title: Modulation of protein C activation by histones, platelet factor 4, and heparinoids: new insights into activated protein C formation.
abstract: OBJECTIVE
  Histones are detrimental in late sepsis. Both activated protein C (aPC) and heparin can reverse their effect. Here, we investigated whether histones can modulate aPC generation in a manner similar to another positively charged molecule, platelet factor 4, and how heparinoids (unfractionated heparin or oxygen-desulfated unfractionated heparin with marked decrease anticoagulant activity) may modulate this effect.
  
  
  RESULTS
  We measured in vitro and in vivo effects of histones, platelet factor 4, and heparinoids on aPC formation, activated partial thromboplastin time, and murine survival. In vitro, histones and platelet factor 4 both affect thrombin/thrombomodulin aPC generation following a bell-shaped curve, with a peak of >5-fold enhancement. Heparinoids shift these curves rightward. Murine aPC generation studies after infusions of histones, platelet factor 4, and heparinoids supported the in vitro data. Importantly, although unfractionated heparin and 2-O, 3-O desulfated heparin both reversed the lethality of high-dose histone infusions, only mice treated with 2-O, 3-O desulfated heparin demonstrated corrected activated partial thromboplastin times and had significant levels of aPC.
  
  
  CONCLUSIONS
  Our data provide a new contextual model of how histones affect aPC generation, and how heparinoid therapy may be beneficial in sepsis. These studies provide new insights into the complex interactions controlling aPC formation and suggest a novel therapeutic interventional strategy.
authors.affiliation: From the Department of Pediatrics, The Children's Hospital of Philadelphia, PA (M.A.K., G.Z., L.Z., G.D., S.K., M.P.); ParinGenix, Weston, FL (S.M.); and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA (SK., M.P.).
authors.forename: M Anna
authors.initials: MA
authors.lastname: Kowalska
authors.forename: Guohua
authors.initials: G
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Zhai
authors.forename: George
authors.initials: G
authors.lastname: David
authors.forename: Stephen
authors.initials: S
authors.lastname: Marcus
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswamy
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006493:Heparin / Q000031:analogs & derivatives / Q000494:pharmacology; D006496:Heparinoids / Q000494:pharmacology*; D006657:Histones / Q000097:blood*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010314:Partial Thromboplastin Time; D010978:Platelet Factor 4 / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D011486:Protein C / Q000378:metabolism*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D006496:Heparinoids; D006657:Histones; C520325:N-desulfated,2-O,3-O-desulfated heparin; D011486:Protein C; C546931:THBD protein, human; C569169:THBD protein, mouse; D018180:Thrombomodulin; D010978:Platelet Factor 4; D006493:Heparin; D013917:Thrombin
keywords: activated protein C resistance; heparin; histones; platelet factor 4