Two missense mutations, Thr37Met and Cys206Phe, have been found in the protein S (PS) gene of two patients with a PS deficiency associated with deep vein thrombosis.The two patients were both heterozygous for the respective mutations.To determine whether these mutations play a causative role in the PS deficiency of the patient, the PS molecule harboring the mutation was stably expressed in the human embryo kidney (HEK) 293 cells.The amount of the Thr37Met mutant PS protein in the culture medium was as much as that of the mild-type, while its specific activity was decreased to 33% of that of the wild-type.On the other hand, the Cys206Phe mutant secreted into the medium was determined below the dectection limit.Because a chimera molecule of Cys206Phe mutatnt PS and green flueorescence protein (GFP) was found to accumulate in the HEK 293 cells, secretion of the Cys206Phe mutant into the medium may be impaired.These results suggest that the Thr37Met and Cys206Phe mutations are responsible at least in part for the observed PS deficiency in the respective patients.

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A multi-center post-marketing surveillance study was conducted in previously treated patients with hemophilia A in order to evaluate the safety and efficacy of a recombinant factor VIII (Recombinate) in the long term (2 years) management and prevention of bleeding episodes. One hundred thirty-four patients were enrolled into this study and 129 patients were found to be evaluable.In total, 4,171 bleeding episodes were assessed during the study period and, hemostatic efficacy was judged to be excellent in 1,769 and good in 2,031 episodes with an overall efficacy rate of 91.1%. Twenty-one patients received at least one regular replacement therapy per week with the recombinant factor VIII during this study. These patients manifested much less spontaneous bleeding episodes than the patients who had received on-demand treatments. Three adverse reactions were reported in three patients (2.3%): i.e., urticaria in one, and headache in two patients, each being only mild and transient.One patient developed an IgM antibody to recombinant the factor VIII, which was not associated with any clinical symptoms.No patients developed the inhibitor to factor VIII in Bethesda assay. These results indicate that the recombinant factor VIII, Recombinate, is safe and efficacious for the long-term management and prevention of bleeding episodes in patients with hemophilia A, who had previously received replacement treatments with factor VIII concentrates.

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Arteial thrombotic diseases including myocardial infarction and stroke is the leading cause of death in the world. In the industrialized countries such as Japan, the increase incidence of atrial fibrillation also contribute to the increased risk of thrombotic disease especially in the elderlies. We are attempting to generate basic database of the thrombotic disease in the Japan Thrombosis registry for atrial fibrillation, coronary or cerebrovascular events (J-TRACE) .In this study, we are planning to include 15,000 at risk patients from January, 2005 toJune, 2006. Those registered patients were observed for at least 2 years. The following information will be recorded at time of registration; Patient background, events and date of the onset, past medical history, risk factors/concurrent conditions, and the use of drugs at time of registration. Only the onset of vascular events will be recorded during the follow-up period to simplify the study.

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