title: Traumatic brain injury causes platelet adenosine diphosphate and arachidonic acid receptor inhibition independent of hemorrhagic shock in humans and rats.
abstract: BACKGROUND
  Coagulopathy in traumatic brain injury (CTBI) is a well-established phenomenon, but its mechanism is poorly understood. Various studies implicate protein C activation related to the global insult of hemorrhagic shock or brain tissue factor release with resultant platelet dysfunction and depletion of coagulation factors. We hypothesized that the platelet dysfunction of CTBI is a distinct phenomenon from the coagulopathy following hemorrhagic shock.
  
  
  METHODS
  We used thrombelastography with platelet mapping as a measure of platelet function, assessing the degree of inhibition of the adenosine diphosphate (ADP) and arachidonic acid (AA) receptor pathways. First, we studied the early effect of TBI on platelet inhibition by performing thrombelastography with platelet mapping on rats. We then conducted an analysis of admission blood samples from trauma patients with isolated head injury (n = 70). Patients in shock or on clopidogrel or aspirin were excluded.
  
  
  RESULTS
  In rats, ADP receptor inhibition at 15 minutes after injury was 77.6% ± 6.7% versus 39.0% ± 5.3% for controls (p < 0.0001). Humans with severe TBI (Glasgow Coma Scale [GCS] score ≤ 8) showed an increase in ADP receptor inhibition at 93.1% (interquartile range [IQR], 44.8-98.3%; n = 29) compared with 56.5% (IQR, 35-79.1%; n = 41) in milder TBI and 15.5% (IQR, 13.2-29.1%) in controls (p = 0.0014 and p < 0.0001, respectively). No patient had significant hypotension or acidosis. Parallel trends were noted in AA receptor inhibition.
  
  
  CONCLUSIONS
  Platelet ADP and AA receptor inhibition is a prominent early feature of CTBI in humans and rats and is linked to the severity of brain injury in patients with isolated head trauma. This phenomenon is observed in the absence of hemorrhagic shock or multisystem injury. Thus, TBI alone is shown to be sufficient to induce a profound platelet dysfunction.
authors.affiliation: From the W. M Keck Center for Transgene Research (F.J.C., D.L.D., V.P., P.D., M.W.), University of Notre Dame, Notre Dame; and Memorial Hospital of South Bend (S.T., R.Y., E.E., M.W.), Emergency Trauma Center; and Indiana University School of Medicine at Notre Dame Campus (B.F., P.D., M.W.), South Bend, Indiana; Department of Surgery (M.P.C., E.E.M., M.V.W.), University of Colorado; and Department of Surgery (M.P.C., E.E.M., M.V.W.), Denver Health Medical Center, Denver, Colorado; Department of Surgery (M.P.C.), Georgia Health Sciences University, Augusta, Georgia.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: Michael P
authors.initials: MP
authors.lastname: Chapman
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Donahue
authors.forename: Scott
authors.initials: S
authors.lastname: Thomas
authors.forename: Ernest E
authors.initials: EE
authors.lastname: Moore
authors.forename: Max V
authors.initials: MV
authors.lastname: Wohlauer
authors.forename: Braxton
authors.initials: B
authors.lastname: Fritz
authors.forename: Robert
authors.initials: R
authors.lastname: Yount
authors.forename: Victoria
authors.initials: V
authors.lastname: Ploplis
authors.forename: Patrick
authors.initials: P
authors.lastname: Davis
authors.forename: Edward
authors.initials: E
authors.lastname: Evans
authors.forename: Mark
authors.initials: M
authors.lastname: Walsh
mesh_terms: D000328:Adult; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000097:blood; D001778:Blood Coagulation Disorders / Q000097:blood / Q000209:etiology*; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000502:physiology; D001930:Brain Injuries / Q000097:blood* / Q000150:complications*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000502:physiology; D010979:Platelet Function Tests; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D018570:Risk Assessment; D012771:Shock, Hemorrhagic / Q000097:blood* / Q000209:etiology*; D018709:Statistics, Nonparametric; D013916:Thrombelastography
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D016718:Arachidonic Acid
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