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428 Part V: Therapeutic Principles Chapter 28: Therapeutic Apheresis: Indications, Efficacy, and Complications 429

TABLE 28–1. Indication Categories for Therapeutic 37°C. They can be isolated monoclonal immunoglobulins (type I), a
mixture of immunoglobulins including a monoclonal component that
Apheresis According to the American Society for Apheresis
exhibits antibody activity toward polyclonal IgG (type II) or mixed
Category Definition of Category polyclonal immunoglobulins of one or more classes (type III). Whereas
I Apheresis is an accepted first-line therapy for these type I cryoglobulinemia is largely associated with lymphoproliferative
disorders. disorders, and type III with chronic infections or autoimmune disor-
ders, type II is almost always associated with infection with hepatitis
II Apheresis is an accepted second-line therapy for
these disorders. C. Clinical sequelae may include purpura, arthralgia and arthritis, Ray-
naud phenomenon, peripheral sensory or sensorimotor neuropathy,
III Individualize decision making. The optimal role of nephropathy, skin ulcers, or widespread vasculitis. 20,21 The removal of cryo-
apheresis has not been conclusively determined in globulins by plasma exchange can be effective in treating the renal, vaso-
these disorders.
motor, vasculitic, and neurologic manifestations of cryoglobulinemia, 22–24
IV Published evidence indicates that apheresis is but medical treatment of the underlying disorder with which the cryoglob-
ineffective or harmful in these disorders. Seek ulinemia is associated is also necessary for a persistent good result.
institutional review board approval if apheresis is
planned. Myeloma Cast Nephropathy
Myeloma cast nephropathy (“myeloma kidney”) results from combina-
Adapted with permission from Schwartz J, Winters JL, Padmanabhan tion of free light chains with Tamm-Horsfall mucoprotein in the distal
A: et al: Guidelines on the use of therapeutic apheresis in clinical nephron and the resultant precipitation of obstructing casts. A number
25
practice-evidence-based approach from the Writing Committee of early case reports and small clinical trials suggested that combining
of the American Society for Apheresis: the sixth special issue. J Clin
Apher 28(3):145–284, 2013. plasma exchange with chemotherapy improved the likelihood of recov-
ering renal function in patients with myeloma and renal failure. 26–30 The
largest trial to date (104 participants) was unable to demonstrate a dif-
HYPERVISCOSITY IN MONOCLONAL ference in primary outcome based on the composite measure of death,
2
GAMMOPATHIES dialysis dependence, or glomerular filtration rate below 30 mL/min/1.73 m
at 6 months. The effectiveness and rapidity of modern chemother-
31
Hyperviscosity syndrome in the monoclonal gammopathies (Chaps. 106, apy may have subsumed a salutary effect of plasma exchange. Plasma
32
107, and 109) is caused by impaired blood flow from an increase in vis- exchange is not currently considered to be part of first-line treatment
cosity of blood as a result of immunoglobulin–red cell interactions. 10–12 for myeloma with cast nephropathy, but may be a reasonable option
It is most common in Waldenström macroglobulinemia because of the when renal function does not rapidly improve with chemotherapy. 4
highly red-cell-aggregating properties of immunoglobulin (Ig) M and,
less often, in IgG or IgA myeloma. 13–15 Symptoms typically emerge when THROMBOTIC MICROANGIOPATHIES
serum viscosity rises above 4.0 relative viscosity units (normal being 1.4
to 1.8). 12,16 Although the relevant variable is blood viscosity, the mea- Idiopathic Thrombotic Thrombocytopenic Purpura
surement of serum viscosity is relatively simple and can be used as an Idiopathic thrombotic thrombocytopenic purpura (TTP) is a medical
indicator of risk of symptomatic hyperviscosity. Specific symptoms may emergency that presents with microangiopathic hemolytic anemia and
include headache, dizziness, vertigo, nystagmus, hearing loss, visual thrombocytopenia (Chap. 132). It is typically characterized by central
impairment, somnolence or coma and seizures. In addition, conges- nervous system, cardiac, renal, or other organ impairment as a result
tive heart failure, impaired respiration, coagulation abnormalities, ane- of microvascular obstruction by aggregates of platelets and von Wille-
mia or peripheral neuropathy may be seen. Plasma exchange rapidly brand factor. 33,34 It results from inadequate processing of ultralarge
13
relieves symptoms of hyperviscosity by lowering the plasma content of von Willebrand factor multimers by the enzyme ADAMTS-13. 35,36 In
the responsible paraprotein. 2,3,16,17 acquired, idiopathic TTP, this enzymatic defect is caused by an autoan-
The relationship between monoclonal protein level and serum vis- tibody inhibitor of ADAMTS-13 that results in severe deficiency of the
cosity is nonlinear, therefore a relatively small (20 percent) decrease in enzyme. 35,36 An inherited, relapsing form of TTP results from mutations
37
plasma protein can affect a major change in viscosity. 10,17 This is note- in the ADAMTS-13 gene. TPE, using human plasma as the colloid
worthy in that whereas the removal of plasma proteins during plasma exchange fluid, is the only therapy for TTP that has been demonstrated
exchange from patients without monoclonal proteinemia closely fol- highly effective in a randomized clinical trial. 38,39 It has improved the
lows the predictions of the “one compartment model” (i.e., y = y e −0.94x ), survival rate of TTP from approximately 20 percent to upward of
t
0
8
removal of plasma proteins from patients with monoclonal proteinemia 90 percent, but with a relapse rate over 30 percent. TPE should be ini-
).
deviates from the model by as much as 50 percent (i.e., y = y e −0.5x 18 tiated for a patient who presents with unexplained microangiopathic
t
0
The difference likely relates to the underestimated expansion in plasma hemolytic anemia and thrombocytopenia while awaiting the result of
40
volume that occurs in monoclonal proteinemias. But despite this an assay for ADAMTS-13 level and activity. Of note, hemolytic ure-
7
compromised removal of plasma protein, the nonlinear relationship mic syndrome (HUS), a thrombotic microangiopathy with acute olig-
between serum monoclonal protein level and serum viscosity results in uric or anuric renal failure, is rarely associated with severe deficiency of
plasma exchange remaining highly effective in alleviating clinical man- ADAMTS-13. Shiga toxin-associated HUS does not respond to TPE;
ifestations of hyperviscosity. 19 atypical HUS (i.e., with defects in regulation of the complement system)
has shown only limited responses to TPE and is more appropriately
OTHER PLASMA PROTEIN-ASSOCIATED treated with eculizumab. 40
CONDITIONS Drug-Associated Thrombotic Microangiopathy
Cryoglobulinemia Several drugs are implicated in thrombotic microangiopathies and a
Cryoglobulins are immunoglobulins or complexes of immunoglob- TTP-like syndrome (see Table 28–2). The two most common drugs
ulins that reversibly precipitate when exposed to temperatures below reported to the FDA as associated with TTP are the antiplatelet

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