Page 651 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 40 Thalassemia Syndromes 553

saturation are already increased as a result of increased iron Transfusion Therapy
absorption. 81
The Hb profile reveals predominantly Hb F. In patients with Transfusion therapy for thalassemia was once sparingly administered
homozygous β°-thalassemia, no Hb A is found throughout life. Hb as a palliative measure when patients became symptomatic. These
+
A may be undetectable in the newborn with β -thalassemia and is periodic transfusion regimens were unsatisfactory even for those
present in reduced amounts in later life. The levels of Hb A 2 in thalas- limited purposes; symptoms of anemia and the cosmetic and other
semia major are variable, probably because of increased numbers of consequences of overgrowth of erythropoietic tissue rendered life
1
F cells that have a decreased Hb A 2 content. Other biochemical unpleasant and uncomfortable for patients. Consequently, several
abnormalities of the RBC in cases of thalassemia major include a centers initiated transfusion programs in which patients received
postnatal persistence of the i antigen and a decrease of RBC carbonic regular transfusions to keep their Hb levels high enough to ameliorate
anhydrase; these findings are probably also caused by the elevated these symptoms, 102,103 but the median survival time of patients
levels of circulating F cells. transfused to maintain Hb levels of 7–8 g/dL in the United States in
The intraerythrocytic inclusions in the peripheral blood cells of the 1960s was only 17 years of age. 103,104 So called “hypertransfusion”
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patients with thalassemia, first described by Fessas, are especially programs were designed initially to maintain Hb levels above 8 g/dL.
prominent after splenectomy. These inclusions, best seen by staining In the more modern application of hypertransfusion therapy, Hb
with supravital staining (Brilliant Cresyl Blue) or by phase microscopy, levels are usually maintained above 9–10.5 g/dL.
83
are aggregates of precipitated, denatured α-chains. They are also The clinical benefits of hypertransfusion programs are dramatic.
found in large numbers within erythroid precursors in the BM. The growth of younger children follows normal percentiles for height
105
The patient is icteric; unconjugated bilirubin levels are in the and weight. Erythropoiesis is significantly suppressed as evidenced
range of 2.0–4.0 mg/dL at the time of diagnosis but may rise by decreased numbers of reticulocytes and normoblasts and TfR1
substantially as the anemia worsens in the absence of transfusion. levels. 106,107 Hypertransfusion reduces or prevents the enlargement of
RBC survival in cases of thalassemia major is variable but usually the liver and spleen. Abnormal facies and bone fractures occur less
53
markedly decreased. The Cr half-life ranges between 6.5 and frequently. The overall sense of well-being allows normal age-appropriate
36
19.5 days compared with the normal half-life of 25–35 days. activities 108,109 (see box on Guidelines for Transfusion Therapy).
Increased plasma iron turnover and poor use of radiolabeled iron A more vigorous transfusion program (supertransfusion) aimed at
110
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indicate IE. Serum aspartate aminotransferase levels are frequently keeping Hb levels above 12.0 g/dL is no longer recommended.
increased at diagnosis because of hemolysis. Alanine aminotrans- This approach rested on the assumption that the benefits of further
ferase levels are usually normal before transfusion therapy but may suppression of erythropoiesis and gastrointestinal iron absorption will
rise subsequently because of iron-induced hepatic damage or viral offset the increased need for RBCs. However, several studies have
hepatitis. Lactate dehydrogenase levels are markedly elevated as a demonstrated that transfusion requirements (and therefore the rates
consequence of IE. Haptoglobin and hemopexin are reduced or of transfusional iron loading) increase as the Hb level is raised in both
absent. 84 splenectomized and nonsplenectomized patients (Fig. 40.7). 105,111,112
As a result, the consistent maintenance of Hb levels above 11 or 12 g/
dL results in excessive iron accumulation without proportional clini-
Later Laboratory Findings cal benefit, and supertransfusion protocols should be reserved for
patients with poor tolerance of lower Hb levels because of cardiac
Serum zinc levels may fall to abnormally low levels. A relationship disease or other reasons.
between this finding and growth failure has been postulated but not Alternative approaches to conventional transfusion therapy have
established. 85,86 Low levels of plasma and leukocyte ascorbic acid are been proposed to reduce the rate of transfusion iron loading. These
common in thalassemic patients because of increased metabolism of approaches have generally relied on the concept that younger RBCs
the vitamin to oxalic acid in the presence of iron overload. 87,88 Bio- (neocytes) will circulate longer in the recipient than older RBCs. Pre-
chemical evidence of folic acid deficiency may occur as a result of clinical experiments based on the difference in density between younger
excessive consumption secondary to increased requirements. 89,90 The and older RBCs established the validity of this approach. 113,114 However,
serum levels of α-tocopherol are often reduced to less than 0.5 mg/ in prospective clinical trials, blood requirements were reduced only by
dL, and increased RBC membrane lipid peroxidation has been 13% to 20%. 115–117 This reduction in iron loading did not outweigh
described. 91–93 the disadvantages of neocyte transfusions that included increased cost,
Coagulation abnormalities consistent with liver disease (i.e., wastage of 50% of the donor RBCs, and increased donor exposures.
lowered levels of factors II, V, VII, IX, and X) may occur in older The use of automated exchange transfusion has been proposed as
94
patients with hepatitis or iron-induced hepatic injury. Only rarely another approach to reducing iron loading in patients with thalasse-
118
are the abnormalities sufficient to require specific therapy. However, mia. With this method, RBCs are removed from the patient at the
the combination of mild thrombocytopenia from hypersplenism and
low coagulation factors and platelet dysfunction from liver disease
may cause or aggravate bleeding. 95 Guidelines for Transfusion Therapy
Numerous laboratory abnormalities reflect the accumulation of
excessive iron and the consequences of iron-induced organ damage, Although some of the details of a transfusion program for patients with
and they are described in the following sections. thalassemia major vary from center to center, the following guidelines
are important for achieving the benefits while controlling the risks of a
transfusion program. The rationales for these guidelines are discussed
Treatment in the text.
1. Obtain a complete RBC antigen profile before the first
transfusion.
The advent of modern therapy has had a major impact on the clinical 2. Administer 10–15 mL/kg of RBCs every 2–4 weeks to maintain
and laboratory features of thalassemia major. Transfusion and chela- the pretransfusion hemoglobin level above 9–10.5 g/dL.
tion therapy, described subsequently in detail, have ameliorated many 3. Use packed leukoreduced RBCs that have been stored for less
of the most striking manifestations of the disease. Bone marrow than 7–10 days.
transplantation (BMT) has allowed for the cure in some patients. 4. Avoid the use of first-degree relatives as blood donors.
However, these therapies have created their own complications; 5. For patients who come to a new center after receiving
therefore, this section addresses the treatment of the complications transfusions elsewhere, contact the previous blood bank for
of thalassemia and its therapy. Current clinical management and information about alloantibodies and transfusion reactions.
associated clinical manifestations and complications have been RBC, red blood cell.
reviewed in a number of publications. 96–101