Patient characteristics in ticlopidine hydrochloride-induced liver injury: Case-control study.

BACKGROUND: Ticlopidine hydrochloride-induced liver abnormalities have been reported in the world. In Japan, the five-year (1995-2000) spontaneous serious reports of ticlopidine finds that liver injury accounts for about half of the reports. OBJECTIVE: Clinical characteristics of ticlopidine-induced liver injury were investigated to establish the prevention strategy. METHODS: We used a medical information system at Hiroshima University Hospital and analyzed statistically. RESULTS: In this study 288 cases were reviewed. Sixty-two cases were identified as the Cases that showed liver function abnormality after ticlopidine administration. And 226 cases were identified as the Controls. There were no significant differences in gender, age or daily dose between the two groups. Fluctuation of liver function was observed within 30 days in the most of Cases and cholestatic type accounted for about 60%. The risk of this abnormality increased significantly in patients with pre-existing abnormal liver or renal function [odds ratio (95% CI): 2.96 (1.43-6.13), p=0.005; 2.47 (1.13-5.39), p=0.037]. The renal protective agent, an oral carbonaceous adsorbent, reduced the risk of ticlopidine-induced liver function abnormalities in patients with renal abnormalities significantly [odds ratio (95% CI): 0.04 (0.002-0.767), p=0.004]. CONCLUSIONS: Liver function tests should be checked frequently, especially in cases with pre-existing liver or renal function abnormalities.

Glanzmann thrombasthenia with acute myeloid leukemia successfully treated by bone marrow transplantation.

We report successful treatment by bone marrow transplantation (BMT) in an acute myeloid leukemia (AML) patient with Glanzmann thrombasthenia (GT). Genetic analysis revealed that a novel point mutation in exon 3 of the GPIIb gene led to abnormal splicing resulting in an amino acid substitution and an in-frame deletion of 3 amino acid residues. Expression studies suggested a rapid degradation of the uncomplexed protein within the cells. Induction therapy for AML was performed with frequent platelet transfusions because of the patient's severe hemorrhagic manifestations. In the second remission, the patient was successfully treated by BMT from an HLA-matched unrelated donor. Platelet function returned to normal, and the GT phenotype completely disappeared. Our experience suggests that BMT is a curative therapeutic strategy for GT. Furthermore, we believe this study is the first to demonstrate that engraftment after BMT for AML can be determined by monitoring the congenital genetic defect of GT.

Glanzmann thrombasthenia associated with a 21-amino acid deletion (Leu817-Gln837) in glycoprotein IIb due to abnormal splicing in exon 25.

We report a novel genetic defect in a Japanese patient with type I Glanzmann thrombasthenia. The glycoprotein (GP) Ilb complementary DNA (cDNA) from platelet messenger RNA had a 63-base pair deletion in the 5' boundary of exon 25, resulting in an in-frame deletion of 21 amino acid residues (Leu817-Gln837) in the calf-2 domain. The deleted region was present in the genomic DNA, but the splice acceptor site (AG) of exon 25 was mutated to AC, leading to the use of an AG sequence in the middle of exon 25 as an abnormal cryptic splice acceptor site. The effect of this deletion on protein synthesis was further analyzed. Mutant GPIIb-IIIa complexes were not detected on the surfaces of cells cotransfected with cDNAs of mutant GPIIb and normal GPIIIa. Mutant pro-GPIIb was detected in cell lysates and was coimmunoprecipitated with an anti-GPIIb-IIIa complex antibody. Immunostaining demonstrated that the mutant pro-GPIIb colocalized with an endoplasmic reticulum protein, calnexin, within the cells. These results indicate that complex formation was not completely prevented and that impairment of the subsequent transport was the major reason for the defect in cell surface expression. The data suggest that the GPIIb calf-2 domain is important for intracellular transport of GPIIIb-IIIa complexes.