Thromboinflammation in Myeloproliferative Neoplasms (MPN)-A Puzzle Still to Be Solved

Abstract

Myeloproliferative neoplasms (MPNs), a group of malignant hematological disorders, occur as a consequence of somatic mutations in the hematopoietic stem cell compartment and show excessive accumulation of mature myeloid cells in the blood. A major cause of morbidity and mortality in these patients is the marked prothrombotic state leading to venous and arterial thrombosis, including myocardial infarction (MI), deep vein thrombosis (DVT), and strokes. Additionally, many MPN patients suffer from inflammation-mediated constitutional symptoms, such as fever, night sweats, fatigue, and cachexia. The chronic inflammatory syndrome in MPNs is associated with the up-regulation of various inflammatory cytokines in patients and is involved in the formation of the so-called MPN thromboinflammation. JAK2-V617F, the most prevalent mutation in MPNs, has been shown to activate a number of integrins on mature myeloid cells, including granulocytes and erythrocytes, which increase adhesion and drive venous thrombosis in murine knock-in/out models. This review aims to shed light on the current understanding of thromboinflammation, involvement of neutrophils in the prothrombotic state, plausible molecular mechanisms triggering the process of thrombosis, and potential novel therapeutic targets for developing effective strategies to reduce the MPN disease burden.

Keywords: MPN; inflammatory cytokines; integrins; neutrophils; thromboinflammation.

Figure 1

Neutrophil-associated thromboinflammation in MPNs. The constitutive activity of mutated JAK2-V617F kinase increases intracellular Ca²⁺ and supports Ca²⁺ influx followed by CalDAG-GEF1 (calcium- and diacylglycerol-regulated GEFI) activation. This results in the activation of small guanosine triphosphate hydrolase enzymes (GTPases), such as RAS-related protein 1 (RAP1), which further stimulate integrin-binding proteins to facilitate integrin conformational changes in neutrophils. The activation of integrins assists neutrophils in inducing thromboinflammation, which is a multistep process where activated neutrophils, inflammatory cytokines, the aggregation of platelets, and induction of plasmatic coagulation synergize. Initially, under flow conditions, neutrophils interact with endothelium-expressed P- and E-selectin with their respective PSGL-1 and ESL1-ligands, which allow neutrophils to slowly roll along the blood vessel. While rolling, neutrophils are arrested upon the binding of β1 and β2 integrins (VLA-4, LFA-1) to the endothelium-expressed VCAM-1 and ICAM-1. Inflammatory cytokines, such as IL-6 and IL-17, foster this process by up-regulating VCAM-1 and ICAM-1 expression. The release of chemokines leads to chromatin decondensation in neutrophils, which then expel granular proteins, including neutrophil elastase (NE), myeloperoxidase (MPO), and DNA material into the extracellular space to form NETs. The formation of NETs further induces thrombosis by activating plasmatic coagulation and by inducing the aggregation of platelets and erythrocytes. (This figure was created with BioRender.com, assessed on 15 February 2022).