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Molecular predictors of venous and arterial thrombotic events in patients with myelofibrosis
Olga Morath1, Jenny Rinke2, Annabell Walter2
1Klinik für Innere Medizin II, Abteilung Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany. olga.morath@med.uni-jena.de.
Abstract:
While patients with myelofibrosis (MF) face an elevated risk of thrombosis, no validated scoring system currently exists to effectively assess this specific risk. This study aimed to explore distinct molecular risk factors for arterial (ATE) and venous (VTE) thrombosis in a cohort of 141 MF patients. Mutation analysis was performed by next-generation sequencing for a panel of 30 target myeloid genes as previously described: 137 driver and 164 non-driver mutations were detected. JAK2-V617F was identified in 77 (55%) patients, CALR in 45 (32%) patients, and seven (5%) patients carried an MPL variant. Patients #58 and #60 harbored JAK2-V617F and MPL; and patient #67 was positive for all three driver genes. The JAK2-V617F variant allele frequency (VAF) was assessed in 66/80 patients, revealing a median of 34.0% (range, 5.0-96.0). ASXL1 (n = 34 patients) were the most common non-driver mutations, followed by TET2 (n = 26), U2AF1 (n = 12), and DNMT3A (n = 11). During a median follow up of 4.8 years, 24 (17%) patients experienced VTE, 15 (11%) ATE, and two patients experienced both. Among the 24 patients with VTE, 12 (50%) experienced splanchnic vein thrombosis. The JAK2-V617F mutation was associated with VTE (OR 2.6, 95% CI 1.01-7.16), while the DNMT3A mutation was an independent predictor of ATE (OR 5.40, 95% CI 1.30-22.42). High JAK2-V617F VAF (> 50%) was not related with an increased thrombotic risk. Results of this study demonstrate the significance of DNMT3A mutations as an independent molecular risk factor for ATE, highlighting the potential to include these somatic non-driver mutations in future thrombosis risk scores.
Insights
This study identifies key genetic mutations in myelofibrosis (MF) patients, revealing DNMT3A mutations as a significant predictor of arterial thrombosis. These findings may lead to improved thrombosis risk assessment in MF.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Patients with myelofibrosis (MF) have an increased risk of thrombosis.
- Currently, no validated scoring system exists to specifically assess thrombosis risk in MF patients.
- Understanding molecular risk factors is crucial for risk stratification.
Purpose of the Study:
- To investigate distinct molecular risk factors for arterial (ATE) and venous (VTE) thrombosis in a cohort of 141 MF patients.
- To identify potential genetic markers for predicting thrombotic events in MF.
Main Methods:
- Next-generation sequencing was used to analyze mutations in 30 target myeloid genes.
- Mutation analysis included driver mutations (JAK2, CALR, MPL) and non-driver mutations (ASXL1, TET2, U2AF1, DNMT3A).
- Patient data were followed for a median of 4.8 years to record thrombotic events (VTE and ATE).
Main Results:
- JAK2-V617F mutation was associated with an increased risk of VTE (OR 2.6).
- DNMT3A mutation was identified as an independent predictor of ATE (OR 5.40).
- High JAK2-V617F variant allele frequency (>50%) did not correlate with increased thrombotic risk.
Conclusions:
- DNMT3A mutations are a significant independent molecular risk factor for arterial thrombosis in MF patients.
- These findings suggest that somatic non-driver mutations, like DNMT3A, could be incorporated into future thrombosis risk scores for MF.
- Further research is warranted to validate these molecular markers for clinical risk assessment.
