Therapeutic apheresis (plasma exchange or cytapheresis): Complications

INTRODUCTION — 

Therapeutic apheresis (TA) is an extracorporeal treatment that removes blood components (plasma and/or cells) from a patient for the management or treatment of conditions in which a pathogenic substance in the blood is associated with morbidity.

●Therapeutic plasma exchange (TPE) denotes the selective removal of plasma and replacement with a suitable fluid.

●Cytapheresis refers to selective removal of abnormal or excessive numbers of blood cells.

This article discusses the complications of therapeutic apheresis.

An overview of terminology used to describe apheresis procedures, indications for and uses of therapeutic apheresis, including American Society for Apheresis (ASFA) therapeutic categories, and practical issues in apheresis are discussed separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

An overview for diagnosing and managing suspected acute transfusion reactions is also presented separately. (See "Approach to the patient with a suspected acute transfusion reaction".)

OVERVIEW OF COMPLICATIONS — 

The basic premise of therapeutic apheresis is that removal of certain pathologic substances or cells (cytapheresis) from the circulation will reduce organ or tissue damage and may permit treatment or reversal of a pathologic process.

To prevent volume depletion during therapeutic plasmapheresis, the volume of patient plasma that is removed should be replaced by appropriate amounts of plasma, colloid, crystalloid, or a combination of these fluids, the specifics of which depend on the type of replacement that is indicated for each clinical situation. Indications for therapeutic apheresis are provided in the American Society of Apheresis guidelines [1].

In general, donor plasma should be avoided, if possible, if apheresis is used to remove a protein or other non-cellular pathological factor. The main exception to this is that donor plasma is used for thrombotic thrombocytopenic purpura (TTP) because it provides the ADAMTS13 enzyme. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology" and "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange (TPE)'.)

Complications may differ based on the type of replacement fluid. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Replacement fluids'.)

Complications are similar using a centrifugal versus a membrane technology, but there are differences, especially in the duration of the procedure and greater platelet loss with centrifugal TPE. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Separation methods'.)

Common complications are summarized in the table (table 1).

The frequency and types of complications depend on patient factors and overall patient condition, the number of procedures, replacement fluid, and the approach to venous access. The frequency of complications in >50,000 procedures (7142 patients) was reported to be 5.8 percent, the most common of which were paresthesias (citrate anticoagulant-associated hypocalcemia) and vascular access issues [2]. A review of complications in >15,000 therapeutic plasma exchange (TPE) treatments found that adverse reactions were substantially more common with plasma than albumin replacement (20 versus 1.4 percent) [3].

In therapeutic cytapheresis, levels of the target cells are decreased. When erythrocytapheresis is performed as treatment or prophylaxis for complications of sickle cell disease, red blood cells (RBCs) from allogeneic blood donors who test negative for sickle cell trait are used for cellular replacement. Most other types of cytapheresis such as leukapheresis for hyperleukocytosis or platelet apheresis for thrombocytosis generally do not require replacement infusion.

For therapeutic apheresis in which a citrate-containing solution is used as an anticoagulant, patients may be at risk for citrate-induced hypocalcemia. Metabolic alkalosis or complications related to a vascular catheter may also occur. When blood products such as plasma or RBCs are infused, the risk of citrate-related complications is also higher due to the presence of citrate in additive solutions that are routinely added to donor blood components at the time of collection or manufacture. In addition, patients who receive blood products for fluid replacement are at risk of transfusion complications and transfusion-transmitted infections. When albumin and/or crystalloid is used as replacement fluid and consecutive daily or frequent procedures are used, patients may also be at risk for coagulation factor or immunoglobulin depletion.

●Any replacement fluid – A common issue is citrate-induced hypocalcemia due to binding of ionized (free) calcium by citrate that is used as an anticoagulant during the procedure. Symptoms include paresthesias, nausea and vomiting, muscle cramps, chest pain, hypotension, and, in the extreme, tetany or arrhythmias such as QT prolongation. (See 'Any replacement fluid' below.)

●Non-plasma replacement fluids for plasma exchange – Non-plasma replacement fluids may cause hypokalemia, reduction in coagulation factor and/or immunoglobulins levels, or hypotension if the patient is taking an angiotensin converting enzyme (ACE) inhibitor. (See 'Non-plasma replacement fluids' below.)

●Donor plasma or RBC exposure – Exposure to allogeneic (donor) plasma or RBCs may cause serious complications such as hemolytic transfusion reactions especially if incompatible products are given; severe anaphylactic reactions; transfusion-related acute lung injury (TRALI); and a potential increase in the risk of exposure to transfusion-transmitted pathogens [4]. Use of blood products should comply with accreditation standards and regulations [5,6]. (See 'Donor plasma or red blood cell exposure' below.)

The TPE procedure should be discontinued and symptoms investigated if any change in the patient's status occurs such as but not limited to dyspnea, seizures, chest pain, hypotension not responsive to one or two fluid boluses or other significant symptoms. (See 'Evaluation for suspected complications' below.)

The reported overall incidence of death from TPE is 0.03 to 0.05 percent [3,4,7]. (See 'Mortality' below.)

ANY REPLACEMENT FLUID

Citrate-induced hypocalcemia — Generally, a solution of sodium citrate is infused as the extracorporeal systemic anticoagulant. Citrate binds ionized calcium to form soluble calcium citrate, lowering the ionized and possibly total serum calcium levels. In patients with normal liver function, citrate is generally metabolized within approximately 1.5 hours. However, because of the length of most therapeutic plasma exchange (TPE) or red blood cell (RBC) exchange procedures, symptoms of citrate toxicity frequently occur if not mitigated.

Early symptoms of hypocalcemia include perioral and distal extremity paresthesias or numbness. Severe reactions can include tetany, prolongation of the QT interval, arrhythmias, or hypotension. (See "Clinical manifestations of hypocalcemia", section on 'Acute manifestations'.)

Electrocardiographic monitoring and intra-procedural evaluation of ionized calcium levels may be appropriate in patients who are receiving intravenous calcium infusions, become symptomatic, or are at risk of significant citrate sensitivity, including patients with altered mental status or pediatric patients who may not be able to communicate early symptoms of hypocalcemia [8].

Strategies to reduce citrate-induced hypocalcemia include:

●Slowing the exchange rate.

●Administer by slow intravenous push one 10 mL ampule of 10 percent calcium chloride over 15 to 30 minutes, beginning 15 minutes after the start of TPE [3,9]. A calcium infusion can be considered if the therapy will last substantially longer than an hour or symptoms of significant hypocalcemia occur.

•In one of the authors' experience (AAK), this regimen reduced the incidence of symptomatic hypocalcemia from 9.1 to 1 percent [3].

•The other author (JLF) has observed that pre- and intra-procedural oral calcium supplements can mitigate and/or possibly treat mild hypocalcemia in certain groups such as stable outpatients. Intravenous calcium infusion may be indicated for patients who cannot take oral calcium or for the occasional patient who develops severe hypocalcemia or has symptoms unresponsive to oral calcium. Administration of 5 to 10 mL of 10 percent calcium gluconate intravenously over 10 to 15 minutes as in intravenous push can reduce symptoms when oral calcium is not effective; muscle contractions can develop if calcium chloride or calcium gluconate is administered too rapidly [8].

●Intravenous calcium gluconate, administered as a continuous infusion of 10 mL of 10 percent calcium gluconate per liter of non-plasma fluid, has been shown to prevent citrate toxicity [10]. One gram of calcium gluconate per liter of non-plasma infusion fluid may alleviate citrate-associated symptoms [11].

Citrate-induced metabolic alkalosis — Another complication of citrate administration is the development of metabolic alkalosis in patients with concurrent kidney failure due to as anti-glomerular basement membrane (anti-GBM) antibody disease (Goodpasture disease) [12]. Metabolism of excess citrate generates bicarbonate, the excretion of which is limited by kidney failure.

Citrate-induced metabolic alkalosis in individuals with kidney insufficiency can be managed by hemodialysis. Patients with kidney failure requiring therapeutic apheresis may require hemodialysis following apheresis to restore acid-base, electrolyte, and fluid balance as needed. Additional information regarding dialysis is presented in separate topic reviews. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose" and "Acute hemodialysis prescription".)

Removal of/reduction in medications — Substantial drug removal by TPE should be anticipated for medications that are highly protein-bound and have a small volume of distribution and would be primarily limited to the vascular space; this also applies to therapeutic antibodies. Consequently, administration of these medications should occur after TPE rather than immediately before the procedure.

●Therapeutic monoclonal antibodies (mAbs) such as rituximab and eculizumab are generally removed by TPE. This can be minimized by administration of the mAb after each apheresis procedure. The hematologist or treating physician should determine when to administer these drugs in collaboration with the therapeutic apheresis team. (See "Overview of therapeutic monoclonal antibodies", section on 'Timing related to plasmapheresis or plasma exchange'.)

●Total parenteral nutrition (TPN) solutions should be infused after the exchange.

●Intravenous immune globulin (IVIG) should be given post-exchange.

●Pharmacokinetic data for specific medications are limited. For medications such as cyclophosphamide, administration after the exchange is prudent and removes any concern about possible reduction due to the exchange.

Vascular catheter complications — Potential complications of central venous catheters include infection, pain, nerve damage, thrombosis, perforation, dissecting hematomas, air embolism, or arteriovenous fistulas. Some of these complications may also occur if peripheral veins are used for access.

Use of peripheral veins may avoid complications associated with central venous catheters, but this approach may not be possible in some cases due to slower blood flow that increases procedure time and may be uncomfortable for the patient.

Confirmation of correct central access device placement is required by Association for the Advancement of Blood & Biotherapies (AABB) and Foundation for Cellular Therapy (FACT) standards [13,14]. (See "Central venous catheters: Overview of complications and prevention in adults".)

NON-PLASMA REPLACEMENT FLUIDS

Hypokalemia — Due to dilutional factors, non-plasma replacement fluids can induce a 25 percent reduction in plasma potassium concentration in the post-apheresis period [15]. For individuals at risk of hypokalemia due, eg, to depletion, dilution, or citrate-induced alkalemia, the potassium level should be immediately checked and treated if hypokalemia is present. (See "Clinical manifestations and treatment of hypokalemia in adults".)

Hypocalcemia — Infusion of large volumes of albumin may cause hypocalcemia. This was demonstrated in a study that randomly assigned 32 patients to receive 10 percent pentastarch versus 5 percent albumin during the first half of an apheresis procedure [16]. The occurrence of hypocalcemia was lower with pentastarch (8 percent) than with albumin (33 percent). This difference was likely caused by binding of calcium to infused albumin.

Coagulation factor depletion — Therapeutic plasma exchange (TPE) with albumin or other non-plasma replacement fluids produces a predictable decrease in blood coagulation factors that may predispose to bleeding. Immediately after a single plasma volume exchange, the prothrombin time (PT) may increase by 30 percent and the activated partial thromboplastin time (aPTT) may double; these changes tend to return to baseline within four hours [9,17]. However, more pronounced and longer-lasting changes can result if multiple exchanges are performed over a short interval such as on multiple consecutive days or several treatments a week. [18].

If multiple TPE procedures are needed, a baseline assessment of coagulation parameters should be done. The PT, aPTT, and/or fibrinogen level should be performed prior to initiating TPE; this could be repeated daily or on alternate days. For patients at risk of bleeding, such as immediately after a kidney biopsy for anti-GBM disease, one or more liters of plasma may be substituted as the replacement fluid; the plasma should be administered at the end of the procedure. An alternative to plasma infusion is to allow coagulation parameters or factor levels to return to normal prior to performing procedures such as the removal of a large bore vascular catheter after the last TPE.

Immunoglobulin depletion — Repeated TPE with a non-plasma replacement fluid will predictably deplete the patient's immunoglobulins and result in low serum IgG and other immunoglobulin levels. The indication for monitoring serum IgG levels depends on a number of factors including the frequency of exchanges, the number of blood volume exchanges per procedure, the immune status of the patient, and the patient's innate immunoglobulin production.

Removal of immunoglobulins and complement may lead to an immunodeficient state, leaving the patient susceptible to infection. Reports of patients treated with TPE for glomerulonephritis suggested an increase in opportunistic infections. However, these patients also received immunosuppressive agents and were often granulocytopenic [19]. In a trial that randomized 86 patients with lupus nephritis to TPE or immunosuppressive therapy, TPE was not associated with a greater risk of infection and patients were not more prone to infection [20].

For a patient undergoing aggressive TPE, such as two to three plasma volume replacements per procedure and/or consecutive daily procedures without plasma replacement, a baseline IgG level should be obtained [21,22]. For patients whose IgG level falls below 500 mg/dL and who have a systemic infection, or for whom concerns about infection exist, author AAK uses a single infusion of intravenous immune globulin (IVIG; 100 to 400 mg/kg), although IgG replacement has not been tested in this setting. (See "Overview of intravenous immune globulin (IVIG) therapy".)

ACE inhibitor-related complications — Rarely, symptoms resembling anaphylaxis such as flushing, hypotension, abdominal cramping, and other gastrointestinal symptoms, have been reported during TPE in patients receiving angiotensin-converting enzyme (ACE) inhibitors. These symptoms have been observed when albumin was used for replacement fluid and the patient had taken an ACE inhibitor within 24 to 30 hours of TPE [23,24]. In one report of 299 consecutive patients undergoing TPE, these symptoms occurred in all 14 patients receiving an ACE inhibitor versus 7 percent in those not receiving an ACE inhibitor [23]. The etiology of these symptoms is unclear; one possibility is increased kinin generation, which has been thought to account for angioedema that can occur with ACE inhibitors. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)

Based on these observations, it has been recommended that ACE inhibitors be withheld for 24 to 48 hours prior to TPE if the patient can tolerate a temporary discontinuation; transitioning to an angiotensin receptor blocker should be considered [11,25]. Management of this complication involves supportive care. If future TPE is required, a different lot of albumin should be used, as kinin concentrations vary by manufacturers' lots.

DONOR PLASMA OR RED BLOOD CELL EXPOSURE

Anaphylactic reactions — Anaphylactic reactions to plasma have been reported and are a possible cause of death associated with therapeutic plasma exchange (TPE) [4,26]. These reactions have been reported in up to 21 percent of patients and are most often characterized by fever, rigors, urticaria, wheezing, and hypotension [27,28]. Cardiopulmonary collapse is rare. (See "Immunologic transfusion reactions", section on 'Anaphylactic transfusion reactions'.)

Management of anaphylactic reactions may include antihistamines, epinephrine, glucocorticoids, or more aggressive measures, depending upon the severity of the symptoms. (See "Immunologic transfusion reactions", section on 'Treatment of anaphylactic reactions'.)

Anaphylaxis may be due to the presence of anti-IgA antibodies in IgA-deficient patients that react with IgA in donor plasma. If anaphylaxis is due to anti-IgA, plasma from IgA-deficient donors should be used. This product is usually only available from rare donor registries, and it may be difficult to obtain enough plasma to perform multiple procedures. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Selective IgA deficiency: Management and prognosis".)

If plasma from an IgA-deficient donor is unavailable, a non-plasma replacement fluid such as albumin could be considered. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Replacement fluids'.)

In rare cases, one of the authors (AAK) has been able to use pretreatment with ephedrine, glucocorticoids, and diphenhydramine in a patient with a history of anaphylactic reactions to plasma and thus successfully performed TPE for thrombotic thrombocytopenic purpura during two pregnancies [29].

Hives — In contrast to anaphylactic reactions, allergic reactions characterized by urticaria and/or pruritus can be managed by pausing the procedure, administering diphenhydramine or glucocorticoids if the latter is warranted by symptoms, and monitoring the patient for worsening symptoms. The infusion can be restarted if symptoms abate. Allergic reactions such as hives are thought to be due to preformed IgE antibodies in the recipient or donor that react with a substance in the donor or recipient, respectively (eg, donor peanut allergy, with hives triggered due to recent peanut ingestion by the recipient) [29,30]. (See "Immunologic transfusion reactions", section on 'Allergic reactions'.)

Transfusion-related acute lung injury (TRALI) — TRALI is a form of acute lung injury usually caused by antibodies in donor plasma that react with "cognate" or "matching" antigens on patient neutrophils, leading to leukoagglutination in the pulmonary circulation and noncardiogenic pulmonary edema. TRALI typically presents as sudden onset of hypoxic respiratory insufficiency, with bilateral pulmonary infiltrates on chest imaging studies during or within several hours of blood product exposure. Treatment is supportive, but in severe cases intubation may be necessary. The pathogenesis, diagnosis, and management of TRALI are discussed separately. (See "Transfusion-related acute lung injury (TRALI)".)

Infectious risks of plasma or RBC — The table lists estimates of the per-unit risk of transfusion-acquired viral disease in the United States (table 2). (See "Blood donor screening: Laboratory testing".)

EVALUATION FOR SUSPECTED COMPLICATIONS — 

Symptoms occurring during apheresis are multifactorial and include volume shifts, metabolic complications, or reactions to plasma or red blood cells (RBCs). The table summarizes these complications (table 1).

Blood pressure, temperature, and other vital signs should be checked often during apheresis, eg, every 10 to 15 minutes depending on the hemodynamic status of the patient. We consider the following in evaluating the patient who develops symptoms:

●Shortness of breath – Causes of shortness of breath include the following:

•Transfusion-related acute lung injury should be considered if plasma is infused. (See "Transfusion-related acute lung injury (TRALI)".)

•Pulmonary edema due to fluid overload.

•Bronchospasm, hives, or mucous membrane swelling may be a sign of an impending anaphylactic reaction that can be due to plasma in RBCs.

•Air emboli caused by air or bubbles in the line, or pulmonary emboli due to inadequately anticoagulated blood that contains clots. This is unlikely because sensors in cell separators are designed to detect these and are programmed to trigger alarms. Anticoagulant volumes are controlled by state-of-the-art cell separators.

•Very rarely, dyspnea, wheezing, chest pain, and hypotension unresponsive to fluid boluses may be produced by complement-mediated membrane bioincompatibility or sensitivity to ethylene oxide used as a membrane sterilant [31,32].

●Hypotension – Causes of hypotension include the following:

•Citrate-induced hypocalcemia can occur with any blood product but would likely be more pronounced with plasma. (See 'Citrate-induced hypocalcemia' above.)

•Decreased intravascular volume can occur with any procedure. This is because up to 200 mL of extracorporeal patient blood remains in the apheresis kit tubing and centrifuge during and at the end of the procedure. The extracorporeal volume of each kit type is included in the manufacturer's information. With continuous flow technology, the extracorporeal volume is usually no more than 15 percent of the patient's intravascular volume. However, instruments that use discontinuous flow technology may have higher extracorporeal volumes. Infusing additional intravascular fluid, slowing the procedure, or increasing the return rate can return the blood pressure toward the baseline level if hypotension is related to fluid shifts.

•A coronary event such as acute coronary syndrome may present with hypotension and chest pain. If this occurs, the procedure should be stopped and the patient evaluated for possible cardiac ischemia. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department".)

•Vasovagal reactions are uncommon but would present as hypotension accompanied by a decrease in pulse rate, diaphoresis, syncope, and/or gastrointestinal symptoms. Lowering the patient's head, using ammonium salts, and temporarily pausing the procedure are appropriate management strategies. Modest fluid boluses with normal saline can also improve the patient's symptoms if the additional fluid can be tolerated. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation", section on 'Vasovagal syncope'.)

•Additional evaluation for hypotension is discussed in more detail separately. (See "Definition, classification, etiology, and pathophysiology of shock in adults".)

The approach to a suspected acute transfusion reaction is presented separately (algorithm 1 and table 3). (See "Approach to the patient with a suspected acute transfusion reaction".)

MORTALITY — 

The reported case fatality rate for therapeutic plasma exchange (TPE) is 3 to 5 per 10,000 (0.03 to 0.05 percent) [3,4,7]. In more than 50 TPE-associated deaths since 1989, respiratory or cardiac complications were most common [30]. Cardiac arrhythmias were frequently observed, especially in those receiving plasma. The suspected etiology was a reduction in the ionized calcium concentration, but a cause-and-effect relationship has not been proven.

Among respiratory deaths, acute respiratory distress and symptoms of noncardiogenic pulmonary edema were observed shortly before death; these patients were being infused with plasma. Anaphylaxis, vascular complications, hepatitis, sepsis, and thrombosis were other, less common causes of death. Because of advances in donor testing, HIV, hepatitis, and other transfusion-transmitted infections are considered rare complications.

SUMMARY AND RECOMMENDATIONS

●Risk of complications – To prevent volume depletion, patient plasma must be replaced by a clinically appropriate fluid which may be allogeneic plasma, colloid, or crystalloid. The frequency and types of complications from therapeutic apheresis depend on the overall condition of the patient, the number of plasma exchanges, the type of replacement fluid, and venous access approach. Common complications are listed in the table (table 1). Adverse reactions are more common when plasma is used as the replacement fluid. (See 'Overview of complications' above.)

●Hypocalcemia – Citrate causes hypocalcemia by binding ionized calcium. Citrate-induced hypocalcemia can occur with any blood product used in therapeutic plasma exchange (TPE) and red blood cell (RBC) exchange, and symptoms of citrate toxicity can occur frequently. Potential early symptoms include perioral and distal extremity paresthesias or numbness; severe reactions can include tetany, prolongation of the QT interval, arrhythmias, or hypotension. Various strategies can reduce this complication. (See 'Citrate-induced hypocalcemia' above.)

●Complications with non-plasma fluid replacement – Complications include metabolic alkalosis, removal of or decrease in the concentration of a drug, or complications related to a vascular access catheter. (See 'Citrate-induced metabolic alkalosis' above and 'Removal of/reduction in medications' above and 'Vascular catheter complications' above.)

●Complications with saline replacement – Non-plasma replacement fluids may cause hypokalemia or depletion of coagulation factors or immunoglobulins. Baseline assessment of the PT, aPTT, and/or fibrinogen level should be done prior to initiating apheresis for patients expected to undergo multiple procedures, and a baseline IgG level should be obtained for those expected to undergo aggressive plasma exchange. (See 'Coagulation factor depletion' above and 'Immunoglobulin depletion' above.)

Flushing, hypotension, abdominal cramping, and other gastrointestinal symptoms have been reported, although rarely, during TPE in patients receiving an angiotensin-converting enzyme (ACE) inhibitor. To reduce this complication, it has been recommended that ACE inhibitors be withheld for 24 to 48 hours prior to TPE if the patient can tolerate short-term interruption. (See 'ACE inhibitor-related complications' above.)

●Complications with plasma or RBC replacement – Exposure to donor plasma or RBCs may cause hemolytic transfusion reactions if incompatible blood is administered, anaphylactic reactions, allergic reactions (eg, hives), transfusion-related acute lung injury (TRALI), exposure to infectious pathogens, or other complications (see 'Donor plasma or red blood cell exposure' above). A general approach to evaluating and managing an acute transfusion reaction is presented in detail separately (algorithm 1 and table 3). (See "Approach to the patient with a suspected acute transfusion reaction".)

●Monitoring – Blood pressure, temperature, and other vital signs should be monitored often during therapeutic apheresis; any change from the pre-procedure baseline should be promptly evaluated. (See 'Evaluation for suspected complications' above.)

●Mortality – The overall mortality of TPE has been reported to be 0.03 to 0.05 percent; death is most commonly due to respiratory or cardiac complications. (See 'Mortality' above.)

●Definitions and indications – An overview of the terminology used to describe apheresis procedures; the types of indications for which therapeutic apheresis is effective, including American Society for Apheresis (ASFA) therapeutic categories; and practical issues in apheresis techniques are discussed in detail separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

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.