plasma followed by replacement with allogeneic or autologous plasma. Plasma removed during an exchange procedure must not be used for allogeneic transfusion (transfusion to another individual), according to US Food and Drug Administration (FDA) regulations. TPE is also referred to as plasma exchange or therapeutic plasmapheresis.

●Therapeutic cytapheresis (hemapheresis) – Denotes selective removal of abnormal blood cells such as sickled red blood cells, and when used for removing or decreasing the concentration of RBCs, is more specifically referred to as erythrocytapheresis or RBC exchange. If therapeutic cytapheresis is performed for thrombocytosis, it is referred to as thrombocytapheresis. If performed for leukocytosis, it is referred to as leukocytapheresis.

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

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

●Hemoperfusion – A technique that passes blood through a device containing adsorbent particles such as charcoal or a type of resin. (See "Hemoperfusion".)

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 or pathologic cells from the blood, prevention of further damage or reversal of a deleterious process can occur [1-6].

Examples of targeted substances include autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxins, cholesterol-containing lipoprotein, and others (table 1).

TA involves the passing of venous blood through an extracorporeal device that separates blood into its component cells and plasma, shunts much of the targeted pathologic cells or plasma into a separate container for regulated waste disposal and returns most of the remaining blood to the patient along with a short-acting anticoagulant (usually citrate), replacement fluid, and, when indicated, normal cells. (See 'Anticoagulation' below.)

Replacement fluids include the patient's own plasma from which a harmful substance has been removed, allogeneic (donor) plasma, pharmaceutical colloid, or crystalloid.

For thrombotic thrombocytopenic purpura (TTP), therapeutic plasma exchange (TPE) should be performed using allogeneic plasma as replacement fluid; this is essential to supply ADAMSTS13. TTP is the main condition for which plasma replacement is indicated.

In other clinical situations, an appropriate non-plasma replacement fluid should be used because this reduces exposure to allogeneic plasma.

An exception to the practice of using plasma as the replacement fluid only for TTP would be the infusion of an appropriate volume of plasma at the end of a procedure if the use of non-plasma replacement fluid may have decreased immunoglobulins, coagulation factors, or other essential plasma elements.

At least one of the following conditions should be present for TA to be considered a therapeutic option:

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

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

●The substance targeted for removal should have a molecular weight >15,000 daltons so that it cannot be easily removed by less expensive purification techniques such as high-flux hemodialysis.

TA is highly effective for the removal of pathologic autoantibodies (immunoglobulins [Igs]). IgG has an average molecular weight >150,000 daltons and a half-life of approximately 21 days based on metabolic studies in human volunteers [7]. Half-life in individual patients may be longer or shorter. IgM is larger (pentameric) and has a shorter half-life.

Thus, even if immunosuppressive therapy could rapidly inhibit new antibody production, the plasma concentration of the antibody remains elevated for extended periods of time. 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".)

Other potential benefits of TA include 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 [8,9].

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".)

TA is considered first-line therapy for some conditions such as TTP or acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome), or hyperviscosity in hypergammaglobulinemia. In some conditions 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 — The use of TA should be evidence-based and, depending on the specific condition or indication, may be first line, second line, or adjunct treatment for neurologic, inflammatory, hematologic or other diseases. It is medically supervised or performed by in-house or contracted specialists in, for example, transfusion medicine, nephrology, or hematology. The clinical care team is multidisciplinary, and the planning of TA requires close coordination among physicians, nurses, interventional radiology, the transfusion service/blood bank, and other relevant departments.

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 [10,11].

In one study, the Canadian Apheresis Group reported a growing use of TA for hematologic disorders, which constituted 55 percent of all TA procedures; use of TA for neurologic conditions had decreased from 50 percent in 1988 to 40 percent in 2003 [12,13]. This change likely reflected the growing use of evidence-based practice and perhaps advances in pharmacologic treatment that in some instances have replaced apheresis as standard treatment.

The more common indications for TA are discussed in separate topic reviews, such as:

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

●Kidney 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 trials. 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. Consequently, recommendations for some Category IV conditions such as rheumatoid arthritis, amyotrophic lateral sclerosis, and schizophrenia have been "retired" (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/or to remove abnormal cells. This may include red blood cells (RBCs), white blood cells (WBCs), or, less commonly, platelets.

An example is in sickle cell disease, in which erythrocytapheresis (also called RBC exchange) can be used to remove RBCs containing sickle hemoglobin S (Hb S), with replacement by RBCs from blood donors who are negative for Hb S.

Erythrocytapheresis in patients with sickle cell disease enables reduction of the Hb S fraction without incurring transfusion-associated iron burden. This is because iron (incorporated into hemoglobin) is removed in approximately the same amount as is infused. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Exchange blood transfusion'.)

For RBC exchange in sickle cell disease, the total hemoglobin (Hb) and percent Hb S are measured to determine the efficacy of apheresis. Serum ferritin and liver iron are measured longitudinally to assess for iron accumulation. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Simple versus exchange transfusion' and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Monitoring iron stores'.)

In most conditions, a post-procedure complete blood count (CBC) will demonstrate whether cell counts have been decreased.

●For hyperleukocytosis associated with a risk of leukostasis, the post-procedure target white blood cell count (WBC) is <100,000/microL. (See "Hyperleukocytosis and leukostasis in hematologic malignancies", section on 'Leukapheresis'.)

●For thrombocytosis, the target platelet count is <1,000,000/microL [14]. (See "Essential thrombocythemia: Treatment and prognosis", section on 'Alternative approaches'.)

ASFA therapeutic categories — A comprehensive review of conditions and indications based on detailed literature reviews is published approximately every two to three years by the American Society for Apheresis (ASFA) [1,15-18].

Conditions and indications 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 TA, however, the guidelines provide a framework for clinical decision-making and should be consulted when TA is under consideration.

ASFA categorizations are summarized in the 2023 guidelines (9^th edition) (table 2) [1]:

●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 immune TTP, acute inflammatory demyelinating polyradiculoneuropathy, and sickle cell disease with certain complications such as stroke. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", 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 certain drug-induced thrombotic microangiopathies. Involvement of the institutional review board (IRB) or equivalent medical center committee should be sought when determining whether to employ TA for Category IV conditions. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)

The efficacy of TPE in some conditions and intoxications that are not addressed in the ASFA guidelines may be available in a separate publication [19].

●COVID-19 – 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. Using the ASFA guideline development methodology, ISBT assigned a Category III, 2B classification to COVID-19 associated CRS; however, the authors cited lack of high-quality evidence for TA [20].

●VITT – A new category III indication was added in the 2023 ASFA guidelines for refractory vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare complication of adenovirus-based vaccines that includes some vaccines developed for COVID-19 [1]. After the implicated adenoviral-vectored vaccines were removed from the market, the VITT acronym was adapted to refer to a syndrome with nearly identical autoantibodies caused by adenoviral infection (virus-induced) rather than vaccination. (See "Virus-induced immune thrombotic thrombocytopenia (VITT) and VITT-like disorders".)

The value of the ASFA guidelines lies not only in the comprehensive nature of the literature reviews but also the concise format for each of the conditions and indications. Information is presented in Fact Sheets that include categories, evidence-based grades (1A-C and 2A-C), a succinct literature synopsis, a recommended treatment schedule, replacement fluids, exchange volumes, procedure frequency, and other practical information.

TECHNOLOGY

Separation methods — Therapeutic apheresis (TA) is most commonly performed with centrifugation devices referred to as apheresis instruments that may play a role in blood component collection in healthy donors. Some instruments can also be employed for cytapheresis.

TA using membrane separation is an alternative to TA using centrifugation in some institutions [21]. The use of a highly permeable filter with standard hemodialysis equipment is discussed separately. (See "Therapeutic plasma exchange (plasmapheresis) with hemodialysis equipment".)

In the United States, a centrifuge is often used to separate the patient's plasma. In some countries such as Japan and Germany, and in some nephrology departments in the United States, a filter may be used instead.

Venous access — Successful TA requires reliable vascular access with two durable peripheral veins or a central dual-lumen catheter that is rigid enough to withstand significant flow pressures; appropriate devices are apheresis/dialysis catheters. It may be more practical and effective to insert a central catheter to manage conditions that warrant serial procedures or TA over a longer period of time.

Radiographic confirmation of the location of the catheter tip is critical to ensure optimal placement and to prevent perforation of adjacent tissues or organs. A catheter tip that is close to the sinoatrial node can result in cardiac arrythmias due to reduction of ionized calcium when citrate is used as the anticoagulant. (See 'Anticoagulation' below.)

Use of peripheral veins may avoid complications associated with central venous catheters but is associated with slower flow rates and longer procedures that could eventually render peripheral veins unusable or cause patient discomfort. In a pediatric study involving retrospective review of 72 therapeutic plasma exchange (TPE) procedures in 20 children and adolescents, use of a peripheral arterial line for inlet access (mostly 20 or 22 gauge) and peripheral venous for blood return had a 94 percent success rate [22]. The remaining 6 percent had transient delays due to malfunction of the arterial line and were successfully completed after arterial line replacement.

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

In general, large molecular weight compounds equilibrate slowly between the vascular space and the interstitium. 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 [23,24].

The following formula can be used to estimate the plasma volume in most adults [25]:

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 [26].

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 — Fluid removed by apheresis must be replaced to prevent volume depletion. The optimal choice of replacement fluid often varies with the clinical setting.

Depending on the disease or condition, options include plasma, 5% albumin (colloid), normal saline (crystalloid), or a combination of 5% albumin and normal saline. For most conditions, 5% albumin is used.

Normal saline may be preferable in conditions with hyperviscosity. A combination of 5% albumin and normal saline can be used if cost is a consideration.

Plasma is reserved for selected indications such as immune thrombotic thrombocytopenic purpura (immune TTP).

A 5% albumin or a crystalloid-colloid (normal saline-albumin) combination as the replacement fluid, rather than normal saline alone, is preferred. A 25% albumin solution should not be used unless it is diluted to 5% albumin by the medical center pharmacy.

●Albumin – The advantages of 5% albumin are lowered risks of pathogen transmission and anaphylactic reactions [27]. 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 volume 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% albumin to whole blood and a 2:1 ratio of saline to whole blood for the remainder. For example, if a 3000 mL exchange of the intravascular compartment with an albumin/physiologic saline combination were intended, 1500 mL of 5% albumin would be infused, and, keeping in mind that some saline will diffuse to the extravascular compartment, 3000 mL of saline solution would be infused with the 5% albumin [14,28].

●Saline – Physiologic saline alone provides insufficient oncotic pressure and tends to lead to significant edema and/or hypotension. Thus, 5% albumin or an albumin/physiologic saline combination is preferable.

However, there may be medically warranted reasons for the use of physiologic saline, if, for example, albumin is not available or for complications such as allergies that may be associated 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 [5,6]. (See "Clinical use of plasma components", section on 'Plasma products'.)

Plasma replaces proteins that are removed by apheresis. Consequently, significant depletion of coagulation factors or immunoglobulins would be less likely in multiple or consecutive daily procedures if plasma is used as the replacement fluid. 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'.)

Apheresis schedule — The TA schedule should be based on the nature of the targeted pathologic substance and the desired endpoint, such as 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 [14]. In many of these cases, TA 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, one or two procedures are usually sufficient to significantly reduce IgM levels.

●IgG – Approximately 45 percent of IgG is intravascular, and within 48 hours, plasma IgG returns to about 60 percent of the pre-apheresis level [19,24]. This is primarily due to redistribution of IgG from extravascular compartments into the intravascular space [29]. Consequently, a more rigorous regimen involving several TA procedures to remove existing IgG and the institution of immunosuppressive therapy to halt IgG production are both important to significantly reduce IgG levels [30].

If, as a result of concurrent immunosuppressive therapy, one assumes a negligible production rate of immunoglobulin, and the rate of extravascular to intravascular equilibration is approximately 1 to 2 percent per hour, five separate procedures over 7 to 10 days are required to remove 90 percent of the total initial body immunoglobulin burden [31]. Additional treatments may be required if new antibody production occurs.

The ASFA general recommendations for conditions employing TA is that one exchange be performed every other or every third day, with each exchange consisting of 1 to 1.5 plasma volumes for, in most cases, a total of three to five procedures [1]. Exceptions include the following:

●Usually in immune TTP, TPE is initially 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".)

Anticoagulation

●Use of anticoagulation as part of the apheresis procedure – To avoid the formation of clots in the extracorporeal circuit and infused blood and fluids, an anticoagulant must be used with TA procedures [32,33].

•Citrate – Citrate anticoagulation, administered in Acid Citrate Dextrose (ACD) solution, is used most frequently for TA. It is metabolized within approximately 60 to 90 minutes, predominantly by the liver and to a lesser extent the kidneys.

Depending on the duration and number of exchanges and other variables, prophylaxis and treatment of citrate side effects that are due to reduced ionized calcium levels can be managed alone or in combination with oral calcium supplements, calcium gluconate by intravenous push, or calcium gluconate infusion. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

•Heparin – Heparin is the standard anticoagulant for extracorporeal phototherapy and lipoprotein apheresis.

Heparin may be used for large volume exchanges alone or with citrate to shorten the length of certain procedures in patients who may be more prone to hypocalcemia, in the setting of severe metabolic alkalosis, or in liver or kidney failure that could result in clinically significant levels of unmetabolized citrate.

Disadvantages include a greater possibility of bleeding, more complex reversal (with protamine sulfate), and the risk of heparin-induced thrombocytopenia (HIT). (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding risk' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Other complications'.)

●Use of apheresis in a patient already receiving a therapeutic anticoagulant – This is discussed below. (See 'Patient receiving an anticoagulant' below.)

Laboratory evaluation — Laboratory assessment is based on the patient's condition and indication for TA, desired therapeutic endpoint, the number of procedures, the type of replacement fluid, and other variables.

Baseline assays should include levels of the target substance (whenever possible), a complete blood count (CBC), metabolic/chemistry panels, ionized plasma calcium, and immunoglobulin and coagulation levels. The latter two assay categories warrant special attention if plasma is not the replacement fluid. If serial or several closely spaced procedures are planned, more frequent laboratory evaluation may be warranted, including assays of measurable target substances to determine efficacy and status of the treatment plan.

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

SPECIAL POPULATIONS

Patient receiving an anticoagulant — In patients who are receiving (or need to start) systemic anticoagulation for indications such as atrial fibrillation, venous thromboembolism, or catastrophic antiphospholipid syndrome, the choice of anticoagulant should balance the risk of bleeding and thrombosis and consider the effects of apheresis on the anticoagulant levels and activity [32,34].

●Apheresis reduces circulating levels of many anticoagulants, including direct oral anticoagulants (DOACs), fondaparinux, low molecular weight (LMW) heparin, and unfractionated heparin. These anticoagulants may therefore need to be adjusted or supplemented during or after apheresis. When feasible, laboratory monitoring of the anticoagulant effect is recommended; however, the impact of changes in plasma binding proteins should be considered when assessing drug concentration. In contrast to drug levels, functional assays of drug effect should not be impacted by variations in plasma binding proteins.

Clinicians should also be attentive to the risk of coagulation factor depletion with serial apheresis procedures, as reductions in coagulation factor levels probably increase bleeding risk in anticoagulated patients.

●Guidelines have not been published for managing patients who are receiving anticoagulation therapy and undergoing therapeutic apheresis, and studies are needed. In the absence of high-quality evidence, the following represents a reasonable approach:

•Unfractionated heparin – For people who require apheresis and are receiving an intravenous heparin drip, maintain the same heparin dose, with close monitoring and dose adjustments as required.

-There is no good evidence to prefer the activated partial thromboplastin time (aPTT) or anti-factor Xa activity for this purpose, as discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring and dose titration (unfractionated heparin)'.)

-The approach is the same regardless of whether the apheresis replacement fluid is albumin or plasma; however, the risk of overanticoagulation may be greater with albumin due to coagulation factor depletion, whereas plasma contains coagulation factors. Anticoagulation status should be monitored closely. This is not a reason to substitute plasma as a replacement fluid unless there are other concerns related to clotting factor depletion and bleeding. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'Coagulation factor depletion'.)

•LMW heparin, fondaparinux, DOACs, and warfarin – For a patient anticoagulated with one of these medications, the dose can be administered shortly after apheresis (ideally within one hour) without adjusting the dose, since there will be an approximately 24-hour period until the next apheresis procedure.

Readers are also referred to other published discussions [32].

Sickle cell disease (red cell exchange) — (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Exchange blood transfusion'.)

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 [WBCs], platelets, or red blood cells [RBCs]) 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, physiologic saline, or a combination of albumin and physiologic 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.)

●Special populations – Special considerations apply to patients who are receiving systemic anticoagulation for prevention or management of thrombotic conditions and to patients with sickle cell disease undergoing RBC exchange. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Exchange blood transfusion' and 'Patient receiving an anticoagulant' 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 — 

We are saddened by the death of Arthur J Silvergleid, MD, who passed away in April 2024. The UpToDate editorial staff gratefully acknowledges the extensive contributions of Dr. Silvergleid to earlier versions of this and many other topic reviews.