Page 2498 - Hematology_ Basic Principles and Practice ( PDFDrive )

2230 Part XIII Consultative Hematology

factor H or I deficiency. However, other genetic abnormalities of the agents as well. In a study of children after liver transplant, half of the
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complement system are not associated with this high rate of recur- cases of anemia were attributed to ISD. The diagnosis was usually
rence. Genetic screening is recommended before transplant, not only made by excluding other causes of anemia and on the basis of evidence
to determine risk but also to develop posttransplant management of resolution of the anemia after a change in the ISD dose or switch-
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plans (see later). ing to an alternative drug (median time for resolution, 4 months).
The calcineurin inhibitors CsA and tacrolimus (TAC) have trig- In a study of children and young adults after cardiothoracic
gered the HUS in all of the nonrenal transplant cases and half of the transplant, approximately 25% of the cases of anemia were attributed
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renal transplant cases. Sirolimus alone and especially in combination to TAC, primarily because no other cause was found. The nadir
with cyclosporin has been associated with development of thrombotic hemoglobin in these patients was 7.3 to 8.8 g/dL, with reticulocytes
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microangiopathy. The possibility of an infectious trigger has been ranging from 1.5% to 6.7%. Only one patient had a direct antiglobu-
suggested for the development of MAHA. lin study performed, and the results were negative. Four of five
Treatment consists of discontinuing or decreasing the dose or patients with simultaneous anemia and neutropenia recovered counts
switching the calcineurin inhibitor. Plasma exchange is an unproven within 5 weeks of switching to CsA. In another study of 50 pediatric
therapy. The outcome for graft survival is 60% for de novo HUS but renal transplant patients, the prevalence of anemia was 60%, with
only about 33% for recurrent HUS. In children who undergo trans- 30% having hemoglobin levels below 10 g/dL. The TAC dose was
plants for atypical HUS, especially those with a known high-risk found to be significantly associated with the presence of anemia. 328
genetic mutation, perioperative plasma exchange and the use of the The association of PRCA and TAC was first reported in adults.
terminal complement inhibitor eculizumab have shown promising Two children were reported to develop PRCA while taking TAC 8
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efficacy in preventing HUS recurrence. Eculizumab has been and 47 months after liver transplant. Neither had evidence of
approved by the US Food and Drug Administration for the treatment parvovirus B19 infection. When there was no evidence of spontane-
of pediatric and adult patients with atypical HUS. ous recovery after 2 to 3 months of observation, they were switched
from TAC to CsA, and both recovered within 3 weeks. Of interest,
in a study of adults after liver transplant, erythropoietin production
Late Posttransplant Anemia was found to be reduced in patients receiving cyclosporin but not
TAC. 330
Anemia occurring more than 6 months after transplant is termed late There are a number of case series of AIHA associated with the use
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posttransplant anemia. Causes of late anemia that are common to all of TAC and other ISDs in both children and adults. AIHA has
solid organ transplants include the following 312–314,316,318 : been seen after liver, small bowel, multivisceral, kidney, and heart
transplants. Onset of severe anemia has occurred from 2 months to
1. Infection with viruses, particularly EBV and parvovirus, and, many years after transplant. The direct antiglobulin test has revealed
more rarely, CMV warm, mixed, or cold antibodies. The common finding in all cases
2. Drug effect caused by myelosuppression, hemolytic anemia, or was use of TAC immunosuppression, although other ISDs were also
other drug effects (e.g., trimethoprim/sulfamethoxazole, dapsone) used in a few cases. Treatment was variable, including corticosteroids,
3. Rejection or PTLD IVIg, plasmapheresis, rituximab, and splenomegaly. TAC was discon-
4. Anemia of chronic disease tinued in many cases with replacement by alternative ISDs, including
5. Iron deficiency cyclosporine or sirolimus. Resolution of the AIHA was the usual
6. Acute renal failure outcome with some rapid and apparently sustained responses to
7. Uncommon or multifactorial rituximab and switching to an alternative ISD. 332–336
Nonimmune hemolysis has also been documented in adults. In a
Etiologies of late anemia in the renal transplant setting include end- retrospective study of 81 patients (median age, 39 years; range, 12 to
stage renal disease or low erythropoietin levels (68% of patients will 66 years) after lung transplant, 20% developed hemolytic anemia in
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have levels <2 standard deviations below the norm). After renal the first year after transplant. All were taking CsA, and none
transplant, young children have less anemia than older children and received TAC. The anemia was mild to moderate; there was no evi-
young adults. This may be because of the large donor kidney with dence of autoantibody formation or MAHA; and other causes of
higher erythropoietin levels and creatinine clearance relative to the anemia were excluded. The researchers in that study postulated an
size of the patient. auto- or alloimmune mechanism to explain this phenomenon.
Risk factors for chronic anemia in children after liver transplant Anemia has been reported to be associated with all of the currently
were determined in a cohort of 1026 children followed prospec- used ISDs, including mycophenolate mofetil (MMF) and sirolimus.
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tively. The late anemia in this group was mild to moderate, with a Although direct comparison of all of the drugs has not been per-
mean hemoglobin of 10.24 g/dL. In multivariate analysis, the follow- formed, it appears that TAC and CsA are associated with a similar
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ing factors were found to be significantly associated with chronic incidence of anemia, occurring less commonly with the other drugs.
anemia: One possible mechanism of the development of autoimmune anti-
bodies posttransplant is the chronic T-cell suppression resulting from
1. History of GI bleeding the use of these agents followed by release of B-cell control. As noted
2. Leukopenia earlier, treatment has been empiric and has included the standard
3. CsA-based therapy treatments for AIHA, including rituximab. Reduction in dose or
4. Glomerular filtration rate less than 90 mL/min/1.73 m 2 switching the type of the ISD appears to be an effective therapy.
5. Corticosteroid use
6. Antihypertensive drug use Pure Red Blood Cell Aplasia Associated
With Parvovirus B19
PRCA was initially reported in adults in 1986, and multiple reports
Immunosuppressant Drugs have been published since then. Authors of a review of the literature
There is a wide variation—1% to 53%—in the reported incidence in 2006 reported 91 cases of parvovirus B19 infection posttransplant
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of anemia secondary to ISDs. This variation may be a result of the in adults. Seventy-four were in solid organ recipients, with the
lack of a specific test for drug-associated anemia and the lack of majority after kidney transplant (71%), followed by heart–lung
prospective studies. Indirect evidence for the association, however, is transplant (16%) and then liver transplant (12%). Ninety-nine
quite strong—that is, the ISD is stopped or changed and the anemia percent of the patients were anemic, and one-third also had leukope-
improves. There is a clear association of HUS/MAHA with the ISDs nia and 18% also had thrombocytopenia. The average time to onset
CsA and TAC in the early posttransplant period, but a number of was 1.75 months posttransplant, with a range of 1 week to 96
studies have documented the association of late anemia with these months. The most reliable test to diagnose infection was the