Publications by authors named "Atsuki Yamashita"

8 Publications

  • Page 1 of 1

C-terminal residues of activated protein C light chain contribute to its anticoagulant and cytoprotective activities.

J Thromb Haemost 2020 05 5;18(5):1027-1038. Epub 2020 Mar 5.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.

Background: Activated protein C (APC) is an important homeostatic blood coagulation protease that conveys anticoagulant and cytoprotective activities. Proteolytic inactivation of factors Va and VIIIa facilitated by cofactor protein S is responsible for APC's anticoagulant effects, whereas cytoprotective effects of APC involve primarily the endothelial protein C receptor (EPCR), protease activated receptor (PAR)1 and PAR3.

Objective: To date, several binding exosites in the protease domain of APC have been identified that contribute to APC's interaction with its substrates but potential contributions of the C-terminus of the light chain have not been studied in detail.

Methods: Site-directed Ala-scanning mutagenesis of six positively charged residues within G142-L155 was used to characterize their contributions to APC's anticoagulant and cytoprotective activities.

Results And Conclusions: K151 was involved in protein S dependent-anticoagulant activity of APC with some contribution of K150. 3D structural analysis supported that these two residues were exposed in an extended protein S binding site on one face of APC. Both K150 and K151 were important for PAR1 and PAR3 cleavage by APC, suggesting that this region may also mediate interactions with PARs. Accordingly, APC's cytoprotective activity as determined by endothelial barrier protection was impaired by Ala substitutions of these residues. Thus, both K150 and K151 are involved in APC's anticoagulant and cytoprotective activities. The differential contribution of K150 relative to K151 for protein S-dependent anticoagulant activity and PAR cleavage highlights that binding exosites for protein S binding and for PAR cleavage in the C-terminal region of APC's light chain overlap.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380734PMC
May 2020

Activated protein C anticoagulant activity is enhanced by skeletal muscle myosin.

Haematologica 2020 08 19;105(8):e424-e427. Epub 2019 Dec 19.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.242982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395292PMC
August 2020

Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice.

Blood 2019 01 15;133(3):193-204. Epub 2018 Nov 15.

Department of Medicine, University of California, San Diego, La Jolla, CA.

Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of ( ) or ( ), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of or Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the gene decreases brain hemorrhage in mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-06-856062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337879PMC
January 2019

First case report of hemophilia B Leyden in Japan.

Int J Hematol 2017 Jul 7;106(1):135-137. Epub 2017 Feb 7.

Department of Pediatrics, St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Kanagawa, Japan.

Hemophilia B Leyden is a unique subtype of hemophilia B, characterized by increasing factor IX activity (FIX:C) after puberty and a lower normal range of FIX:C throughout adulthood. However, to date, no Japanese case has been reported. Here, we report a case of hemophilia B Leyden in a 22-year-old male. He suffered from subgaleal hematoma, and was subsequently diagnosed with hemophilia B (FIX:C 0.2%) in the neonatal period. Both his parents are Japanese. There was no history of hemophilia in his family. FIX:C gradually increased with age (8% at age = 1; 14% at age = 7; 19% at age = 12; 32% at age = 18). FIX:C is within the range 30-40% in recent several years. He once required administration of FIX concentrate against traumatic tongue bleeding at 7 years of age. Genotyping analysis of FIX was performed after informed consent at 21 years of age, and a point mutation (c.-35G>A) was detected. This mutation has been reported previously as the Leyden mutation. Although it has been reported that hemophilia B Leyden is seen in 1.9% of patients with hemophilia B, the present case is the first report of hemophilia B Leyden from Japan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-017-2194-4DOI Listing
July 2017

Erratum to: A cohort study of the usefulness of primary prophylaxis in patients with severe haemophilia A.

Int J Hematol 2016 08;104(2):268

Department of Pediatrics, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Kanagawa, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-016-2055-6DOI Listing
August 2016

A cohort study of the usefulness of primary prophylaxis in patients with severe haemophilia A.

Int J Hematol 2016 08 28;104(2):208-15. Epub 2016 Apr 28.

Department of Pediatrics, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Kanagawa, Japan.

Primary prophylaxis is a method of haemostatic management to prevent bleeding and arthropathy in patients with severe haemophilia. The aim of this study was to evaluate the usefulness of primary prophylaxis in patients with severe haemophilia A. This study included 15 patients with haemophilia A who received primary prophylaxis at our institution for a minimum of 5 years. We evaluated the annualized bleeding ratio of joints or other sites, current joint function, and X-ray images and MRI scans taken when patients were 6 years old. The range of patients' ages at the end of the study was 6.2-16.8 years, and at the start of primary prophylaxis it was 0.8-2.4 years. Factor VIII concentrates (25-40 units kg(-1) dose(-1)) were administered 3 times/week or every other day, according to the Swedish protocol. Mean joint and non-joint annualized bleeding ratios were 0.49 ± 0.5 and 1.54 ± 1.69, respectively. At the final evaluation, all patients displayed a normal range of motion for both elbows, knees, and ankles. The radiography and MRI findings at the age of 6 were unremarkable in all patients. Overall, primary prophylaxis for patients with severe haemophilia A was performed safely, reduced the number of bleeding events, and prevented progression to arthropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-016-2005-3DOI Listing
August 2016

[Efficacy of chemotherapy combined with bortezomib for two cases of relapsed/refractory acute lymphoblastic leukemia].

Rinsho Ketsueki 2014 03;55(3):327-33

Department of Pediatrics, St. Marianna University School of Medicine Hospital.

Bortezomib (BZM), a proteasome inhibitor, was recently reported to be effective against acute lymphoblastic leukemia (ALL). We report two cases of relapsed/refractory ALL, who were treated with BZM (1.3 mg/m2/dose, 2 doses/week for 2 weeks) in combination with vincristine, doxorubicin, dexamethasone, and L-asparaginase (L-ASP). The first patient was a 16-year-old girl who developed a bone marrow relapse 8 months after the initial diagnosis during consolidation chemotherapy. She received BZM-combined chemotherapy without L-ASP considering her previous history of an allergic reaction to L-ASP. The BZM-combined regimen was discontinued due to interstitial pneumonia development on day 13, and the interstitial pneumonia was successfully treated with steroid pulse therapy. Although her elevated serum LDH transiently normalized on day 16, blasts in peripheral blood did not disappear, and she died of leukemia without achieving remission. The second patient was a 17-year-old girl who developed a third bone marrow relapse after cord blood transplantation. She was given the same BZM combined regimen. Although the BZM-combined regimen was discontinued due to acute pancreatitis development on day 12, complete remission without platelet recovery was confirmed on day 62. Our experience suggests not only the effectiveness of BZM-combined chemotherapy but also the importance of controlling its toxicities when administered as a salvage therapy for advanced ALL patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
March 2014
-->