title: Contact system activation and high thrombin generation in hyperthyroidism.
abstract: BACKGROUND
  Hyperthyroidism is associated with increased thrombotic risk. As contact system activation through formation of neutrophil extracellular traps (NET) has emerged as an important trigger of thrombosis, we hypothesized that the contact system is activated along with active NET formation in hyperthyroidism and that their markers correlate with disease severity.
  
  
  METHODS
  In 61 patients with hyperthyroidism and 40 normal controls, the levels of coagulation factors (fibrinogen, and factor VII, VIII, IX, XI and XII), D-dimer, thrombin generation assay (TGA) markers, NET formation markers (histone-DNA complex, double-stranded DNA and neutrophil elastase) and contact system markers (activated factor XII (XIIa), high-molecular-weight kininogen (HMWK), prekallikrein and bradykinin) were measured.
  
  
  RESULTS
  Patients with hyperthyroidism showed higher levels of fibrinogen (median (interquartile range), 315 (280-344) vs 262 (223-300),P= 0.001), D-dimer (103.8 (64.8-151.5) vs 50.7 (37.4-76.0),P< 0.001), peak thrombin (131.9 (102.2-159.4) vs 31.6 (14.8-83.7),P< 0.001) and endogenous thrombin potential (649 (538-736) vs 367 (197-1147),P= 0.021) in TGA with 1 pM tissue factor, neutrophil elastase (1.10 (0.39-2.18) vs 0.23 (0.20-0.35),P< 0.001), factor XIIa (66.9 (52.8-87.0) vs 73.0 (57.1-86.6),P< 0.001), HMWK (6.11 (4.95-7.98) vs 3.83 (2.60-5.68),P< 0.001), prekallikrein (2.15 (1.00-6.36) vs 1.41 (0.63-2.22),P= 0.026) and bradykinin (152.4 (137.6-180.4) vs 118.3 (97.1-137.9),P< 0.001) than did normal controls. In age- and sex-adjusted logistic regression analysis, fibrinogen, factor VIII, IX and XIIa, D-dimer, peak thrombin, neutrophil elastase, HMWK and bradykinin showed significant odds ratios representing hyperthyroidism's contribution to coagulation and contact system activation. Free T4 was significantly correlated with factors VIII and IX, D-dimer, double-stranded DNA and bradykinin.
  
  
  CONCLUSIONS
  This study demonstrated that contact system activation and abundant NET formation occurred in the high thrombin generation state in hyperthyroidism and were correlated with free T4 level.
authors.affiliation: Department of Laboratory Medicine and Cancer Research InstituteSeoul National University College of Medicine, Seoul, Korea.
authors.forename: Namhee
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Cancer Research InstituteSeoul National University College of Medicine, Seoul, Korea.
authors.forename: Ja-Yoon
authors.initials: JY
authors.lastname: Gu
authors.affiliation: Department of Laboratory Medicine and Cancer Research InstituteSeoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Yoo
authors.affiliation: Department of Internal MedicineUlsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Han
authors.affiliation: Department of Internal MedicineUlsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Kim
authors.affiliation: Department of Internal MedicineUlsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: Il Sung
authors.initials: IS
authors.lastname: Nam-Goong
authors.affiliation: Department of Internal MedicineUlsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Cancer Research InstituteSeoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Kim
mesh_terms: D000328:Adult; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000032:analysis; D001920:Bradykinin / Q000097:blood; D004247:DNA / Q000097:blood / Q000378:metabolism; D065206:Extracellular Traps / Q000502:physiology*; D015956:Factor XIIa / Q000032:analysis; D005260:Female; D006657:Histones / Q000097:blood / Q000378:metabolism; D006801:Humans; D006980:Hyperthyroidism / Q000378:metabolism*; D019679:Kininogen, High-Molecular-Weight / Q000097:blood; D019272:Leukocyte Elastase / Q000097:blood; D008297:Male; D008875:Middle Aged; D011288:Prekallikrein / Q000032:analysis; D013917:Thrombin / Q000096:biosynthesis*; D013974:Thyroxine / Q000097:blood
chemical_list: D001779:Blood Coagulation Factors; D006657:Histones; D019679:Kininogen, High-Molecular-Weight; D004247:DNA; D011288:Prekallikrein; D019272:Leukocyte Elastase; D015956:Factor XIIa; D013917:Thrombin; D013974:Thyroxine; D001920:Bradykinin