Therapeutic Apheresis—Applications for Hemorrhagic and Thrombotic Disorders

Targets and Goals for Therapy

The goal of therapeutic apheresis is removal of a solute or cell component that is considered pathogenic to the disease process. Plasmapheresis refers to removal of bulk plasma from the blood. Therapeutic plasma exchange (TPE) denotes plasmapheresis in conjunction with replacement of a fluid or colloid, such as albumin or donor plasma. More than 79% of therapeutic apheresis procedures involve TPE. For most TPE indications, the specific target is an immunoglobulin (Ig), such as anti-ADAMTS13 IgG antibody in the case of idiopathic thrombotic thrombocytopenic purpura (TTP) (see Chapter 24 ).

The efficacy of antibody removal with TPE depends on the Ig class, the volume of distribution, the amount of plasma exchanged, and the rates of reequilibration and ongoing production. Exchanges of 1 or 1.5 plasma volumes will remove approximately 63% or 80%, respectively, of the intravascular Ig ( Fig. 29.1 ). Approximately 45% of IgG is distributed intravascularly and 55% is extravascular. Because IgG reequilibrates from the extravascular space, a TPE course usually requires repeated procedures over multiple days to achieve a beneficial decrease in the whole body amount of pathologic Ig. If, for example, a patient with myeloma and an IgG paraprotein at 8 g/dL undergoes a 1× plasma volume exchange, the immediate postprocedure IgG paraprotein level would be approximately 2.1 g/dL. Reequilibration from the extravascular compartment would result in a fairly rapid increase of the IgG level, back to 4 to 5 g/dL in 2 days, even if the patient is receiving anti-myeloma therapy that slows ongoing production (see Fig. 29.1 ). For malignant paraproteins the therapeutic end point is often based on clinical manifestations of hyperviscosity or, more rarely, hemostatic complications associated with the monoclonal antibody.

For many autoimmune disorders the treatment end point with TPE is often empirical because the pathologic antibody is not well defined, it cannot be measured, and/or the plasma level does not correlate with disease activity in the extravascular tissue, and even if defined, it may not be able to be monitored with clinical lab testing. For example, the therapeutic response to TPE for myasthenia gravis, an IgG-mediated condition, often requires a reduction of at least 70% to 80% of the pretreatment pathologic IgG antibody level. This entails approximately five to six procedures exchanging 1× plasma volumes when the treatment interval is every other day. As with paraprotein disorders, ongoing production of a pathologic autoantibody, in addition to the extravascular distribution, contributes to persistent intravascular levels. Thus the treatment plan for TPE indications often includes medical therapy that abrogates ongoing antibody production, such as chemotherapy, immunotherapy, and/or immunosuppression.

Compared with IgG, other Ig classes, such as IgM and IgD, and larger molecular weight plasma proteins, such as fibrinogen, have higher intravascular distribution (~75% to 80%). Thus pathologic IgM paraproteins, such as occur with lymphoplasmacytoid lymphoma (Waldenström macroglobinemia), or IgM autoantibodies can be more rapidly treated by TPE because of effective removal of intravascular Ig and less reequilibration from the extravascular space.

Bulk removal of plasma during TPE and replacement with albumin or saline will reduce by dilution the levels of nonpathologic plasma proteins such as fibrinogen, coagulation factors, and normal Igs. In general, coagulation disruption and spontaneous bleeding will not develop in patients who are not actively bleeding at the outset of a TPE procedure, even when using albumin rather than plasma as replacement fluid. For patients with preprocedure bleeding/oozing or for those at high risk of bleeding, donor plasma should be used as part of the replacement fluid to prevent depletion of fibrinogen and other procoagulants. This risk is especially great for patients who require daily procedures.

Apheresis techniques that reduce circulating pathologic cells, rather than solute, include plateletpheresis (also known as thrombocytapheresis), leukapheresis, and erythrocytapheresis, which remove platelets, white blood cells, and red cells, respectively. Red cell exchange refers to the combination of erythrocyte removal, either by automated erythrocytapheresis or by manual phlebotomy, followed by infusion of donor red blood cells (which may be part of the return fluid during apheresis). Centrifugation instruments use specific kits that are designed to efficiently separate and remove the desired cell types, based on their relative specific gravities and separation properties (see Table 29.1 ).

The therapeutic goals and end points for any apheresis procedure should be considered before commencing a course of treatment. For example, the end points for TPE of patients with idiopathic TTP usually include normalization of platelet count and significant decrease in lactate dehydrogenase (LDH). For paraprotein-associated coagulation factor inhibitors, the therapeutic end point may be a decrease or resolution of clinical bleeding. For many clinical indications, apheresis is an adjunctive therapy combined with several other interventions, such as corticosteroids, chemotherapy, and/or immunosuppressive agents. In these cases the determination of clinical response specifically attributable to the apheresis component may be difficult. In some instances, therapeutic apheresis serves as a bridge until definitive medical therapy can take effect. In other cases a specified number of apheresis procedures is established when the patient begins therapy, often because the pathologic solute cannot be directly identified, quantified, and/or prospectively monitored.

Indications for Therapeutic Apheresis

Many of the conditions for which therapeutic apheresis may be indicated are relatively rare or are for selected subgroups of patients with more common diseases. Therefore few randomized controlled trials (RCTs) or high-quality, large clinical studies exist to guide clinical decision making. To address these shortcomings, the American Society for Apheresis (ASFA) has published evidence-based clinical practice guidelines (the sixth edition of which was published in 2016) to provide systematic categorization of therapeutic apheresis indications. The four-tiered categories for apheresis indications include: (I) accepted as first-line therapy; (II) accepted as second line therapy; (III) optimum role of apheresis is not established, decisions about care should be individualized to the patient; and (IV) evidence demonstrates or suggests that apheresis is ineffective or harmful. The guidelines also incorporate the GRADE system to qualify the assigned category based on the quality of evidence available in the published literature. The GRADE schema ranges from grade 1A (strongly recommended based on well-designed RCT[s]) to grade 2C (weak recommendation based on observational studies or case series). The ASFA guidelines also review information on the rationale for apheresis intervention for each disease or condition, the standard treatment approaches, technical considerations and duration of apheresis treatment, response data, and outcomes. An overview of disorders relevant to hematology, hemostasis, and thrombosis with category I, II, or III recommendations, along with the apheresis modality and grade of evidence is provided in Table 29.2a . Table 29.2b provides the nonhematologic indications for additional reference.

Therapeutic Apheresis Procedural Considerations: Replacement Fluids, Venous Access and Extracorporeal Anticoagulation

After the decision has been made to intervene with a therapeutic apheresis procedure, three main issues must be addressed: (1) the type of replacement fluid (especially for TPE and erythrocytapheresis); (2) venous access; and (3) extracorporeal anticoagulation. Replacement fluid is used in TPE procedures to substitute for the patient's own plasma, which is being removed in bulk and discarded. Plasma proteins, particularly albumin, are required to maintain oncotic pressure; therefore a colloid replacement fluid is usually chosen to avoid intravascular fluid shifts that could lower the blood pressure and cause peripheral edema.

Procedural Adverse Events

AEs occur in approximately 4.6% to 18% of therapeutic apheresis procedures. The rates of procedure-related complications in critically ill and pediatric patients have been reported as much higher, at 45.5% and 55%, respectively. Severe adverse events (SAEs) requiring procedure discontinuation, medication administration, or other interventions occur in only approximately 1% of procedures. Plasma exchange is associated with more toxicity than other therapeutic apheresis procedures, and patients with TTP and Guillain-Barré syndrome appear to suffer the highest rates of TPE-related AEs. Membrane-based TPE procedures may induce allergic and anaphylactoid reactions.

Hypotension or vasovagal episodes, hypocalcemic paresthesias, and urticarial are among the most frequent procedural AEs. Blood pressure alterations due to fluid shifts occur most commonly at the commencement of processing when extracorporeal blood is drawn into the machine. The amount of extracorporeal blood needed for a procedure is determined by the volume of red cells required to fill the separation chamber and to establish the cell/plasma interface. These volumes are determined by the type of kit and the apheresis instrument. Thus patients with lower hematocrit will lose more intravascular volume to deliver the required red cell volume to the separation chamber. Smaller adults, pediatric patients, and those with more severe anemia can be safely managed by priming the apheresis circuit with homologous red blood cells. An alternative approach is to administer extra IV fluid to the patient at the start or during the procedure to compensate for the extracorporeal volume, particularly if it exceeds 10% (pediatric) to 15% (adult) of the patient's total blood volume. Overall, approximately 0.5% to 1% of apheresis adverse reactions are due to fluid shifts.

Hypocalcemia signs and symptoms are common during therapeutic apheresis procedures that use citrate as anticoagulant. Citrate-induced hypocalcemia causes spontaneous depolarization of nerve membranes, leading to perioral and/or peripheral paresthesias, nausea, vomiting, carpopedal spasm, Chvostek sign, and electrocardiogram QT prolongation. Hypocalcemia is a greater risk during apheresis procedures that use plasma for the return fluid because of the additional citrate load from the plasma product. To prevent hypocalcemia, a prophylactic continuous infusion of calcium gluconate or calcium chloride can be used. For patients who are noncommunicative, because of illness, sedation, or young age, blood-ionized calcium levels should be monitored to assess the need for calcium replacement. IV calcium boluses can be administered, as needed, in addition to continuous infusion. Oral calcium supplementation is not a reliable replacement method for patients at greater risk of citrate toxicity. IV calcium replacement strategies have also been effectively used for pediatric patients undergoing procedures with citrate anticoagulation.

The use of red cells as a blood prime or incorporation of plasma as replacement fluid introduce the risk of adverse transfusion reactions. These can range from mild urticarial rash to fever to anaphylactic reactions or other severe entities, such as transfusion-related acute lung injury (TRALIs) (see Chapter 28 ). Mild febrile or allergic reactions may be treated symptomatically or prevented with antipyretics and/or antihistamines. More severe transfusion reactions require discontinuation of the procedure for urgent diagnostic and therapeutic interventions. If severe reactions persist with subsequent procedures, replacement fluid should not include plasma.