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838 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 839

THERAPY OF WARM-ANTIBODY AUTOIMMUNE Continuation of hemolysis after splenectomy is partly related to persist-
HEMOLYTIC ANEMIA ing high levels of autoantibody, favoring RBC destruction in the liver by
hepatic Kupffer cells.
169,171,174
Glucocorticoids Several investigators noted the amount of RBC-bound autoanti-
Therapy with glucocorticoids has reduced the mortality associated with body decreased in AHA patients following splenectomy. 10,309,313 How-
severe idiopathic warm-antibody AHA. Glucocorticoids were first used ever, a significant proportion of patients show no change in cell-bound
308
for this disorder more than 60 years ago. Glucocorticoids can cause autoantibody following splenectomy. The processes determining the
dramatic cessation or marked slowing of hemolysis in about two-thirds rate of autoantibody production are poorly understood. The beneficial
of patients. 10,11,123,309,310 Approximately 20 percent of treated patients effect of splenectomy may be related to several factors interacting in
with warm-antibody AHA achieve complete remission. Approximately complex fashion. 314
10 percent show minimal or no response to glucocorticoids. The best A patient’s clinical data constitute the best selection criteria for
responses are seen in idiopathic cases or in those related to SLE. splenectomy. Attempts to select potential responders by Cr RBC
51
Most patients should be treated with oral prednisone at an initial sequestration studies have been disappointing. 10,309,315 In most cases, a
daily dose of 1 to 1.5 mg/kg (e.g., 50 to 100 mg). Critically ill patients reasonable approach is to continue glucocorticoids for 1 to 2 months
with rapid hemolysis may receive intravenous methylprednisolone 100 while waiting for a maximal response. However, if no response is noted
to 200 mg in divided doses over the first 24 hours. High doses of pred- within 3 weeks, the patient’s condition deteriorates, or the anemia is
nisone may be required for 10 to 14 days. When the hematocrit sta- very severe, splenectomy should be performed sooner.
bilizes or begins to increase, the prednisone dose can be decreased in Results of splenectomy are variable. Approximately two-thirds
rapid-step dose reductions to approximately 30 mg/day. With continued of AHA patients have a partial or complete remission following sple-
improvement, the prednisone dose can be further decreased at a rate of nectomy. 309,314 However, the relapse rate is disappointingly high. Many
5 mg/day every week, to a dose of 15 to 20 mg/day. These doses should patients require further glucocorticoid therapy to maintain acceptable
be administered for 2 to 3 months after the acute hemolytic episode has hemoglobin levels, although often at a lower dose than required prior to
subsided, after which the patient can be weaned from the drug over 1 splenectomy. 10,123,309 Alternate-day therapy is preferable to daily therapy
to 2 months or treatment switched to an alternate-day therapy schedule in these cases if adequate control of the anemia can be achieved.
(e.g., 20 to 40 mg every other day). Alternate-day therapy reduces glu- The immediate mortality and morbidity from splenectomy depend
cocorticoid side effects but should be attempted only after the patient upon the presence of underlying disease and the preoperative clinical
has achieved stable remission on daily prednisone in the range of status but generally are quite low. Following splenectomy, children,
316
15 to 20 mg/day. Therapy should not be stopped until the DAT becomes more than adults, have an increased risk for developing sepsis as a result
negative. Although many patients achieve full remission of their first of encapsulated organisms. Vaccination against H. influenzae type b
317
hemolytic episode, relapses may occur after the glucocorticoids are dis- and pneumococcal and meningococcal organisms is recommended at
continued. Consequently, patients should be followed for at least several least 2 weeks prior to surgery (Chap. 56). 318
years after treatment. A relapse may require repeat glucocorticoid ther-
apy, splenectomy, or immunosuppression. Rituximab
Occasionally, patients who present with only a positive DAT, min- Rituximab is a monoclonal antibody directed against the CD20 antigen
imal hemolysis, and stable hematocrit require no treatment. However, expressed on B lymphocytes and is used for treatment of B-cell lym-
these patients should be observed for clinical deterioration because the phoma. Its use for treatment of AHA is based on the antibody’s ability
rate of RBC destruction may increase spontaneously. to eliminate B lymphocytes, including, presumably, those making auto-
Glucocorticoids may influence hemolysis in warm-antibody AHA antibodies to RBCs. However, the mechanism of action is more com-
by several mechanisms. Earlier investigators noted that hematologic plex than that, as the effect of rituximab can occur very early, before the
improvement was often, but not always, accompanied by reduction in autoantibodies can recede. In fact, sometimes in responding patients,
10
the strength of the DAT. The subsequent observation of a decrease in autoantibody levels are not significantly affected. 319,320 Opsonized B
cell-bound and/or free serum autoantibody during stable glucocorti- lymphocytes may decoy effector monocytes and macrophages from
coid-induced remission suggested improved RBC survival following autoantibody complexes and normalize autoreactive T lymphocyte
treatment with glucocorticoids resulted from a decrease in synthesis of responses. 319
anti-RBC autoantibodies. 169,252 However, this finding cannot explain why Rituximab was used initially in refractory AHA either unrespon-
glucocorticoid-treated patients often improve within 24 to 72 hours, a sive to or relapsed after oral glucocorticoid therapy. In a prospective
time much shorter than the half-life of anti-RBC autoantibody. Rather, series, 13 of 15 children with warm-antibody AHA responded to
321
glucocorticoids may suppress RBC sequestration by splenic macropha rituximab 375 mg/m weekly for 2 to 4 weeks, intravenously. Other
2
ges. 171,172,183,311 A quantitative decrease in one of the three known classes case series support the use of similar doses of rituximab in adults, with
of Fcγ receptors 170,171 has been observed in the blood monocytes of AHA response rates ranging from 40 to 100 percent. 320,322 Another prospec-
patients during glucocorticoid therapy. 312
tive study in adults exhibited a 100 percent response using rituximab
100 mg/m weekly for 4 weeks along with a short course of oral gluco-
2
Splenectomy corticoid as first- or second-line therapy. Sustained responses were
323
Nearly one-third of patients with warm-antibody AHA require pred- observed at 3 years in more than two-thirds of the cases. 324
nisone chronically in doses greater than 15 mg/day to maintain an A phase 3 randomized controlled trial compared glucocorticoid
2
acceptable hemoglobin concentration. These patients are candidates for monotherapy versus glucocorticoid and rituximab 375 mg/m as first-
325
laparoscopic splenectomy. line therapy in patients with warm-antibody AHA. The complete and
Splenectomy removes the primary site of RBC trapping. Investiga- partial response rates were similar (approximately 50 percent) in the
169
171
tions in human and animal subjects confirm that maintenance of a two groups at 3 and 6 months. At 12 and 36 months after randomization
given rate of RBC destruction requires 6 to 10 times more RBC-bound the relapse-free survival was superior for the combination of glucocor-
IgG in splenectomized subjects than in nonsplenectomized subjects. ticoids and rituximab.

Kaushansky_chapter 54_p0823-0846.indd 838 9/19/15 12:28 AM