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. 2015 Aug 1;5(2):101-9.
eCollection 2015.

Subtle renal dysfunction and bleeding risk in atrial fibrillation: symmetric dimethylarginine predicts HAS-BLED score

Nathan Ek Procter  1 , Jocasta Ball  2 , Tamila Heresztyn  1 , Vivek B Nooney  3 , Saifei Liu  1 , Cher-Rin Chong  1 , Doan Tm Ngo  1 , Jeffrey S Isenberg  4 , Yuliy Y Chirkov  1 , Simon Stewart  5 , John D Horowitz  1
Affiliations

Subtle renal dysfunction and bleeding risk in atrial fibrillation: symmetric dimethylarginine predicts HAS-BLED score

Nathan Ek Procter et al. Am J Cardiovasc Dis. .

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.

Keywords: Atrial fibrillation; platelet aggregation; symmetric dimethylarginine; thioredoxin-interacting protein; thrombospondin-1.

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Figures

Figure 1
Figure 1
Extent of ADP-induced platelet aggregation correlated significantly with HAS-BLED scores (r=-0.220, p<0.05).
Figure 2
Figure 2
Biochemical correlates of platelet aggregability in chronic atrial fibrillation. (A) Plasma asymmetric dimethylarginine (ADMA, r=-0.226, p<0.05); (B) Plasma symmetric dimethylarginine (SDMA, r=-0.308, p<0.01) concentrations correlated inversely with ADP-induced aggregation; (C) Estimated glomerular filtration rate (eGFR, r=0.250, p<0.05); (D) Plasma thrombospondin-1 (TSP-1) concentrations (r=0.262, p<0.01), and (E) platelet thioredoxin-interacting protein (Txnip) content (r=0.298, p<0.01) were all direct correlates of ADP-induced aggregation.
Figure 3
Figure 3
HAS-BLED scores correlated directly with (A), plasma symmetric dimethylarginine (SDMA) concentrations (r=0.478, p<0.001) and inversely with (B), glomerular filtration rate (eGFR, r=-0.573, p<0.001).
Figure 4
Figure 4
Symmetric dimethylarginine (SDMA) increased platelet aggregatory response to ADP when compared to controls (6.9±0.5 Ω vs 5.8±0.5 Ω, n=7, p<0.01 paired t-test).
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