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Biomedical subjects

Yoshihiro Fujimura

Publications and source records attributed to Yoshihiro Fujimura.

At least 19 recordsLinked to original sources
PubMed2006

Successful treatment of primitive neuroectodermal tumor-associated microangiopathy with multiple bone metastases.

We report here a 16-year-old male with primitive neuroectodermal tumor (PNET)-associated probable microangiopathy with multiple bone metastases. Laboratory findings excluded the possibility of amegakaryocytic or immune thrombocytopenia and/or disseminated intravascular coagulation. He was first treated with plasma-exchange (PE), followed by platelet transfusions, steroid pulse therapy and combined chemotherapy. PE and steroid pulse therapy reduced his plasma CRP level. Combined chemotherapy drastically increased his platelet count until it had almost normalized without further transfusion. The plasma level of von Willebrand factor-cleaving protease (ADAMTS13) activity measured before PE was not severely deficient (48% of normal) and an unusually large von Willebrand factor multimer (UL-VWFM) was detected. We consider that this therapeutic strategy has the following benefits: (1) reduction of plasma levels of factors that are harmful to both platelet activation and endothelial cell injury; and (2) the safe transfusion of platelet concentrate in thrombotic microangiopathy. This strategy should be confirmed in further cases.

Adolescent↗
PubMed2006

Intravenous gamma globulin for thrombotic microangiopathy of unknown etiology.

We encountered the case of a 4-year-old boy with thrombotic microangiopathy (TMA) of unknown etiology. Verotoxin-induced hemolytic uremic syndrome (HUS), Streptococcus-pneumoniae-related HUS, factor H deficiency, drug-induced thrombotic thrombocytopenic purpura (TTP), and ADAMTS13 (von Willebrand factor-cleaving protease; a disintegrin-like and metalloprotease with thrombospondin type 1 repeats)-related TTP were excluded. His condition was refractory to anticoagulants and plasma exchange, and his clinical course was catastrophic, with central nervous system symptoms and progressive renal failure. However, factual treatment of intravenous gamma globulin (IVIG) ended the hemolysis and resulted in a rise in platelet count. He fully recovered except for end-stage renal failure, but he underwent a successful renal transplant after peritoneal dialysis. He has not suffered a relapse of TMA or an allograft rejection for 4 years. IVIG might be an option for some patients with TMA of unknown etiology refractory to conventional treatment.

Biopsy↗
PubMed2006

Decreased ADAMTS13 activity in plasma from patients with thrombotic thrombocytopenic purpura.

The ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) activity was measured by a fluorescence resonance energy transfer (FRET) assay in the plasma of healthy volunteers and thrombotic thrombocytopenic purpura (TTP) patients to examine its usefulness in the diagnosis of TTP. The plasma levels of the ADAMTS13 activity did not show a normal distribution. Its median value was 107% (range: 55-170%) in healthy volunteers, but was significantly lower in patients with TTP (acquired or familial) and in patients with hematopoietic stem cell transplantation. However, it was not significantly lower in patients with antiphospholipid syndrome (APS). The ADAMTS13 activity by a FRET assay was closely correlated with that by the ADAMTS13 multimer method (r=0.816; p<0.001). In 18 patients with less than 10% of ADAMTS13 activity by FRET assay, less than 10% of that by multimer assay was 16, thus suggesting a good correlation for a low level of ADAMTS13. These findings suggest that the ADAMTS13 FRET assay correlates well with the ADAMTS13 multimer method and it is therefore useful for making a diagnosis of TTP.

ADAM Proteins↗
PubMed2006

Novel compound heterozygote mutations (H234Q/R1206X) of the ADAMTS13 gene in an adult patient with Upshaw-Schulman syndrome showing predominant episodes of repeated acute renal failure.

BACKGROUND: Unlike acquired thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome, which are often intractable, thrombotic microangiopathy in patients with Upshaw-Schulman syndrome (USS)--a congenital deficiency of von Willebrand factor-cleaving protease (ADAMTS13) activity--responds very well to plasma infusion and does not even require plasma exchange. However, the symptoms significantly vary in each individual and thus clinicians often overlook this diagnosis. METHODS: A 31-year-old adult male patient with thrombotic microangiopathy, which was complicated with repeated episodes of acute renal failure, is reported. We suspected that the patient had USS and performed assays of ADAMT13 activity and its inhibitor, followed by ADAMTS13 gene analysis of the patient and his parents. RESULTS: The patient had extremely low ADAMTS13 activity and has no inhibitors of ADAMTS13. Through an ADAMTS13 gene analysis of this family, we found two novel mutations responsible for the disease: a missense mutation in exon 7 [702 C --> A (H234Q)] from the father and a nonsense mutation in exon 26 [3616 C --> T (R1206X)] from the mother. CONCLUSIONS: Our experience appears to indicate the importance of assays of ADAMTS13 activity and its inhibitor in patients who have episodes of renal insufficiency in association with thrombotic microangiopathy, for diagnosis and choice of treatment.

ADAM Proteins↗
PubMed2006

Plasma ADAMTS13 activity may predict early adverse events in living donor liver transplantation: observations in 3 cases.

A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves the multimeric von Willebrand factor (VWF). Deficiency of ADAMTS13 increases the unusually large VWF multimers (UL-VWFM), which leads to platelet clumping and/or thrombus formation, resulting in microcirculatory disturbance. We serially determined the activity of plasma ADAMTS13, together with VWF antigen (VWF:Ag) and UL-VWFM, in association with the development of early graft dysfunction in 3 liver transplant recipients and 4 patients with major hepatectomy as controls. In case 1, ADAMTS13 activity decreased markedly from 108% to less than 3% with concomitant thrombocytopenia on posttransplantation day 7, when acute rejection occurred. Simultaneously, UL-VWFM were detected. During the second episode of rejection, VWF:Ag increased to 368% with the appearance of UL-VWFM, while ADAMTS13 activity was as low as 18%, indicating an imbalance between a large amount of UL-VWFM and low activity of ADAMTS13. Administration of fresh frozen plasma (FFP) together with treatment for acute rejection resulted in an improvement of ADAMTS13 activity and disappearance of the UL-VWFM. In case 2, ADAMTS13 activity promptly decreased to 9% with thrombocytopenia on day 1, when ischemia-reperfusion injury occurred. Subsequently, the ADAMTS13 activity increased steadily without appearance of UL-VWFM, and the patient recovered uneventfully. ADAMTS13 activity decreased to 15% immediately after transplantation in case 3 as well. In contrast, ADAMTS13 activity never decreased below 20% in 4 patients with major hepatectomy as controls. In conclusion, these results indicate that the kinetics of ADAMTS13 and UL-VWFM could be good indicators of adverse events after liver transplantation. Our findings not only suggest a novel mechanism for thrombocytopenia, but also provide a useful tool for diagnosis of graft dysfunction in the early stage after transplantation.

ADAM Proteins↗
PubMed2006

Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity.

BACKGROUND: ADAMTS13 specifically cleaves unusually large von Willebrand factor (VWF) multimers, which induce platelet thrombi formation under high shear stress. ADAMTS13 activity is deficient in patients with thrombotic thrombocytopenic purpura (TTP). The determination of plasma levels of ADAMTS13 activity is a prerequisite for a differential diagnosis of thrombotic microangiopathies. Here, a unique and highly sensitive enzyme immunoassay (EIA) of ADAMTS13 activity is described. STUDY DESIGN AND METHODS: ADAMTS13 hydrolyzes the peptide bond between Y1605 and M1606 of VWF. In this assay, a recombinant fusion protein (GST-VWF73-His) is used as a substrate. A panel of mouse monoclonal antibodies (MoAbs) that specifically recognizes Y1605, which is the C-terminal edge residue of the VWF-A2 domain and is generated by the enzymatic cleavage, has been produced. These antibodies were prepared with a synthetic decapeptide, termed N-10 (1596-DREQAPNLVY-1605), as the immunogen. Twenty-six clones specific to N10 were obtained, and one anti-N10 MoAb was used in this study. RESULTS: With horseradish peroxidase-conjugated anti-N10 MoAb, a standard enzyme assay was established. This assay was highly sensitive, and the detection limit was 0.5 percent of the normal. Further, an inhibitor of ADAMTS13 was measured to a level of 0.1 Bethesda units per mL. ADAMTS13 activity was measured in 20 patients with Upshaw-Schulman syndrome, a congenital TTP, and 61 acquired TTP patients. The activity measured by this assay and by the classic VWF multimer assay showed high correlation. CONCLUSION: A convenient and highly sensitive EIA for ADAMTS13 activity has been established. This assay can be introduced for routine laboratory work in transfusion medicine.

ADAM Proteins↗
PubMed2006

Thrombotic thrombocytopenic purpura associated with pegylated-interferon alpha-2a by an ADAMTS13 inhibitor in a patient with chronic hepatitis C.

A deficiency of ADAMTS13 leads to platelet clumping and/or thrombi formation, finally resulting in thrombotic thrombocytopenic purpura (TTP). In this study, a 62-year-old male with chronic hepatitis C developed TTP a month after long-term pegylated-interferon (PEG-IFN) treatment. The observed low level of activity of plasma ADAMTS13 following PEG-IFN treatment was shown to gradually increase with the improvement of TTP, while the titer of an inhibitory anti- ADAMTS13 IgG antibody decreased concomitant with the increase in ADAMTS13 activity. Serial determination of ADAMTS13 activity and its inhibitor may provide useful information for the diagnosis and treatment of IFN-associated TTP, as well as its pathogenesis.

ADAM Proteins↗
PubMed2006

[Rituximab provided long-term remission in a patient with severe thrombotic thrombocytopenic purpura refractory to plasma exchange].

We report a patient with severe thrombotic thrombocytopenic purpura (TTP) refractory to plasmapheresis who was successfully treated with rituximab. A 57-year-old male patient was referred to our department for further differential diagnosis and treatment of anemia and severe thrombocytopenia. Progressive psychoneurotic symptoms, hemolytic anemia, thrombocytopenia, renal function insufficiency and fever led us to the diagnosis of TTP. ADAMTS13 activity was below 3% and an inhibitor for ADAMTS13 was detected. Treatment with plasmapheresis and high-dose steroid was initiated but without clinical benefit. Two weeks following the initiation of plasmapheresis, we decided to treat the patient with 7 cycles of rituximab. No severe rituximab-related adverse effects were observed. After treatment with rituximab, the disease remitted, and the ADAMTS13 activity level increased. The patient has remained in complete remission for more than 1 year. Our data suggest that rituximab may be the optimal immunosuppressive therapy for refractory thrombotic thrombocytopenic purpura caused by an anti-ADAMTS 13 inhibitor.

ADAM Proteins↗
PubMed2005

Localization of ADAMTS13 to the stellate cells of human liver.

Although the chromosomal localization (9q34) of the gene encoding the human form of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) and its exclusive expression in the liver have been established, the cells that produce this enzyme are yet to be determined. We investigated the expression of ADAMTS13 mRNA and protein in fresh frozen specimens obtained during liver biopsies of 8 patients with liver diseases. In situ hybridizations to localize ADAMTS13 mRNA showed positive signals exclusively in perisinusoidal cells with irregularly elongated dendritic processes extending between hepatocytes. Furthermore, ADAMTS13 was detected immunohistochemically in perisinusoidal cells, whereas no staining was observed in hepatocytes. The positive cells varied in shape from unipolar to dendritic with irregularly elongated cytoplasmic processes, features common to hepatic stellate cells (HSCs). Double-labeling experiments revealed that the ADAMTS13-positive cells also expressed alpha-smooth muscle actin, confirming that these cells were activated HSCs. These results suggest that HSCs may be major cells producing ADAMTS13 in human liver.

ADAM Proteins↗
PubMed2005

Relation of CD39 to plaque instability and thrombus formation in directional atherectomy specimens from patients with stable and unstable angina pectoris.

To determine whether the expression of CD39 in coronary atherosclerotic lesions is related to plaque instability and thrombus formation, we assessed directional coronary atherectomy (DCA) specimens from patients with stable and unstable angina pectoris. CD39 immunoreactivity was decreased in culprit lesions in patients with unstable angina pectoris compared with those with stable angina pectoris, and was reduced in DCA specimens with thrombus formation. These results suggest that CD39 expressed in atheromatous plaque plays an important role in preventing acute coronary syndromes.

Adenosine Triphosphatases↗
PubMed2005

Adenovirus-mediated transfer of human placental ectonucleoside triphosphate diphosphohydrolase to vascular smooth muscle cells suppresses platelet aggregation in vitro and arterial thrombus formation in vivo.

BACKGROUND: Platelet-rich thrombus formation is a critical event in the onset of cardiovascular disease. Because ADP plays a significant role in platelet aggregation, its metabolism is important in the regulation of platelet activation and recruitment. Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) is a key enzyme involved in vascular ADP metabolism. We recently isolated 2 isoforms of E-NTPDase from the human placenta. The present study examined whether these isoforms suppress platelet aggregation and thrombus formation after adenovirus-mediated gene transfer to vascular smooth muscle cells (SMCs). METHODS AND RESULTS: We constructed adenovirus vectors expressing human placental E-NTPDase isoforms I (AdPlac I) and II (AdPlac II) or bacterial beta-galactosidase (AdLacZ). Vascular SMCs infected with AdPlac I expressed significant NTPDase activity and inhibited the platelet aggregation induced by ADP and collagen in vitro. In contrast, SMCs infected with AdPlac II and AdLacZ did not exert antiplatelet effects. To investigate the antithrombotic and antiproliferative effects of placental E-NTPDase isoform I in vivo, we generated thrombosis in rat carotid arteries by systemically administered rose Bengal and transluminal green light 5 days after gene transfer and examined neointimal growth 3 weeks after thrombus formation. Blood flow in AdLacZ-infected arteries rapidly deteriorated and vanished within 96+/-18 seconds of occlusive thrombus formation. In contrast, blood flow in AdPlac I-infected arteries was preserved for at least 10 minutes during irradiation. In addition, thrombus formation and subsequent neointimal growth were obviously suppressed. CONCLUSIONS: The local expression of placental E-NTPDase in injured arteries might prevent arterial thrombosis and subsequent neointimal growth.

Adenosine Triphosphatases↗
PubMed2005

Decreased activity of plasma ADAMTS13 may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis.

BACKGROUND: The pathogenesis of alcoholic hepatitis (AH) remains unclear and the prognosis of severe alcoholic hepatitis (SAH) is very poor. Deficiency of von Willebrand factor (VWF)-cleaving protease (VWF-CP/ADAMTS13) results in an increase of the plasma unusually large VWF multimer and leads to platelet clumping, which causes microcirculatory disturbance and finally multiorgan failure. The aim of this study was to explore the potential role of ADAMTS13 on the development of liver disturbance and multiorgan failure in AH. METHODS: The activity of plasma ADAMTS13 and its clinical correlation were determined in 14 patients with AH, 4 with SAH (Maddrey score, mean 62), and 10 with alcoholic liver cirrhosis (LC). RESULTS: The activity of the plasma ADAMTS13 significantly decreased in patients with AH (mean 59%, p < 0.001), SAH (17%, p < 0.001) and LC (76%, p < 0.02) as compared with the healthy subjects (102%, n = 60). The activity was markedly lower in SAH than in AH (p < 0.02) and LC (p < 0.02). In three nonsurvivors with SAH who had multiorgan failure, it was extremely low (4.5%, 5.0%, and 16.0%, respectively), but in a survivor with SAH it remained mild decrease (44%). In AH, the protease activity increased at the recovery stage (42% --> 75%, p < 0.05). In the univariate analysis, the activity correlated with 10 clinical variables including functional liver capacity, inflammation signs, renal function, and platelet count in patients with AH and SAH. Among these, multivariate analysis showed that serum total bilirubin and C-reactive protein independently correlated with the protease activity. CONCLUSION: The activity of plasma ADAMTS13 markedly decreased in SAH in addition to AH. The activity was closely related to hyperbilirubinemia and inflammation signs, and was extremely low in nonsurvivors with SAH and multiorgan failure. The marked decrease of plasma ADAMTS13 may, in part, contribute to not only the progression of liver disturbance in AH, but also the development of multiorgan failure in SAH through microcirculatory disturbance.

ADAM Proteins↗
PubMed2005

Von Willebrand factor-cleaving protease activity remains at the intermediate level in thrombotic thrombocytopenic purpura.

A 59-year-old woman, diagnosed with chronic myelogenous leukemia (chronic phase) and treated with interferon-alpha for 13 years, developed renal failure. Renal biopsy showed thrombotic thrombocytopenic purpura, but intensive therapy including plasma exchange and steroid administration was not effective. The activity of von Willebrand factor-cleaving protease was detectable at the intermediate level (15-46%) during the clinical course, suggesting that this case was not compatible with the previously reported pattern of idiopathic or drug-induced thrombotic thrombocytopenic purpura, but with the pattern associated with malignant disease or immunological disorders. Further studies to determine the effects of interferon-alpha on endothelial cells in chronic myelogenous leukemia patients are needed.

ADAM Proteins↗
PubMed2005

Rituximab provided long-term remission in a patient with refractory relapsing thrombotic thrombocytopenic purpura.

We describe a 69-year-old man with refractory relapsing thrombotic thrombocytopenic purpura (TTP) successfully treated with rituximab. The patient had once been successfully treated with plasmapheresis and vincristine, but he had relapsed after a short period. Although plasmapheresis, vincristine, and splenectomy could not achieve a consistent elevation of the platelet count, rituximab administration provided sustained remission for more than 7 months. Rituximab should be considered as a therapeutic alternative for refractory TTP.

ADAM Proteins↗
PubMed2004

Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura.

Congenital thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) is associated with an inherited von Willebrand factor-cleaving protease (ADAMTS13 [a disintegrin and metalloprotease with thrombospondin type I domains 13]) deficiency. In this study, we identified novel mutations in the ADAMTS13 gene in a patient with TTP. The patient was a 51-year-old Japanese male who exhibited TTP symptoms at frequent intervals. The ADAMTS13 activity during acute episodes was less than 3% that of normal. The enzyme activities of the patient's father and mother were both 46%, and both parents were asymptomatic. Genetic analysis revealed that the patient was a compound heterozygote for 2 mutations. One mutation was a missense mutation in the metalloprotease domain (A250V, exon 7), and the other was a guanine to adenine substitution at the 5' end of intron 3 (intron 3 G-->A). In vitro expression studies revealed that the A250V mutation markedly reduced ADAMTS13 activity and the intron 3 G-->A mutation caused abnormal mRNA synthesis.

ADAM Proteins↗