title: Hypercoagulation following brain death cannot be reversed by the neutralization of systemic tissue factor.
abstract: BACKGROUND
  Cerebral injury and brain death is associated with apparent hypercoagulation and poor organ outcome. This experimental study challenges the hypotheses that i) brain death causes hypercoagulation and microvascular thrombosis and that ii) neutralizing systemic tissue factor (TF) by in vitro addition of a TF inhibitor (recombinant active site-inhibited factor VIIa (ASIS)) can reverse the hypercoagulable profile.
  
  
  METHODS
  Using a validated pig model of intracranial hemorrhage and brain death, 20 pigs were randomized to either control or brain death. The primary endpoints were coagulation parameters measured with whole blood thromboelastometry (ROTEM), thrombin generation and a porcine TF-sensitive plasma clotting time assay. In vitro spiking experiments with ASIS were performed in parallel with the latter two assessments. The kidneys were examined histologically for microvascular thromboses.
  
  
  RESULTS
  Brain death induced hypercoagulation, as demonstrated with ROTEM, thrombin generation, and reduced TF-sensitive plasma clotting time. In vitro inhibition of TF with ASIS did not reverse the hypercoagulation. No microvascular thromboses were found in the kidneys.
  
  
  CONCLUSIONS
  Brain death causes hypercoagulation; however, inhibition of TF does not reverse the coagulopathy. Thus, TF release does not seem to be the primary cause of this hypercoagulation. Minor changes in the levels of protein C suggest that the protein C pathway may be linked to the observed coagulopathy.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, 8000 Aarhus C, Denmark; Institute of Clinical Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark. Electronic address: c.hvas@ki.au.dk.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hvas
authors.forename: Christian
authors.initials: C
authors.lastname: Fenger-Eriksen
authors.forename: Søren
authors.initials: S
authors.lastname: Høyer
authors.forename: Benny
authors.initials: B
authors.lastname: Sørensen
authors.forename: Else
authors.initials: E
authors.lastname: Tønnesen
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D001926:Brain Death / Q000097:blood* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D011897:Random Allocation; D013552:Swine; D013916:Thrombelastography; D019851:Thrombophilia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
chemical_list: D013925:Thromboplastin
keywords: APTT; ASIS; Activated partial thromboplastin time; BD; BSA; Bovine serum albumin; Brain death; CCP; CT; CTI; Cerebral perfusion pressure; Clotting time; Corn trypsin inhibitor; ETP; Experimental animal models; Hypercoagulability; ICP; Intracerebral hemorrhage; MAP; MCF; MaxVel; Maximum clot firmness; Maximum velocity; Mean arterial pressure; PAI-1; PCT; PT; Plasminogen activator inhibitor-1; Protein C; Prothrombin time; ROTEM; SD; TF; Time to maximum velocity; Time to peak; Tissue factor; Tissue plasminogen activator; brain dead; endogenous thrombin potential; intracranial pressure; plasma clotting time; recombinant active site-inhibited factor VIIa; standard deviation; t; t, MaxVel; tPa; time; tissue factor; ttPeak; whole blood thromboelastometry