Chronic myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal haematopoietic stem cell neoplasms characterised by increased blood cell proliferation. Individuals with MPNs experience a significantly increased risk of both venous and arterial thrombosis, such that 1 in 3 of all MPN patients will suffer a thrombotic event during their lifetime. Leucocytosis is an independent risk factor for thrombosis in individuals with MPNs and various data supports a mechanistic role for different leukocytes in mediating enhanced thrombogenicity in this setting. The specific role of monocytes as agents of procoagulant activity in MPN patients, however, remains largely uncharacterised. Notably, monocytes isolated from MPN patients are more likely to exhibit an ‘activated’ phenotype, characterised by increased pro-inflammatory activity and fuelled by a metabolic shift that favours aerobic glycolysis to meet increased energetic requirements. Nevertheless, how these cellular features combine to enhance thrombotic risk is unknown. In this study, we aim to explore the intersection of myeloid cell activation and metabolic reprogramming as novel mechanism(s) underlying increased thrombotic risk in individuals with MPNs. Exciting preliminary data from our lab indicates that activated myeloid cell hypercoagulability is dependent upon pro-inflammatory metabolic reprogramming. Using a novel myeloid cell-based plasma thrombin generation assay, we propose to determine whether MPN patient monocytes exhibit enhanced procoagulant activity via increased tissue factor decryption and monocyte receptor-mediated inhibition of activated protein C anticoagulant activity. Furthermore, we seek to leverage these new insights to evaluate new anticoagulant approaches that ‘re-wire’ activated monocyte metabolism and transcriptional programs to mitigate inflammation-induced procoagulant activity. In doing so, we aim to provide proof-of-concept evidence for regulation of innate immune cell metabolism as a novel strategy to mitigate the elevated risk of thrombosis experienced by MPN patients.
