Do arterial and venous thrombotic events have different molecular risk factors in patients with myelofibrosis?

Introduction The risk of thrombotic events in myelofibrosis (MF), compared with patients with other myeloproliferative neoplasms (MPN), has been underestimated for a long time. Patients with MF are rarely studied as separate in most cases small cohorts. We sought to independently explore potential molecular risk factors for venous (VTE) and arterial (ATE) events in a substantial cohort of MF patients.

Method Monocentric retrospective data of 122 MF patients were analyzed. 27 (22.1%) patients had prefibrotic MF, 69 (56.6%) – overt MF, and 26 (21.3%) had secondary MF. All patients were tested for driver mutations (JAK2-V617F, CALR, and MPL). JAK2 allele burden was evaluated in 57/69 mutated patients. Non-driver mutations were analyzed by next-generation sequencing. The primary outcome was the occurrence of a thrombotic event, acute leukemia transformation, or death at any time.

Results The median age at diagnosis was 62 years (range, 26-82), 55.7% of patients were male. The median follow up was 4.75 years. Nine (7.4%) patients had prior thrombosis: history of ATE had 3 of them, prior VTE – 4, both – 2. At the time of the diagnosis of MF and during follow-up, 14 (11.5%) patients had ATE, 22 (18%) had VTE, and 2 patients had both. Driver mutations: 68 (55.7%) patients showed a JAK2V617F, 39 (32%) CALR, and 4 (3.3%) MPL mutation. Other patients were triple negative or had a combined mutation (n=3). The median JAK2 allele burden was 38% (range, 0.28-96). In total, 92 mutations of these genes were found: ASXL1 (n=29), DNMT3A (n=11), TET2 (n=25), IDH2 (n=2), SRSF2 (n=5), SF3B1 (n=10), and U2AF1 (n=10). A significant association between JAK2 mutation (OR 2.49, 95% CI 1.11-5.59) and an increased risk of venous, but not arterial, thrombotic events was found. The JAK2 allele burden did not impact the risk of VTE. Patients with co-occurrence of JAK2 and TET2 or JAK2 and ASXL1 mutations did not have a higher risk of VTE (p=0.22 and p=0.42, retrospectively). The multivariable analysis showed a significant association between a DNMTA3 mutation (OR 5.2, 95% CI 1.3-21.5) and increased risk of ATE [1] [2] [3] [4].

Conclusion Arterial and venous thrombotic events had different molecular risk factors in patients with myelofibrosis in this cohort. JAK2 mutation was associated with an increased risk of venous thrombosis. Patients have also a high risk of VTE even if they carry a low JAK2 allelic burden. DNMT3A mutation showed an independent effect on the risk of arterial thrombosis. Despite the small number of patients with non-driver mutations, these findings warrant consideration of arterial and venous thrombosis separately for future risk stratification and preventive treatment recommendations in patients with MF.

Conflict of Interest

None

• References

• 1 Barbui T, Carobbio A. "Thrombosis in myeloproliferative neoplasms during cytoreductive and antithrombotic drug treatment". Research and Practice in Thrombosis and Haemostasis 2022; 6 (01) E12657 Italy
• 2 Hernández-Boluda JC, Pastor-Galán I. "Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis". British Journal of Haematology 2022; 199 (04) 529-538 Spain
• 3 Pasquer H, Daltro De Oliveira R. "Distinct clinico-molecular arterial and venous thrombotic scoring systems for MPN patients risk stratification. Blood. 2022. 140. 01 830-831 France
• 4 Bankar A, Smith E. "Clinical and molecular factors associated with thrombosis in myelofibrosis", HemaSphere. 2021. 5. e566 Canada

Publication History

Article published online:
26 February 2024