Physicians' Academy for Cardiovascular Education

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,

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


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.


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