title: Histone deacetylase inhibitor treatment attenuates coagulation imbalance in a lethal murine model of sepsis.
abstract: BACKGROUND
  Sepsis has a profound impact on the inflammatory and hemostatic systems. In addition to systemic inflammation, it can produce disseminated intravascular coagulation, microvascular thrombosis, consumptive coagulopathy, and multiple organ failure. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice, but its effect on coagulation remains unknown. The goal of this study was to quantify the impact of SAHA treatment on coagulopathy in sepsis.
  
  
  METHODS
  C57BL/6J mice were subjected to CLP, and 1 hour later given intraperitoneally either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Sham-operated animals were handled in similar manner without CLP. Blood samples were collected by cardiac puncture and evaluated using the TEG 5000 Thrombelastograph Hemostasis Analyzer System.
  
  
  RESULTS
  Compared with the sham group, all animals in DMSO vehicle group died within 72 hours, and developed coagulopathy that manifested as prolonged initial fibrin formation and fibrin cross-linkage time, and decreased clot formation speed, platelet function, and clot rigidity. SAHA treatment significantly improved survival and was associated with improvement in fibrin cross-linkage and clot formation, as well as platelet function and clot rigidity, without a significant impact on the clot initiation parameters.
  
  
  CONCLUSIONS
  SAHA treatment enhances survival and attenuates sepsis-associated coagulopathy by improving fibrin cross-linkage, rate of clot formation, platelet function, and clot strength. HDACI may represent a novel therapeutic strategy for correcting sepsis-associated coagulopathy.
authors: Department of Surgery, Division of Trauma, Emergency Surgery & Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors: Ting
authors: T
authors: Zhao
authors: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors: Yongqing
authors: Y
authors: Li
authors: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors: Baoling
authors: B
authors: Liu
authors: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND.
authors: Erxi
authors: E
authors: Wu
authors: Department of Surgery, Division of Trauma, Emergency Surgery & Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA; Department of Anesthesia, Center of Head and Orthopedics, Copenhagen University Hospital, Copenhagen, Denmark.
authors: Martin
authors: M
authors: Sillesen
authors: Department of Surgery, Division of Trauma, Emergency Surgery & Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors: George C
authors: GC
authors: Velmahos
authors: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors: Ihab
authors: I
authors: Halaweish
authors: Department of Surgery, University of Michigan, Ann Arbor, MI. Electronic address: alamh@med.umich.edu.
authors: Hasan B
authors: HB
authors: Alam
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001778:Blood Coagulation Disorders / Q000209:etiology / Q000517:prevention & control; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000517:prevention & control; D005337:Fibrin / Q000737:chemistry / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D013916:Thrombelastography; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D005337:Fibrin