Publications by authors named "JaYoon Gu"

8 Publications

  • Page 1 of 1

Double positivity of anti-β-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies enhances both thrombosis and positivity of anti-ADAMTS13 antibody.

J Thromb Thrombolysis 2021 Apr 29. Epub 2021 Apr 29.

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

Although a few antiphospholipid syndrome (APS) occurs with acquired thrombotic thrombocytopenic purpura (TTP), the relationship between antiphospholipid antibodies (aPL) and anti-ADAMTS13 (anti-a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) antibody remains uncertain. We investigated the relationship between high-risk thrombotic aPL and anti-ADAMTS13 antibody. Two hundred and thirty-seven patients with positive lupus anticoagulant and/or anticardiolipin antibody were included. Anti-βGPI (anti-β-glycoprotein I), anti-βGPIdI (anti-β2-glycoprotein I domain I), anti-PS/PT (anti-phosphatidylserine and prothrombin), ADAMTS13 activity, and anti-ADAMTS13 antibody were measured. Double positivity of anti-βGPI and anti-PS/PT increased thrombotic risk more than three-fold and showed increased positivity of anti-ADAMTS13 antibody in comparison with the double negative group. Double positivity of anti-βGPIdI and anti-PS/PT presented both effects even more. In the linear regression analysis, double positivity of anti-βGPI and anti-PS/PT independently affected the anti-ADAMTS13 antibody level (β = 1.982, P = 0.042). Our results revealed that double positivity of anti-βGPI or anti-βGPIdI and anti-PS/PT increased not only thrombotic risk but also the positivity of anti-ADAMTS13 antibody, especially indicating anti-βGPIdI showed a higher synergistic effect with anti-PS/PT. We suggest a possible association of anti-ADAMTS13 antibody with a high thrombotic risk of APS. Double positivity of anti-βGPI (anti-β-glycoprotein I) and anti-PS/PT (anti-phosphatidylserine and prothrombin) antibodies enhanced not only thrombotic risk but also positivity of anti-ADAMTS13 (anti-a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) antibody. Furthermore, double positivity of anti-βGPIdI (anti-β2-glycoprotein I domain I) combined with anti-PS/PT even more elevated both thrombosis and positivity of anti-ADAMTS13 antibody. Double positivity of βGPI and anti-PS/PT was found as an independently significant contributing factor to anti-ADAMTS13 antibody level. We suggest the association between anti-ADAMTS13 antibody and the pathophysiology of antiphospholipid syndrome, which should be further evaluated.
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http://dx.doi.org/10.1007/s11239-021-02406-6DOI Listing
April 2021

Cancer cell-induced neutrophil extracellular traps promote both hypercoagulability and cancer progression.

PLoS One 2019 29;14(4):e0216055. Epub 2019 Apr 29.

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

Introduction: Neutrophils can generate extracellular net-like structures by releasing their DNA-histone complexes and antimicrobial peptides, which is called neutrophil extracellular traps (NETs). Various stimuli can induce NET formation. In particular, neutrophils and NET formation are abundant in tumor tissue. This study investigated how cancer cells induce NET formation and whether this NET formation promotes plasma thrombin generation and cancer progression.

Methods: Induction of NET formation by a pancreatic cancer cell line (AsPC-1) was assessed by measuring the histone-DNA complex level. The endogenous thrombin potential (ETP) was measured by thrombin generation assay. In vitro migration, invasion, and tubule formation assays were performed. The circulating levels of NET markers and hypercoagulability markers were assessed in 62 patients with pancreatobiliary malignancy and 30 healthy controls.

Results: AsPC-1 significantly induced NET formation in a dose-dependent manner. Conditioned medium (CM) from AsPC-1 also induced NETs. Interestingly, NET-formation was abolished by heat-inactivated CM, but not by lipid-extracted CM, suggesting an important role of protein components. A reactive oxygen species inhibitor did not inhibit cancer cell-induced NET formation, but prostaglandin E1 (PGE1, cyclic adenosine monophosphate inducer) and antithrombin did. NETs significantly increased ETP of normal plasma. Of note, NETs promoted cancer cell migration and invasion as well as angiogenesis, which were inhibited by histone-binding agents (heparin, polysialic acid), a DNA-degrading enzyme, and Toll-like receptor neutralizing antibodies. In patients with pancreatobiliary malignancy, elevated NET markers correlated well with hypercoagulability makers.

Conclusion: Our findings indicate that cancer cell-induced NET formation enhances both hypercoagulability and cancer progression and suggest that inhibitors of NET formation such as PGE1 and antithrombin can be potential therapeutics to reduce both hypercoagulability and cancer progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488070PMC
January 2020

A Novel Mutation Resulting in Variable Phenotypes and Pyridoxine Response in a Family with X-linked Sideroblastic Anemia.

Ann Clin Lab Sci 2017 May;47(3):319-322

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea

We report a novel gene mutation c.1315A>G (p.Lys439Glu) identified in a family, which caused evidently different hematologic phenotypes. The proband was a 17-year-old man with severe microcytic hypochromic anemia, excessive ring sideroblasts in the bone marrow, and iron overload. A hemizygous mutation in exon 9, c.1315A>G (p.Lys439Glu), was identified through sequence analysis. We assume that this amino acid substitution affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5'-phosphate, since the patient was responsive to pyridoxine treatment. This novel mutation likely accounts for variable hematologic phenotypes in the family of this patient: his 15-year-old hemizygous brother was asymptomatic, while his heterozygous mother was mildly anemic.
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May 2017

Coexistence of anti-β2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk.

Clin Chem Lab Med 2017 May;55(6):882-889

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of.

Background: Highly specific assays for measuring antiphospholipid antibodies (aPLs) are required for accurate assessment of thrombotic risk. aPLs against β2-glycoprotein I domain I (anti-β2GPIdI) and against prothrombin complexed with phosphatidylserine (anti-PS/PT) have been recently identified as being associated with a hypercoagulable state. This study evaluated the synergism between anti-β2GPIdI and anti-PS/PT for predicting thrombotic events.

Methods: A total of 180 patients with clinical suspicion of hypercoagulability were evaluated. The plasma levels of lupus anticoagulant (LA) and antibodies against anticardiolipin (anti-CL) (IgG and IgM), β2GPI (IgG and IgM), PS/PT (IgG and IgM), and β2GPI dI (IgG) were measured.

Results: IgG anti-β2GPIdI and LA were highly associated with thrombosis. Mean values and positivity rates of IgG anti-β2GPI dI and IgG anti-PS/PT were significantly higher in the triple-positive group (LA+, IgG anti-CL+, IgG anti-β2GPI+) than in the other groups. Interestingly, the thrombotic risk [odds ratio (OR) 24.400, 95% confidence interval (CI) 1.976-63.273, p<0.001] of the newly defined triple positive group (LA+, IgG anti-CL+, IgG anti-β2GPIdI+; OR 11.182, 95% CI 1.976-63.273, p=0.006) was more than twice that of the triple-positive group (LA+, IgG anti-CL+, IgG anti-β2GPI+). Double positivity for IgG anti-PS/PT and IgG anti-β2GPI also indicated significant thrombotic risk (OR 7.467, 95% CI 2.350-23.729, p=0.001). Furthermore, the thrombotic risk associated with double positivity for IgG anti-PS/PT and IgG anti-β2GPIdI was markedly elevated (OR 33.654, 95% CI 6.322-179.141, p<0.001).

Conclusions: Our data suggest that simultaneous measurement of IgG anti-β2GPIdI and IgG anti-PS/PT may improve clinical decision-making for aPL-positive patients.
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http://dx.doi.org/10.1515/cclm-2016-0676DOI Listing
May 2017

Acquired Dysfibrinogenemia Caused by Autoantibody Inhibiting Fibrin Polymerization in a Patient with MELAS Syndrome and Bleeding Tendency.

Ann Clin Lab Sci 2016 Dec;46(6):696-700

Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea

We present a case of acquired dysfibrinogenemia caused by an autoantibody that inhibited fibrin polymerization in a patient previously diagnosed with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes). The patient showed prolonged PT, aPTT, and thrombin time. There was no factor deficiency but fibrinogen antigen and activity were decreased. ELISA for detection of fibrinogen antibodies were performed and IgG purified from the patient's plasma bound to fibrinogen more strongly than did control IgG, indicating the presence of a fibrinogen-specific antibody. Thrombin-mediated fibrin polymerization was severely impaired in the patient, although thrombin-induced fibrinopeptide A release was normal. Scanning electron microscopy was used to investigate the structure of fibrin clots and revealed many pores on the surface of patient's fibrin clots. Since MELAS is often associated with autoimmune disorders, a work-up for the presence of anti-fibrinogen antibody is necessary when bleeding tendency occurs in MELAS patients along with prolonged thrombin time.
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December 2016

Extracellular Histone Released from Leukemic Cells Increases Their Adhesion to Endothelium and Protects them from Spontaneous and Chemotherapy-Induced Leukemic Cell Death.

PLoS One 2016 5;11(10):e0163982. Epub 2016 Oct 5.

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.

Introduction: When leukocytes are stimulated by reactive oxygen species (ROS), they release nuclear contents into the extracellular milieu, called by extracellular traps (ET). The nuclear contents are mainly composed of the histone-DNA complex and neutrophil elastase. This study investigated whether leukemic cells could release ET and the released histone could induce endothelial activation, eventually resulting in leukemic progression.

Methods: The circulating ET were measured in 80 patients with hematologic diseases and 40 healthy controls. ET formation and ROS levels were investigated during leukemic cell proliferation in vitro. Histone-induced endothelial adhesion molecules expression and cell survival were measured by flow cytometry.

Results: Acute leukemia patients had high levels of ET, which correlated with peripheral blast count. Leukemic cells produced high ROS levels and released extracellular histone, which was significantly blocked by antioxidants. Histone significantly induced 3 endothelial adhesion molecules expression, and promoted leukemic cell adhesion to endothelial cells, which was inhibited by histone inhibitors (heparin, polysialic acid, and activated protein C), neutralizing antibodies against these adhesion molecules, and a Toll like receptor(TLR)9 antagonist. When leukemic cells were co-cultured with endothelial cells, adherent leukemic cells showed better survival than the non-adherent ones, demonstrating that histone-treated endothelial cells protected leukemic cells from both spontaneous and chemotherapy-induced death.

Conclusion: Our data demonstrate for the first time that extracellular histone can be released from leukemic cells through a ROS-dependent mechanism. The released histone promotes leukemic cell adhesion by inducting the surface expression of endothelial adhesion molecules and eventually protects leukemic cells from cell death.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163982PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051947PMC
June 2017

Factor XII-mediated contact activation related to poor prognosis in disseminated intravascular coagulation.

Thromb Res 2016 Feb 15;138:103-107. Epub 2015 Dec 15.

Department of Laboratory Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: The contact system that initiates the intrinsic coagulation pathway plays a role in thrombus formation. Since neutrophil extracellular traps (NET), which are mainly composed of histone and DNA, are actively formed in disseminated intravascular coagulation (DIC) and the NET can activate factor XII, it is plausible that a NET component strongly activates the contact system in patients with DIC.

Methods: In 146 patients suspected of having DIC, the plasma levels of contact system factors including factor XII, activated factor XII (XIIa), prekallikrein, high-molecular-weight kininogen (HMWK), bradykinin, extrinsic factor VII and histone–DNA complex were measured. In an in vitro plasma clotting assay, factor XII–deficient plasma was stimulated with silica or histone.

Results: The levels of not only extrinsic coagulation factor VII but also intrinsic coagulation factors including factors XI and XII were significantly decreased in patients with overt DIC in comparison with those with no overt DIC. Factor XIIa and histone-DNA complex were also significantly increased in patients with overt DIC. However,HMWK, prekallikrein and bradykin inw ere not significantly different between patients with and without overt DIC. Interestingly, factors XII and XIIa were revealed as significantly independent potential prognostic markers for DIC. The histone-DNA complex level significantly contributed to the factor XIIa level (20.6%). In an in vitro clotting assay, histone, a major component of NET, activated coagulation that was dependent, in part, on the presence of factor XII.

Conclusion: These findings suggest that active NET formation can induce factor XII-mediated coagulation activation in patients with DIC with poor prognosis. The resulting factor XIIa release can be used as an independent potential prognostic marker for DIC. Activation of factor XII-mediated coagulation may be a potential therapeutic target in DIC,
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http://dx.doi.org/10.1016/j.thromres.2015.12.011DOI Listing
February 2016

Beneficial effect of a nitric oxide donor in an ex vivo model of pig-to-human pulmonary xenotransplantation.

Xenotransplantation 2015 Sep-Oct;22(5):391-8

Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Background: Nitric oxide (NO) can reduce platelet adhesion and vascular resistance. Tempol can scavenge the reactive oxygen species (ROS) that induce tissue injury. As xenograft rejection attenuates endogenous NO production and generates ROS, we evaluated the potential effect of an NO donor (SIN-1, 3-morpholinosydnonimine) and tempol on hyperacute xenograft dysfunction using an ex vivo porcine lung perfusion model.

Methods: For the evaluation of von Willebrand factor (vWF) secretion, human endothelial cells were stimulated with thrombin. Porcine lungs were perfused with either fresh human whole blood (unmodified control group [n = 4]), SIN-1 (n = 4), or SIN and tempol (n = 4).

Results: SIN-1 and tempol significantly inhibited vWF secretion from endothelial cells in vitro. However, they did not suppress xenogeneic complement activation. In an ex vivo pulmonary perfusion model, SIN-1 improved pulmonary xenograft function by reducing pulmonary vascular resistance (PVR), inhibiting complement activation, and inhibiting thrombin generation. Combined treatment with tempol and SIN-1 potentiated PVR reduction, but slightly enhanced complement activation.

Conclusions: An NO donor is expected to improve pulmonary xenograft function through inhibition of vWF secretion, vasoconstriction, thrombin generation, and indirectly through inhibition of complement activation. The additional effects of tempol on an NO donor were not considered significant in an ex vivo xenograft system.
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http://dx.doi.org/10.1111/xen.12195DOI Listing
June 2016
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