scholarly journals Unexpected low expression of platelet fibrinogen receptor in patients with chronic myeloproliferative neoplasms: how does it change with aspirin?

2019 ◽  
Vol 189 (2) ◽  
pp. 335-338 ◽  
Author(s):  
Alessandro Lucchesi ◽  
Silvia Carloni ◽  
Serena De Matteis ◽  
Martina Ghetti ◽  
Gerardo Musuraca ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Chronic Myeloproliferative Neoplasms ◽  
Fibrinogen Receptor ◽  
Low Expression

scholarly journals Unexpected Low Expression of Platelet Fibrinogen Receptor in Patients with Chronic Myeloproliferative Neoplasms: How Does It Change with Aspirin?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1794-1794
Author(s):  
Alessandro Lucchesi ◽  
Silvia Carloni ◽  
Martina Ghetti ◽  
Serena De Matteis ◽  
Gerardo Musuraca ◽  
...  
Keyword(s):  
Blood Flow ◽  
Platelet Count ◽  
Platelet Activation ◽  
Binding Capacity ◽  
Myeloproliferative Neoplasms ◽  
Positive Control ◽  
Vascular Events ◽  
Chronic Myeloproliferative Neoplasms ◽  
Fibrinogen Receptor ◽  
Microcirculatory Disorders

Abstract INTRODUCTION Patients affected by Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered at high risk of thrombo-haemorrhagic events, but the role of the platelet count in the assessment of the risk of vascular events is still controversial. A tight correlation was found between the platelet count and plasma sCD40L, which appears to be required for thrombus formation in vivo. However sCD40L is increased both in MPNs and reactive thrombocytosis. Intravascular aggregates of platelets and leukocytes, mediated by P-selectin and CD11b on the former and the latter, respectively, have been observed. Both of this processes should imply a perpetual - and measurable - platelet activation. Several studies on platelet function have been already proposed, nevertheless the mechanisms through which platelets are able to trigger vascular events, are not yet adequately clarified. A refined method for the determination of platelet activation appears to be the use of platelet PAC-1 antibody, able to identify the expression of the fibrinogen receptor of platelet glycoprotein IIb/IIIa. This expression is indeed unique in the process of platelet activation, and yet rarely analyzed. Moreover, since the platelet fibrinogen receptor exposure seems to be influenced by turbulence in blood flow, we have thought that its evaluation could provide important biological evidences to explain some clinical manifestations, such as microvascular disturbances. METHODS Blood samples from 40 consecutive MPNs patients who never received cytoreductive agents, were obtained. 28/40 patients were receiving a continuative antiplatelet prophylaxis with low dose aspirin (ASA, 75-100 mg) at the time of collection, while 12/40 of them were not on such therapy. Our aim was to verify the expression of platelet fibrinogen receptors (PFRs) in the two different groups of patients compared to healthy volunteers, using whole blood flow cytometry. In each experiment sodium citrate and heparin (positive control of platelet activation) tubes were collected from the same patient. Within 10 minutes from blood sampling, 5 ml of whole blood from each tube was incubated for 20 minutes at room temperature in the dark with saturating concentration of CD61 PerCP, CD62P PE and PAC-1 FITC. Positive control was also incubated with PAC-1 in the presence of Arg-Gly-Asp-Ser (RGDS) in order to test the specific antibody binding. Samples were fixed with paraformaldehyde 1% for 30 minutes at 4°C in the dark and analyzed on a flow cytometer. RESULTS Surprisingly, we have been able to verify a very low PAC-1 binding to platelets in patients with MPNs not receiving cytoreduction nor antiplatelet agents (33%) if compared to that observed in healthy subjects (61%; p<0.0001). The use of aspirin seems conversely to restore the expression of platelet fibrinogen receptor, as PAC-1 binding capacity is comparable to that of healthy volunteers (56%). No difference was found with respect to the JAK2 Val617Phe mutation and its allele burden. Interestingly, by focusing on the group of patients under antiplatelet prophylaxis and with no history of thrombosis, it was found that subjects with persistent microcirculatory disorders show a higher PAC-1 binding capacity if compared to the asymptomatic ones (67% vs 52%, p= 0.04). CONCLUSION In untreated MPNs, a large amount of platelets are resting in a conformation that is unable to bind fibrinogen, as demonstrated by the low PAC-1 expression in cytofluorimetry. This lack of activity can be reversed by administering ASA, which is also known for its fibrinolytic and hypoprothrombinemic effects. We hypotesize that the hypercoagulable states observed in these patient could depend on a primarly plasma-driven impairment of fibrin turnover and thrombin generation. Further investigations are going to be promoted by our Group. PAC-1 could be at the same time a good marker of aspirin resistance in patients experiencing microcirculatory disorders. Figure. Figure. Disclosures Martinelli: Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy; Ariad/Incyte: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy; Roche: Consultancy; Novartis: Speakers Bureau.

Interferon-Alpha in the Treatment of Philadelphia-Negative Chronic Myeloproliferative Neoplasms. Status and Perspectives

2011 ◽  
Vol 12 (3) ◽  
pp. 392-419 ◽  
Author(s):  
Hans Carl Hasselbalch ◽  
Thomas Stauffer Larsen ◽  
Caroline Hasselbalch Riley ◽  
Morten Krogh Jensen ◽  
Jean-Jacques Kiladjian
Keyword(s):  
Interferon Alpha ◽  
Myeloproliferative Neoplasms ◽  
Chronic Myeloproliferative Neoplasms

scholarly journals Methylation status of SOCS1 and SOCS3 in BCR-ABL negative and JAK2V617F negative chronic myeloproliferative neoplasms

2008 ◽  
Vol 32 (10) ◽  
pp. 1638-1640 ◽  
Author(s):  
Marta Fernández-Mercado ◽  
Virginia Cebrián ◽  
Begoña Euba ◽  
Marta García-Granero ◽  
María J. Calasanz ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Methylation Status ◽  
Chronic Myeloproliferative Neoplasms

scholarly journals Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Cecilia P. Marin Oyarzún ◽  
Agostina Carestia ◽  
Paola R. Lev ◽  
Ana C. Glembotsky ◽  
Miguel A. Castro Ríos ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Neutrophil Extracellular Trap ◽  
Chronic Myeloproliferative Neoplasms ◽  
Trap Formation ◽  
Extracellular Trap

scholarly journals THE JAK2V617F POINT MUTATION INCREASES THE OSTEOCLAST FORMING ABILITY OF MONOCYTES IN PATIENTS WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS AND MAKES THEIR OSTEOCLASTS MORE SUSCEPTIBLE TO JAK2 INHIBITION

2018 ◽  
Vol 10 ◽  
pp. e2018058
Author(s):  
Emmanouil Spanoudakis ◽  
Menelaos Papoutselis ◽  
Ioanna Bazntiara ◽  
Eleftheria Lamprianidou ◽  
Xrisa Kordella ◽  
...  
Keyword(s):  
Point Mutation ◽  
Genomic Dna ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Cellular Level ◽  
Hemopoietic Stem Cell ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms ◽  
Cell Niche ◽  
Jak2 Inhibition

JAK2V617F is a gain of function point mutation that occurs in Myeloproliferative Neoplasm (MPN) patients and deranges their hemopoiesis at cellular level. We speculate that hyperfunctioning JAK2 can modify osteoclast (OCL) homeostasis in MPN patients. We studied 18 newly diagnosed MPN patients and four age-matched normal donors (ND). Osteoclast forming assays started from selected monocytes also and under titrated concentrations of the JAK2 Inhibitor AG-490 (Tyrphostin). Genomic DNA was extracted from the formed osteoclasts, and the JAK2V617F/JAK2WT genomic DNA ratio was calculated. OCLs formed from monocytes derived from heterozygous (Het) for the JAK2V617F mutation MPN patients, were three times more compared to those from JAK2 wild type (WT) MPN patients (p=0,05) and from ND as well (p=0,03). The ratio of JAK2V617F/JAK2WT genomic DNA was increased in OCLs compared to the input monocyte cells showing a survival advantage of the mutated clone. In comparison to ND and JAK2 WT MPN patients, OCLs from patients JAK2V617F (Het) were more susceptible to JAK2 inhibition. These alterations in osteoclast homeostasis, attributed to mutated JAK2, can deregulate the hemopoietic stem cell niche in MPN patients.

Progressive and predictive markers of disease evolution: platelet transcriptome in chronic myeloproliferative neoplasms

2021 ◽  
Author(s):  
Zhu Shen ◽  
Wenfei Du ◽  
Cecelia Perkins ◽  
Lenn Fechter ◽  
Vanita Natu ◽  
...  
Keyword(s):  
Machine Learning ◽  
Risk Stratification ◽  
Disease Risk ◽  
Myeloproliferative Neoplasms ◽  
Penalized Regression ◽  
Machine Learning Algorithms ◽  
Disease Evolution ◽  
Chronic Myeloproliferative Neoplasms ◽  
Age Related ◽  
Wide Range

Predicting disease natural history remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the spectrum of chronic myeloproliferative neoplasms (MPNs), as a model, we identify the blood platelet transcriptome as a generalizable strategy for highly sensitive progression biomarkers that also enable prediction via machine learning algorithms. Using RNA sequencing (RNA seq), we derive disease relevant gene expression and alternative splicing in purified platelets from 120 peripheral blood samples constituting two independently collected and mutually validating patient cohorts of the three MPN subtypes: essential thrombocythemia, ET (n=24), polycythemia vera, PV (n=33), and primary or post ET/PV secondary myelofibrosis, MF (n=42), as well as healthy donors (n=21). The MPN platelet transcriptome discriminates each clinical phenotype and reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy. Leveraging this dataset, in particular the progressive expression gradient noted across MPN, we develop a machine learning model (Lasso-penalized regression) predictive of the advanced subtype MF at high accuracy (AUC-ROC of 0.95-0.96) with validation under two conditions: i) temporal, with training on the first cohort (n=71) and independent testing on the second (n=49) and ii) 10 fold cross validation on the entire dataset. Lasso-derived signatures offer a robust core set of < 10 MPN progression markers. Mechanistic insights from our data highlight impaired protein homeostasis as a prominent driver of MPN evolution, with persistent integrated stress response. We also identify JAK inhibitor-specific signatures and other interferon, proliferation, and proteostasis associated markers as putative targets for MPN-directed therapy. Our platelet transcriptome snapshot of chronic MPNs establishes a methodological foundation for deciphering disease risk stratification and progression beyond genetic data alone, thus presenting a promising avenue toward potential utility in a wide range of age-related disorders.

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