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776 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 777

Cord blood and HLA haploidentical transplantation have been morbidity and mortality when compared to transfused thalassemic
used in a small number of patients with SCD, but graft failure remains patients and nontransfused SCD patients. 389
a significant issue. 371,375,376 Diagnosing significant iron overload accurately and early can be
difficult. Serum ferritin is an easy, widely employed method, but is unre-
liable in SCD as it is an acute phase reactant. Its measurement can result
Transfusion in over- or underestimation and is poorly correlated to liver iron con-
Red cell transfusions are used frequently in SCD on an acute or chronic tent. A serum ferritin value of greater than 1000 mg/mL in the steady-
390
basis. The rationale for transfusion in SCD is twofold. Besides increas- state has been used as an indication of iron overload. Liver iron content
ing Hb concentration, thereby increasing the oxygen-carrying capacity is the current accepted standard and a value of 7.7 mg/g dry weight
of the blood, transfusion also decreases the percentage of circulating is used as indication for treatment. However, noninvasive methods
391
HbS-containing red cells. Hb level alone should not constitute an indi- of assessment of iron overload, like superconducting quantum interfer-
cation to transfusion as patients adapt to their level, making it impor- ence device (SQUID) or MRI T2* (Chap. 43), are becoming standard.
tant to know the patient’s baseline Hb concentration. It is also important Transfusion of 120 mL of red blood cells/kg of body weight can also be
to calculate whether the reticulocyte count, a measure of marrow red used as a chelation trigger. 382
cell production, is adequate or not. Iron chelation (Chap. 43) was typically carried out with desferri-
Indications for red cell transfusion include symptomatic anemia, oxamine at a dose of 25 to 40 mg/kg per day given over 8 hours sub-
ACS, stroke, aplastic and sequestration crises, other major organ dam- cutaneously. Desferrioxamine can reverse cardiac iron overload. A
392
age secondary to vasoocclusion, and occurrence of unrelenting pri- once-daily oral iron chelator, deferasirox, is now approved and available
apism. Transfusion is also required prior to major surgery or surgery for use in the United States. It is a tridentate ligand that binds iron with a
involving critical organs. The best-established indication for chronic high affinity in a 2:1 ratio. It has a half-life of 8 to 16 hours and is metab-
transfusion is stroke and an abnormal TCD velocity. Patients with other olized by glucuronidation and excreted in the feces. In an open-label
chronic or recurrent events are sometimes placed on chronic transfu- phase II trial of deferasirox versus desferrioxamine in a 2:1 random-
sion as well. Inappropriate indications for transfusion include chronic ization, safety and tolerability were established. Nausea and vomiting,
steady-state anemia, uncomplicated VOE, pregnancy, minor surgeries, abdominal pain, rash, reversible increase in liver function tests, and
infection, and avascular necrosis. 377 stable increases in serum creatinine were reported. Rare cases of ana-
378
Simple red cell or exchange transfusion can be used. Simple phylaxis occurring mostly in the first month of starting treatment have
transfusion is easier to perform and is generally associated with fewer also been reported. Postmarketing reports suggest an increased inci-
complications. Exchange transfusion, however, has the advantage of not dence of renal failure, and caution is to be exercised in a patient pop-
raising total Hb, and thereby blood viscosity, while decreasing percent- ulation where renal insufficiency may not be readily appreciated prior
age of circulating sickle cells because sickle cell patients transport less to starting treatment. Postmarketing experience has also reported cases
oxygen to their tissues beyond a hematocrit of 30 percent as a result of fatal hepatotoxicity and agranulocytosis. Auditory and ophthalmic
of increased blood viscosity. 379–381 Exchange transfusion has also the side effects occur in less than 1 percent of patients; however, annual eye
advantage of not causing iron overload. and auditory examinations are recommended for deferasirox as they are
Alloimmunization occurs in 20 to 50 percent of transfused SCD for desferrioxamine. The recommended daily dose is 20 mg/kg body
patients. 382–384 In the United States, the majority of blood donors are weight; this dose may be adjusted every 3 to 5 months in increments of
of European descent, and the majority of SCD patients are of African 5 to 10 mg/kg if the therapeutic goal is not achieved, although the total
descent (Chaps. 136 and 138). This results in blood group antigenic dis- dose should not exceed 40 mg/kg. Safety in combination with other iron
parity, and antibodies to E, C, K, Jkb, S, and Fyb antigens are common. chelators has not been established. Deferiprone is not available in the
393
Age at first transfusion, total number of transfusions, transfusion in the United States but has been used in other parts of the world. It is orally
context of inflammation, and influence of immunoregulatory genes may administered and is considered a better chelator of cardiac iron because
384
affect the rate and extent of alloimmunization. Extended antigen phe- of its ability to cross cell membranes. Although iron chelation in SCD
394
notyping (Kell, Duffy, Kidd, Lewis, Lutheran, P, and M&S) in addition follows the general guidelines of iron chelation in other iron overloaded
to the usual ABO and D antigens (Chaps. 136 and 138) and leukodeple- populations, rigorous studies of its effects on morbidity and mortality
tion of blood products are recommended. 378,382,384,385 Delayed hemolytic in SCD are lacking. 394,395
transfusion reaction complicates 4 to 11 percent of transfusions in
386
SCD and may present as a painful crises. It typically occurs a week after Evolving Therapies
transfusion and is caused by alloantibodies to non-ABO antigens. It can Given the complex pathophysiology of SCD, numerous therapies tar-
cause the Hb to fall lower than the prior pretransfusion Hb and can geting different pathways have been tried to ameliorate disease manifes-
be associated with a depressed reticulocyte count and autoantibodies. tations. Many drugs have failed to show efficacy, especially in phase II/
Alloantibody mediated hemolysis will present as a rapid decrease in the III trials, because of failure to choose appropriate end points or because
percent of HbA as opposed to HbS. A failure to demonstrate a new allo- they were too narrowly focused. Table 49–4 is a comprehensive list of
antibody posttransfusion should not exclude the diagnosis of delayed trials and their outcomes. A few of the novel and promising studies are
hemolytic transfusion reaction (Chaps. 136 and 138). Patients should with immunomodulatory agents (thalidomide/pomalidomide), E- and
be transfused only if symptomatic under such circumstances as further P-selectin inhibitors, iNKT agonists, and Aes-103, and all are in trials
transfusion can exacerbate the problem. 377,384 as of this writing.
Iron overload and its attendant complications and infection trans-
mission are the other major complications of transfusion.
OTHER ABNORMAL HEMOGLOBINS
Iron Overload The number of Hb variants discovered to the time of writing this chap-
Iron overload (Chap. 43) in SCD is similar to other chronically trans- ter totals 1187. The vast majority of these variants are benign, without
fused populations. 169,387,388 The multicenter study of the iron overload any significant clinical or hematologic problems, but are of interest to
research group showed that transfused sickle cell patients had increased geneticists and biochemists (http://globin.cse.psu.edu). Most of the

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