title: Continuous thrombin infusion leads to a bleeding phenotype in sheep.
abstract: BACKGROUND
  In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We aimed to establish an ovine model to study thrombin effects in vivo.
  
  
  METHODS
  Thrombin (0.0004-0.42 IU/kg/min) was continuously infused in Austrian Mountain Sheep over five hours in the dose escalation study (n=5 animals; 15 experiments). In the dose verification study animals received 0.42 IU/kg/min of thrombin vs. saline solution in a cross-over design (n=3 animals; 7 experiments).
  
  
  RESULTS
  Thrombin at an infusion rate of 0.42 IU/kg/min decreased fibrinogen levels by 75% (p<0.001) and increased degradation products of the fibrinogen beta-chain as shown in a proteomic analysis. Thrombin decreased platelet counts by 36% (p=0.006), prolonged thrombin time by 70% (p=0.012) and activated partial thromboplastin time by 32%. Interestingly, thrombin infusion significantly increased the activity of coagulation factors V and X (p<0.05) and decreased the activity of the coagulation factors VIII and XIII (p<0.05). Accordingly, thrombin displayed predominantly anti-coagulant and anti-platelet effects: 1) thrombin prolonged clotting time/clot formation time 7-fold (p=0.019) and induced a 65% decrease in maximal clot firmness (p<0.001); 2) thrombin reduced collagen- induced platelet aggregation by 85% and prolonged collagen/adenosine diphosphate closure time 3-fold; and 3) thrombin caused lung haemorrhage but not thromboembolism.
  
  
  CONCLUSIONS
  Protracted intravenous infusion of thrombin over a period of five hours offers a new experimental model to study thrombin effects in a large animal species.
authors.affiliation: Department of Cardiology, Medical University of Vienna, Austria. jolanta.siller-matula@meduniwien.ac.at
authors.forename: Jolanta M
authors.initials: JM
authors.lastname: Siller-Matula
authors.forename: Ingrid
authors.initials: I
authors.lastname: Miller
authors.forename: Manfred
authors.initials: M
authors.lastname: Gemeiner
authors.forename: Roberto
authors.initials: R
authors.lastname: Plasenzotti
authors.forename: Guenther
authors.initials: G
authors.lastname: Bayer
authors.forename: Ildiko
authors.initials: I
authors.lastname: Mesteri
authors.forename: Astrid
authors.initials: A
authors.lastname: Fabry
authors.forename: Karin
authors.initials: K
authors.lastname: Petroczi
authors.forename: Katharina
authors.initials: K
authors.lastname: Nöbauer
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Razzazi-Fazeli
authors.forename: Sébastien
authors.initials: S
authors.lastname: Planchon
authors.forename: Jenny
authors.initials: J
authors.lastname: Renaut
authors.forename: Peter
authors.initials: P
authors.lastname: Quehenberger
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D061605:Administration, Intravenous; D000595:Amino Acid Sequence; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism; D005340:Fibrinogen / Q000032:analysis / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced* / Q000473:pathology; D006490:Hemostatics / Q000008:administration & dosage / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010976:Platelet Count; D010979:Platelet Function Tests; D040901:Proteomics; D012756:Sheep / Q000097:blood* / Q000378:metabolism; D013916:Thrombelastography; D013917:Thrombin / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D001798:Blood Proteins; D006490:Hemostatics; D005340:Fibrinogen; D013917:Thrombin