Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.

The incidence of drug‐induced neutropenia has not changed in the western hemisphere over the last 30 years. Yet, the drug panorama has changed considerably. This implies that host factors may play an intriguing role for this idiosyncratic reaction. The knowledge as to mechanisms for the reaction has advanced with emerging understanding of neutropoiesis and immune regulation. Nonetheless, it is still remarkably difficult to pinpoint why and how a drug causes this unexpected, severe adverse event in a patient. Patient characteristics, e.g. genetics, appear to be keys for better understanding, predictions and prevention. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.

Ximelagatran was the first orally available direct thrombin inhibitor under clinical development that also reached the market. Ximelagatran was tested in an extensive clinical programme. Short-term use (<12 days) in humans including the phase III clinical trials did not indicate any hepatotoxic potential. Increased hepatic enzyme levels were first observed at a higher frequency when evaluating the long-term (>35 days) use of ximelagatran (incidence of >3x upper limit of normal (ULN) plasma ALT was 7.9%). The frequency of elevated total bilirubin levels was similar in the ximelagatran and the comparator groups. However, the combination of ALT > 3x ULN and total bilirubin > 2xULN was 0.5% among patients treated with ximelagatran and 0.1% among patients in the comparator group. Symptoms such as fever and rash potentially indicating hypersensitivity (immunologic type of reaction) were low and did not differ between ximelagatran and the comparators. The withdrawal of ximelagatran from the market and termination of the ximelagatran development program was triggered by safety data from a 35-day study, indicating that severe hepatic injury in a patient could develop after exposure to the drug has been completed and that regular liver function monitoring may not mitigate the possible risk of severe hepatic injury. As for many drugs causing liver injury, the standard preclinical toxicological studies provided no indication that ximelagatran affected hepatic functions. In addition, extensive investigations using human-based in vitro models have not been able to define mechanisms explaining the pattern of hepatic injury observed in long-term clinical trials. A pharmacogenomic study provided evidence that the ALT increases were associated with major histocompatibility complex (MHC) alleles DRB1'07 and DQA1*02 suggesting a possible immunogenic pathogenesis. This example provides important clues to the mechanism of idiosyncratic drug-induced liver toxicity.

During the 10-year period 1976-1985, a total of 154 cases of blood dyscrasia were reported in Sweden which were evaluated as having a probable or possible causal relationship with trimethoprim-sulphamethoxazole (T-SM). There were 61 cases of leucopenia (of which 16 had agranulocytosis), 28 cases of thrombocytopenia, and two of non-haemolytic anaemia. There were also 32 cases of bicytopenia and 31 cases of tricytopenia. The median age varied from 38 years in the leucopenia group to 81 years in those with tricytopenia. The overall fatality rate was 17%, ranging from 2% in the group with mild leucopenia to 52% in the group with tricytopenia. In relation to sales and prescription data, the overall incidence of reported T-SM blood dyscrasias was 5.3 per million defined daily doses, and among out-patients the incidence was one case per 18,000 prescriptions. Thus the overall incidence of any blood reaction to T-SM appears to be low. In relation to prescription data, elderly people were overrepresented among the serious reactions.

There were 100 patients with pancytopenia notified to the Swedish part of an international study of aplastic anemia (Aa) (1983–1986). Aa was the cause in 16 patients and 50 patients had different conditions explaining their pancytopenia, whereas in 34 patients no obvious explanation was found at the time of discovery of their pancytopenia. A follow‐up study in 1987 comprised the patients with Aa (n = 16) and the patients with uncharacterized pancytopenia (n = 34.3 additional patients had then been diagnosed as having Aa whereas 3 patients had a diagnosis of a low‐grade NHL and 8 patients a diagnosis of MDS. No (or an inadequate) bone marrow sample had been taken in 9 of the 34 patients. This study shows that pancytopenia may be found in many serious conditions. Patients with pancytopenia should be carefully followed as Aa can develop slowly and as the MDS diagnosis can be difficult to establish at an early stage.