title: NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation.
abstract: BACKGROUND
  Large elevations of high sensitive Troponin T (hsTnT) in ischemic stroke patients is associated with a poor outcome. In a pilot study we found a high prevalence of malignancies among these patients. Since neutrophil extracellular traps (NETs) have been linked to cancer-associated thrombosis, we hypothesized that the concomitant cerebral and myocardial ischemia could be the result of a NET-induced hypercoagulable state.
  
  
  METHODS
  Clinical assessments, plasma analyses and autopsies with histopathology (in cases of in-hospital mortality) were performed on ischemic stroke patients with high elevations of hsTnT (N=12) and normal hsTnT (N=19).
  
  
  RESULTS
  Patients with hsTnT elevation had an unexpectedly higher prevalence of cancer (p=0.002), half of which were diagnosed post-mortem. Autopsies of these patients revealed widespread myocardial, cerebral and pulmonary microthrombosis with H3Cit in thrombi. A pro-coagulant state and an increase of the NET specific marker citrullinated histone H3 (H3Cit) was found in plasma of patients with elevated hsTnT compared to patients with normal levels (p<0.001). Plasma analyses in cancer patients showed even higher H3Cit levels (p<0.001), and an increase in granulocyte colony-stimulating factor, known to prime neutrophils towards NETosis. H3Cit correlated positively with thrombin-antithrombin complex (p=0.004) and soluble P-selectin (p<0.001), further linking NETosis to the pro-thrombotic state.
  
  
  CONCLUSIONS
  The high prevalence of known or occult cancer in our study suggests that cancer-associated arterial microthrombosis may be underestimated. By linking the thrombosis to NETs, we suggest markers of NETosis that could aid in revealing cancer in arterial microthrombosis as well as arterial microthrombosis in cancer.
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Thålin
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Demers
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Blomgren
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Siu Ling
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Arbin
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Department of Radiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: von Heijne
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ann Charlotte
authors.initials: AC
authors.lastname: Laska
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Wallén
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Electronic address: denisa.wagner@childrens.harvard.edu.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Aspberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D065206:Extracellular Traps / Q000378:metabolism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015539:Platelet Activation; D013927:Thrombosis / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020107:Troponin T / Q000097:blood* / Q000378:metabolism
chemical_list: D020107:Troponin T; D016179:Granulocyte Colony-Stimulating Factor
keywords: Cancer-associated microvascular thrombosis; Ischemic stroke; Neutrophil extracellular traps; Troponin elevation