PLATELET IMMUNOMETABOLIC REPROGRAMMING LINKS IMMUNE CELL CROSSTALK TO THROMBOINFLAMMATION IN PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS
- 1Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (FCFRP-USP), Ribeirão Preto, SP, Brazil
- 2Department of Clinical Images, Hematology and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil
Abstract
Backgroun and aim: Myeloproliferative neoplasms (MPN) are hematological malignancies driven by JAK2, CALR, or MPL mutations. Chronic inflammation and increased thrombotic risk are major MPN features. Although frequent, thrombocytosis poorly correlates with thrombosis rate in MPN. Qualitative platelet alterations seem to influence more significantly thrombotic complications than platelet count. Therefore, we investigated platelet-leukocyte interactions and platelet lipidomic profiles in controls (n = 25) and patients with polycythemia vera (PV, n = 25), essential thrombocythemia (ET, n = 25), and primary myelofibrosis (MF, n = 25). Methods: Purified platelets were isolated from platelet-rich plasma by sequential centrifugation (200 × g, 15 min and 420 × g, 10 min, respectively) and submitted to high-resolution LC-MS/MS lipidomics. Platelet-monocyte, platelet-neutrophil, and platelet-T or B lymphocyte aggregates were identified in whole blood by flow cytometry as leukocyte populations expressing the platelet marker CD41a after antibody staining, erythrocyte lysis, and fixation. Bioactive lipid signatures were analyzed according to treatment status, previous cardiovascular events, and pharmacological inhibition of COX and LOX pathways. Results: MPN patients exhibited increased spontaneous formation of platelet-monocyte, -neutrophil, and -lymphocyte aggregates compared to controls (p < 0.0001). Platelet-bound monocytes showed higher expression of tissue factor (CD42; p < 0.0001) and CD36 (p < 0.0001), indicating a platelet-monocyte thromboinflammatory and pro-coagulant cooperation. Untargeted lipidomics revealed a depletion of key lipid substrates, including arachidonic acid, DGLA, EPA, DHA, LPC, and GPC, consistent with lipid consumption for activation. Despite substrate depletion, inflammatory omega-6-derived lipid mediators were preserved, revealing a disease-specific remodeling of the COX, LOX, and CYP pathways. Targeted lipidomics mainly identified that 5-HETE levels were increased in PV (p = 0.0008), ET (p < 0.0001), and MF (p = 0.0135) platelets. PGE₂ was elevated in ET (p < 0.0001) and MF (p = 0.0038), whereas PGD₂ was increased in MF versus controls (p = 0.0230) and PV (p = 0.0014). In vitro inhibition with indomethacin or MK-591 showed that LOX inhibition more effectively decreased BLTR-1 expression and pro-coagulant platelet phenotype, suggesting a central role for the LOX/5-HETE axis and revealing a persistent residual COX/eicosanoid activity. Sphingolipid remodeling was disease-specific, with depletion of ceramides in PV and enrichment of multiple sphingolipid subclasses in ET. These signatures persisted despite cytoreductive and antiplatelet therapy, while patients with previous cardiovascular events exhibited increased platelet sphingolipid abundance. Conclusions: MPN platelets present a sustained immunometabolic dysfunction, characterized by enhanced interaction with leukocytes and reprogrammed lipid metabolism. The persistence of these alterations despite hydroxycarbamide and acetylsalicylic acid therapy, together with evidence of residual COX pathway activity and a dominant LOX/5-HETE axis, indicates that current standard therapies do not fully normalize platelet function, which seem to be reprogrammed. These findings identify platelet lipid metabolism as a mechanistic driver of thromboinflammation and a promising source of therapeutic targets to treat MPN.
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BibTeX
@article{bassan2026platelet,
title = {{PLATELET IMMUNOMETABOLIC REPROGRAMMING LINKS IMMUNE CELL CROSSTALK TO THROMBOINFLAMMATION IN PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS}},
author = {Vitor Leonardo BASSAN and Lilian Maria Garcia RAMOS and Pietra Perondi SATER and Fabiana Rossetto de MORAIS and Lorena Garcia AZEVEDO and Beatriz De Castro VIEIRA and Jovelina Samara Ferreira ALVES and Andreia Machado LEOPOLDINO and Lúcia Helena FACCIOLI and Lorena Lobo de FIGUEIREDO PONTES and Fabíola Attié de CASTRO},
journal = {Hematology, Transfusion and Cell Therapy},
year = {2026},
month = oct,
doi = {10.1016/j.htct.2026.107530},
url = {https://doi.org/10.1016/j.htct.2026.107530},
note = {CC BY},
}
RIS
TY - JOUR
TI - PLATELET IMMUNOMETABOLIC REPROGRAMMING LINKS IMMUNE CELL CROSSTALK TO THROMBOINFLAMMATION IN PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS
AU - Vitor Leonardo BASSAN
AU - Lilian Maria Garcia RAMOS
AU - Pietra Perondi SATER
AU - Fabiana Rossetto de MORAIS
AU - Lorena Garcia AZEVEDO
AU - Beatriz De Castro VIEIRA
AU - Jovelina Samara Ferreira ALVES
AU - Andreia Machado LEOPOLDINO
AU - Lúcia Helena FACCIOLI
AU - Lorena Lobo de FIGUEIREDO PONTES
AU - Fabíola Attié de CASTRO
PY - 2026
DA - 2026/10/23
JO - Hematology, Transfusion and Cell Therapy
DO - 10.1016/j.htct.2026.107530
UR - https://doi.org/10.1016/j.htct.2026.107530
AB - Backgroun and aim: Myeloproliferative neoplasms (MPN) are hematological malignancies driven by JAK2, CALR, or MPL mutations. Chronic inflammation and increased thrombotic risk are major MPN features. Although frequent, thrombocytosis poorly correlates with thrombosis rate in MPN. Qualitative platelet alterations seem to influence more significantly thrombotic complications than platelet count. Therefore, we investigated platelet-leukocyte interactions and platelet lipidomic profiles in controls (n = 25) and patients with polycythemia vera (PV, n = 25), essential thrombocythemia (ET, n = 25), and primary myelofibrosis (MF, n = 25). Methods: Purified platelets were isolated from platelet-rich plasma by sequential centrifugation (200 × g, 15 min and 420 × g, 10 min, respectively) and submitted to high-resolution LC-MS/MS lipidomics. Platelet-monocyte, platelet-neutrophil, and platelet-T or B lymphocyte aggregates were identified in whole blood by flow cytometry as leukocyte populations expressing the platelet marker CD41a after antibody staining, erythrocyte lysis, and fixation. Bioactive lipid signatures were analyzed according to treatment status, previous cardiovascular events, and pharmacological inhibition of COX and LOX pathways. Results: MPN patients exhibited increased spontaneous formation of platelet-monocyte, -neutrophil, and -lymphocyte aggregates compared to controls (p < 0.0001). Platelet-bound monocytes showed higher expression of tissue factor (CD42; p < 0.0001) and CD36 (p < 0.0001), indicating a platelet-monocyte thromboinflammatory and pro-coagulant cooperation. Untargeted lipidomics revealed a depletion of key lipid substrates, including arachidonic acid, DGLA, EPA, DHA, LPC, and GPC, consistent with lipid consumption for activation. Despite substrate depletion, inflammatory omega-6-derived lipid mediators were preserved, revealing a disease-specific remodeling of the COX, LOX, and CYP pathways. Targeted lipidomics mainly identified that 5-HETE levels were increased in PV (p = 0.0008), ET (p < 0.0001), and MF (p = 0.0135) platelets. PGE₂ was elevated in ET (p < 0.0001) and MF (p = 0.0038), whereas PGD₂ was increased in MF versus controls (p = 0.0230) and PV (p = 0.0014). In vitro inhibition with indomethacin or MK-591 showed that LOX inhibition more effectively decreased BLTR-1 expression and pro-coagulant platelet phenotype, suggesting a central role for the LOX/5-HETE axis and revealing a persistent residual COX/eicosanoid activity. Sphingolipid remodeling was disease-specific, with depletion of ceramides in PV and enrichment of multiple sphingolipid subclasses in ET. These signatures persisted despite cytoreductive and antiplatelet therapy, while patients with previous cardiovascular events exhibited increased platelet sphingolipid abundance. Conclusions: MPN platelets present a sustained immunometabolic dysfunction, characterized by enhanced interaction with leukocytes and reprogrammed lipid metabolism. The persistence of these alterations despite hydroxycarbamide and acetylsalicylic acid therapy, together with evidence of residual COX pathway activity and a dominant LOX/5-HETE axis, indicates that current standard therapies do not fully normalize platelet function, which seem to be reprogrammed. These findings identify platelet lipid metabolism as a mechanistic driver of thromboinflammation and a promising source of therapeutic targets to treat MPN.
SN - 2531-1379
SN - 2531-1387
ER -