Platelets as Mediators of Thromboinflammation in Chronic Myeloproliferative Neoplasms

Abstract

Chronic myeloproliferative neoplasms (MPN) are stem cell disorders driven by mutations in JAK2, CALR , or MPL genes and characterized by myeloid proliferation and increased blood cell counts. They encompass three closely related conditions, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Elevated levels of cytokines released by clonal and non-clonal cells generate a chronic proinflammatory state that contributes to disease pathogenesis. Thrombosis represents the most common cause of morbidity and mortality in MPN, although paradoxically, patients may also present with a bleeding diathesis. The mechanisms leading to thrombosis are complex and multiple and include increased blood cells together with qualitative abnormalities of red cells, leukocytes, and platelets that favor a prothrombotic activated phenotype. The functional interplay between blood cells, the clotting cascade, and dysfunctional endothelium contributes to hypercoagulability and this process is perpetuated by the effect of inflammatory cytokines. In addition to their well-known function in hemostasis, platelets contribute to innate immunity and inflammation and play a key role in MPN thromboinflammatory state. In vivo platelet activation leads to platelet aggregate formation and exposure of adhesion molecules which favor their interaction with activated neutrophils and monocytes leading to circulating platelet-leukocyte heterotypic aggregates. Platelets are recruited to the activated endothelium further enhancing the reciprocal activation of both cell types. Crosstalk between activated cells drives cytokine production, further fuelling the self-reinforcing thromboinflammatory loop. In addition, MPN platelets provide a procoagulant scaffold which triggers the coagulation cascade and platelet-derived microparticles amplify this response. Markers of platelet, leukocyte, endothelial and coagulation activation are increased in MPN patients although prospective studies are required to determine the potential value of these parameters for identifying patients at increased thrombotic risk. Thrombosis remains the main complication of MPN patients, with a high risk of recurrence despite adequate cytoreductive and antithrombotic treatment. Deeper insight into the mechanism favoring thrombosis development in this setting may lead to novel therapeutic approaches for MPN thrombosis. Considering the critical role of inflammation in the vascular risk, concomitant targeting of inflammatory pathways could potentially impact on primary or secondary prevention strategies.

Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia

“…In this study, we show that upon ligand binding, activation of TLR2 and TLR4 leads to exacerbated platelet responses in ET patients, potentially contributing to thromboinflammation and vascular disease. The MPN thromboinflammatory scenario involves multiple closely connected players, including activated platelets and leukocytes (3,4). Platelet activation leads to surface translocation of α-granule-derived P-selectin which engages PSGL-1 on neutrophils and monocytes, initiating platelet-leukocyte crosstalk (12).…”

“…The thrombotic predisposition in MPN results from the complex interplay among multiple factors (3). Those derived from the MPN clone comprise both excessive numbers and qualitative abnormalities in blood cells, which give rise to an activated prothrombotic phenotype that favors cellular interactions, endothelial activation and triggers the coagulation cascade (3,4). In addition, inflammation has been shown to play a major role in MPN pathogenesis and, in this context, hostderived inflammatory cytokines impact on the MPN clone and further foster cellular activation, generating a self-reinforcing thromboinflammatory loop (4,5).…”

“…Factors leading to platelet activation remain incompletely defined. Both intrinsic platelet features induced by clonal mutations, cellular interaction with activated leukocytes and endothelial cells and hyperresponsiveness to soluble mediators have been proposed as likely mechanisms (4). Paradoxically, platelet activation may occur concomitantly with platelet dysfunction, which may be explained, at least in part, by in vivo degranulation of activated platelets and secondary storage pool deficiency (2).…”

Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR–ABL-Negative Myeloproliferative Neoplasm

“…The main problem is the relapsing course of this event if correct therapy is not promptly adopted. Interfering with the inflammatory status of these patients seems to be fundamental [116].…”

Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

“…Some MkP populations display selective expression of AURKA, a kinase that has previously been proposed as a therapeutic target in MF ( 39 ). In addition, there have been several studies focused on the contributions of platelets to inflammation in MPN, a topic that was recently reviewed by Oyarzún and Heller ( 49 ).…”