Blood dyscrasias related to non-steroidal anti-inflammatory drug (NSAID) therapy are clinically important, although rare. In the Danish study, one third of reported deaths associated with NSAIDs had hematologic causes. All blood cell lines can be affected, resulting in red cell aplasia, hemolytic anemia, agranulocytosis, thrombocytopenia, and aplastic anemia. Reduced platelet aggregation also occurs.
The exact incidence of NSAID-related blood dyscrasias is unknown. The most recent investigation was the International Agranulocytosis and Aplastic Anaemia Study (IAAAS), in which the risk of aplastic anemia was estimated to be on the order of six to 10 events per million subjects per year, following an exposure of at least 5 months.
Most of the hematologic effects of NSAIDs (agranulocytosis, red cell aplasia, aplastic anemia, hemolytic anemia, thrombocytopenia) are thought to result from an immune reaction and are, therefore, drug specific. Drugs that bind strongly to proteins, such as non-steroidal anti-inflammatory drugs, can act as haptens and elicit antibody production and other immune responses.
Nonimmune hematologic effects of non-steroidal anti-inflammatory drugs include inhibition of platelet aggregation and hemolysis. Reversible inhibition of platelet cyclooxygenase occurs for all NSAIDs except acetylsalicylic acid (ASA), which irreversibly acetylates the cyclooxygenase for the lifetime of the platelet. Hemolysis can occur owing to the ability of non-steroidal anti-inflammatory drugs to oxidize hemoglobin to methemoglobin or sulfhemoglobin.
Populations at risk
Patients of all ages appear to be at risk for NSAID-related blood dyscrasias. Aplastic anemia associated with phenylbutazone and oxyphenbutazone use has occurred mainly in women older than 60 years. In the IAAAS study, only indomethacin, diclofenac, phenylbutazone, and oxyphenbutazone were significantly associated with aplastic anemia, although there have been reports of an association with acetylsalicylic acid. Agranulocytosis has been associated with the use of indomethacin, phenylbutazone, oxyphenbutazone, sulindac, tolmetin, naproxen and mefenamic acid.
The pharmacologic reactions (platelet aggregation inhibition, hemolysis) could be caused by any member of this class of drugs, in a dose-dependent manner. But nonacetylated salicylates are weak, reversible inhibitors of prostaglandin synthesis and are less likely to inhibit platelet aggregation.
Interestingly, ibuprofen has been used without reported adverse effects in hemophiliacs. Patients with glucose-6-dehydrogenase deficiency who take NSAIDs are at risk of hemolysis. Patients with defective platelet function, gastrointestinal lesions, or a bleeding diathesis are at increased risk of hemorrhage, as are patients receiving anticoagulant therapy. Two deaths from hemorrhage have been reported associated with the combined use of non-steroidal anti-inflammatory drugs and coumarins.
Monitoring strategies (Table 2) include 1) informing the patient of the warning symptoms of agranulocytosis (sore throat, fever, muscle pain, headache) and of thrombocytopenia (ecchymoses, purpura); and 2) monitoring blood cell counts at initiation, at 3 weeks, and regularly over the long term (the risk of allergic reactions is usually highest when a drug is initiated or re-instituted, but can occur after long-term drug therapy).
|Table 2. Monitoring And Preventing Hematologic Problems: Strategies to help you manage hematologic effects|
Non-steroidal anti-inflammatory drugs should be avoided in patients at risk for hematologic adverse effects: avoid NSAIDs, if possible, in those with platelet dysfunction, gastrointestinal lesions likely to bleed, or other bleeding diathesis and in patients on anticoagulants; use non-steroidal anti-inflammatory drugs with caution in patients with glucose-6-phosphate dehydrogenase deficiency; and avoid phenylbutazone and oxyphenbutazone, or use only for a short time and monitor closely.