Peripheral Leukocyte TET Protein Expression Is Associated with Plasma Coagulation Parameters in Patients with Heart Failure with Reduced Ejection Fraction: A Two-Center Cross-Sectional Study.

Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) involves coexisting inflammatory and hemostatic dysregulation contributing to thromboembolic and bleeding risk. Ten-eleven translocation (TET1-3) proteins regulate immune-cell phenotype, but their relationship to plasma coagulation parameters in HFrEF is poorly defined. We aimed to determine whether TET1-3 protein expression in peripheral blood leukocyte subpopulations is associated with routinely available plasma coagulation parameters in HFrEF, and whether associations differ by direct oral anticoagulant (DOAC) exposure and clinical phase. Methods: In this cross-sectional, observational, two-center study, 107 patients with HFrEF were enrolled (39 receiving a DOAC, non-randomized; 68 not receiving a DOAC, of whom seven received a vitamin K antagonist and 61 received no oral anticoagulant). TET1-3 protein expression was assessed by flow cytometry in T lymphocytes, B lymphocytes, natural killer (NK) cells, monocytes, and granulocytes, expressed as the ratio of test-to-negative-control geometric mean fluorescence intensity. Associations with activated partial thromboplastin time (aPTT) and international normalized ratio (INR) were analyzed using nonparametric tests and Spearman correlations; DOAC samples were drawn at steady-state trough. Results: DOAC-treated patients constituted a distinct clinical subgroup (older, predominantly AF/AFL) and showed longer aPTT and higher TET expression in selected immune-cell subsets; these between-group differences cannot be attributed to DOAC therapy. Patients with aPTT at or above the median showed higher TET expression in T cells, B cells, NK cells, and selected leukocyte indices, whereas INR-based stratification did not. In continuous analyses, TET indices showed multiple moderate positive Spearman correlations (R = 0.25-0.49) with both aPTT and INR-with INR showing the strongest single association-and no associations with composite inflammatory indices (NLR, SII, SIRI); all comparisons were exploratory and uncorrected for multiplicity. Associations appeared stronger in stable than in worsening HFrEF (exploratory). Conclusions: Peripheral leukocyte TET protein expression was associated with plasma coagulation parameters in HFrEF; the aPTT-specific pattern was confined to the categorical (median-split) analysis, whereas continuous analyses showed associations with both aPTT and INR. Because of the cross-sectional design, moderate sample size, and potential confounding by indication, these findings should be considered hypothesis-generating. TET-related immune-cell phenotyping may capture a non-redundant immune-coagulation signal in HFrEF and warrants prospective validation.