Noncutaneous Adverse Drug Reactions. Part 2. Hematologic Toxicity

Part 2: Hematologic Toxicity

Part 1 of this 2-part series (Noncutaneous Adverse Drug Reactions: Hepatotoxicity, February 2008) reviewed adverse drug reactions in the liver of dogs and cats. This part will discuss hematologic toxicity.

Types of Reactions As discussed in Part 1, adverse drug reactions can be categorized as dose-dependent or idiosyncratic, although some overlap occurs.

Dose-dependent reactions increase with increasing dose in a particular species, and virtually all members of a population are affected at high enough dosages. Dose-dependent reactions may be caused by the drug itself, or by a consistently generated metabolite.

Idiosyncratic drug reactions lead to toxicity at therapeutic doses in a small proportion of patients. Toxicity does not increase with dose in the general population, but probably does increase with dose in susceptible individuals. Idiosyncratic reactions are by definition unpredictable, and therapeutic drug monitoring is generally not helpful. These reactions are usually not related to the desired pharmacologic action of the drug, and are believed to most commonly be caused by variable metabolism of the drug in certain individuals.

Hematologic Toxicity The bone marrow and peripheral blood cells are common targets of both dose-dependent and idiosyncratic drug toxicity because of their large tissue mass and numbers of rapidly dividing cells. Bone marrow precursors and peripheral blood cells also contain cytochrome P450, myeloperoxidase, and cyclooxygenase enzymes that can bioactivate drugs to reactive intermediates.

Blood dyscrasias caused by drugs include thrombocytopenia (Figure 1), neutropenia, hemolytic anemia, pure red cell aplasia, and aplastic anemia. Recognized mechanisms of acute bone marrow damage include cytotoxic destruction of stem cells by the drug or reactive drug metabolites, immune-mediated stem or peripheral cell damage, and suppression of hematopoiesis due to deranged cytokine production.

Dose-Dependent ReactionsMost cancer chemotherapeutic agents are associated with dose-dependent bone marrow toxicity with fairly predictable nadirs and will not be reviewed here. Estrogen is well known to cause aplastic anemia (Figure 2), although the little-used estradiol cypionate is usually responsible. Bone marrow suppression from diethylstilbestrol (as used for urinary incontinence) is very uncommon unless overdosed; there is 1 report of aplastic anemia in a male dog given 10 mg of the drug daily for 5 days.

Azathioprine Azathioprine causes dose-dependent neutropenia and thrombocytopenia in dogs, with lesser effects on hematocrit. In humans, bone marrow suppression from azathioprine is associated with deficient activity of thiopurine methyltransferase (TPMT), an enzyme that, on whole, acts to detoxify azathioprine metabolites. TPMT activity varies at least 9-fold in dogs, and breed-related deficiency in TPMT activity has been demonstrated in a group of giant schnauzers.¹ It is unclear whether TPMT deficiency in individual dogs is a risk factor for azathioprine bone marrow suppression, as it is in humans. Compared with dogs and humans, cats are particularly susceptible to bone marrow suppression from azathioprine. This phenomenon is probably caused by a species-wide deficiency in TPMT activity-average levels in cats are only about 20% of those found in dogs.²

Sulfonamides At high dosages potentiated sulfonamides can cause dose-dependent anemia due to secondary folate deficiency. In humans, the anemia is macrocytic, but in dogs and cats, the anemia is mild to moderate and normocytic. This toxic reaction has been reproduced at dosages greater than 90 mg/kg Q 24 H for 8 weeks and seems to be duration-dependent (ie, much higher doses for a shorter duration do not lead to anemia). Sulfonamide-associated nonregenerative anemia can be managed by drug discontinuation, dose reduction, or supplementation with folinic acid (leucovorin; empirical dose, 0.2 mg/kg Q 24 H).

Chloramphenicol Chloramphenicol leads to reversible, dose-dependent leukopenia and/or thrombocytopenia in cats.³ A similar dose-dependent reaction in humans has been attributed to inhibition of mitochondrial protein synthesis. These reactions are in contrast to idiosyncratic aplastic anemia caused by chloramphenicol in humans, which is relatively rare (< 1 per 30,000 cases), appears to have a genetic predisposition, and can be fatal. This human aplastic anemia has been attributed to generation of a reactive intermediate from the nitro group (-NO2) of chloramphenicol and has not been reported in dogs or cats. -NO2 production is absent from the newer, related drug florfenicol, which is approved for use in food animals.

Acetaminophen Acetaminophen causes Heinz body anemia (Figure 3), methemoglobinemia, and hemolysis in cats at doses greater than 20 mg/kg. Other compounds that cause hemolysis or methemoglobinemia in cats include lidocaine, benzocaine, methionine, propylene glycol, and onion powder. These reactions may be managed with ascorbic acid (90 mg/kg Q 24 H) or the glutathione precursors S-adenosylmethionine or N-acetylcysteine. Idiosyncratic Reactions Sulfonamides In addition to dose-dependent anemia, potentiated sulfonamides have been associated with idiosyncratic thrombocytopenia, neutropenia, and hemolytic anemia in dogs.⁴ We have found antiplatelet antibodies in dogs with sulfonamide-associated thrombocytopenia, suggesting an immune pathogenesis. The neutropenia associated with sulfonamides is an early, transient, and usually modest finding. One possible mechanism for this neutropenia is myeloperoxidase-mediated conversion of the sulfonamide to the cytotoxic nitroso metabolite.

Methimazole Methimazole causes severe thrombocytopenia or neutropenia in about 4% of cats.⁵ In humans, this neutropenia is associated with an arrest in myeloid progenitors in the bone marrow, possibly due to antibody or cytokine suppression of granulocyte-macrophage CFUs. Treatment with GM-CSF has been advocated in humans but does not seem to hasten recovery in most cases. The transdermal route does not reduce the incidence of idiosyncratic reactions to methimazole.6

Phenobarbital In dogs, phenobarbital has been associated very rarely with blood dyscrasias, such as thrombocytopenia, neutropenia, anemia, or with myelofibrosis.^7,8 Possible mechanisms include deranged folate metabolism, antibody or T-cell responses to drug haptens, or direct marrow toxicity from reactive metabolites. Drug discontinuation is recommended.

NONCUTANEOUS ADVERSE DRUG REACTIONS-PART 2: HEMATOLOGIC TOXICITY • Lauren A. Trepanier

References1. Thiopurine methyltransferase activity in red blood cells of dogs. Kidd LB, Salavaggione OE, Szumlanski CL, et al. J Vet Intern Med 18:214-218, 2004.2. Cat red blood cell thiopurine S-methyltransferase: Companion animal pharmacogenetics. Salavaggione OE, Yang C, Kidd LB, et al. J Pharmacol Exp Ther 308:617-626, 2004.

1. Further observations on chloramphenicol toxicosis in cats. Watson AD. Am J Vet Res 41:293-294, 1980.

2. Idiosyncratic toxicity associated with potentiated sulfonamides in the dog. Trepanier LA. J Vet Pharmacol Ther 27:129-138, 2004.5. Methimazole treatment of 262 cats with hyperthyroidism. Peterson ME, Kintzer PP, Hurvitz AI. J Vet Intern Med 2:150-157, 1988.

3. Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthyroidism. Sartor LL, Trepanier LA, Kroll MM, et al. J Vet Intern Med 18:651-655, 2004.

4. Neutropenia and thrombocytopenia in three dogs treated with anticonvulsants. Jacobs G, Calvert C, Kaufman A. JAVMA 212:681-684, 1998.

5. A retrospective study of 19 cases of canine myelofibrosis. Weiss DJ, Smith SA. J Vet Intern Med 16:174-178, 2002.