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CHAPTER 144 THERAPEUTIC HEMAPHERESIS: INDICATIONS, EFFICACY,

CHAPTER 144 THERAPEUTIC HEMAPHERESIS: INDICATIONS, EFFICACY, COMPLICATIONS
Williams Hematology

CHAPTER 144 THERAPEUTIC HEMAPHERESIS: INDICATIONS, EFFICACY, COMPLICATIONS

BRUCE C. MCLEOD

Introduction
Cell Depletion

Plateletpheresis

Leukapheresis
Blood Component Exchanges

Physiology

Plasma Exchange

Red Cell Exchange
Chapter References

Therapeutic hemapheresis provides a means to rapidly alter the composition of components of the blood. It can be a valuable and safe initial treatment in a number of illnesses associated with quantitative and/or qualitative abnormalities of blood cells or plasma. Cell depletions are useful in symptomatic thrombocythemia and hyperleukocytosis. Plasma exchange is useful in certain paraproteinemias, antibody-mediated disorders, and toxin-mediated diseases; it can also be used to replete a deficient plasma constituent. Red cell exchange is used primarily for severe manifestations of sickle cell disease. Selective extraction techniques are available for IgG and low-density lipoprotein, and modulation of certain immune responses is possible with photopheresis. Adverse effects with current techniques are infrequent and usually mild.

INTRODUCTION
Therapeutic hemapheresis comprises a set of related techniques in which the amount or composition of a component of the blood is manipulated for a direct therapeutic purpose, usually with a continuous-flow centrifugal blood separation instrument. Available techniques fall into the three main categories of blood cell depletion, blood component exchange, and blood component modification, as shown in Table 144-1. Excess platelets or leukocytes are the usual targets for cell depletion procedures. These procedures are currently done almost exclusively for hematologic diseases. Blood component exchanges will target plasma or red cells. Plasma exchange is beneficial in a number of antibody-mediated conditions, many of which are not usually considered hematologic diseases. Specialized techniques have been developed for on-line selective extraction of certain individual constituents such as IgG and low-density lipoproteins from plasma separated by an apheresis instrument, and for photochemical modification of separated lymphocytes (photopheresis). Donation of autologous peripheral blood stem cells with an apheresis instrument is discussed in Chapter 141.

TABLE 144-1 THERAPEUTIC HEMAPHERESIS TECHNIQUES

The goal of therapeutic apheresis is usually therapeutic depletion, although infusion of normal blood constituents in quantity may also be important in some instances. Apheresis therapy depletes rapidly but does not decrease production of an abnormal blood constituent. Therefore, in most illnesses it is best used acutely to control symptoms until more definitive therapy takes effect. Chronic apheresis therapy is seldom appropriate unless more convenient treatments are ineffective or contraindicated.
Adverse effects of therapeutic apheresis with modern instruments are relatively infrequent and generally mild. Hypotension will occur in 1 to 2 percent of procedures. Hypocalcemia due to citrate infusion may also occur. Urticaria may be seen when donor plasma is infused in plasma exchange. Deaths associated with plasma exchange are rare, and most are attributable to the disease being treated rather than the apheresis therapy.1,2 and 3
CELL DEPLETION
PLATELETPHERESIS
With the use of hydroxyurea or anagrelide, thrombocythemia can usually be managed pharmacologically. Therapeutic plateletpheresis, however, can be valuable in patients with symptomatic thrombocythemia who require rapid reduction in their platelet count or who cannot tolerate drug therapy.4,5,6,7,8,9 and 10 The platelet count can usually be lowered by about 50 percent with each procedure,5 though the decrement may be less if platelets are mobilized from an enlarged spleen during apheresis. Plateletpheresis can reverse clinical manifestations of myocardial or cerebral ischemia, pulmonary embolism, and gastrointestinal bleeding. Multiple procedures at intervals of a few days are usually needed until chemotherapy takes effect. It is not known whether prophylactic plateletpheresis lowers the incidence of thrombosis or hemorrhage; however, it may prevent placental infarction and fetal death in pregnant patients with thrombocythemia.11 Long-term plateletpheresis is logistically and financially burdensome and is seldom indicated as the sole therapy for thrombocythemia6,12 (see Chap. 118).
LEUKAPHERESIS
The most common application of therapeutic leukapheresis is the removal of malignant leukocytes. It has been performed in both acute and chronic leukemias and in the leukemic phase of lymphoma. The usual goal is to relieve or forestall acute symptoms of hyperleukocytosis, but it has occasionally been used as a primary method of disease control.13 Immunomodulation by removal of nonmalignant lymphocytes has also been tried14,15 but has not become an accepted treatment for any illness.
The threshold white cell count for pulmonary and/or cerebral dysfunction (leukostasis) in patients with leukemia is not known; it may depend on rheologic variables that differ among different leukemias, and even among different patients with the same type of leukemia. Clinical manifestations of hyperleukocytosis may occur in acute myelogenous leukemia (AML) with a white cell count of 75,000/µl16,17 but are more likely when the white cell count exceeds 200,000/µl.18 Although controlled trials documenting benefit are lacking, therapeutic leukapheresis is often performed urgently in AML if the white cell count is greater than 100,000/µl because this is a risk factor for early death.19 Patients with acute lymphocytic leukemia (ALL) are often treated similarly, even though symptoms are less frequent in this condition.20,21 and 22 In one study of ALL patients, leukapheresis led to a lower incidence of electrolyte abnormalities.22
White cell removal in chronic myelogenous leukemia (CML) was one of the earliest applications of apheresis instruments in patients.23 Repeated leukapheresis as therapy for CML also provided leukocytes for transfusion to infected neutropenic patients with acute leukemia.24 Some CML patients had a reduction in organomegaly and amelioration of constitutional symptoms, but chronic leukapheresis did not prolong life or delay the onset of blast transformation.25 Logistical and financial issues make this approach impractical except in unusual circumstances such as pregnancy26 in which a delay in chemotherapy is desirable. Currently, leukapheresis therapy in CML is usually reserved for patients who have white cell counts of 300,000 to 500,000/µl and signs of leukostasis. The same may be said of chronic lymphocytic leukemia.27,28
In Sézary syndrome, a leukemic phase of cutaneous T cell lymphoma (CTCL), repeated leukapheresis has resulted in reduction of the number of circulating malignant (Sézary) cells and improvement or resolution of skin lesions.29,30 and 31 More recently, photopheresis (extracorporeal photochemotherapy) has been used to treat CTCL, especially in the erythrodermic phase.32 In this technique, leukocytes removed by apheresis are exposed to ultraviolet A light in the presence of 8-methoxypsoralen and then returned to the patient. It is believed that photochemical damage to DNA renders the malignant cells immunomodulatory and thereby stimulates host antitumor immunity.33,34 Photopheresis has brought about sustained remissions in CTCL.34
The extent to which the white cell count should be lowered is not known with certainty for any application of therapeutic leukapheresis. Processing at least two patient blood volumes has been recommended, with reductions in white cell count of 15 to 86 percent reported in acute leukemias.13 It is difficult to predict the outcome of a procedure because of mobilization of cells into the bloodstream, underestimation of patient blood volume by standard formulas, and patient-specific differences in the behavior of leukemic cells in a centrifugal instrument. In practice it is worthwhile to monitor the white cell count during a procedure and to continue until there is a 30 to 50 percent decline.
BLOOD COMPONENT EXCHANGES
PHYSIOLOGY
Therapeutic blood component exchange reduces the concentration of a harmful blood constituent by removal of patient material and its simultaneous replacement with a substitute lacking the unwanted constituent. In a plasma exchange, the extent of depletion of an unwanted macromolecule, X, can be estimated at any point by the formula35:
Xn = Xoe–n, where
n = volume exchanged, expressed in patient plasma volumes
Xo = starting concentration of X
Xn = concentration of X after exchange of n plasma volumes
e = base natural log
This formula describes an asymptotic function which predicts (assuming equilibration with extravascular substance is slow) that exchange of one plasma volume will lower the intravascular concentration of a substance by about 65 percent, while exchange of a second plasma volume will lower it by only about 23 percent more. Removal is thus more efficient in the early portion of an exchange, and for this reason many exchanges are limited to a single plasma volume. For IgG antibodies, the existence of a substantial extravascular reservoir provides a further rationale for a series of single plasma-volume exchanges separated by intervals adequate to allow reequilibration between intra- and extravascular spaces. Applied in a reciprocal manner, the formula works equally well for predicting the outcome of a red cell exchange, although the concentration of normal red cells can be increased efficiently beyond the predicted level at the end of a procedure by infusing red cells while removing plasma.
A protein-containing replacement fluid must be given during plasma exchange. Either normal plasma or 5 percent albumin is usually chosen. The latter is preferred for most applications because it does not transmit viral infections or cause urticarial reactions and can be administered without regard to blood type. As expected, levels of IgG and IgM fall by about 63 percent after a one-plasma-volume exchange for albumin and then take several weeks to recover.36 Coagulation factor levels also fall, with transient prolongation of the prothrombin time and partial thromboplastin time; however, clinical bleeding is not usually encountered, and all coagulant proteins except fibrinogen return to the normal range within 6 to 24 h after an exchange.37,38 Because levels of most other plasma proteins also recover quickly between exchanges, a series of thrice-weekly exchanges of patient plasma for 5 percent albumin produces a rather selective depression in immunoglobulin levels.39 Plasma replacement may be necessary in certain illnesses, such as thrombotic thrombocytopenic purpura (TTP), for the desired therapeutic effect. Also, plasma may be given in the final portion of an exchange to replete coagulation factors when a patient has a preexisting bleeding diathesis.
PLASMA EXCHANGE
Therapeutic plasma exchange has been used to treat several types of plasma constituent abnormalities (Table 144-2). In most instances, the goal is to remove a pathogenic immunoglobulin from the patient’s blood. These cases can be subdivided depending on whether it is the antigenic specificity of the immunoglobulin or an abnormal physical property imparted to the blood by its presence (e.g., hyperviscosity) that mediates the disease process. In a few instances plasma exchange can be helpful by removing substances other than immunoglobulin (e.g., low-density lipoproteins). Finally, plasma exchange can replete a deficient factor to a higher level than plasma infusion alone.

TABLE 144-2 INDICATION CATEGORIES FOR PLASMA EXCHANGE

IMMUNOGLOBULINS WITH PATHOGENIC PHYSICAL PROPERTIES
Almost all of the conditions in this category are due to monoclonal proteins. The hyperviscosity syndrome, which can be a feature of macroglobulinemia, is probably the oldest indication for therapeutic apheresis.40,41 and 42 It is particularly amenable to plasmapheresis because IgM is distributed largely in the plasma and not in the extravascular fluid. Furthermore, since the relationship between paraprotein concentration and viscosity is nonlinear, a reduction in viscosity sufficient to relieve both hemorrhagic and ischemic symptoms can sometimes be achieved with exchange of only 500 to 1000 ml plasma by manual bag techniques. Larger automated exchanges are even more effective. Plasma exchange can also reverse clinical manifestations of cryoglobulinemia such as vasculitis, glomerulonephritis, and Raynaud phenomenon.43,44 and 45 In both instances it is best used as a temporizing strategy until more definitive therapy directed at the protein-producing cells can take effect. However, in unusual circumstances long-term treatment can also be effective.
Plasma exchange may also be beneficial in renal failure associated with multiple myeloma.46,47 In one prospective, randomized study of oliguric patients requiring dialysis, only patients treated with both plasma exchange and chemotherapy recovered renal function.47
IMMUNOGLOBULINS WITH PATHOGENIC SPECIFICITY
A number of diseases are mediated by circulating antibody specific for a host tissue antigen. Although autoreactive, some of these antibodies are probably stimulated by exposure to alloantigens (e.g., anti-HPA-1a in posttransfusion purpura). Plasma exchange therapy is useful in many such illnesses, including the examples listed in Table 144-3.

TABLE 144-3 EXAMPLES OF SPECIFIC ANTIBODIES IN DISEASES TREATED WITH PLASMA EXCHANGE

Hematologic Diseases In posttransfusion purpura, thrombocytopenia develops abruptly about a week after a blood transfusion, in association with an alloantibody response to a platelet-specific antigen. It remains unclear how the patient’s antigen-negative platelets are destroyed.48 Plasma exchange will hasten recovery from this self-limited syndrome,49 as will intravenous (IV) gamma globulin infusions.50
Plasma exchange was also reported to be beneficial in some trials in acute idiopathic thrombocytopenic purpura51,52 and 53 but has since been superseded by IV gamma globulin.54 In chronic idiopathic thrombocytopenic purpura associated with HIV infection or unresponsive to glucocorticoids and splenectomy, the platelet count has been reported to improve after infusions of autologous plasma that has passed through a protein A/silica affinity column.55,56 The procedure can be done off-line on stored plasma or on-line in series with the plasma circuit of an apheresis device. The exposure to protein A is apparently immunomodulatory rather than subtractive, since the amounts of immune complexes and platelet-associated antibodies removed by the column are insufficient to account for the salutary effects.56
Plasma exchange is not routinely recommended in warm autoimmune hemolytic anemia57 but may be helpful in refractory cases in combination with IV gamma globulin58 or pulse cyclophosphamide.59 In cold agglutinin disease, significant but transient reductions in antibody titer and in the severity of hemolysis have been reported.60,61,62 and 63 Warming the extracorporeal circuit and replacement fluids in such cases is very important.
Coagulation factor inhibitors (both auto- and alloantibodies) can be removed by plasma exchange.64,65 and 66 This alone will not control bleeding due to a high-titer inhibitor, but it may reduce the titer enough to allow replacement factor to circulate temporarily.67,68 The replacement fluid for such exchanges should be fresh-frozen plasma. Repeated antibody removal by on-line immunoadsorption with a protein A-Sepharose affinity column, in combination with factor replacement and immunosuppression, may induce tolerance in alloimmunized hemophiliacs.69,70
Plasma exchange has also been tried in patients with disorders of blood cell production that can be linked to circulating antibody, including aplastic anemia,71 pure red cell aplasia,72,73 and lymphopenia.74,75
Removal of alloantibodies to red blood cells may also be accomplished by therapeutic apheresis. Both plasma exchange and isoagglutinin-specific immunoadsorption have been used to prepare patients for ABO-incompatible marrow transplants.76,77 and 78 Alternatively, apheresis instruments can be used to remove red cells from the graft.79 In sensitized Rh-negative women, removal of maternal IgG by plasma exchange during pregnancy to ameliorate destruction of fetal red cells80 has been largely supplanted by intrauterine transfusion of compatible cells. Plasma exchange may still be tried, however, if therapy is needed prior to 18 to 20 weeks gestation, when intrauterine transfusion is not technically feasible.81,82
Neurologic Diseases Neurologic diseases account for more plasma exchange treatments than any other category. The effectiveness of this treatment complements other evidence supporting an autoimmune etiology for several neuropathic and neuromuscular disorders.
In Guillain-Barré syndrome, early treatment with plasma exchange clearly hastens recovery83,84 and 85 from an illness in which antibodies to myelin are frequently found,86 possibly in response to infection with Campylobacter jejuni in some cases.87,88 and 89 Antimyelin antibodies may also be found in chronic inflammatory demyelinating polyneuropathy,90,91 and 92 and a controlled trial in this condition has shown significant improvement in patients treated with plasma exchange.93 Chronic neuropathy in the context of a monoclonal gammopathy may also respond to plasma exchange.94
Myasthenia gravis and Lambert-Eaton syndrome are both mediated by autoantibodies to structures in the neuromuscular junction.95 In the former the target is the acetylcholine receptor on the muscle cell, while antibodies in Lambert-Eaton syndrome are directed against structures in the nerve ending. Both illnesses respond to plasma exchange,96,97 which has been most useful in severe myasthenia gravis.
Several paraneoplastic syndromes with neurologic manifestations are associated with autoantibodies; e.g., encephalomyelitis with anti-Hu, cerebellar degeneration with anti-Yo, opsoclonus-myoclonus with anti-Ri, and retinal degeneration with anti-CAR. Results from plasma exchange, however, have been disappointing.98,99
Renal and Rheumatic Diseases Goodpasture syndrome of glomerulonephritis and lung hemorrhage is due to linear deposition of autoantibody to a collagen found in pulmonary and renal basement membranes.100 Prompt intervention with plasma exchange and cyclophosphamide is the treatment of choice. By contrast, in nephritis associated with systemic lupus erythematosus, controlled trials have shown that oral cyclophosphamide plus plasma exchange is no better than oral cyclophosphamide alone.101,102 In pauci-immune rapidly progressive glomerulonephritis, one study suggested benefit from plasma exchange in patients with dialysis-dependent renal failure103; however, benefit has not been seen in controlled trials in dialysis-independent patients.103,104 and 105 Plasma exchange has been tried in patients with several categories of severe vasculitis,106,107 and 108 but in recent studies in severe nonrenal lupus erythematosus there were excess deaths from infection when plasma exchange was added to pulse intravenous cyclophosphamide therapy.109,110 Multiple controlled trials have shown that plasma exchange is ineffective in reversing renal transplant rejection.111,112,113 and 114
NONIMMUNOGLOBULIN CONSTITUENTS
Removal of low-density lipoproteins by plasma exchange can lower cholesterol levels and promote resorption of xanthomas and atheromas in patients with familial hypercholesterolemia.115,116 On-line selective extraction of lipoproteins from patient plasma can be accomplished by several chemical and immunological means,117,118 and 119 one of which has been approved by the Food and Drug Administration for patients with severe hypercholesterolemia resistant to dietary and drug therapy.119 Removal of phytanic acid can prevent or reverse neurologic manifestations in Refsum disease.120 Plasma exchange can also remove excessive levels of low molecular weight drugs, toxins, and hormones that are bound to plasma proteins.121,122 and 123
NORMAL FACTOR REPLACEMENT
Conceptually, one could use plasma exchange (normal plasma for the patient’s deficient plasma) to correct a deficiency of any plasma factor that is not available in a concentrated form. Plasma exchange can achieve higher levels (theoretically 65 percent of normal with a one-plasma-volume exchange) than simple plasma infusion, without inducing volume overload.
Thrombotic thrombocytopenic purpura responds to plasma exchange, but only if the replacement fluid is normal plasma.124,125 and 126 Some patients will respond to simple plasma infusion, but results of treatment are better with plasma exchange,127 suggesting that replacement of a deficient plasma factor is an important element of the therapeutic effect. The missing factor may be a specific protease, active in limiting the size of circulating von Willebrand factor multimers, which is absent from the plasma of patients.128,129 and 130 In adult patients with idiopathic “acquired” thrombotic thrombocytopenic purpura, the deficiency may be due to an IgG inhibitor, most likely an autoantibody,129,130 removal of which would be an additional mechanism for the beneficial effect of plasma exchange.
Repletion of coagulation factors is part of the rationale for use of plasma exchange to support patients with acute liver failure until recovery or liver transplantation.131
RED CELL EXCHANGE
Most red cell exchanges are done for patients with complications of sickle cell disease. Simply stated, the goal of exchanging patient cells for cells containing hemoglobin A is to create a hemoglobin mixture approximating sickle trait cells and to interrupt thereby the vicious cycle of sickling, stasis, and progressive hypoxia.132 The proportions of hemoglobins A and S needed to accomplish this are not known with certainty, but many exchanges aim for a posttreatment hemoglobin A level above 70 percent so that a level above 50 percent will persist for several weeks. Exchange may be indicated in severe crises such as stroke,133,134 chest syndrome,135,136 cholestasis,137,138 and priapism.139,140 Exchange in the last condition is sometimes associated with neurologic events occurring up to 11 days later.141 Although not indicated for simple pain crisis,142 prophylactic exchange may prevent future events for patients with frequent or overlapping crises. Prophylactic red cell exchange has been recommended for pregnant patients143,144 and prior to general anesthesia,145 but both of these indications are currently considered controversial.146,147 and 148
In other applications, red cell exchange may be employed to lower parasite load in severe falciparum malaria149,150 and babesiosis.151,152 Exchange of red cells for a plasma substitute can be used to lower hematocrit rapidly, yet without hypovolemia, in polycythemic states153 and to deplete iron more rapidly than simple phlebotomy in hemochromatosis.154 Finally, exchange of plasma for red cells can rapidly raise the hematocrit without producing hypervolemia.155
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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