Page 700 - Hematology_ Basic Principles and Practice ( PDFDrive )

592 Part V Red Blood Cells

accomplished during routine visits. Parents of small children are may include increased inflammation-mediated suppression of
instructed regarding early detection of infection and palpating enlarg- erythropoiesis. 91
ing spleens. EPO therapy is probably not indicated in patients receiving
chronic transfusion therapy in whom encouraging endogenous Hb S
containing erythropoiesis may be counterproductive.
Phlebotomy

As mentioned, an Hb level of more than 10–11 g/dL (hematocrit Iron Chelation
30%) in the presence of substantial amounts of Hb S (>30%)
is associated with hyperviscosity. Some data indicate that phle- Early death is well described in association with iron overload from
botomy to reduce the hematocrit and viscosity (and which may β-thalassemia and hereditary hemochromatosis. 92,93 Similarly, iron
also address iron-overload) can decrease the frequency of crises in overload is likely to be a problem in chronically transfused patients
+
85
Hb SC or Hb S–β disease. In Hb SS disease, phlebotomy has with SCD, although the clinical significance may critically depend
successfully been used in combination with HU (which increases on the degree and duration of overload. Chelation guidelines for
the Hb level) in secondary stroke prevention in patients previously patients with SCD are similar to those for other chronically trans-
86
treated with chronic transfusion. Phlebotomy alone has also been fused, iron-overloaded patients; iron chelation is indicated when the
used in Hb SS disease with baseline Hb levels of more than 9.5 g/ total body iron level is elevated (ferritin >2000 µg/L, quantitative
dL with favorable results on the frequency and duration of pain liver iron of 2000 µg/g dry weight, transfusion history >1 year of
94
crises. This benefit may have resulted from decreased hematocrit monthly transfusions). Notably, the serum ferritin level may under-
and viscosity and from a decrease in intracellular Hb concentra- estimate clinically significant iron overload. 95,96 Iron chelation options
87
tion from iron deficiency. One approach to phlebotomy is to in the United States are deferoxamine (via continuous intravenous or
remove approximately 10 mL/kg of blood over 20–30 minutes fol- subcutaneous infusion), deferasirox (orally), and deferiprone. There
lowed by infusion of an equal volume of normal saline. This is is some data to support greater effectiveness of the oral agents, in
repeated every 2 weeks until the target Hb level of 9–9.5 g/dL is particular deferiprone, in cardiac iron unloading, and together with
achieved. the oral route of administration and toxicity profile, deferasirox or
deferiprone are favored over deferoxamine. 97–99
Newer US Food and Drug Administration (FDA)–approved
Erythropoietin or Darbepoetin methods of quantitating iron burden by Ferriscan of the liver can
100
avoid the need for liver biopsies. T2-weighted MRI of the heart
The chronic hemolytic anemia of SCD is partially compensated by indicates hemosiderosis of cardiac tissue, and when the results are
vigorous reticulocytosis. A decrease in compensatory reticulocytosis abnormal, aggressive chelation is mandated. 101
will exacerbate already existent anemia and can be expected to increase
clinical risk. Accordingly, chronic relative reticulocytopenia (defined
9
−1
as Hb <9 g/dL and absolute reticulocyte count <250,000 × 10 L ) Alternatives to Hydroxyurea for Hb F Induction
was identified as a significant risk factor for early mortality in a
prospective cohort study of patients with SCD. 88 Alternatives to HU for pharmacologic induction of Hb F that are
In the general population, evaluation of EPO levels is usually being studied in clinical trials include the methyltransferase inhibitor
prompted by the combination of anemia and abnormal serum creati- 5-aza-2′-deoxycytidine (decitabine) and histone deacetylase inhibi-
102
nine level. EPO levels are then interpreted in relationship to the Hb tors. These classes of agents act on chromatin processes that regulate
level to assess for the possibility of EPO deficiency. In patients with gene transcription.
SCD, this approach to diagnosis has pitfalls. Patients with SCD are The methyltransferase inhibitors 5-azacytidine and 5-aza-2′-
already anemic; therefore, gradual anemia exacerbation is easily deoxycytidine have produced the largest increases in Hb F of any of
missed, and clinicians must weigh many possible causes in the context the pharmacologic reactivators of Hb F that have been tested. 103,104
of complex, multisystem SCD pathology. Furthermore, patients with Responding patients include those who did not respond to HU,
SCD have low serum creatinine levels at baseline. Therefore a sub- consistent with a different mechanism of action. Although improve-
stantial increase in serum creatinine from baseline may nonetheless ments in a number of surrogate clinical endpoints have been dem-
remain below the threshold defined as abnormal for the general onstrated, larger studies to confirm safety and clinical effectiveness
population, potentially disguising the presence of renal damage that with chronic use are required. In the United States, 5-azacytidine and
is sufficient to decrease renal endocrine function. Furthermore, EPO decitabine have been approved by the FDA for the treatment of
levels are not readily interpreted in the individual patient with SCD: myelodysplastic syndrome. The efficacy of the class of agents known
89
EPO levels in SCD are generally low for the level of Hb. One as histone deacetylase inhibitors in Hb F reactivation has been
contributing factor could be increased uptake by the massive com- reviewed. 104–106 As per the methyltransferase inhibitors, further clini-
pensatory reticulocytosis. However, EPO levels are lower in SCD cal trials are needed. Other classes of drugs being evaluated for
89
adults than in children, and EPO levels are inappropriately lower potential Hb F reactivation are the “imid” class of drugs (analogues
19
in patients with chronic relative reticulocytopenia. Hence, EPO of thalidomide such as pomalidomide) and inhibitors of lysine
deficiency should be considered as a possible cause of progressive demethylase (LSD1/KDM1A). 107
anemia in patients with absolute reticulocyte counts below 250,000
−1
9
× 10 L even if their serum creatinine levels are in the normal range.
The cumulative published experience of EPO use in SCD is limited Preventing Red Blood Cell Dehydration With Ion
90
(52 patients). Although EPO by itself has been reported to increase Channel Inhibitors
Hb F levels, the most important role for EPO may be as replacement
therapy for EPO deficiency that causes relative reticulocytopenia and Polymerization of Hb S is related to the Hb S concentration within
progressive anemia. EPO replacement can also facilitate enhanced the cell. Therefore a therapeutic strategy could be to reduce the
90
HU dosing and Hb F augmentation. In using recombinant human intracellular Hb S concentration. It is possible to reduce the Hb
EPO, caution must be exercised not to elevate the hematocrit to levels concentration by reducing the Hb content with iron deficiency. It
that result in hyperviscosity. Also, the reticulocyte fraction is the most has been observed that spontaneous or induced iron deficiency (see
adhesive, and it is possible that EPO could exacerbate or trigger sickle Phlebotomy, earlier) sufficient to reduce the serum ferritin, MCV,
90
cell crises. Patients with SCD may be relatively resistant to EPO and mean cell Hb concentration (MCHC) resulted in variably
and require doses higher than those used in other patients with improved Hb S polymerization, RBC survival, level of anemia, and
chronic renal failure. The reasons for EPO resistance are unclear but clinical status. 108