Evaluation of Suspected Hematologic Adverse Drug Events

Many therapeutic drugs have been associated with hematologic adverse drug events (ADEs) in animals. Some drugs, notably chemotherapeutic agents and oxidant compounds, cause dose-dependent bone marrow suppression, while others induce idiosyncratic ADEs. Major mechanisms associated with ADEs include immuneor oxidant-mediated destruction of blood cells and toxic bone marrow injury. General classes of drugs that can cause idiosyncratic ADEs include estrogenic compounds, NSAIDs, antibiotics, antifungals, antithyroid drugs, anticonvulsants, antiparasitics, and cardiac drugs. ADEs associated with chemotherapeutic agents, phenylbutazone, phenobarbital, propylthiouracil (in cats), methimazole (in cats), and azathioprine occur frequently enough to warrant performing periodic complete blood counts during the course of treatment. Drug-Associated Blood Cell Dyscrasias Many therapeutic drugs have been associated with adverse drug events (ADEs) affecting the hematologic system in dogs and cats.1–4 These ADEs have been categorized as type A or type B reactions.5 Type A ADEs are dose-dependent responses that may be exaggerated in an individual patient.5 Type B ADEs are idiosyncratic reactions that are unrelated to a drug’s pharmacologic effects. Idiosyncratic drug reactions are the most challenging to define because of their unpredictability and may involve a variety of mechanisms.5,6 A unique genetic or acquired susceptibility of the individual patient is usually involved. Genetic susceptibility frequently involves mutations that alter drug metabolism or induce immune responses to the drug or its metabolites.7 Acquired susceptibility may occur because of hepatic or renal disease leading to altered metabolism or excretion of the drug or its metabolites.7 The site at and mechanism by which a drug acts are important in determining prognosis; however, some drugs act at multiple sites or by several mechanisms, making this determination difficult. Sites of action include the blood and various bone marrow components, including hematopoietic stem cells, proliferating hematopoietic cells, and bone marrow stromal tissue.6,7 Erythrocytes are particularly sensitive to oxidative injury.8 Blood cells also appear to be uniquely susceptible to immune-mediated destruction. This susceptibility may be related to the fact that antibodies bind to blood cells in healthy animals as a means of identifying aged cells for removal.9 Therefore, immune-mediated ADEs could be seen as a normal immune mechanism gone awry. Bone marrow progenitor and proliferative cells are rapidly dividing cells and are, therefore, susceptible to chemotherapeutic agents. Capillaries and sinusoids within marrow are vulnerable to injury. Vascular injury can be seen in bone marrow core biopsy sections as interstitial edema, hemorrhage, necrosis, myelofibrosis, or inflammation.4,10–12 Evaluation of Suspected Hematologic Adverse Drug Events The temporal association of a drug treatment with a hematologic disorder does not in itself provide proof of an ADE. Other potential causes of the hematologic condition should be eliminated by evaluation of the history, clinical, and clinicopathologic findings. An overall diagnostic approach to evaluation of hematologic disorders has been presented elsewhere.13 Standard criteria for the definition of drug-induced cytopenias have not been defined for animals but have been proposed for humans.14 In humans, neutropenia has been defined as <1500 neutrophils/μL.14 Neutropenia is defined as compatible with an ADE if it is discovered during treatment with a drug. Its relation to therapy is considered to be inconclusive if it is discovered within 1 month after stopping administration of a drug or more than 1 month after administration if no leukocyte counts have been obtained in the interim. An increase in the neutrophil Key Facts • Idiosyncratic ADEs are frequently associated with immuneor oxidant-mediated destruction of blood cells or toxic injury to bone marrow. • Suspected ADEs should be reported to the US Food and Drug Administration. • Drugs most frequently reported to induce ADEs include chemotherapeutic agents, estradiol (in dogs), phenylbutazone, acetaminophen, sulfadiazine, phenobarbital, azathioprine, propylthiouracil (in cats), and methimazole (in cats). • Dogs and cats given drugs with a high probability of inducing hematologic dyscrasias, including chemotherapeutic agents, phenylbutazone, phenobarbital, azathioprine, propylthiouracil, and methimazole, should be monitored with periodic complete blood counts.