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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

To assess the effects between MPL and JAK2V617F on the thrombosis risk and peripheral blood cell counts in patients with essential thrombocythemia (ET), we identified eligible studies from PubMed, Embase, and the Cochrane Library. Seven studies were ultimately included in this meta-analysis. All studies reported the peripheral blood cell counts of ET patients, and three of them reported the eligible thrombotic events. In comparing the effect of MPL versus JAK2V617F on thrombosis, 1257 ET patients (73 MPL + and 1184 JAK2V617F +) were included. MPL-positive (MPL +) ET patients had a higher risk of thrombosis than JAK2V617F-positive (JAK2V617F +) ET patients [RR = 1.80 (1.08-3.01), P = 0.025]. And 3453 ET patients (138 MPL + and 3315 JAK2V617F +) were included in the comparison of peripheral blood cell counts. Platelet counts of MPL + ET patients were higher than that of JAK2V617F + ET patients [WMD = 81.18 (31.77-130.60), P = 0.001]. MPL + ET patients had lower hemoglobin [WMD =  - 11.66 (- 14.32 to - 9.00), P = 0.000] and white blood cell counts [WMD =  - 1.01 (- 1.47 to - 0.56), P = 0.000] than JAK2V617F + ET patients. These findings indicate that the MPL mutation is a high-risk factor for thrombosis in ET patients, and it may be rational to include MPL mutation in the revised IPSET as a criterion for thrombosis prediction scores. And given the differences in peripheral blood, it is necessary to further study whether MPL + ET patients differ from JAK2V617F + ET patients in bleeding and survival., (© 2021. The Author(s).)

Heparin-induced thrombocytopenia/thrombosis (HIT/T) is a common complication of heparin therapy that is caused by antibodies to platelet factor 4 (PF4) complexed with heparin. The immune response is polyclonal and polyspecific, ie, more than one neoepitope on PF4 is recognized by HIT/T antibodies. One such epitope has been previously identified; it involves the domain between the third and fourth cysteine residues in PF4 (site 1). However, the binding sites for other HIT/T antibodies remain to be defined. To explore this issue, the binding site of KKO, an HIT/T-like murine monoclonal antibody, was defined. KKO shares a binding site with many HIT/T antibodies on PF4/heparin, but does not bind to site 1 or recognize mouse PF4/heparin. Therefore, the binding of KKO to a series of mouse/human PF4 chimeras complexed with heparin was examined. KKO recognizes a site that requires both the N terminus of PF4 and Pro34, which immediately precedes the third cysteine. Both regions lie on the surface of the PF4 tetramer in sufficient proximity (within 0.74 nm) to form a contiguous antigenic determinant. The 10 of 14 HIT/T sera that require the N terminus of PF4 for antigen recognition also require Pro34 to bind. This epitope, termed site 2, lies adjacent to site 1 in the crystal structure of the PF4 tetramer. Yet sites 1 and 2 can be recognized by distinct populations of antibodies. These studies further help to define a portion of the PF4 tetramer to which self-reactive antibodies develop in patients exposed to heparin.

ObjectiveTo further understand the factors that promote thrombosis in essential thrombocythemia （ET） that were not included in IPSET-thrombosis （International Prognostic Score of Thrombosis for ET）. MethodsA systematic evaluation was conducted on 292 studies by retrieving PubMed，Web of Science, and The Cochrane Library. The incidence and relative risk ratio （RR） of thrombosis in ET patients with different risk factors were calculated. The confidence levels for the outcome were analyzed in combination with RR values and recommendation scores (RS) to find the thrombotic risk factors in ET patients. ResultsOut of 9 risk factors that promoted ET thrombosis, there were 4 factors in IPSET-thrombosis, including history of thrombosis （35.0%, RR=3.30, 95% CI : 2.30-4.75）, JAK2V617F positive （21.0%, RR=2.28, 95%CI : 1.14-4.56）, age over 60 years old （ 22.4% , RR=1.95, 95%CI : 1.17-3.23） and cardiovascular risk factors （17.7%, RR =1.90, 95%CI : 1.08-3.35）. The remaining five risk factors, not listed in IPSET-thrombosis, included monoclonal type of ET based on X-chromosome inactivation pattern （XCIP, 30.6%, RR=4.49, 95% CI: 1.58-12.77）, high JAK2V617F burden （33.9%, RR=3.69, 95%CI: 1.70-7.99）, leukocytosis （18.7%, RR=3.05, 95%CI: 1.81-5.13）, MPL mutation （22.1%, RR=2.40, 95%CI: 1.08-5.33） and splenomegaly （25.6%, RR=1.76, 95%CI：1.29-2.40）. ConclusionAmong the risk factors promoting thrombosis in ET patients, five thrombotic risk factors not included in the IPSET-thrombosis have been identified.

Thrombosis is a common complication of myeloproliferative neoplasm (MPN), and it is a major cause of disability and death. With the development of next-generation gene-sequencing technology, the relationship between non-driver mutations and thrombotic risk factors has also attracted considerable attention. To analyze the risk factors of thrombosis in patients with essential thrombocythemia (ET) and polycythemia vera (PV), we retrospectively analyzed the clinical data of 125 MPN patients (75 ET and 50 PV) and performed a multivariate analysis of the risk factors of thrombosis using a Cox proportional risk model. Among the 125 patients, 35 (28.0%) had thrombotic events, and the incidence of thrombotic events was 21.3% and 38.0% in ET and PV patients, respectively. In ET patients, the multivariate analysis showed that a TET2 mutation and history of remote thrombosis were independent risk factors for thrombosis in ET patients, with an HR of 4.1 (95% CI: 1.40–12.01; p = 0.01) for TET2 mutation and 6.89 (95% CI: 1.45–32.68; p = 0.015) for a history of remote thrombosis. In PV patients, the multivariate analysis presented the neutrophil-to-lymphocyte ratio (NLR) (HR: 4.77, 95% CI: 1.33–17.16; p = 0.017) and a history of remote thrombosis (HR: 1.67, 95% CI: 1.03–1.32; p = 0.014) as independent risk factors for thrombosis, with no significant change in the risk of thrombosis in patients with TET2 mutations. A further analysis of the clinical characteristics and coagulation occurring in ET patients with a TET2 mutation revealed that the values of age and D-dimer were significantly higher and antithrombin III was significantly lower in TET2-mutated ET patients compared to TET2-unmutated patients. In summary, TET2 mutation may be more valuable in predicting thrombosis in ET patients than in PV patients. ET patients with a TET2 mutation are older and present differences in coagulation compared to TET2-unmutated patients. [ABSTRACT FROM AUTHOR]