Myeloproliferative neoplasm thrombosis risk characterized by MerTK biomarker Free

Thrombosis remains a major cause of morbidity and mortality in patients with myeloproliferative neoplasms (MPN). Identifying a reliable biomarker that can stratify MPN patients at risk for thrombosis and is essential for improving clinical management. Growth arrest-specific gene 6 (GAS6) and Protein S are vitamin K-dependent proteins that bind phosphatidylserine and serve as ligands for the TAM receptor family (Tyro3, Axl, and Mer tyrosine kinase [MerTK]). Protein S-GAS6-TAM signaling plays a critical role in promoting cell survival, proliferation, and migration. Protein S is an anticoagulant as it serves as an activated protein C cofactor to reduce thrombin generation. GAS6-TAM signaling contributes to pro-thrombotic platelet and endothelial cell activation. In prior studies, compared to healthy controls, we found elevated GAS-TAM and low free protein S levels in MPN subjects. We hypothesized that Protein S and GAS6-TAM levels may serve as a thrombosis biomarker in MPN patients.

Single-center collection of blood samples from 2019-2025 occurred at M Health Fairview from ≥18 years old patients diagnosed with MPN according to the 2022 WHO criteria. after written informed consent obtained from all participants. Clinical data was abstracted from patient charts and placed in REDCAP. Plasma levels of GAS6, free protein S, Von Willebrand factorA2 (VWFA2), TYRO3, AXL, and MerTK were measured using commercial ELISA kits. GraphPad Prism was used to assess the association between thrombosis, and candidate biomarker levels were analyzed using the Mann–Whitney U test. Correlation analyses between biomarker levels were performed using Spearman's correlation.

During the collection period, 220 blood MPN samples were assessed. The cohort consisted of 48.87% females and 51.13% males with a median age of 65 years. Median white blood cell count, hemoglobin level and platelet counts were 6.0 x10³/ µL , 13.6 g/dL, 375.5x10³/µL respectively. MPN molecular mutations included 74.21% with JAK2^V617F+ mutations, 3.62% with JAK2 exon 12 mutation, and 10.86% with CALR (type 1 and 2). No subjects had Mpl mutation and 5.88 % were triple-negative. In the cohort, arterial and venous thrombosis incidence was 19.0 % with 15.38% of subjects experiencing venous thromboembolism and 5.43% with arterial thrombosis. There was no association between complete blood count (CBC) parameters (WBC, Hgb/Hct, Platelet count) and thrombosis. For the biomarkers, a significant inverse correlation was observed between free protein S and MerTK levels (p = 0.02, rs = –0.40) and GAS6 and MerTK (p = 0.03, rs = –0.30). GAS6 levels were not correlated with free protein S and VWF-A2 levels. Looking at relationship between candidate biomarkers and CBC parameters, there was a significantly inverse association between MerTK levels and platelet count (p = 0.04, rs = –0.27) as well as free protein S levels and hemoglobin (p < 0.01, rs = –0.39). Among the biological markers assessed, MerTK levels were significantly elevated in patients with thrombosis (p = 0.04).

Prior studies have identified that MerTK mRNA is significantly elevated in JAK2^V617F+ granulocytes. Similarily, compared to healthy controls, our prior studies found elevated MerTK in JAK2^V617F+ individuals. However, the association between MerTK and MPN pathogenesis is undefined. In this single-center MPN biorepository, MerTK levels were associated with elevated platelet counts and inversely correlated with GAS6 and free protein S levels. Notably, MerTK levels were higher in MPN individuals with thrombosis history. Our work suggests that in MPN, MerTK levels are a potential candidate biomarker for thrombosis risk.