Fatal aplastic anemia associated with ticlopidine therapy – Approaches to an adverse drug reaction: COMMENTS(2)

Approaches to an adverse drug reaction: COMMENTS(2)

Differential diagnoses: For aplastic anemia, nondrug causes could include viral infections, paroxysmal nocturnal hemoglobinuria, malignancies, immune disorders, other toxins and idiopathic marrow failure. There were no clinical or laboratory features to support these etiologies.

Literature review: Six cases of aplastic anemia have been reported in European experience. These patients had features similar to the presented case with the exception that all those patients recovered after two to 12 weeks. Reversible neutropenia has also been observed in up to 2% ofpatients in clinical trials.

Confirmative testing: Results of rechallenge give strong evidence but this process is often not feasible when serious adrs are being considered. Knowledge of biochemical mechanisms
may also be helpful in understanding why certain individuals develop seemingly idiopathic toxicity. Ticlopidine is known to inhibit the proliferation of granulocyte-macrophage colony forming units in a dose dependent manner. This might be related to the structure of the parent compound (Figure 2) or new products derived in vivo. The formation of reactive metabolites such as thiophene-S-oxides have been demonstrated in experiments with ticlopidine, and these may be important in hypersensitivity reactions, as in the case ofticrynafen (another thiophene-containing compound associated with frequent adverse events). Furthermore, there may be individual differences in the ability to detoxify such metabolites, also predisposing to reactions including aplastic anemia. This has been shown with sulfonamides and anticonvulsants. There is therefore a plausible mechanistic explanation for ticlopidine being responsible for this reaction. This systematic approach (Table 1) gives one a qualitative opinion about the likelihood of a drug etiology, but there still remains a question about the degree of certainty.

Fatal apastic anemia associated with ticlopidine therapy
Figure 2) Structure of ticlopidine; metabolism of the sulphur-containing thiophene ring on the left might generate a reactive intermediate that is responsible for toxi city in susceptible individuals

Table 1. Comprehensive clinical approach to an adverse drug reaction
Table 3. Fatal apastic anemia

This entry was posted in Fatal aplastic and tagged A plastic anemia, Adverse drug reaction, Ticlopidine.