Publications by authors named "Tadashi Matsushita"

142 Publications

[The management strategy for von Willebrand disease].

Rinsho Ketsueki 2021 ;62(5):435-444

Department of Transfusion Medicine, Nagoya University Hospital.

The von Willebrand factor (VWF), one of the largest plasma proteins in mammals, is an essential factor in primary hemostasis. It forms a bridge between platelet membrane glycoprotein Ib and extracellular matrix constituents, thereby playing a critical role in platelet adhesion to vascular injury sites. Its deficiency, known as von Willebrand disease is the most common inherited bleeding disorder. VWF is also a carrier protein for blood clotting factor VIII, an interaction required for normal factor VIII survival in circulation. As its symptoms are less severe than those of hemophilia and due to its wide variety, a large number of cases may not have actually been diagnosed. In the selection of therapeutic measures and patient management for bleeding symptoms, introduction of recombinant VWF concentrates is expected to expand the range of therapeutic options.
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http://dx.doi.org/10.11406/rinketsu.62.435DOI Listing
June 2021

Anemia in older adults as a geriatric syndrome: A review.

Geriatr Gerontol Int 2021 Jul 3;21(7):549-554. Epub 2021 Jun 3.

Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.

Anemia, a frequently occurring condition in older patients, has no standard definition; however, in most studies, it is defined as hemoglobin level <12 and <13 g/dL in women and men, respectively. Approximately 10% of older adults living in the community have anemia. The prevalence of anemia is significantly correlated with advanced age and male sex. Anemia is associated with falls, frailty and other negative outcomes, including early mortality. However, there remains little consensus regarding whether anemia treatment favorably affects these adverse outcomes. Therefore, this article reviews the prevalence of anemia, and provides updates on its common causes and treatments in older adults. While excluding well-established hematopoietic diseases, the etiology of anemia in older adults has been grouped into four categories: (i) nutritional deficiency; (ii) inflammation; (iii) clonal hematopoiesis; and (iv) "unexplained anemia," when there is no clear mechanism to account for the anemia. Recently, clonal leukocytes were detected in a considerable number of older individuals. The number of somatic mutations in blood leukocytes increases with age; however, single mutations of DNMT3A, TET2 and ASXL1 are not correlated with the presence of unexplained anemia in older adults. With an increased understanding of anemia etiology and the availability of innovative anti-anemic drugs, future studies that evaluate the causes and benefits of treatment are required. Geriatr Gerontol Int 2021; 21: 549-554.
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http://dx.doi.org/10.1111/ggi.14183DOI Listing
July 2021

Concomitant use of bypassing agents with emicizumab for people with haemophilia A and inhibitors undergoing surgery.

Haemophilia 2021 Jul 14;27(4):519-530. Epub 2021 May 14.

Department of Hematology, Oslo University Hospital, Oslo, Norway.

Introduction: Surgery in people with haemophilia and factor VIII inhibitors is typically managed with perioperative administration of haemostatic agents to prevent or control the occurrence of bleeding events. Practical experience of surgery in patients with inhibitors who are receiving treatment with emicizumab is growing; however, the novelty of the situation means that standardised guidelines are lacking with regard to the concomitant administration of haemostatic agents, including dose and laboratory monitoring.

Aim: To review approaches to haemostatic management during major and minor invasive procedures in patients with haemophilia A and inhibitors, and to provide recommendations for controlling bleeding events.

Methods: A search was conducted, limited to the past 4 years (January 2016-April 2020), pertaining to published evidence of surgery for patients receiving emicizumab. Publications identified from the search were manually reviewed to determine studies and case reports relevant for inclusion.

Results: Identified literature and practical experience of the authors were used to build a consensus of practical recommendations for the concomitant administration of haemostatic agents during the perioperative period for elective surgery in patients with inhibitors who are receiving emicizumab.

Conclusions: The current evidence base indicates that surgery can be successfully performed in patients with inhibitors who are receiving emicizumab and that bypassing agents can be used concomitantly. Data from prospective studies are required to further support recommendations for haemostatic management of surgery in patients receiving emicizumab.
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http://dx.doi.org/10.1111/hae.14322DOI Listing
July 2021

Tolerability of Molecular-targeted Agents for Hepatocellular Carcinoma Treatment in Haemophiliacs.

Anticancer Res 2021 May;41(5):2569-2573

Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Hepatocellular carcinoma (HCC) is considered a leading cause of death in patients with haemophilia. Recent advances in the treatment of unresectable HCC with molecular-targeted agents (MTAs) have led to better clinical outcomes. However, the tolerability of MTAs by haemophilic patients with HCC remains unclear.

Aim: This study aimed to compare the tolerability of MTAs in such patients.

Patients And Methods: From January 2011 to October 2020, five haemophilic patients with HCC were treated with MTAs. Adverse events were assessed in comparison with 265 non-haemophilic patients with HCC.

Results: The prevalence of hand-foot skin reaction was not higher in the haemophiliacs than in the non-haemophiliacs, whereas the rate of haemorrhagic events was higher in the haemophiliacs (6.0% versus 40.0%, p=0.037).

Conclusion: Haemophiliacs tolerate long-term MTA use, without the occurrence of life-threatening complications. However, careful observation and prevention are needed for MTA-related gastrointestinal bleeding in haemophiliacs.
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http://dx.doi.org/10.21873/anticanres.15035DOI Listing
May 2021

R702C is associated with erythroid abnormality with splenomegaly in mice.

Nagoya J Med Sci 2021 Feb;83(1):75-86

Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan.

disorders are characterized by giant platelets, thrombocytopenia, and Döhle body-like cytoplasmic inclusion bodies in granulocytes. However, whether these disorders cause any changes in erythroid cells has yet to be determined. This study analyzed the influence of R702C, as one of the most commonly detected disorders, on erythroid cells in a mouse model. Knock-in mice expressing R702C mutation either systemically or specific to hematological cells (R702C and R702C vav1 mice, respectively) were used in this study. Both displayed lower hemoglobin and higher erythropoietin levels than wild-type (WT) mice, along with significant splenomegaly. Flow cytometric analysis revealed erythroblasts present at a higher rate than WT mice in the spleen. However, no obvious abnormalities were seen in erythroid differentiation from megakaryocyte/erythroid progenitor to erythrocyte. Cell culture assay by fetal liver and colony assay also showed normal progression of erythroid differentiation from erythroid burst-forming unit to red blood cell. In conclusion, R702C and R702C vav1 mice displayed erythroid abnormality with splenomegaly. However, erythroid differentiation showed no obvious abnormality. Further research is required to elucidate the underlying mechanisms.
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http://dx.doi.org/10.18999/nagjms.83.1.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938085PMC
February 2021

Essential role of a carboxyl-terminal α-helix motif in the secretion of coagulation factor XI.

J Thromb Haemost 2021 04 10;19(4):920-930. Epub 2021 Feb 10.

Division of Cellular and Genetic Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Coagulation factor XI (FXI) is a plasma serine protease zymogen that contributes to hemostasis. However, the mechanism of its secretion remains unclear.

Objective: To determine the molecular mechanism of FXI secretion by characterizing a novel FXI mutant identified in a FXI-deficient Japanese patient.

Patient/methods: The FXI gene (F11) was analyzed by direct sequencing. Mutant recombinant FXI (rFXI) was overexpressed in HEK293 or COS-7 cells. Western blotting and enzyme-linked immunosorbent assay were performed to examine the FXI extracellular secretion profile. Immunofluorescence microscopy was used to investigate the subcellular localization of the rFXI mutant.

Results: We identified a novel homozygous frameshift mutation in F11 [c.1788dupC (p.E597Rfs*65)], resulting in a unique and extended carboxyl-terminal (C-terminal) structure in FXI. Although rFXI-E597Rfs*65 was intracellularly synthesized, its extracellular secretion was markedly reduced. Subcellular localization analysis revealed that rFXI-E597Rfs*65 was abnormally retained in the endoplasmic reticulum (ER). We generated a series of C-terminal-truncated rFXI mutants to further investigate the role of the C-terminal region in FXI secretion. Serial rFXI experiments revealed that a threonine at position 622, the fourth residue from the C-terminus, was essential for secretion. Notably, Thr622 engages in the formation of an α-helix motif, indicating the importance of the C-terminal α-helix in FXI intracellular behavior and secretion.

Conclusion: FXI E597Rfs*65 results in the pathogenesis of a severe secretory defect resulting from aberrant ER-to-Golgi trafficking caused by the lack of a C-terminal α-helix motif. This study demonstrates the impact of the C-terminal structure, especially the α-helix motif, on FXI secretion.
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http://dx.doi.org/10.1111/jth.15242DOI Listing
April 2021

Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation.

Stem Cells Transl Med 2021 Apr 14;10(4):542-553. Epub 2020 Dec 14.

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy to not only prevent graft-vs-host disease (GVHD) but also to enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra-BM injection of MSCs (MSC-CBT) was designed. Third-party BM-derived MSCs were injected intra-BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra-BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC-CBT, and no adverse events related to intra-BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38 days, respectively, comparable with controls. Grade II-IV acute GVHD developed in three controls but not in MSC-CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC-CBT patients survived without relapse. This study shows the safety of MSC-CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as number 000024291.
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http://dx.doi.org/10.1002/sctm.20-0381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980216PMC
April 2021

Safety and efficacy of percutaneous radiofrequency ablation for hepatocellular carcinoma patients with haemophilia.

Haemophilia 2021 Jan 27;27(1):100-107. Epub 2020 Nov 27.

Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya-shi, Japan.

Haemophilia is an X-linked inherited bleeding disorder caused by coagulation factor deficiency. Hepatocellular carcinoma (HCC) is a major complication associated with the disease. No study thus far has investigated the safety and efficacy of percutaneous radiofrequency ablation (RFA) for HCC in patients with haemophilia.

Aim: This study aimed to evaluate the safety and efficacy of RFA for HCC in haemophilia patients.

Methods: From July 2008 to June 2019, 217 patients with HCC underwent 300 RFA sessions. Of these, 18 sessions were performed in ten haemophilia patients (H group) and 282 in 207 non-haemophilia patients (NH group). The patients' characteristics, incidence of haemorrhagic complications and rates of local tumour recurrence were compared between the groups.

Results: A majority of the haemophilia patients received clotting factor concentrate replacement therapy before and after RFA treatment, with the aim of reaching a plasma clotting factor level of higher than 60%-80%. Twelve haemorrhagic complications were observed in the NH group (4.2%; 12/282). Major bleeding requiring control procedures was observed in two patients and minor bleeding with careful observation was noted in ten patients. No bleeding complications were observed in the H group (0/18). There were no significant differences in the 5-year local tumour recurrence rates after RFA treatment between the groups (35.0% in the H group and 32.1% in the NH group).

Conclusion: RFA could be an effective and a safe method for HCC treatment in patients with haemophilia.
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http://dx.doi.org/10.1111/hae.14220DOI Listing
January 2021

Long-term safety and efficacy of emicizumab for up to 5.8 years and patients' perceptions of symptoms and daily life: A phase 1/2 study in patients with severe haemophilia A.

Haemophilia 2021 Jan 24;27(1):81-89. Epub 2020 Nov 24.

Department of Pediatrics, Nara Medical University, Kashihara, Japan.

Introduction: Safety and efficacy results of the phase 1 study and phase 1/2 extension study of the bispecific antibody emicizumab in patients with severe haemophilia A with or without factor VIII inhibitors for up to 2.8 years were reported previously.

Aim: To evaluate further longer-term data including patients' perceptions at study completion.

Methods: Emicizumab was administered subcutaneously once weekly at maintenance doses of 0.3, 1 or 3 mg/kg with potential up-titration. All patients were later switched to the approved maintenance dose of 1.5 mg/kg.

Results: Eighteen patients received emicizumab for up to 5.8 years. Most adverse events were mild and unrelated to emicizumab. Annualized bleeding rates (ABRs) for bleeds treated with coagulation factors decreased from pre-emicizumab rates or remained zero in all patients. The median ABRs were low at 1.25, 0.83 and 0.22 during the 0.3, 1 and 3 mg/kg dosing periods, respectively. Of 8 patients who decreased their doses from 3 to 1.5 mg/kg, ABRs decreased in 4, remained at zero in 2, and increased in 2. Total time spent with symptoms associated with treated bleeds decreased in all patients except 2. All patients answered 'improved' for bleeding severity and time until bleeding stops, except 1 answering 'slightly improved'. Most patients answered 'improved' or 'slightly improved'' for daily life and feelings; in particular, all patients except 1 answered 'improved' or 'slightly improved' for anxiety.

Conclusions: Long-term emicizumab prophylaxis for up to 5.8 years was safe and efficacious, and may improve patients' daily lives and feelings, regardless of inhibitor status.
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http://dx.doi.org/10.1111/hae.14205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894561PMC
January 2021

Indoxyl Sulfate-induced Vascular Calcification is mediated through Altered Notch Signaling Pathway in Vascular Smooth Muscle Cells.

Int J Med Sci 2020 23;17(17):2703-2717. Epub 2020 Sep 23.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

The aim of this study was to determine the role of Notch in indoxyl sulfate (IS)-induced vascular calcification (VC). VC and expression of Notch-related and osteogenic molecules were examined in Dahl salt-sensitive (DS), DS hypertensive (DH), and DH IS-treated rats (DH+IS). The effects of IS on expression of Notch receptors, apoptotic activity, and calcification were examined in cultured aortic smooth muscle cells (SMCs). Medial calcification was noted only in aortas and coronary arteries of DH+IS rats. Notch1, Notch3, and Hes-1 were expressed in aortic SMCs of all rats, but only weakly in the central areas of the media and around the calcified lesions in DH+IS rats. RT-PCR and western blotting of DH+IS rat aortas showed downregulation of Notch ligands, Notch1 and Notch3, downstream transcriptional factors, and SM22, and conversely, overexpression of osteogenic markers. Expression of Notch1 and Notch3 in aortic SMCs was highest in incubation under 500 μM IS for 24hrs, and then decreased time- and dose-dependently. Coupled with this decrease, IS increased caspase 3/7 activity and TUNEL-positive aortic SMCs. In addition, pharmacological Notch signal inhibition with DAPT induced apoptosis in aortic SMCs. ZVAD, a caspase inhibitor abrogated IS-induced and DAPT-induced vascular calcification. Knockdown of Notch1 and Notch3 cooperatively increased expression of osteogenic transcriptional factors and decreased expression of SM22. Our results suggested that IS-induced VC is mediated through suppression of Notch activity in aortic SMCs, induction of osteogenic differentiation and apoptosis.
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http://dx.doi.org/10.7150/ijms.43184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645353PMC
September 2020

Vascular endothelial growth factor (VEGF)-A and VEGF-Ab are associated with time to remission of granulomatosis with polyangiitis in a nationwide Japanese prospective cohort study.

Ann Clin Biochem 2021 03 22;58(2):86-94. Epub 2020 Nov 22.

Nagoya University, Nagoya, Japan.

Background: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-Ab (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort.

Methods: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-Ab concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA).

Results: Results revealed significant reductions in sVEGF-A and sVEGF-Ab concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-Ab during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log-transformed concentrations of sVEGF-A and sVEGF-Ab were inversely correlated with time to remission in granulomatosis with polyangiitis patients.

Conclusion: These results suggest that sVEGF-A and -Ab can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.
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http://dx.doi.org/10.1177/0004563220968371DOI Listing
March 2021

Impact of variation in reagent combinations for one-stage clotting assay on assay discrepancy in nonsevere haemophilia A.

Int J Lab Hematol 2021 Feb 11;43(1):131-138. Epub 2020 Sep 11.

Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.

Introduction: Factor VIII activity (FVIII:C) is measured by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). Significant differences in FVIII:C between OSA (FVIII:C ) and CSA (FVIII:C ) are described as assay discrepancy in nonsevere haemophilia A (HA). A large number of reagent combinations (APTT reagent and FVIII-deficient plasma) are used for OSA, but the impact of variations in reagent combinations on assay discrepancy has not been fully characterized.

Aim: To clarify the variations in FVIII:C /FVIII:C ratios according to OSA reagent combination in HA subjects with/without assay discrepancy.

Methods: Thirty-nine patients previously diagnosed with nonsevere HA were enrolled, and their FVIII genes were investigated and FVIII:C levels were assessed by a single CSA reagent and 11 OSA reagent combinations. Receiver operating characteristic (ROC) curve analysis was used to predict possible cut-off values of the FVIII:C /FVIII:C ratio to define FVIII assay discrepancy for each reagent combination.

Results: Patients were categorized into nondiscrepant (n = 25), discrepant (n = 5) and unclassified (n = 9) groups according to their genotypes and information in the database. The FVIII:C /FVIII:C ratio in nondiscrepant HA varied widely, depending on the APTT reagents and FVIII-deficient plasma used. The ratio in discrepant HA patients differed with respect to their genotype and the reagent combination used. ROC curve analyses revealed that cut-off values to distinguish the assay discrepancy differed depending on the reagents used, but revealed two novel genotype variants, p.Cys573Gly and p.Gly582Arg, associated with FVIII assay discrepancy.

Conclusion: Our findings showed that the FVIII:C /FVIII:C ratio is dependent on the reagent combination used for OSA.
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http://dx.doi.org/10.1111/ijlh.13335DOI Listing
February 2021

Periodic Elastic Motion in a Self-Assembled Monolayer under Spontaneous Oscillations of Surface Tension: Molecules in a Scrum Push Back a Marangoni Flow.

J Phys Chem Lett 2020 Aug 23;11(15):6330-6336. Epub 2020 Jul 23.

Photon Factory, Institute of Materials Structure Science, KEK, 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan.

Regularly recurring phenomena are a common and important part of life. Such rhythmic behaviors are often seen in nonliving systems under far-from-equilibrium conditions. The study of simple nonliving systems provides clues for improving our understanding of the origin of biological rhythms. Here, we focus on the spontaneous oscillation of surface tension associated with an intermittent Marangoni convective flow generated by two types of surfactants, those that are partially soluble (long chain alcohols) and insoluble (lipids) in water. In this system, we find that the collective motions of two surfactants interact with each other in a systematic manner to control a stable periodic motion: the alcohol molecules (donor) produce a Marangoni flow, and the lipid molecules (acceptor) in a monolayer push the flow back. The shape of the surface tension oscillation can be explained by the viscoelastic properties of the acceptor surfactant, whereas the period of the surface tension oscillation has been explained by the physical properties of the donor surfactant. A recently developed time-resolved X-ray surface scattering technique enables the dynamic structure of the water surface under flow to be determined. We have repeatedly observed that lipid molecules at the air-water interface become regularly oriented normal to the surface at every onset of the Marangoni convective flow.
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http://dx.doi.org/10.1021/acs.jpclett.0c01205DOI Listing
August 2020

Aberrant X chromosomal rearrangement through multi-step template switching during sister chromatid formation in a patient with severe hemophilia A.

Mol Genet Genomic Med 2020 09 5;8(9):e1390. Epub 2020 Jul 5.

Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Hemophilia A (HA) is an X-linked recessive bleeding disorder caused by pathogenic variants of the coagulation factor VIII gene (F8). Half of the patients with severe HA have a recurrent inversion in the X chromosome, that is, F8 intron 22 or intron 1 inversion. Here, we characterized an abnormal F8 due to atypical complex X chromosome rearrangements in a Japanese patient with severe HA.

Methods: Recurrent F8 inversions were tested with inverse shifting-PCR. The genomic structure was investigated using PCR-based direct sequencing or quantitative PCR.

Results: The proband's X chromosome had a 119.5 kb insertion, a reverse duplex of an extragenic sequence on the F8 telomere region into the F8 intron 1 with two breakpoints. The telomeric breakpoint was a joining from the F8 intron 1 to the inverted FUNDC2 via a two-base microhomology, and the centromeric breakpoint was a recombination between F8 intron 1 homologous sequences. The rearrangement mechanism was suggested as a multi-step rearrangement with template switching such as fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR) and/or homologous sequence-associated recombination during a sister chromatid formation.

Conclusion: We identified the aberrant X chromosome with a split F8 due to a multi-step rearrangement in a patient with severe HA.
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http://dx.doi.org/10.1002/mgg3.1390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507428PMC
September 2020

An overview of the pathfinder clinical trials program: Long-term efficacy and safety of N8-GP in patients with hemophilia A.

J Thromb Haemost 2020 09;18 Suppl 1:26-33

Haemophilia, Haemostasis and Thrombosis Centre, Hampshire Hospitals NHS Foundation Trust, Basingstoke, UK.

N8-GP (turoctocog alfa pegol, Esperoct ; Novo Nordisk A/S, Bagsvaerd, Denmark) is a state-of-the-art, extended half-life factor VIII (FVIII) molecule used for prophylactic and on-demand treatment of patients with hemophilia A. The pathfinder clinical trial program, which began with the pathfinder1 trial in 2010, was developed to assess the long-term efficacy and safety of N8-GP in children, adolescents, and adults. The pivotal pathfinder2 (adolescents and adults) and pathfinder5 (children) trials were completed in late 2018, and comprehensive analyses of the end-of-trial results are published together with this article as part of an N8-GP Supplement. Furthermore, results from the pathfinder3 trial, which was designed to evaluate the safety and efficacy of N8-GP during major surgery, have also recently been finalized. Here, we provide an overview of the pathfinder clinical development program and summarize key data from the completed pathfinder trials. We also provide perspectives on the future of extended half-life FVIII molecules in the treatment of patients with hemophilia A and describe currently ongoing pathfinder trials.
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http://dx.doi.org/10.1111/jth.14958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540506PMC
September 2020

Long-term safety and sustained efficacy for up to 5 years of treatment with recombinant factor IX Fc fusion protein in subjects with haemophilia B: Results from the B-YOND extension study.

Haemophilia 2020 Nov 4;26(6):e262-e271. Epub 2020 Jun 4.

Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.

Introduction: Recombinant factor IX Fc fusion protein (rFIXFc) has demonstrated efficacy for treatment of haemophilia B in the Phase 3 B-LONG and Kids B-LONG studies. However, long-term rFIXFc safety and efficacy data have not yet been reported.

Aim: To report long-term rFIXFc safety and efficacy in subjects with haemophilia B.

Methods: B-YOND (NCT01425723) was an open-label extension for eligibl previously treated subjects who completed B-LONG or Kids B-LONG. Subjects received ≥1 treatment regimen: weekly prophylaxis (WP), individualized interval prophylaxis (IP), modified prophylaxis or episodic treatment. Subjects could switch regimens at any time. The primary endpoint was inhibitor development.

Results: Ninety-three subjects from B-LONG and 27 from Kids B-LONG (aged 3-63 years) were enrolled. Most subjects received WP (B-LONG: n = 51; Kids B-LONG: n = 23). For subjects from B-LONG, median (range) treatment duration was 4.0 (0.3-5.4) years and median (range) number of exposure days (EDs) was 146 (8-462) EDs. Corresponding values for paediatric subjects were 2.6 (0.2-3.9) years and 132 (50-256) EDs. No inhibitors were observed (0 per 1000 subject-years; 95% confidence interval, 0-8.9) and the overall rFIXFc safety profile was consistent with prior studies. Annualized bleed rates remained low and extended-dosing intervals were maintained for most subjects. Median dosing interval for the IP group was approximately 14 days for adults and adolescents (n = 31) and 10 days for paediatric subjects (n = 5).

Conclusions: B-YOND results confirm the long-term (up to 5 years, with cumulative duration up to 6.5 years) well-characterized safety and efficacy of rFIXFc treatment for haemophilia B.
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http://dx.doi.org/10.1111/hae.14036DOI Listing
November 2020

A Japanese multi-institutional collaborative study of antigen-positive red blood cell (RBC) transfusions in patients with corresponding RBC antibodies.

Vox Sang 2020 Jul 2;115(5):456-465. Epub 2020 Mar 2.

Blood Service Headquarters, Japanese Red Cross Society, Minato-ku, Japan.

Background And Objectives: It is sometimes difficult to obtain antigen-negative red blood cells (RBCs) for patients with antibodies against RBCs. However, the frequency and severity of the adverse reactions have not been well elucidated. Here, we conducted a multi-institutional collaborative study to clarify the background, frequency and clinical significance of antigen-positive RBC transfusions to patients with the respective antibodies.

Materials And Methods: The survey included the background of patients, antigens on RBCs transfused, total amount of antigen-positive RBCs transfused, results from antibody screen and direct antiglobulin tests, specificity of antibodies, adverse reactions and efficacies. All antibodies were surveyed regardless of their clinical significance.

Results: In all, 826 cases containing 878 antibodies were registered from 45 institutions. The main reasons for antigen-positive RBC transfusions included 'negative by indirect antiglobulin test' (39%) and 'detection of warm autoantibodies' (25%). In 23 cases (3% of total), some adverse reactions were observed after antigen-positive RBC transfusion, and 25 antibodies (9 of 119 clinically significant and 16 of 646 insignificant antibodies) were detected. Non-specific warm autoantibodies were detected in 9 cases, anti-E in 5 cases, 2 cases each of anti-Le , anti-Jr or cold alloantibodies, and 1 case each of anti-Di , anti-Le or anti-P1. Other antibodies were detected in 2 further cases. Five (22%) of these 23 cases, who had anti-E (3 cases) or anti-Jr (2 cases), experienced clinically apparent haemolysis.

Conclusions: Adverse reactions, especially haemolysis, were more frequently observed in cases with clinically significant antibodies than those with clinically insignificant antibodies (P < 0·001).
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http://dx.doi.org/10.1111/vox.12906DOI Listing
July 2020

A survey of blood transfusion errors in Aichi Prefecture in Japan: Identifying major lapses threatening the safety of transfusion recipients.

Transfus Apher Sci 2020 Jun 27;59(3):102735. Epub 2020 Jan 27.

Aichi Prefectural Joint Committee of Blood Transfusion Therapy, Nagoya, Japan; Department of Transfusion Medicine, Aichi Medical University Hospital, Nagakute, Japan.

Background: Despite recent progress in blood systems, transfusion errors can occur at any time from the moment of collection through to the transfusion of blood and blood products. This study investigated the actual statuses of blood transfusion errors at institutions of all sizes in Aichi prefecture.

Materials And Methods: We investigated 104 institutions that perform 98 % of the blood transfusions in Aichi prefecture, and investigated the errors (incidents/accidents) that occurred at these facilities over 6 months (April to September, 2017). Incident/accident data were collected from responses to questionnaires sent to each institution; these were classified according to the categories and risk levels.

Results: Ninety-seven of the 104 institutions (93.3 %) responded to the questionnaire; a total of 688 incidents/accidents were reported. Most (682 cases; 99.2 %), were classified as risk level 2; however, 6 were level 3 and over, which included problems with autologous transfusion and inventory control. Approximately one-half of the incidents/accidents (394 cases; 57.3 %), were related to verification and the actual administration of blood products at the bedside; more than half of these incidents/accidents occurred at large-volume institutions. Meanwhile, a high frequency of incidents/accidents related to transfusion examination and labeling of blood products was observed at small- or medium-sized institutions. The reasons for most of these errors were simple mistakes and carelessness by the medical staff.

Conclusions: Our results emphasize the importance of education, operational training, and compliance instruction for all members of the medical staff despite advances in electronic devices meant to streamline transfusion procedures.
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http://dx.doi.org/10.1016/j.transci.2020.102735DOI Listing
June 2020

Safety and efficacy of turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: Results from the guardian 4 multinational clinical trial.

Haemophilia 2020 Jan 9;26(1):64-72. Epub 2019 Dec 9.

Beijing Children's Hospital, Capital Medical University, Beijing, China.

Introduction: Turoctocog alfa is a recombinant, B domain-truncated factor VIII (FVIII) approved for patients with haemophilia A.

Aim: To evaluate the safety and efficacy of turoctocog alfa in previously untreated patients (PUPs) with severe haemophilia A.

Methods: Guardian 4 was a multicentre, multinational, non-randomized, open-label phase 3 trial comprising a main and extension phase. The former concluded once ≥ 50 patients had received treatment for ≥ 50 exposure days (EDs) or developed inhibitors. Patients received turoctocog alfa intravenously for prevention and treatment of bleeds. The primary endpoint was the incidence rate of FVIII inhibitors (≥0.6 Bethesda Units) reported during the first 50 EDs.

Results: Of the 58 patients who completed the main phase, 25 (43.1%) patients developed inhibitors (detected within 6-24 [mean: 14.2] EDs from treatment start). High-risk mutations were identified in 60% of patients who developed inhibitors in the main phase and were a significant predictor of inhibitor development (P = .003). Of the 21 patients who started immune tolerance induction therapy, 85.7% completed treatment with a negative inhibitor test (note that data on the last 3 patients completing ITI are based on information collated from sites prior to the final database lock). Haemostatic response (including missing values as failure) was rated as 'excellent' or 'good' for 86.1% of bleeds occurring during prophylaxis. The estimated mean annualized bleeding rate for patients on prophylaxis was 4.26 bleeds/patient/year (95% CI: 3.34 - 5.44).

Conclusions: Turoctocog alfa was effective at preventing and stopping bleeds and was well tolerated. Inhibitor development was within the expected range for this PUP population.
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http://dx.doi.org/10.1111/hae.13883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028046PMC
January 2020

Successful Perioperative Combination of High-Dose FVIII Therapy Followed by Emicizumab in a Patient with Hemophilia A with Inhibitors.

TH Open 2019 Oct 5;3(4):e364-e366. Epub 2019 Dec 5.

Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.

We managed perioperative hemostasis for a 72-year-old man with hemophilia A and low inhibitor titers (3 BU/mL), who underwent osteosynthesis for supracondylar fracture of the left humerus. He was treated perioperatively using the combination of high doses of factor VIII (FVIII) with recombinant human Factor VIII Fc fusion protein (rFVIIIFc), followed by emicizumab. On the day of surgery (day 0), he was administered bolus infusion of 150 IU/kg rFVIIIFc, followed by continuous infusion at a dose of 4 IU/kg/h. Emicizumab, 3 mg/kg, was injected subcutaneously once a week, on days 5, 12, 19, and 26. Inhibitors were detected on day 6 at a titer of 4 BU/mL and FVIII:C decreased to below assay sensitivity limits on day 10. The rate of increase in inhibitor titers was high, with inhibitors increasing to 343.4 BU/mL on day 14. The transition of thrombin production by thrombin generation assay (TGA) showed temporary decrease in thrombin production on day 7, although it was restored by day 10, i.e., five days after commencement of emicizumab therapy. Rotational thromboelastometry displayed consistent results with TGA, showing that clotting time was prolonged and the alpha angle decreased to less than measurable levels on day 6, although they were improved by day 10. There were no bleeding-related events or other adverse events throughout the perioperative period. In conclusion, emicizumab was effective for the management of perioperative hemostasis after development of an anamnestic response in a patient with hemophilia A with inhibitors. Combination therapy with high doses of FVIII followed by emicizumab could be a workable alternative for patients with hemophilia A with inhibitors.
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http://dx.doi.org/10.1055/s-0039-3401001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894946PMC
October 2019

Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results.

Blood 2019 11;134(22):1973-1982

Department of Immunohematology and.

Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.
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http://dx.doi.org/10.1182/blood.2019001542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895373PMC
November 2019

Performance evaluation of Revohem FVIII chromogenic and Revohem FIX chromogenic in the CS-5100 autoanalyser.

Int J Lab Hematol 2019 Oct 4;41(5):664-670. Epub 2019 Jul 4.

Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.

Introduction: Chromogenic substrate assay (CSA) reagents Revohem FVIII and Revohem FIX are now available as in vitro diagnostic reagents for autoanalysers in Japan. In this study, we evaluated the performance of these reagents in the CS-5100 automated coagulation analyser.

Methods: We assessed within-run and between-day imprecision, on-board stability and frozen-storage stability of Revohem FVIII and FIX. Sensitivity to lupus anticoagulant (LA) was examined using LA-positive patient plasma. Correlations were analysed using plasma samples from normal individuals and patients with haemophilia A (HA) or B (HB) or von Willebrand disease (VWD).

Results: Imprecision was <2% for Revohem FVIII and <6.5% for Revohem FIX. On-board storage of Revohem FVIII resulted in a <10% decrease in FVIII levels from baseline at 24 hours, whereas Revohem FIX showed a >10% decrease at 8 hours. Revohem FVIII showed good stability while frozen for 22 days. Although Revohem FIX showed degradation due to freeze-thawing, a new calibration improved stability up to 22 days. Interference from LA was not observed with Revohem FVIII or FIX. The FVIII CSA-CSA correlation was excellent in normal (r = 0.9924), HA (r = 0.9945) and VWD (r = 0.9914). The FVIII CSA-OSA correlation was good in normal (r = 0.8468) and excellent in HA (r = 0.975) and VWD (r = 0.9936). The FIX CSA-OSA correlation was fair in normal (r = 0.4791) and excellent in HB (r = 0.9501).

Conclusion: Revohem FVIII and FIX both showed excellent performance in the CS-5100 analyser. These reagents could be useful in routine laboratory testing for diagnosing and treating haemophilia.
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http://dx.doi.org/10.1111/ijlh.13083DOI Listing
October 2019

Postmarketing safety and effectiveness of recombinant factor IX (nonacog alfa) in Japanese patients with haemophilia B.

Haemophilia 2019 Jul 6;25(4):e247-e256. Epub 2019 Jun 6.

Pfizer Japan, Tokyo, Japan.

Introduction: In 2010, nonacog alfa became the first recombinant factor IX (rFIX) available in Japan for patients with haemophilia B.

Aim: To determine real-world safety (adverse events, incidence of inhibitors) and effectiveness of nonacog alfa in Japan.

Methods: This multicentre, prospective, observational, postmarketing surveillance study enrolled previously treated and untreated patients (PTPs and PUPs, respectively) who were observed for 1 and 2 years, respectively, after initiating nonacog alfa therapy. Safety and effectiveness were assessed for each treatment type. Annualized bleeding rate (ABR) and incremental recovery of rFIX were also evaluated.

Results: Overall, 312 of 314 patients enrolled from 173 sites were eligible for the safety analysis set (PTPs, 281; PUPs, 28; other, 3). Mean age was 25.4 (PTPs) and 14.8 (PUPs) years. Haemophilic severity ranged from mild to severe, and 133 (42.6%) patients had haemophilic arthropathy. Of 285 patients (PTPs, 257; PUPs, 28) in the effectiveness set, 112 received on-demand treatment for 1161 bleeding episodes (effectiveness rate, 93.7%) and 185 received routine prophylaxis (effectiveness rate, 95.5%). No spontaneous bleeding was observed in 52.4% of patients during prophylactic treatment. Median ABR was lower during routine prophylaxis (2.0) vs the rest of the observation period (8.3). A weak negative correlation was found between body weight and the reciprocal of rFIX recovery. Eleven adverse drug reactions occurred in 7 PTPs (2.2% [7/312]); recurrence of inhibitor was observed in 1 patient, but no new inhibitor developed in PTPs or PUPs.

Conclusion: Nonacog alfa therapy is safe and effective in the real-world scenario in Japan.
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http://dx.doi.org/10.1111/hae.13783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852692PMC
July 2019

Apolipoprotein E binds to and reduces serum levels of DNA-mimicking, pyrrolated proteins.

J Biol Chem 2019 07 5;294(28):11035-11045. Epub 2019 Jun 5.

Graduate School of Bioagricultural Sciences and; Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan, and; Japan Agency for Medical Research and Development, CREST, Tokyo 102-0076, Japan. Electronic address:

Lysine -pyrrolation, converting lysine residues to -pyrrole-l-lysine, is a recently discovered post-translational modification. This naturally occurring reaction confers electrochemical properties onto proteins that potentially produce an electrical mimic to DNA and result in specificity toward DNA-binding molecules such as anti-DNA autoantibodies. The discovery of this unique covalent protein modification provides a rationale for establishing the molecular mechanism and broad functional significance of the formation and regulation of -pyrrole-l-lysine-containing proteins. In this study, we used microbeads coupled to pyrrolated or nonpyrrolated protein to screen for binding activities of human serum-resident nonimmunoglobin proteins to the pyrrolated proteins. This screen identified apolipoprotein E (apoE) as a protein that innately binds the DNA-mimicking proteins in serum. Using an array of biochemical assays, we observed that the pyrrolated proteins bind to the N-terminal domain of apoE and that oligomeric apoE binds these proteins better than does monomeric apoE. Employing surface plasmon resonance and confocal microscopy, we further observed that apoE deficiency leads to significant accumulation of pyrrolated serum albumin and is associated with an enhanced immune response. These results, along with the observation that apoE facilitates the binding of pyrrolated proteins to cells, suggest that apoE may contribute to the clearance of pyrrolated serum proteins. Our findings uncover apoE as a binding target of pyrrolated proteins, providing a key link connecting covalent protein modification, lipoprotein metabolism, and innate immunity.
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http://dx.doi.org/10.1074/jbc.RA118.006629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635438PMC
July 2019

Apparent synonymous mutation F9 c.87A>G causes secretion failure by in-frame mutation with aberrant splicing.

Thromb Res 2019 Jul 1;179:95-103. Epub 2019 May 1.

Department of Pathophysiological Laboratory Science, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Introduction: Hemophilia B is an X-linked recessive bleeding disorder caused by coagulation factor IX (FIX) gene (F9) mutations. Several F9 synonymous mutations have been known to cause hemophilia B; however, the deleterious mechanisms underlying the development of hemophilia B have not been completely understood. To elucidate the molecular pathogenesis causing hemophilia B, we investigated the synonymous F9 mutation: c.87A>G, p.(Thr29=).

Materials And Methods: The influence of F9 c.87A>G on mRNA splicing was analyzed by exon-trap assay and in silico prediction. We prepared FIX expression vectors using mutant F9 cDNA and transfected HepG2 cells to investigate intracellular transport and extracellular secretion of FIX. Intracellular kinetics of the expressed FIX was examined by treatment with the proteasome inhibitor MG132.

Results: Exon-trap analysis revealed that F9 c.87A>G resulted in almost (99.1%) aberrant splicing (r.83_88del). In silico analysis predicted that F9 c.87A>G influenced the splicing pattern by generating an available aberrant 5' splice site. The aberrant F9 mRNA (r.83_88del) was translated to a mutant FIX p.Cys28_Val30delinsPhe with an in-frame mutation at the signal peptide cleavage site. Simultaneously, a small amount (0.9%) of mutant F9 r.87A>G translating into WT FIX p.Thr29 = was also observed. The mutant FIX was abnormally retained in the endoplasmic reticulum (ER) and was not extracellularly secreted. It appeared to be intracellularly degraded via proteasome-dependent degradation machinery.

Conclusion: F9 c.87A>G was found to cause abnormal mRNA splicing, r.83_88del, and produce the mutant FIX p.Cys28_Val30delinsPhe. The mutant FIX is an abnormal protein with extracellular secretory defects and is intracellularly eliminated via proteasome-dependent ER-associated degradation.
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http://dx.doi.org/10.1016/j.thromres.2019.04.022DOI Listing
July 2019

Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP.

J Med Econ 2019 Oct 5;22(10):1014-1021. Epub 2019 Jun 5.

Foundation IRCCS Ca ' Granda Maggiore Hospital Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center , Milan , Italy.

Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals, and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated hemophilia B patients aged ≥12 years (FIX ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A -test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. Seven articles investigating six rFIX products were identified. Median ABR, AsBR, and AjBR ranged from 0-3.0, 0-1.0, and 0-1.1 (means = 0.8-4.26, 0.13-2.6, and 0.34-2.85), respectively. rIX-FP achieved the lowest median and mean values in all three parameters. -tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. The low number of appropriate trials available for comparison limits the quantity of data available for comparison, and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably vs other rFIX products for prophylaxis in hemophilia B.
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http://dx.doi.org/10.1080/13696998.2019.1620246DOI Listing
October 2019

Ischaemic events are rare, and the prevalence of hypertension is not high in Japanese adults with haemophilia: First multicentre study in Asia.

Haemophilia 2019 Jul 2;25(4):e223-e230. Epub 2019 May 2.

Department of Blood Coagulation, Ogikubo Hospital, Tokyo, Japan.

Introduction: With the increasing life expectancy of patients with haemophilia (PWH), the number of PWH with age-related comorbidities, such as ischaemic events, is increasing.

Aim: We conducted this multicentre observational study to identify the risk factors for major ischaemic events in PWH.

Methods: This study was the first multicentre observational study, conducted with the participation of five haemophilia treatment centres in Japan, conducted in ≥30-year-old adult PWH. The latest data recorded in the medical charts between 1 January and 31 December 2016 were reviewed. Healthcare data collected from the National Health and Nutrition Survey were used as the control data.

Results: Data of a total of 711 patients were collected. Only two PWH (0.3%) had a history of ischaemic events. Age-adjusted analysis indicated that the prevalence of hypertension defined as a blood pressure of 140/90 mm Hg or over was similar in the PWH to that in the males of the general population. However, when hypertension was defined more strictly (≥130/85 mm Hg), the prevalence was significantly lower in PWH than in the general male population. The hypertension in PWH was associated with the age, BMI, CKD, HIV infection and inhibitors. In particular, the odds ratio for the presence of inhibitors was high (odds ratio = 7.529).

Conclusion: Whether the present results can be attributed to Japanese ethnicity or to the presence of haemophilia per se remains uncertain. We propose to initiate a prospective study for further investigation.
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http://dx.doi.org/10.1111/hae.13749DOI Listing
July 2019

Molecular basis of SERPINC1 mutations in Japanese patients with antithrombin deficiency.

Thromb Res 2019 Jun 11;178:159-170. Epub 2019 Apr 11.

Department of Pathophysiological Laboratory Science, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Background: Congenital antithrombin (AT) deficiency, which arises from various SERPINC1 defects, is an autosomal-dominant thrombophilic disorder associated with a high risk of recurrent venous thromboembolism.

Patients/methods: We investigated SERPINC1 defects in Japanese patients with congenital AT deficiency who developed venous thromboembolism or had a family history of deep vein thrombosis. We analyzed the full DNA sequences of SERPINC1 exons and exon-intron junctions by PCR-mediated direct sequencing. If no mutation was found, multiplex ligation-dependent probe amplification (MLPA) was conducted for the relative quantification of the copy number of all exons in SERPINC1. If splice-site mutations were detected, mRNA splicing abnormalities were further investigated using an in vitro cell-based exontrap assay.

Results: We identified 19 different SERPINC1 abnormalities, including 8 novel mutations, in 21 Japanese patients with AT deficiency. These abnormalities were distributed as follows: 9 missense mutations (42.9%), 3 nonsense mutations (14.3%), 1 splice-site mutation (4.8%), 2 small insertions (9.5%), 2 deletion mutations (9.5%) and 4 large deletions (19.0%). Cases with large deletions of SERPINC1 included Alu-mediated gene rearrangements and non-Alu-mediated complex gene rearrangements; the latter could conceivably be explained using the fork stalling and template switching (FoSTeS) model.

Conclusions: We identified a variety of SERPINC1 defects in Japanese patients with AT deficiency. The SERPINC1 mutations detected in patients with type I AT deficiency included single nucleotide missense or nonsense mutations, small intragenic insertions or deletions, and large genomic structural deletions. Large deletions of SERPINC1 were caused by various recurrent or non-recurrent complex genomic rearrangement mutations.
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http://dx.doi.org/10.1016/j.thromres.2019.04.004DOI Listing
June 2019

Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis.

Blood Rev 2019 05 3;35:43-50. Epub 2019 Mar 3.

Georgetown University Medical Center, Washington, DC, USA.

Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.
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http://dx.doi.org/10.1016/j.blre.2019.03.002DOI Listing
May 2019
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