Platelet thrombus formation at sites of vessel wall damage is critical in both physiologic hemostasis and pathologic thrombosis. Although this crucial event occurs in vivo under blood flow conditions, most previous studies of platelet function were performed in a static or closed stirring experimental systems. In this regard, a flow chamber system that can reproduce an experimental blood flow in vitro has recently been developed, and has drastically revised the concept of mechanisms for platelet adhesion and aggregation. In this review, I describe the recently-established new concept of platelet thrombus formation, and discuss the pathogenic mechanisms of major congenital platelet adhesion/aggregation disorders under physiologic blood flow conditions with various shear rates.

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Hemophilia treatment in Japan is mainly on-demand therapy in which a deficient coagulation factor VIII or IX concentrate is administered to stop bleeding when it occurs. Although home infusion therapy on demand has improved QOL in hemophiliacs in Japan, progressive musculoskeletal damage such as hemophilic arthropathy still remains a problem due to frequent hemarthroses. In recent years, prophylactic therapy in which a deficient coagulation factor is regularly administered for a long period to prevent bleeding and joint damage from early infancy (primary prophylaxis) has been adopted in Europe, and prevention of the onset and progression of musculoskeletal disease has been reported. Regular long-term continuous replacement therapy (primary and secondary prophylaxis), however, has been studied by retrospective observations, and many issues, including its effectiveness and safety, still remain to be clarified. In the response to these situations, the Hemophilia Committee of the Japanese Society of Pediatric Hematology has commenced clinical research of regular long-term continuous replacement therapy for young children with severe hemophilia. In this article, background, definition, advantages and risks, current overseas situation, and the future issues of regular long-term continuous replacement therapy are discussed.

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Castleman's disease is a lymphoproliferative disorder that is rarely seen in childhood. A case of Castleman's disease in an 11-year-old girl is reported. In July 2002, when the patient visited a nearby doctor for treatment of a common cold, she was found to have a persistently high value of CRP. After a detailed examination, which failed to identify the cause of the high CRP value, the patient was referred to our pediatric department in August 2003 for further examination. The result of examination showed a low-grade fever, a CRP value of 6.25 mg/dl, an ESR value of 60 mm/h and microcytic anemia. In a PET examination, a hot spot image was observed in the epigastric region. An abdominal operation was performed to remove the tumor. The pathological diagnosis was Castleman's disease (hyaline vascular type). This case indicated that PET is useful for whole-body examination in patients with chronic inflammation of unknown cause and that Castleman's disease should be considered in differential diagnoses of chronic inflammation.

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We report a case of one-year-old boy with juvenile myelomonocytic leukemia (JMML) complicated with mutant cytomegalovirus (CMV) infection after an unrelated allogeneic bone marrow transplantation (UBMT) in whom long term foscarnet (PFA) therapy was effective. As he was three months old at the onset of the disease, it was difficult to distinguish between JMML and perinatal CMV infection because of the presence of CMV antigenemia. He was referred to our hospital for UBMT. CMV antigenemia was negative before UBMT, but became positive on the 26th day after UBMT. The boy was first treated with ganciclovir (GCV) but this was not effective, and treatment was changed to PFA, which was effective for the CMV infection. CMV genotype analysis showed mutation of the CMV DNA polymerase (UL54 subunit) that induced the resistance to GCV but not to PFA. This case suggests that if GCV is not effective for CMV infection, genotype analysis and administration of PFA should be quickly done as the treatment.

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Graft-versus-host disease (GVHD) develops when donor T cells recognize host alloantigens expressed on host-derived antigen presenting cells. Langerhans cells and donor-derived antigen presenting cells are also involved in the development of GVHD. Innate immunity can potentiate antigen-specific donor T cell responses toward host alloantigens. Effectors of acute GVHD include both cytotoxic T lymphocytes and inflammatory cytokines. Alloantigen expression on host target epithelium is not always necessary to induce acute GVHD, augments acute GVHD, and may suppress graft-versus-leukemia (GVL) effects. Impaired thymic function may be involved in the development of chronic GVHD.

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The NK cell receptor, killer immunoglobulin-like receptor (KIR), recognizes an epitope on HLA class I antigens called KIR-ligand specificity and regulates the response of NK cells. The KIR-ligand compatibility from donors of unrelated bone marrow transplantation was retrospectively analyzed and their influences on the transplantation outcomes were evaluated. The KIR ligand incompatibility was mostly disadvantageous for the transplantation outcomes in conventional (non-T cell-depleted), unrelated bone marrow transplantations. On the other hand, KIR-ligand incompatibility was demonstrated to be associated with an improved outcome of related, T cell-depleted, CD34-positive cell-selected, HLA haplo-identical peripheral blood stem cell transplantations. The effects of NK cell alloreactivity on the GVHD were varied in different regimens of hematopoietic stem cell transplantations.

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Thrombotic microangiopathy (TMA) after stem cell transplantation is characterized by arteriolar thrombi associated with intimal damage of the vessel walls and by ischemic and hemorrhagic organ damage. Recently, intestinal TMA has been introduced and the discrimination of TMA from acute GVHD has been getting obscure because of the lack of diagnostic criteria for TMA, and moreover because of the definition of acute GVHD without the recognition of TMA. The risk factors for TMA are the immunosuppressive drugs, such as FK 506 and cyclosporine, unrelated donors, HLA-mismatched related donors, ABO-incompatibility and veno-occlusive disease. TMA is difficult to treat once established. Successful treatment for TMA by diminishing immunosuppressive drugs after early diagnosis of TMA with colonoscopic biopsies is warranted.

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There are growing numbers of patients who can receive hematopoietic stem cell transplantation with alternative donors, resulting in increasing numbers of patients complicated with chronic graft-versus-host disease (GVHD). However, the incidence of chronic GVHD among the Japanese population is lower than those reported from European and American countries. There is no effective prophylaxis for chronic GVHD and the secondary treatment for cases refractory to corticosteroids. Extensive clinical research to focus on chronic GVHD is required.

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In allogeneic hematopoietic transplantation, donor lymphocytes have important effects on both immunological reconstitution and graft versus leukemia effect. While we can treat leukemia relapsed after a stem cell transplantation by donor lymphocyte infusion (DLI), the indication of DLI is limited by the risk of graft versus host disease (GVHD). A clinical trial was started in the 1990s in Italy and was continued in Europe, which is a suicide gene therapy for a treatment of GVHD after DLI. Herpes simplex virus thymidine kinase (HSV-TK) was used as a suicide enzyme. A human cell does not have HSV-TK, and gancyclovir has no effect on it. Gancyclovir can be activated in the cell and expresses a cytotoxic effect after HSV-TK is transduced into a genome of a human cell. In our HSV-TK DLI project, we use HSV-TK transduced donor lymphocytes for DLI, and GVHD can be controled by gancyclovir-induced elimination of the transduced donor lymphocytes. In November of 2004, we carried out the HSV-TK DLI for the first case of our clinical protocol. It should be expanded to more patients for analysis of safety, efficacy and clinical contribution of this treatment.

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