PB1313 - Platelet Multi-omics Analysis Confirms Hyperglycemia as a Risk Factor for Thrombosis in JAK2V617F-positive Essential Thrombocythemia

Tuesday, June 25, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Jia Chen, MD

tianjin
Chinese academy of medical sciences
Tianjin, Tianjin, China (People's Republic)

Co-Author(s)

HD

Huan Dong

Tianjin
Chinese academy of medical cience
Tianjin, Tianjin, China (People's Republic)
Yang Li, Master student

Tianjin
Chinese Academy of Medical Sciences and Peking Union Medical College
Tianjin, Tianjin, China (People's Republic)
RF

Rongfeng Fu

Tianjin
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases
Tianjin, Tianjin, China (People's Republic)
Renchi Yang, MD

Head of Thrombosis and Hemostasis Center
Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Tianjin, Hebei, China (People's Republic)
LZ

Lei Zhang

professor
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Tianjin 300020, China
Tianjin, Tianjin, China (People's Republic)

Background: Age>60 years, thrombosis history, cardiovascular risk factors (CVF), and JAK2V617F mutation were verified as independent risk factors for predicting thrombosis in the current International Prognostic Score for Thrombosis in essential thrombocythemia (IPSET-thrombosis). However, the predictive value of blood glucose levels regarding thrombotic risk among patients with JAK2V617F-positive ET remains unclear.

Aims: To elucidate the clinical relevance of blood glucose levels concerning thrombotic risk in JAK2V617F-positive ET patients, and to explore the molecular mechanism of platelets on thrombosis in a murine model of JAK2V617F-positive ET.

Methods: 291 consecutive JAK2V617F-positive ET patients who were admitted in our center were investigated. Platelet was isolated from a transgenic mouse model expressing JAK2V617F under the Vav promoter. The platelets underwent subsequent transcriptomics, proteomics, and metabolomics sequencing analyses.

Results: To determine the clinical impact of hyperglycemia in JAK2V617F-positive ET patients, we analyzed data from 291 ET patients in our center. Using restricted cubic splines in logistic regression, there were a nonlinear correlation between glucose level and risk for thrombosis-free survival (Figure 1A). Further analysis using a threshold value of 5.99 mmol/L revealed an inferior thrombosis-free survival among patients with >5.99 mmol/L compared to those with ≤ 5.99 mmol/L (p=0.047; Figure 1B). Compared with the lower glucose patients, higher glucose patients more commonly had high risk stratifications by IPSET-revised and MIPSSET models (p=0.037, p=0.032; Figure 1C, D). Unsupervised clustering revealed upregulated RNA were associated with platelet activation, and glycolysis via glucose-6-phosphate. Meanwhile, glycolysis by glucose-6-phosphate was primarily enriched in upregulated proteins. The co-upregulation of differential gene functions within the transcriptome and proteome related to glucose metabolism, lipid metabolism, and the activation of platelets. The metabolomic findings indicate a correlation between platelet activation and fatty acid metabolism.

Conclusion(s): Hyperglycemia and the reprogramming of platelet metabolism emerge as pivotal factors contributing to thrombotic events in JAK2V617F-positive ET.