Comparative efficacy and hematologic safety of different dosages of JAK inhibitors in the treatment of myelofibrosis: a network meta-analysis.

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis associated with substantial morbidity and mortality. The therapeutic landscape for MF has advanced with the development of Janus kinase inhibitors (JAKis) like ruxolitinib (RUX), fedratinib (FED), pacritinib (PAC), and momelotinib (MMB), aiming to alleviate symptoms and enhance patient comfort. Methods: A network meta-analysis was conducted to assess the efficacy and safety of eleven JAKi treatment regimens across nine randomized controlled trials (RCTs) with a total of 2340 participants. Outcomes were evaluated in terms of spleen volume reduction (SVR), total symptom score reduction (TSSR), hematological safety profiles, and overall survival (OS). Results: RUX and MMB were superior in achieving SVR and TSSR, with significant dose-response relationships observed. PAC and MMB were associated with a decreased risk of grade 3/4 anemia and thrombocytopenia compared to other JAKis. However, no substantial benefits in OS were observed with newer JAKis compared to RUX. The poorer OS outcomes with certain PAC dosages were likely influenced by baseline patient characteristics, particularly severe cytopenias. Conclusion: The introduction of JAKis significantly changed the treatment of MF. This meta-analysis reaffirms the core role of RUX and positions MMB as a potentially powerful alternative for treating symptoms and reducing spleen size. Meanwhile, MMB and PAC have a positive effect on anemia in MF while FED is more tolerable for patients with thrombocytopenia. However, it should be noted that these results are influenced by baseline patient characteristics, particularly cytopenias, which affects both management and overall survival. Therefore, there is an urgent need for personalized dosing strategies to optimize the balance between efficacy and safety, with careful consideration of patient-specific factors. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023424179.

[Comparison of Clinical Characteristics of JAK2, CALR and Tri-Negative Driving Mutant Type in Patients with Essential Thrombocythemia].

OBJECTIVE: To investigate the relationship between mutated genes and clinical features in patients with essential thrombocythemia (ET). METHODS: The clinical data of 69 patients with ET from October 2018 to March 2022 were retrospectively analyzed. According to driver mutation type, patients were divided into JAK2 group, CALR group and triple-negative group. The sex, age, cardiovascular risk factors, thrombosis, splenomegaly, routine blood test and coagulation status of patients in three groups were analyzed. RESULTS: Among 69 ET patients, 46 cases were associated with JAK2 mutation, 14 cases with CALR mutation, 8 cases with triple-negative mutation, and one with MPL gene mutation. There were no significant differences in age and sex among the three groups (P >0.05). The highest thrombotic rate was 26.09% (12/46) in JAK2 group, then 12.5% (1/8) in triple-negative group, while no thrombotic events occurred in CALR group. The incidence of splenomegaly was the highest in JAK2 group (34.78%), while no splenomegaly occurred in triple-negative group. The white blood cell (WBC) count in JAK2 group was (9.00±4.86)×109/L, which was significantly higher than (6.03±2.32)×109/L in CALR group (P <0.05). The hemoglobin (Hb) and hematocrit (HCT) in JAK2 group were (148.42±18.79) g/L and (0.44±0.06)%, respectively, which were both significantly higher than (131.00±15.17) g/L and (0.39±0.05)% in triple-negative group (P <0.05). The platelet (PLT) in JAK2 group was (584.17±175.77)×109/L, which was significantly lower than (703.07±225.60)×109/L in CALR group (P <0.05). The fibrinogen (Fg) in JAK2 and triple-negative group were (2.64±0.69) g/L and (3.05±0.77) g/L, respectively, which were both significantly higher than (2.24±0.47) g/L in CALR group (P <0.05, P <0.01). The activated partial thromboplastin time (APTT) in triple-negative group was (28.61±1.99) s, which was significantly decreased compared with (31.45±3.35) s in CALR group (P <0.05). CONCLUSIONS: There are differences in blood cell count and coagulation status among ET patients with different driver gene mutations. Among ET patients, JAK2 mutation is most common. Compared with CALR group, the thrombotic rate, WBC and Fg significantly increase in JAK2 group, while PLT decrease. Compared with triple-negative group, the incidence of splenomegaly and HCT significantly increase. Compared with CALR group, Fg significantly increases but APTT decreases in triple-negative group.

Activated PRKCD-mediated neutrophil extracellular traps pathway may be the prothrombotic mechanism of neutrophils in polycythemia vera patients based on clinical retrospective analysis and bioinformatics study.

Thrombosis is a major cause of morbimortality in patients with polycythemia vera (PV). Furthermore, neutrophils play a significant role in thrombosis, but their role in the pathogenetic mechanisms of PV is not well characterized. Therefore, we investigated the role and mechanisms by which neutrophils regulate thrombosis in PV patients. Univariate and multivariate logistic regression analysis of clinicopathological factors was performed to determine the independent risk factors of thrombosis in PV. Pearson's correlation analysis was performed to determine the relationship between absolute neutrophil count (ANC) and the hypercoagulable state in PV patients. Bioinformatics analysis of the GSE54644 dataset was used to identify hemostasis-related pathways in neutrophils of PV patients. Weighted gene co-expression network analysis (WGCNA) of the integrated dataset (GSE57793, GSE26049 and GSE61629) was used to identify neutrophils-related genes and pathways associated with thrombosis in PV. Ingenuity pathway analysis (IPA) was performed to identify the differentially activated pathways in PV patients with or without thrombosis using GSE47018 dataset. Our data showed increased ANC in PV patients. Multivariate logistic regression analysis showed that ANC was an independent risk factor for the thrombotic events in PV patients before or at diagnosis. ANC correlated with the hypercoagulable state in PV patients. Neutrophil extracellular traps (NETs) pathway was significantly enriched in the neutrophils of PV patients. IPA results demonstrated that PRKCD-mediated NETs pathway was hyperactivated in PV patients with thrombosis. In summary, ANC was an independent risk factor for the thrombotic events in PV patients before or at diagnosis, and PRKCD-mediated NETs pathway was aberrantly activated in the neutrophils of PV patients and was associated with the thrombotic events.

[Possible Risk Factors for Bone Marrow Fibroplasia in Patients with Polycythemia Vera].

OBJECTIVE: To understand the biological characteristics of polycythemia vera (PV) patients with myeloid fibroplasia, and further analyze the risk factors affecting myeloid fibroplasia in PV patients, so as to provide ideas for predicting the occurrence of myeloid fibroplasia in PV patients. METHODS: Forty patients with PV in the Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences were collected and divided into two groups, with (hyperplasia group) and without (Non-proliferative group) hyperplasia of bone marrow fibers. The differences of basic clinical characteristics, blood routine, biochemistry, bone marrow cells, coagulation function and other indicators between the two groups were compared, and the independent risk factors affecting the proliferation of bone marrow fibrous tissue in PV patients were further analyzed by multivariate regression. RESULTS: Compared with Non-proliferative group, the JAK2 mutation rate (95% vs 70%，P=0.037), eosinophilic cell count (0.19 vs 0.11, P=0.047) and eosinophilic percentage (1.84 vs 1.27, P=0.001) in PV patients with hyperplasia were significantly increased, triglycerides (1.55 vs 1.91, P=0.038) and low-density lipoprotein (1.50 vs 3.08, P=0.000) were significantly reduced, bone marrow hematopoietic volume (0.85 vs 0.6, P=0.001), granulocyte/erythrocyte ratio (3.40 vs 1.89, P=0.033), lymphocyte/erythrocyte ratio (0.60 vs 0.42, P=0.033), and granulocyte+lymphocyte/erythrocyte ratio (3.72 vs 2.37, P=0.026) were significantly increased, thrombin time (18.84 vs 18.12, P=0.043) was significantly prolonged. Multivariate regression analysis results showed that peripheral blood eosinophil ≥2% and low-density lipoprotein ≤2 mmol/L were independent risk factors for bone marrow fibrous tissue hyperplasia in PV patients (P<0.05). CONCLUSION: Increased proportion of peripheral blood eosinophils and decreased low density lipoprotein are risk factors for bone marrow fibrous tissue hyperplasia in PV patients.

Incidence of Thrombosis at Different Sites During the Follow-Up Period in Essential Thrombocythemia: A Systematic Review and Meta-Analysis.

Thrombotic events are the most frequent manifestations of essential thrombocythemia (ET). The objective of this study is to determine the incidence of thrombosis at different sites on follow-up in patients with ET. We searched PubMed, Web of Science, and The Cochrane Library databases and calculated the incidence of thrombosis by pooling and analyzing the extracted data using a random-effects model. A total of 70 studies (N = 25,805) were included in the analysis. The total and annual incidences of arterial thrombosis on follow-up were 13.4% and 2.0%, respectively. The total and annual incidences of the different manifestations of arterial thrombosis were as follows: stroke (5.3% and 0.8%), transient ischemic attack (5.1% and 1.2%), myocardial infarction (2.4% and 0.5%), unstable angina (0.9% and 0.2%), and peripheral arterial thrombosis (2.0% and 0.2%), respectively. In contrast, the total and annual incidences of arterial thrombosis in JAK2-positive patients were 18.4% and 2.7%, respectively. The total and annual incidences of arterial thrombosis in JAK2-negative patients were 5.9% and 0.8%, respectively. The total and annual incidences of venous thrombosis were 5.5% and 0.7%, respectively, and the incidences of the different manifestations of venous thrombosis at different sites were as follows: peripheral venous thrombosis (2.9% and 0.5%), superficial venous thrombosis (1.8% and 0.7%), deep venous thrombosis (1.6% and 0.3%), abdominal venous thrombosis (0.8% and 0.1%), pulmonary embolism (0.3% and 0.1%), and cerebral venous thrombosis (0.2% and 0%), respectively. The total and annual incidences of venous thrombosis in JAK2-positive patients were 7.4% and 1.2%, respectively. The total and annual incidences of venous thrombosis in JAK2-negative patients were 1.6% and 0.4%, respectively. The incidence of arterial thrombosis was higher than that of venous thrombosis in patients with ET. Arterial thrombosis manifested with cerebral arterial thrombosis, followed by cardiac thrombosis. Venous thrombosis events were mainly peripheral and superficial venous thrombosis. JAK2-positive patients have a higher incidence of arterial and venous thromboses than JAK2-negative patients, the sequence of thrombsis sites was similar to that of the overall patients.

Proteomic-Based Platelet Activation-Associated Protein SELP May Be a Novel Biomarker for Coagulation and Prognostic in Essential Thrombocythemia.

Abnormal platelet activation can lead to thrombosis in essential thrombocythemia (ET) and thus impact patient prognosis. Platelet activation-associated proteins are key molecules for platelet activation. However, it is unclear which proteins are most closely associated with the disease's prognosis. To determine which platelet activation-related proteins can be employed as ET patient prognosis predictors, we used label-free quantification (LFQ) and parallel reaction monitoring (PRM) technology and first determined the serum proteomic expression levels and the differential proteins of ET patients. Then, based on the IPSET (International Prognostic Score for ET), the differential protein associated with the prognostic score was found. To investigate potential processes affecting prognosis, the connection of this protein with prognostic markers, such as thrombotic history, age, white blood cell count, coagulation factors, and inflammatory factors, were further examined. The levels of platelet activation-related proteins GPIbα, SELP, PF4, MMP1, and FLNA were significantly higher in ET patients, according to LFQ and PRM analyses (p < 0.01). Based on regression analysis of the IPSET prognostic score, it is suggested that the SELP level was positively correlated with the prognostic score and prognostic risk factor analysis (p < 0.05). Further regression analysis of SELP with coagulation factors showed that antithrombin (AT-III) was negatively correlated with SELP levels (p < 0.05). Further regression analysis of the inflammatory factors with AT-III and SELP revealed that IL-10, IL-12P70, and IL-31 were negatively correlated with AT-III and SELP (p < 0.01). Platelet activation pathway-related proteins are expressed more frequently in ET patients, and serum SELP may be a prognostic marker for these individuals by encouraging leukocyte increase and inflammatory factor expression and causing aberrant coagulation.

The efficiency and safety of Shengxuening tablet on treating and preventing iron deficiency anemia: A systematic review and meta-analysis.

Background: Iron deficiency anemia (IDA) is a public health problem worldwide. Shengxuening Tablet (SXN) has been used for the treatment of various types of anemia, attaining high efficacy. Objective: To evaluate the safety of SXN as well as its preventive and therapeutic efficacy against IDA across different population groups. Methods: PubMed, Embase, Web of Science, the Cochrane Library, the China Knowledge Network, the China Biomedical Literature Database, the Wanfang Data Knowledge Service Platform, and the China Science and Technology Journal Database was searched for relevant clinical trials through June 2022 and a systematic review and meta-analysis of the identified studies was undertaken. Results: A total of 39 trials involving 4,562 cases were included in the meta-analysis. The total efficiency of SXN was superior than the control group in improving red blood cell (RBC) count [SMD = 1.31, 95% CI (0.7, 1.91), p < 0.0001], hemoglobin (Hb) [SMD = 1.11, 95% CI (0.75, 1.46), p < 0.00001], mean corpuscular volume (MCV) [SMD = 0.5, 95% CI (0.33, 0.68), p < 0.00001], total serum iron (SI) levels [SMD = 1.87, 95% CI (1.3, 2.44), p < 0.00001], and transferrin saturation (TSAT) levels [SMD = 2.07, 95% CI (1.86, 2.27), p < 0.00001]. Besides, the total effects of SXN to improve mean corpuscular hemoglobin (MCH) [SMD = 0.12, 95% CI (-0.16, 0.4), p = 0.41], mean corpuscular hemoglobin concentration (MCHC) [SMD = 0.03, 95% CI (-0.18, 0.24), p = 0.77], hematocrit (HCT) [SMD = 0.65, 95% CI (-0.25, 1.55), p = 0.16], and serum ferritin (SF) levels [SMD = 0.59, 95% CI (-0.67, 1.85), p = 0.36] and reduce the total iron binding capacity (TIBC) [SMD = 0.34, 95% CI (-0.07, 0.74), p = 0.1] was comparable to that of iron supplementation. SXN significantly raised the total effective rates of IDA [risk ratio (RR) = 1.06, 95% CI (1.02, 1.09), p = 0.0005] and was associated with fewer adverse events [RR = 0.24, 95% CI (0.18, 0.31), p < 0.00001], fewer adverse pregnancy outcomes [RR = 0.34, 95% CI (0.2, 0.57), p < 0.0001], and lower anemia recurrence rates during pregnancy [RR = 0.29, 95% CI (0.1, 0.84), p = 0.02]. Regarding prevention, the effects of SXN to maintain the RBC count, Hb level and other IDA-related parameters were comparable to that of control group and SXN reduced the risk of IDA incidence during pregnancy. Conclusion: SXN demonstrated promising efficacy in the treatment and prevention of IDA and outperformed routine iron formulations in terms of safety, thus rendering SXN a reliable treatment option for IDA. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022353247.

[Analysis of Differential Proteins Related to Platelet Activation in Patients with Essential Thrombocythemia Based on Label-Free Quantitative Technology].

OBJECTIVE: To analysis the specific protein markers of essential thrombocythemia (ET) based on proteomics technology, to explore and verify the differential protein related to platelet activation. METHODS: Blood samples were obtained from ET patients and healthy people and a certain protein mass spectrometry was detected using label-free quantitative technology. The proteins relative abundance increased or down-regulated by 1.3 times in the disease group compared with the control group, and the protein abundance in the two groups t test P＜0.05 were defined as differential proteins. Bioinformatics analysis of the differential proteins was performed using GO and KEGG. The difference in the average protein abundance between the two groups was analyzed by t test and P＜0.05 was considered statistically significant. Differential proteins were selected for verification by parallel reaction monitoring (PRM) technology. RESULTS: A total of 140 differential proteins were found, of which 72 were up-regulated and 68 were down-regulated. KEGG enrichment showed that the differential protein expression was related to the platelet activation pathway. The differential proteins related to platelet activation were GPV, COL1A2, GP1bα, COL1A1 and GPVI. Among them, the expressions of GPV, GP1bα and GPVI were up-regulated, and the expressions of COL1A2 and COL1A1 were down-regulated. PRM verification of COL1A1, GP1bα, GPVI and GPV was consistent with LFP proteomics testing. CONCLUSION: Differential proteins in ET patients are related to platelet activation pathway activation.Differential proteins such as GPV, GPVI, COL1A1 and GP1bα can be used as new targets related to ET platelet activation.

[Analysis of DNA Methylation Gene Mutations and Clinical Features in Patients with Myeloproliferative Neoplasm].

AbstractObjective: To analyze the DNA methylation gene mutations of myeloproliferative neoplasm (MPN), and preliminarily explore its clinical features. METHODS: Next-generation sequencing technology was used to detect 31 MPN-related genes in 105 cases of MPN patients ï¼»40 cases of polycythaemia vera (PV), 65 cases of essential thrombocythemia (ET)ï¼½, and to analyze the relationship between DNA methylation gene mutations and clinical features. RESULTS: 15 mutation types were detected in 105 patients (88 mutations in total), and the total mutation detection rate was 87.6% (92/105). A total of 23 mutations in 4 DNA methylation genes (TET2, DNMT3A, IDH1, IDH2) were detected in 22 patients. The mutation rate of DNA methylation genes was 21.0%, mainly in the form of double mutations, including JAK2 V617F and TET2 (n=10), JAK2 V617F and DNMT3A (n=4), CALR and TET2 (n=2), JAK2 V617F and IDH1 (n=1). Compared with MPN patients without DNA methylation gene mutations, the proportion of women with DNA methylation gene mutations and the white blood cell count (WBC) were significantly higher (P<0.05). Compared with MPN patients with triple-negative driver genes, the proportion of women with DNA methylation gene mutations, age, WBC, platelet count (PLT), and neutrophil-to-lymphocyte ratio (NLR) were significantly higher (P<0.05). The remaining difference was not statistically significant (P>0.05). The MPN10 score, the incidence of thrombotic events, and the proportion of medium-risk and high-risk patients with DNA methylation gene mutations were significantly higher than those of MPN patients without DNA methylation gene mutations (P<0.05). CONCLUSION: The mutation rate of DNA methylation genes was 21.0%, mainly coexisting in the form of double mutations. The proportion of women with DNA methylation gene mutations in MPN patients and WBC is high, the symptom load is heavy, the incidence of thrombosis is high, and the proportion of medium-high-risk patients is high, suggesting that their prognosis may be poor.

Coagulation status and determinants of possible aspirin resistance in patients with essential thrombocythemia.

Objectives: The currently recommended aspirin regimen appears inadequate for thromboprophylaxis in essential thrombocythemia (ET). This study aimed not only to evaluate the curative effect of aspirin but also to explore the coagulation status and determinants of aspirin resistance (AR) of ET patients. Methods: A total of 80 ET patients who underwent coagulation tests, thromboelastography (TEG), and next-generation sequencing (NGS) were involved in the study. Patients were divided into the aspirin sensitivity (AS) group and AR group according to the arachidonic acid inhibition rate. Their clinical features and coagulation function were analyzed. Results: The incidence of AR was 53.75% (43/80) in 80 ET patients. Fbg was significantly higher in coagulation tests in AR patients compared with AS patients (P < 0.05), while the differences in other variables (D-D, PT, PTA, INR, APTT, TT, FDP, and AT-III) were not statistically significant (P > 0.05). Compared with AS patients, the K values, α angles, MA values, and CI values of TEG in AR patients were statistically smaller (P < 0.05), but there was no significant difference in R value between them (P > 0.05). Univariate and multivariate logistic regression analysis showed that age, irregular use of aspirin, smoking, dyslipidemia, and hypertension increased the risk of AR (P < 0.05). In the routine NGS, the driver gene and non-driver gene had no effect on AR in ET patients. Conclusion: Compared with AS patients, AR patients have enhanced platelet aggregation function, are in a relatively hypercoagulable state, and haveelevated fibrinogen function/levels, all of which cause a worse coagulation status. ET patients with increasing age, irregular use of aspirin, smoking, dyslipidemia, and hypertension are possibly at higher risk of AR. The routine NGS may not be helpful for the prediction of AR, therefore we recommend adding relevant drug-resistance genes to NGS.