title: Subtle renal dysfunction and bleeding risk in atrial fibrillation: symmetric dimethylarginine predicts HAS-BLED score.
abstract: BACKGROUND
  Risk of substantial haemorrhage represents a critically important limitation to effective anti-thrombotic treatment in patients with atrial fibrillation (AF). While it is known that this risk is increased in anticoagulated patients either in the presence of anti-aggregatory drugs or concomitant renal insufficiency, there are currently few data on the potential interactions between endogenous platelet aggregability and bleeding risk.
  
  
  OBJECTIVE
  We therefore evaluated in a cohort of AF patients: (1), the putative relationship between platelet aggregability and HAS-BLED score; (2), the potential biochemical bases for such a relationship.
  
  
  METHODS
  Patients were included as part of SAFETY, a randomised controlled trial evaluating outpatient management of AF patients. Platelet response to ADP was evaluated via whole blood impedance aggregometry; clinical and biochemical correlates of platelet aggregation were sought via univariate and multivariate analysis.
  
  
  RESULTS
  Platelet aggregation correlated inversely (r=-0.220, p<0.05) with HAS-BLED score. Univariate biochemical correlates of decreased platelet aggregation were plasma concentrations of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). On multivariate analyses, plasma SDMA concentration (β=-0.318, p<0.01), platelet content of thioredoxin-interacting protein (Txnip, β=0.261, p<0.05) and plasma thrombospondin-1 (TSP-1, β=0.249, p<0.05) concentration were predictive of platelet ADP response. Consistent with previous reports, plasma SDMA concentrations were strongly and inversely correlated with estimated glomerular filtration rate (eGFR, r=-0.780, p<0.001).
  
  
  CONCLUSIONS
  These data therefore suggest that (1), physiologically impaired, like pharmacologically impaired, platelet aggregability may increase bleeding risk in anticoagulated AF patients; (2), the biochemical basis for this may include impaired effects of nitric oxide (via Txnip, TSP-1) but also concomitant renal dysfunction.
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide Australia.
authors: Nathan Ek
authors: NE
authors: Procter
authors: Centre for The Heart and Mind, Mary MacKillop Institute for Health Research, Australian Catholic University Melbourne, Australia.
authors: Jocasta
authors: J
authors: Ball
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide Australia.
authors: Tamila
authors: T
authors: Heresztyn
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of South Australia Australia.
authors: Vivek B
authors: VB
authors: Nooney
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide Australia.
authors: Saifei
authors: S
authors: Liu
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide Australia.
authors: Cher-Rin
authors: CR
authors: Chong
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide Australia.
authors: Doan Tm
authors: DT
authors: Ngo
authors: Heart, Lung, Blood and Vascular Medicine Institute, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Pittsburgh, Pennsylvania, U.S.
authors: Jeffrey S
authors: JS
authors: Isenberg
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide Australia.
authors: Yuliy Y
authors: YY
authors: Chirkov
authors: National Health and Medical Research Council (NHMRC) Centre of Excellence to Reduce Inequality in Heart Disease, Mary MacKillop Institute for Health Research, Australian Catholic University Melbourne, Australia ; Baker IDI Heart and Diabetes Institute Melbourne, Australia.
authors: Simon
authors: S
authors: Stewart
authors: Basil Hetzel Institute, The Queen Elizabeth Hospital, University of Adelaide Australia.
authors: John D
authors: JD
authors: Horowitz
keywords: Atrial fibrillation; platelet aggregation; symmetric dimethylarginine; thioredoxin-interacting protein; thrombospondin-1