PD-L2 as potential novel biomarker of arterial thromboembolic risk in AF

A Targeted Proteomic Approach Identifies Novel Biomarkers of Arterial Thromboembolic Risk in ENGAGE AF-TIMI 48

Literature - Berg DD, Giugliano RP, Ruff CT et al., - JACC 2021;78C (6):632-641, https://doi.org/10.1016/j.jacc.2021.06.008

Introduction and methods


Clinical risk scores such as CHA2DS2-VASc are recommended to estimate thromboembolic risk in patients with AF, but circulating biomarkers may improve risk stratification [1]. Studies of candidate biomarkers may be useful but come with a priori expectations.

In this analysis, multiplex biomarker testing was used to identify novel biological pathways associated with risk of ischemic stroke or systemic embolic event (IS/SEE) in patients with AF.


A nested case-control study was performed in 376 patients enrolled in the biomarker cohort of the ENGAGE AF-TIMI 48 trial. In the ENGAGE AF-TIMI 48 trial, the effect of edoxaban vs. warfarin was examined on prevention of stroke/SEE in patients with AF and CHADS2 score≥2 [2]. Blood samples were collected at randomization. 184 Biomarkers using proteomic panels were analyzed.

Cases were selected among patients with an ischemic stroke or SEE during follow-up (n=188) and control subjects were matched on age, sex, history of stroke or transient ischemic attack and creatine clearance (n=188).

Main results

  • 3 Biomarkers (1.6%) were associated with IS/SEE (at the false discovery rate threshold): programmed cell death 1 ligand 2 (PD-L2) (OR per 1 SD: 1.62, 95%CI:1.26-2.10), GDF-15 (OR per 1 SD: 1.55, 95%CI:1.21-1.99), and NT-proBNP (OR per 1 SD: 1.54, 95%CI: 1.20-1.97.
  • After adjusting for clinical covariates, these 3 biomarkers remained associated with IS/SEE risk.
  • When categorized into quartiles, baseline PD-L2 was stepwise associated with IS/SEE risk (quartile 4 vs quartile 1: OR 4.38, 95%CI:2.11-9.10).
  • PD-L2 was less correlated with NT-proBNP (r=0.18) or GDF-15 (r=0.27) than NT-proBNP and GDF-15 were with each other (r=0.50).
  • In a multimarker model including NT-proBNP, GDF-15, components of the CHA2DS2-VASc score, the association of PD-L2 with IS/SEE was still significant (adjusted OR per 1 SD: 1.54, 95%CI:1.18-2.02).


This targeted proteomic approach identified PD-L2 as a possible novel biomarker of IS/SEE risk in patients with AF.

PD-L2 is 1 of 2 ligands for programmed cell death protein 1 (PD-1), a transmembrane receptor protein expressed on T lymphocytes. PD-1 play an important role in the regulation of T-cells and inhibition of immune activation. A relationship between the PD-1 axis and IS/SEE has not been previously identified.


1. Berg DD, Ruff CT, Morrow DA. Biomarkers for risk assessment in atrial fibrillation. Clin Chem. 2021;67(1):87–95.

2. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104.

Find this article online at JACC

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