Page 784 - Hematology_ Basic Principles and Practice ( PDFDrive )

670 Part V Red Blood Cells

is occupational exposure. Symptoms are predominantly neurologic ITPA activity and accumulation of inosine triphosphate in red
and nephrologic, with variable degrees of anemia, which may be blood cells. The mechanism of this protective effect is not yet fully
caused by a production defect combined with hemolysis. Relatively understood. The anemia in patients treated with ribavirin may
acute poisoning occurs when lead inadvertently finds its way into a be exacerbated by concomitant treatment with pegylated IFN,
food source or is consumed as part of an exotic medication. Subacute which suppresses hematopoiesis, and may also be associated with
lead poisoning leads to central nervous system symptoms, hepatitis, autoimmune hemolytic anemia. Anemia may also be exacerbated
nephrotoxicity, hypertension, and abdominal colic along with seizures when ribavirin and IFN are used in combination with the protease
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and severe hemolytic anemia. Physical examination may reveal a lead inhibitor, a regimen that is efficacious in the treatment of genotype
line on the gums. Peripheral smear shows extensive coarse basophilic 1 disease.
stippling and reticulocytosis; however, RBC morphology is not oth-
erwise characteristic. Some researchers state that intravascular
destruction occurs, but no proof has been provided. Bilirubin levels DRUG-INDUCED OXIDATIVE HEMOLYSIS
are not significantly elevated.
The diagnosis of lead-related hemolysis can be made from the General Concepts
history and findings on physical examination, which include a lead
line on the gingiva and coarse basophilic stippling on RBCs, which The potential for normal RBCs to undergo auto-oxidative destruc-
reflects the pathologic aggregation of ribosomes. The diagnosis is tion is great because the cell is loaded with 20-mM hemoglobin, most
confirmed by measuring blood and urine lead levels. The level of of which is bonded to oxygen at the iron(II) atom in heme. The bond
acuity determines the therapy. that allows the reversible association and dissociation of oxygen from
The cause of the anemia is complex. Lead interferes with several the heme moiety of hemoglobin involves partial transfer of an electron
steps in heme synthesis, particularly those involving heme synthetase from iron(II) to oxygen. That oxygen then has an extra electron,
and δ-aminolevulinic acid dehydratase (see Chapter 38). The inhibi- which makes it a superoxide radical. Ordinarily, when oxygen leaves
tion of heme synthetase probably accounts for the elevation in free hemoglobin, it returns the electron. If it does not, a highly reactive
erythrocyte protoporphyrin, which provides a useful corroborative superoxide ion is released, leaving behind it an iron(III) moiety called
diagnostic test for lead toxicity. Inhibition of heme synthesis also methemoglobin.
probably accounts for the elevated urinary levels of δ-aminolevulinic
2+
3+
acid and coproporphyrin. Lead poisoning mimics the basophilic Hb Fe O 2 → Hb Fe + O 2 − 1
stippling and accumulation of pyrimidines seen in hereditary defi-
ciency of the enzyme pyrimidine 5′-nucleotidase, probably because Methemoglobin cannot reversibly bind oxygen. Methemoglobin in
lead attacks the enzyme (see Chapter 44). itself is not harmful to RBCs, but if the oxidative assault persists,
methemoglobin is converted to hemichromes, which are variably
denatured hemoglobin intermediates in which the distal histidine
Ribavirin unit binds to the oxidized heme. This step is associated with conver-
sion from a high to a low spin state, as measured by electron spin
Current treatment of chronic hepatitis C virus (HCV) infection may resonance. Continued oxidation leads to irreversibility of hemichrome
consist of combination therapy with pegylated interferon (IFN) and oxidation, precipitation, and eventually formation of Heinz bodies.
ribavirin, a nucleoside analogue. Ribavirin’s activity against HCV Hemichromes and Heinz bodies can destroy membrane function
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includes inhibition of inosine monophosphate dehydrogenase, a key directly or by causing oxidation of membrane proteins and lipids.
step in de novo guanine synthesis. Treatment with ribavirin may Approximately 3% of hemoglobin is converted to methemoglobin
produce dose-dependent hemolytic anemia, which is typically revers- each day, but the finding that only 1% of hemoglobin normally is in
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ible 1–2 months after discontinuing treatment. The hemoglobin the form of methemoglobin indicates that a mechanism preventing
drops by an average of 2–3 g/dL and may fall below 11 g/dL in one oxidation in RBCs is in effect. These mechanisms are limited because
third or more of patients. The anemia may necessitate a dose reduc- RBCs lack the ability to either efficiently generate ATP or synthesize
tion of ribavirin or may be treated with recombinant erythropoietin enzymes. The primary means for preventing or addressing oxidant
at 40,000 units weekly. A decrease in the total cumulative dose injury are the generation of the reduced form of nicotinamide adenine
of ribavirin may be associated with decreased sustained virologic dinucleotide (NADH) via the Embden–Meyerhof glycolytic pathway
response, which would suggest that dose reduction secondary to and the generation of NADPH via the hexose monophosphate
anemia would have an adverse impact on treatment efficacy. However, shunt. NADH is used to reduce methemoglobin by cytochrome
in one retrospective study, a drop in hemoglobin of greater than 3 g/ b5 reductase, and NADPH is used to reduce glutathione and for
dL was instead associated with improved sustained virologic response catalase activity. Defects in this defense system against oxidation lead
rate compared with those with a drop in hemoglobin 3 g/dL or to an enhanced tendency to oxidative hemolysis. Examples are G6PD
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less, suggesting conversely that the degree of hemolytic anemia deficiency states. G6PD catalyzes the initial rate-limiting step in the
may serve as a biomarker of efficacy. Ribavirin is transported into hexose monophosphate shunt. Deficiencies lead to a reduced ability
the erythrocytes and accumulates as ribavirin monophosphates, to generate NADPH in response to oxidant stress. Any agent or event
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diphosphates, and triphosphates. The steady-state concentration that interferes with the smooth offloading of oxygen enhances the
−1
of ribavirin in erythrocytes is approximately 100-fold higher than generation of O 2 and methemoglobin, as indicated in the equation.
that of plasma, and higher erythrocyte ribavirin levels correlate with If the reducing power of the RBC is inadequate, hemichromes and
worsened anemia during therapy. Accumulation of phosphates leads Heinz bodies are generated. Many agents appear to cause oxida-
to a decrease in ATP levels compared with control erythrocytes. tive hemolysis by interfering with the smooth functioning of the
Because ATP is required to generate the glucose-6-phosphate needed heme cleft.
for glycolysis and the hexose monophosphate shunt, reduced levels
of ATP may lead to oxidative damage, as evidenced by increased
aggregates of band 3, which bind anti-band 3 IgG and comple- Pathophysiology
ment. The ribavirin prodrug viramidine induces less anemia than
ribavirin, although efficacy was decreased when used at fixed doses After the oxidative attack has been initiated, the sequence proceeds
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compared with a ribavirin-containing regimen. Fellay et al have along a recognizable track. The oxidative attack is directed at
detected two polymorphisms in the inosine triphosphatase (ITPA) hemoglobin and the RBC membrane. However, these structures
gene, which encodes a protein that hydrolyzes inosine triphosphate, are not clearly separable because the precipitated hemichrome and
and were protective against severe anemia in patients treated with Heinz bodies come to lie against the cytosolic face of the mem-
HCV. These two polymorphisms were associated with reduced brane. Methemoglobin may be detectably elevated, with levels as