Data‐Driven Analysis of the Kinetics of the JAK2V617F Allele Burden and Blood Cell Counts During Hydroxyurea Treatment of Patients with Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis

2021 ◽  
Author(s):  
Marc JB Dam ◽  
Rasmus K. Pedersen ◽  
Trine A. Knudsen ◽  
Morten Andersen ◽  
Vibe Skov ◽  
...  
Keyword(s):  
Blood Cell ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Primary Myelofibrosis ◽  
Data Driven ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
Hydroxyurea Treatment ◽  
Kinetics Of ◽  
Jak2v617f Allele Burden

scholarly journals Influence of platelet and white blood cell counts on major thrombosis – analysis from a patient registry in essential thrombocythemia

2016 ◽  
Vol 97 (6) ◽  
pp. 511-516 ◽  
Author(s):  
Veronika Buxhofer‐Ausch ◽  
Michael Steurer ◽  
Siegfried Sormann ◽  
Ernst Schloegl ◽  
Wolfgang Schimetta ◽  
...  
Keyword(s):  
Blood Cell ◽  
White Blood Cell ◽  
Essential Thrombocythemia ◽  
Patient Registry ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
White Blood Cell Counts

scholarly journals Leukocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis

2019 ◽  
Vol 3 (11) ◽  
pp. 1729-1737 ◽  
Author(s):  
Alessandra Carobbio ◽  
Alberto Ferrari ◽  
Arianna Masciulli ◽  
Arianna Ghirardi ◽  
Giovanni Barosi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Blood Cell ◽  
Polycythemia Vera ◽  
White Blood Cell ◽  
Essential Thrombocythemia ◽  
Recurrent Events ◽  
Myeloproliferative Neoplasms ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Cell Counts

Abstract In the last years, a growing amount of evidence has been produced regarding the role of leukocytosis as a risk factor for thrombosis in patients with myeloproliferative neoplasms, predominantly in polycythemia vera (PV) and essential thrombocythemia (ET). Results from epidemiologic studies on this issue, however, are inconclusive. We conducted a systematic review and meta-analysis of articles published in the last 12 years addressing the issue, according to a predefined protocol. Forty-one articles analyzing >30 000 patients met our inclusion criteria and were deemed of acceptable methodologic quality. In addition to data on thrombosis, data were collected on bleeding, hematologic evolution, secondary cancer, and death. The relative risk (RR) of thrombosis in the presence of leukocytosis was 1.59 (95% CI, 1.40-1.80), mainly accounted for by ET (RR, 1.65; 95% CI, 1.43-1.91) and arterial thrombosis (RR, 1.45; 95% CI, 1.13-1.86) subgroups; the effect was not significant in venous thrombosis alone. Sensitivity analyses considering recurrent events as well as white blood cell estimates adjusted or unadjusted for confounding factors confirmed the primary results. In addition, the pooled RR of studies that tested white blood cell counts in time-dependent models suggested a causative effect of leukocytes in the mechanism that triggers thrombosis. The effect of leukocytosis on bleeding (RR, 1.87; 95% CI, 1.26-2.77) and death (RR, 1.89; 95% CI, 1.59-2.23) was confirmed, whereas conclusions on hematologic evolutions and solid tumors were uncertain. To confirm the accuracy of these results, an investigation on individual patient data in a large collective archive of homogeneous patients is warranted.

scholarly journals Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5109-5117 ◽  
Author(s):  
Shu Xing ◽  
Tina Ho Wanting ◽  
Wanming Zhao ◽  
Junfeng Ma ◽  
Shaofeng Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Gene Promoter ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Transgenic Expression ◽  
Cell Counts

Abstract The JAK2V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2V617F, showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2V617F can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2V617F and to develop treatment for MPDs.

scholarly journals White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study

Blood ◽  
2015 ◽  
Vol 126 (4) ◽  
pp. 560-561 ◽  
Author(s):  
Tiziano Barbui ◽  
Arianna Masciulli ◽  
Maria Rosa Marfisi ◽  
Giovanni Tognoni ◽  
Guido Finazzi ◽  
...  
Keyword(s):  
Blood Cell ◽  
Polycythemia Vera ◽  
White Blood Cell ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
White Blood Cell Counts

scholarly journals Comparison of the effects between MPL and JAK2V617F on thrombosis and peripheral blood cell counts in patients with essential thrombocythemia: a meta-analysis

2021 ◽  
Author(s):  
Erpeng Yang ◽  
Mingjing Wang ◽  
Ziqing Wang ◽  
Yujin Li ◽  
Xueying Wang ◽  
...  
Keyword(s):  
Blood Cell ◽  
Essential Thrombocythemia ◽  
Peripheral Blood ◽  
Meta Analysis ◽  
Peripheral Blood Cell ◽  
Cochrane Library ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
High Risk Factor ◽  
White Blood Cell Counts

AbstractTo 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.

scholarly journals Impact of white blood cell counts at diagnosis and during follow-up in patients with essential thrombocythaemia and prefibrotic primary myelofibrosis

2016 ◽  
Vol 179 (1) ◽  
pp. 166-169 ◽  
Author(s):  
Veronika Buxhofer-Ausch ◽  
Bettina Gisslinger ◽  
Martin Schalling ◽  
Andreas Gleiss ◽  
Ana-Iris Schiefer ◽  
...  
Keyword(s):  
Blood Cell ◽  
White Blood Cell ◽  
Primary Myelofibrosis ◽  
Essential Thrombocythaemia ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
White Blood Cell Counts

Superiority of IFN Versus HU Using a Novel Biomarker-Based Tool for Assessment of Disease Burden in MPNs

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2972-2972 ◽  
Author(s):  
Vibe Skov ◽  
Marc JB Dam ◽  
Rasmus K Pedersen ◽  
Morten Andersen ◽  
Trine Alma Knudsen ◽  
...  
Keyword(s):  
Lactic Dehydrogenase ◽  
Large Majority ◽  
Data Driven ◽  
Allele Burden ◽  
Platelet Counts ◽  
Cell Counts ◽  
Using Data ◽  
Kinetics Of ◽  
Over Time ◽  
Jak2v617f Allele Burden

Background: Treatment of polycythemia vera (PV) patients with hydroxyurea (HU) normalizes elevated blood cell counts within weeks in the large majority of patients. Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte and platelets over time are scarce, and results have been reported highly heterogeneous. Purpose: Using data driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU. Material and Methods: Using serial measurements of JAK2V617F and correlation analyzes of routine hematological values (Hb-concentration, leukocyte count, platelet count, lactic dehydrogenase), we present a detailed description and analysis of the kinetics of the JAK2V617F, leukocyte and platelet counts and lactic dehydrogenase in 29 PV patients who were followed in the Danish randomized trial (DALIAH) comparing the efficacy of pegylated interferon-alpha2 (IFN) versus HU in patients older than 60 years. Results: Response patterns were highly heterogeneous. In the large majority of patients, HU treatment was initially associated with a modest decline in the JAK2V617F allele burden in concert with a decline in leukocyte and platelet counts. However, HU did not induce a sustained and continuous decrease in the JAK2V617F allele burden in any patient as previously reported in patients being treated with IFN. Importantly, HU treatment was neither able to induce a sustained normalization of elevated leukocyte and platelet counts, although counts were temporarily normalized in most patients during the first months of therapy. The fluctuating leukocyte and platelet counts contrast the sustained normalization of cell counts in the large majority of patients during long term treatment with IFN. Discussion and Conclusions: Using data-driven analysis of the JAK2V617F allele burden, leukocyte and platelet kinetics during treatment with HU, we have shown that HU does not induce a sustained decrease in the JAK2V617F allele burden and neither induces sustained normalization of elevated cell counts in PV patients. Our results may explain why PV patients during treatment with HU still have a substantially increased risk of thrombosis. Based upon our previous and present findings, obtained by mathematical modelling and data driven analysis studies, a rational and cost-effective treatment might be a combination therapy of HU and IFN, both being used for decades in the treatment of PV but according to the findings in our studies now being proposed to be combined in the initial treatment period, since their combined effects might be highly efficacious and are foreseen to have the potential to minimize the risk of thrombosis and bleeding. By these studies, we have also proven mathematical modelling and data driven analysis to be highly important tools to decipher novel treatment modalities for patients suffering from MPN cancers but likely other cancers as well. Disclosures Hasselbalch: Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. OffLabel Disclosure: Interferon-alpha2 for the treatment of myeloproliferative neoplasms.

An Alternative Elastase-mediated Degradation of Fibrinogen and Fibrin Observed in a Patient with Herpes Simplex Encephalitis and Pneumonia

1996 ◽  
Vol 76 (02) ◽  
pp. 184-186 ◽  
Author(s):  
Kenji lijima ◽  
Fumiyo Murakami ◽  
Yasushi Horie ◽  
Katsumi Nakamura ◽  
Shiro Ikawa ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Blood Cell ◽  
White Blood Cell ◽  
Herpes Simplex Encephalitis ◽  
Pmn Elastase ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
Sds Page ◽  
White Blood Cell Counts ◽  
Pmn Élastase

SummaryA 74-year-old female developed pneumonia following herpes simplex encephalitis. Her white blood cell counts reached 28,400/μl, about 90% of which consisted of granulocytes. The polymorphonuclear (PMN) elastase/α1-arantitrypsin complex levels increased and reached the maximum of 5,019 ng/ml, indicating the release of a large amount of elastase derived from the granulocytes. The mechanism of PMN elastase release was most likely to be granulocyte destruction associated with phagocytosis. The cleavage of fibrinogen and fibrin by PMN elastase, independent of plasmin, was indicated by the presence of the fragments in immunoprecipitated plasma from the patient corresponding to elastase-induced FDP D and DD fragments and the absence of fragments corresponding to plasmin-induced FDP D and DD fragments on SDS-PAGE. These findings suggested that the large amount of PMN elastase released from the excessive numbers of granulocytes in this patient with herpes simplex encephalitis and pneumonia, induced the cleavage of fibrinogen and fibrin without the participation of plasmin.

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