Page 733 - Williams Hematology ( PDFDrive )

708 Part VI: The Erythrocyte Chapter 47: Erythrocyte Enzyme Disorders 709

to proteolysis, oxidation, irreversible cellular shrinkage, phosphatidyl but may be hemolytic when given in excessive doses. A case in point is
exposure and premature clearance. In agreement with this, PFK defi- ascorbic acid, which does not cause hemolytic anemia in normal doses
475
ciency has been shown to result in increased calcium levels, accompa- but which can produce severe, even fatal, hemolysis at doses of 80 g
nied by volume loss and metabolic dysregulation. 476,477 or more intravenously. 480–482 Some drugs, such as chloramphenicol, may
It is possible that, at least in some cases, alteration of the levels of induce mild hemolysis in a person with severe, Mediterranean-type
485
484
red cell intermediate metabolites interferes with synthesis of cell com- G6PD deficiency, but not in those with the milder A– or Canton
ponents in early stages of development of the cell. In agreement with types of deficiency. Furthermore, there appears, to be a difference in the
this, the lack of pyruvate has been implicated in the ineffective matura- severity of the reaction to the same drug of different individuals with
tion of erythroid progenitors in PK-deficient mice. 478 the same G6PD variant. For example, red cells from a single G6PD-
deficient individual were hemolyzed in the circulation of some recip-
CLINICAL FEATURES ients who were given thiazolsulfone, but their survival was normal in
438
the circulation of others. Sulfamethoxazole, which was clearly hemo-
COMMON FORMS OF GLUCOSE-6-PHOSPHATE lytic in experimental studies, does not appear to be a common cause of
486
DEHYDROGENASE DEFICIENCY hemolysis in a clinical setting. Undoubtedly, individual differences in
Individuals who inherit the common (polymorphic) forms of G6PD the metabolism and excretion of drugs influence the extent to which
487,488
G6PD-deficient red cells are destroyed.
deficiency, such as G6PD A– or G6PD Mediterranean, usually have no Several animal models have been developed to serve as a screening
clinical manifestations. The major clinical consequence of G6PD defi- platform for the determination of hemolytic toxicity of pharmacologic
ciency is hemolytic anemia in adults and neonatal icterus in infants. agents in G6PD deficiency. 489,490–492
Usually the anemia is episodic, but some of the unusual variants of G6PD Typically, an episode of drug-induced hemolysis in G6PD-deficient
may cause nonspherocytic congenital hemolytic disease (see “Variants individuals begins 1 to 3 days after drug administration is initiated.
493
Producing Hereditary Nonspherocytic Hemolytic Anemia” above). In Heinz bodies appear in the red cells, and the hemoglobin concentration
general, hemolysis is associated with stress, most notably drug admin- begins to decline rapidly. As hemolysis progresses, Heinz bodies dis-
494
istration, infection, and, in certain individuals, exposure to fava beans. appear from the circulation, presumably as they or the erythrocytes that
contain them are removed by the spleen. In severe cases, abdominal or
Drug-Induced Hemolytic Anemia back pain may occur. The urine may turn dark or even black. Within 4
Table 47–5 is an evidence-based 3,479 list of drugs and other chemicals to 6 days, there is generally an increase in the reticulocyte count, except
that are predicted to precipitate hemolytic reactions in G6PD-deficient in instances in which the patient has received the offending drug for
individuals, and drugs that are innocuous when given in normal doses, treatment of an active infection as infection depresses erythropoiesis
(Chap. 37). Because of the tendency of infections and certain other
stressful situations to precipitate hemolysis in G6PD-deficient individ-
TABLE 47–5. Drugs That Can Trigger Hemolysis in uals, many drugs have been incorrectly implicated as a cause. Other
G6PD-Deficient Individuals drugs, such as aspirin, have appeared on many lists of proscribed
medications because very large doses could slightly reduce the red cell
Predictable
Category of Drug Hemolysis Possible Hemolysis life span. It is important to recognize that such drugs do not produce
clinically significant hemolytic anemia. Advising patients not to ingest
Antimalarials Dapsone Chloroquine these drugs may not only deprive patients of potentially helpful med-
Primaquine Quinine ications, but will also weaken their confidence in the advice that they
Methylene blue have received. Most G6PD-deficient patients, after all, have taken aspi-
Analgesics/ Phenazopyridine Aspirin (high doses) rin without untoward effect and are likely to distrust an advisor who
Antipyretic counsels them that the ingestion of aspirin will have catastrophic effects.
In the A– type of G6PD deficiency, the hemolytic anemia is
Paracetamol self-limited because the young red cells produced in response to
493
(Acetaminophen) hemolysis have nearly normal G6PD levels and are relatively resistant to
Antibacterials Cotrimoxazole Sulfasalazine hemolysis. The hemoglobin level may return to normal even while the
495
Sulfadiazine same dose of drug that initially precipitated hemolysis is administered.
Quinolones (includ- In contrast, hemolysis is not self-limited in the more severe types such
ing nalidixic acid, as Mediterranean deficiency. 496
ciprofloxacin,
ofloxacin) Hemolytic Anemia Occurring During Infection
Nitrofurantoin Anemia often develops rather suddenly in G6PD-deficient individuals
Other Rasburicase Chloramphenicol within a few days of onset of a febrile illness. The anemia is usually rel-
Toluidine blue Isoniazid atively mild, with a decline in the hemoglobin concentration of 3 or
4 g/dL. Hemolysis has been noted particularly in patients suffering from
Ascorbic acid hepatitides A and B, cytomegalovirus, and pneumonia, and in those
Glibenclamide with typhoid fever. 497–499 The fulminating form of the disease occurs par-
Vitamin K ticularly frequently among G6PD-deficient patients who are infected
with Rocky Mountain spotted fever. Jaundice is not a prominent part
500
Isosorbide dinitrate
of the clinical picture, except where hemolysis occurs in association
Reproduced with pemission from Luzzatto L, Seneca E: G6PD defi- with infectious hepatitis. 501,502 In that case, it can be quite intense. Pre-
ciency: A classic example of pharmacogenetics with on-going clinical sumably because of the effect of the infection, reticulocytosis is usually
implications. Br J Haematol 164(4):469–480, 2014. absent, and recovery from the anemia is generally delayed until after the

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