{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T02:47:15Z","timestamp":1792118835653,"version":"4.4.0"},"reference-count":108,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient\u2019s demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify the hypercoagulability states of these conditions is not yet part of clinical practice. Starting from our experience, and after having sifted through the literature, we propose an in-depth narrative report on the contribution of the clonal platelets of MPNs\u2014rich in tissue factor (TF)\u2014in promoting a perpetual procoagulant mechanism. The whole process results in an unbalanced generation of thrombin and is self-maintained by Protease Activated Receptors (PARs). We chose to define this model as a \u201ccirculating wound\u201d, as it indisputably links the coagulation, inflammation, and fibrotic progression of the disease, in analogy with what happens in some solid tumours. The platelet contribution to thrombin generation results in triggering a vicious circle supported by the PARs\/TGF-beta axis. PAR antagonists could therefore be a good option for target therapy, both to contain the risk of vascular events and to slow the progression of the disease towards end-stage forms. Both the new and old strategies, however, will require tools capable of measuring procoagulant or prohaemorrhagic states in a more extensive and dynamic way to favour a less empirical management of MPNs and their potential clinical complications.<\/jats:p>","DOI":"10.3390\/ijms222111343","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T21:29:46Z","timestamp":1634765386000},"page":"11343","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The \u201cCirculating Wound\u201d Model"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-5311","authenticated-orcid":false,"given":"Alessandro","family":"Lucchesi","sequence":"first","affiliation":[{"name":"Hematology Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3682-9606","authenticated-orcid":false,"given":"Roberta","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9299-9189","authenticated-orcid":false,"given":"Maria Teresa","family":"Bochicchio","sequence":"additional","affiliation":[{"name":"Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori\u201d, 47014 Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6932-5028","authenticated-orcid":false,"given":"Giulio","family":"Giordano","sequence":"additional","affiliation":[{"name":"Internal Medicine Division, Hematology Service, Regional Hospital \u201cA. Cardarelli\u201d, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariasanta","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties and Infectious Disease Unit, University Hospital \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1055\/s-0034-1370794","article-title":"Thrombosis in Myeloproliferative Neoplasms","volume":"40","author":"Falanga","year":"2014","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s11899-020-00588-z","article-title":"Thrombocytosis and Thrombosis: Is There Really a Correlation?","volume":"15","author":"Galvez","year":"2020","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/(SICI)1096-8652(199605)52:1<14::AID-AJH3>3.0.CO;2-9","article-title":"Reduction of Antithrombin III, Protein C, and Protein S Levels and Activated Protein C Resistance in Polycythemia Vera and Essential Thrombocythemia Patients with Thrombosis","volume":"52","author":"Bucalossi","year":"1996","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1182\/blood-2012-04-424911","article-title":"Correlation of Blood Counts with Vascular Complications in Essential Thrombocythemia: Analysis of the Prospective PT1 Cohort","volume":"120","author":"Campbell","year":"2012","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1182\/blood.2020008109","article-title":"The Pathobiology of Thrombosis, Microvascular Disease, and Hemorrhage in the Myeloproliferative Neoplasms","volume":"137","author":"Hasselbalch","year":"2021","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1055\/s-2006-949664","article-title":"The Paradox of Platelet Activation and Impaired Function: Platelet-von Willebrand Factor Interactions, and the Etiology of Thrombotic and Hemorrhagic Manifestations in Essential Thrombocythemia and Polycythemia Vera","volume":"32","author":"Michiels","year":"2006","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Marin Oyarz\u00fan, C.P., and Heller, P.G. (2019). Platelets as Mediators of Thromboinflammation in Chronic Myeloproliferative Neoplasms. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01373"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1055\/s-0040-1718873","article-title":"Platelet Function and Turnover in Essential Thrombocythemia: A Systematic Review","volume":"47","author":"Kvernberg","year":"2021","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s00277-007-0386-3","article-title":"Increased Platelet, Leukocyte, and Coagulation Activation in Primary Myelofibrosis","volume":"87","author":"Reverter","year":"2008","journal-title":"Ann. Hematol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3109\/10428199609074363","article-title":"Bleeding Time and Platelet Function in Essential Thrombocythemia and Other Myeloproliferative Syndromes","volume":"22","author":"Finazzi","year":"1996","journal-title":"Leuk. Lymphoma"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1055\/a-1334-3259","article-title":"Prevention and Management of Thrombosis in BCR\/ABL-Negative Myeloproliferative Neoplasms","volume":"41","author":"Falanga","year":"2021","journal-title":"Hamostaseologie"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1111\/jth.12965","article-title":"Regulation of the Genetic Code in Megakaryocytes and Platelets","volume":"13","author":"Rondina","year":"2015","journal-title":"J. Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/s41408-017-0010-2","article-title":"CALR Mutational Status Identifies Different Disease Subtypes of Essential Thrombocythemia Showing Distinct Expression Profiles","volume":"7","author":"Zini","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1182\/blood.2020007265","article-title":"Increased B4GALT1 Expression Is Associated with Platelet Surface Galactosylation and Thrombopoietin Plasma Levels in MPNs","volume":"137","author":"Giannini","year":"2021","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1080\/09537104.2019.1636019","article-title":"Platelet MicroRNA Expression and Association with Platelet Maturity and Function in Patients with Essential Thrombocythemia","volume":"31","author":"Tran","year":"2020","journal-title":"Platelets"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s12185-013-1475-9","article-title":"JAK2V617F Allele Burden Is Associated with Thrombotic Mechanisms Activation in Polycythemia Vera and Essential Thrombocythemia Patients","volume":"99","author":"Coucelo","year":"2014","journal-title":"Int. J. Hematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/ajh.21338","article-title":"Platelet Turnover, Coagulation Factors, and Soluble Markers of Platelet and Endothelial Activation in Essential Thrombocythemia: Relationship with Thrombosis Occurrence and JAK 2 V617F Allele Burden","volume":"84","author":"Reverter","year":"2009","journal-title":"Am. J. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1111\/j.1538-7836.2006.02194.x","article-title":"Inhibition of Tissue Factor Expression by Hydroxyurea in Polymorphonuclear Leukocytes from Patients with Myeloproliferative Disorders: A New Effect for an Old Drug?","volume":"4","author":"Maugeri","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3324\/haematol.2010.038299","article-title":"Pathophysiology of Thrombosis in Myeloproliferative Neoplasms","volume":"96","author":"Landolfi","year":"2011","journal-title":"Haematologica"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nrd.2015.10","article-title":"Integrin-Based Therapeutics: Biological Basis, Clinical Use and New Drugs","volume":"15","author":"Ley","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13045-019-0709-6","article-title":"Platelet Integrin AIIb\u03b23: Signal Transduction, Regulation, and Its Therapeutic Targeting","volume":"12","author":"Huang","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1046\/j.1365-2141.2000.02030.x","article-title":"Increased Platelet Activation and Abnormal Membrane Glycoprotein Content and Redistribution in Myeloproliferative Disorders","volume":"110","author":"Jensen","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1182\/blood-2012-05-431288","article-title":"Dysfunction of the PI3 Kinase\/Rap1\/Integrin AIIb\u03b23 Pathway Underlies Ex Vivo Platelet Hypoactivity in Essential Thrombocythemia","volume":"121","author":"Moore","year":"2013","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1600-0609.1981.tb01634.x","article-title":"Platelets in Myeloproliferative Disorders. III: Glycoprotein Profile in Relation to Platelet Function and Platelet Density","volume":"26","author":"Eche","year":"2009","journal-title":"Scand. J. Haematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/ajh.2830030108","article-title":"Changes in Distribution of Platelet Membrane Glycoproteins in Patients with Myeloproliferative Disorders","volume":"3","author":"Bolin","year":"1977","journal-title":"Am. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/j.1365-2141.1989.tb07755.x","article-title":"Platelet Membrane Abnormalities in Myeloproliferative Disorders: Decrease in Glycoproteins Ib and IIb\/IIIa Complex Is Associated with Deficient Receptor Function","volume":"73","author":"Mazzucato","year":"1989","journal-title":"Br. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1055\/s-0038-1646416","article-title":"125I-Fibrinogen Binding to Platelets in Myeloproliferative Disease","volume":"66","author":"Mistry","year":"1991","journal-title":"Thromb. Haemost."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"705","DOI":"10.3389\/fimmu.2020.00705","article-title":"Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients with Essential Thrombocythemia","volume":"11","author":"Glembotsky","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/bjh.16335","article-title":"Unexpected Low Expression of Platelet Fibrinogen Receptor in Patients with Chronic Myeloproliferative Neoplasms: How Does It Change with Aspirin?","volume":"189","author":"Lucchesi","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_30","first-page":"154","article-title":"Aspirin Acetylates Fibrinogen and Enhances Fibrinolysis. Fibrinolytic Effect Is Independent of Changes in Plasminogen Activator Levels","volume":"250","author":"Bjornsson","year":"1989","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1161\/CIRCULATIONAHA.105.574830","article-title":"Protease-Activated Receptors in Cardiovascular Diseases","volume":"114","author":"Leger","year":"2006","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12959-019-0194-8","article-title":"Protease-Activated Receptors (PARs): Mechanisms of Action and Potential Therapeutic Modulators in PAR-Driven Inflammatory Diseases","volume":"17","author":"Heuberger","year":"2019","journal-title":"Thromb. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3450","DOI":"10.1182\/blood-2014-04-572479","article-title":"Common Variants in the Human Platelet PAR4 Thrombin Receptor Alter Platelet Function and Differ by Race","volume":"124","author":"Edelstein","year":"2014","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10414","DOI":"10.1074\/jbc.M112.341438","article-title":"Mapping Human Protease-Activated Receptor 4 (PAR4) Homodimer Interface to Transmembrane Helix","volume":"287","author":"Noble","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/rth2.12454","article-title":"Protease-activated Receptors: An Illustrated Review","volume":"5","author":"Han","year":"2021","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/29325","article-title":"A Dual Thrombin Receptor System for Platelet Activation","volume":"394","author":"Kahn","year":"1998","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1124\/mol.106.033365","article-title":"PAR1, but Not PAR4, Activates Human Platelets through a G i\/o \/Phosphoinositide-3 Kinase Signaling Axis","volume":"71","author":"Voss","year":"2007","journal-title":"Mol. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6169","DOI":"10.3390\/ijms15046169","article-title":"Differential Signaling by Protease-Activated Receptors: Implications for Therapeutic Targeting","volume":"15","author":"Sidhu","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"L911","DOI":"10.1152\/ajplung.00372.2003","article-title":"P38 MAP Kinase-Dependent Regulation of Endothelial Cell Permeability","volume":"287","author":"Borbiev","year":"2004","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"18S","DOI":"10.1378\/chest.124.3_suppl.18S","article-title":"Thrombin and Platelet Activation","volume":"124","author":"Brass","year":"2003","journal-title":"Chest"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19728","DOI":"10.1074\/jbc.M909960199","article-title":"Structure-Function Analysis of Protease-Activated Receptor 4 Tethered Ligand Peptides","volume":"275","author":"Faruqi","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"25216","DOI":"10.1074\/jbc.M004589200","article-title":"Protease-Activated Receptors 1 and 4 Are Shut Off with Distinct Kinetics after Activation by Thrombin","volume":"275","author":"Shapiro","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1124\/mol.119.118232","article-title":"Proteinase-Activated Receptor 4 Activation Triggers Cell Membrane Blebbing through RhoA and \u03b2 -Arrestin","volume":"97","author":"Vanderboor","year":"2020","journal-title":"Mol. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ajhg.2020.06.008","article-title":"A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling","volume":"107","author":"Rodriguez","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6642","DOI":"10.1073\/pnas.95.12.6642","article-title":"Cloning and Characterization of Human Protease-Activated Receptor","volume":"95","author":"Xu","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.yjmcc.2015.11.030","article-title":"Protease\u2014Activated Receptor 4 Deficiency Offers Cardioprotection after Acute Ischemia Reperfusion Injury","volume":"90","author":"Kolpakov","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_47","first-page":"1614","article-title":"Thrombin Stimulates Integrin \u03921-Dependent Adhesion of Human Pancreatic Cancer Cells to Vitronectin through Protease-Activated Receptor (PAR)","volume":"59","author":"Kanemaru","year":"2012","journal-title":"Hepatogastroenterology"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kothari, A., and Flick, M.J. (2021). Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105138"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/jth.15115","article-title":"Thrombin-PAR1 Signaling in Pancreatic Cancer Promotes an Immunosuppressive Microenvironment","volume":"19","author":"Schweickert","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1158\/0008-5472.CAN-18-3206","article-title":"Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1\u2013Dependent Immune Evasion","volume":"79","author":"Yang","year":"2019","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1002\/ijc.28726","article-title":"Protease-Activated Receptor-1 Drives Pancreatic Cancer Progression and Chemoresistance","volume":"135","author":"Queiroz","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1093\/annonc\/mds634","article-title":"VEGFR-2, CXCR-2 and PAR-1 Germline Polymorphisms as Predictors of Survival in Pancreatic Carcinoma","volume":"24","author":"Uzunoglu","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1158\/0008-5472.CAN-15-1293","article-title":"TGF\u03b2 Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis","volume":"76","author":"Principe","year":"2016","journal-title":"Cancer Res."},{"key":"ref_54","first-page":"5","article-title":"Bone Marrow Fibrosis in Primary Myelofibrosis: Pathogenic Mechanisms and the Role of TGF-\u03b2","volume":"3","author":"Agarwal","year":"2016","journal-title":"Stem Cell Investig."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Ungefroren, H., Gieseler, F., Kaufmann, R., Settmacher, U., Lehnert, H., and Rauch, B. (2018). Signaling Crosstalk of TGF-\u03b2\/ALK5 and PAR2\/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061568"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1056\/NEJMra044440","article-title":"Direct Thrombin Inhibitors","volume":"353","author":"Middeldorp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1111\/jth.13374","article-title":"Protease-Activated Receptor 4 Is More Important than Protease-Activated Receptor 1 for the Thrombin-Induced Procoagulant Effect on Platelets","volume":"14","author":"Lindahl","year":"2016","journal-title":"J. Thromb. Haemost."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/cvr\/cvp066","article-title":"Is Thrombin a Key Player in the \u201ccoagulation-Atherogenesis\u201d Maze?","volume":"82","author":"Borissoff","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0049-3848(00)00347-9","article-title":"Platelet Activation and Its Role in Thrombin Generation in Platelet-Induced Thrombin Generation Time","volume":"100","author":"Radziwon","year":"2000","journal-title":"Thromb. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/ajh.21974","article-title":"Platelet-Induced Thrombin Generation by the Calibrated Automated Thrombogram Assay Is Increased in Patients with Essential Thrombocythemia and Polycythemia Vera","volume":"86","author":"Marchetti","year":"2011","journal-title":"Am. J. Hematol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.exphem.2007.01.053","article-title":"V617F JAK-2 Mutation in Patients with Essential Thrombocythemia: Relation to Platelet, Granulocyte, and Plasma Hemostatic and Inflammatory Molecules","volume":"35","author":"Falanga","year":"2007","journal-title":"Exp. Hematol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e262","DOI":"10.1161\/ATVBAHA.120.314760","article-title":"Platelet Dysfunction and Thrombosis in JAK2 V617F -Mutated Primary Myelofibrotic Mice","volume":"40","author":"Matsuura","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Palova, M., Slavik, L., Hlusi, A., Szotkowski, T., Ulehlova, J., Divoka, M., Navratilova, J., and Papajik, T. (2018). Thrombin Generation Testing in Patients with Myelofibrosis. Clin. Lab., 64.","DOI":"10.7754\/Clin.Lab.2018.180204"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1182\/asheducation.V2012.1.571.3798557","article-title":"Thrombotic Disease in the Myeloproliferative Neoplasms","volume":"2012","author":"Falanga","year":"2012","journal-title":"Hematol. Am. Soc. Hematol. Educ. Progr."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"911","DOI":"10.3324\/haematol.13774","article-title":"Elevated Procoagulant Microparticles Expressing Endothelial and Platelet Markers in Essential Thrombocythemia","volume":"94","author":"Trappenburg","year":"2009","journal-title":"Haematologica"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4061","DOI":"10.1182\/blood-2008-06-164087","article-title":"Thrombin Generation and Activated Protein C Resistance in Patients with Essential Thrombocythemia and Polycythemia Vera","volume":"112","author":"Marchetti","year":"2008","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"50","DOI":"10.5507\/bp.2016.064","article-title":"Thrombin Generation\u2014A Potentially Useful Biomarker of Thrombotic Risk in Philadelphia-Negative Myeloproliferative Neoplasms","volume":"161","author":"Mihaila","year":"2017","journal-title":"Biomed. Pap."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.redox.2015.10.009","article-title":"Thrombin-Induced Reactive Oxygen Species Generation in Platelets: A Novel Role for Protease-Activated Receptor 4 and GPIb\u03b1","volume":"6","author":"Carrim","year":"2015","journal-title":"Redox Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.37358\/RC.19.8.7435","article-title":"Oxidative Stress Levels, JAK2V617F Mutational Status and Thrombotic Complications in Patients with Essential Thrombocythemia","volume":"70","author":"Moisa","year":"2019","journal-title":"Rev. Chim."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1365-2141.2009.07833.x","article-title":"Acquired Coagulation Disorders: Revisited Using Global Coagulation\/Anticoagulation Testing","volume":"147","author":"Tripodi","year":"2009","journal-title":"Br. J. Haematol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1007\/s00277-013-1834-x","article-title":"Global Coagulation in Myeloproliferative Neoplasms","volume":"92","author":"Tripodi","year":"2013","journal-title":"Ann. Hematol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"S185","DOI":"10.1016\/S0049-3848(16)30159-1","article-title":"PO-26\u2014Whole Blood Rotational Thromboelastometry (ROTEM) to Detect Hypercoagulability in Patients with Myeloproliferative Neoplasms (MPN)","volume":"140","author":"Giaccherini","year":"2016","journal-title":"Thromb. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1097\/MBC.0000000000000724","article-title":"An Evaluation of Global Coagulation Assays in Myeloproliferative Neoplasm","volume":"29","author":"Lim","year":"2018","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.thromres.2010.06.025","article-title":"Increased Circulating Procoagulant Activity and Thrombin Generation in Patients with Myeloproliferative Neoplasms","volume":"126","author":"Duchemin","year":"2010","journal-title":"Thromb. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1080\/09537104.2020.1742309","article-title":"Use of Rotational Thromboelastometry for a Global Screening of Coagulation Profile in Patients of Myeloproliferative Neoplasms","volume":"32","author":"Akay","year":"2021","journal-title":"Platelets"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/ajh.21360","article-title":"Long-Term Follow-up of 386 Consecutive Patients with Essential Thrombocythemia: Safety of Cytoreductive Therapy","volume":"84","author":"Palandri","year":"2009","journal-title":"Am. J. Hematol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1182\/bloodadvances.2020003628","article-title":"A Systematic Review of Antithrombotic Treatment of Venous Thromboembolism in Patients with Myeloproliferative Neoplasms","volume":"5","author":"Daams","year":"2021","journal-title":"Blood Adv."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s11899-014-0226-1","article-title":"Antiplatelet Therapy in the Management of Myeloproliferative Neoplasms","volume":"9","author":"Besses","year":"2014","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"926","DOI":"10.3324\/haematol.2016.146654","article-title":"Antiplatelet Therapy versus Observation in Low-Risk Essential Thrombocythemia with a CALR Mutation","volume":"101","author":"Pereira","year":"2016","journal-title":"Haematologica"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1056\/NEJMoa035572","article-title":"Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera","volume":"350","author":"Landolfi","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.exphem.2005.01.015","article-title":"Leukocyte-Platelet Interaction in Patients with Essential Thrombocythemia and Polycythemia Vera","volume":"33","author":"Falanga","year":"2005","journal-title":"Exp. Hematol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1182\/blood-2012-02-406645","article-title":"Overcoming \u201cAspirin Resistance\u201d in MPN","volume":"119","author":"Tefferi","year":"2012","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3595","DOI":"10.1182\/blood-2011-06-359224","article-title":"Aspirin-Insensitive Thromboxane Biosynthesis in Essential Thrombocythemia Is Explained by Accelerated Renewal of the Drug Target","volume":"119","author":"Pascale","year":"2012","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1080\/09537104.2017.1361018","article-title":"Decreased Turnover Aspirin Resistance by Bidaily Aspirin Intake and Efficient Cytoreduction in Myeloproliferative Neoplasms","volume":"29","author":"Ianotto","year":"2018","journal-title":"Platelets"},{"key":"ref_85","first-page":"279","article-title":"Evaluation of Thrombin Generation in Classical Philadelphianegative Myeloproliferative Neoplasms \/ Evaluarea Gener\u0103rii Trombinei \u00cen Neoplasmele Mieloproliferative Philadelphia- Negative","volume":"24","author":"Olteanu","year":"2016","journal-title":"Rev. Rom. Med. Lab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3324\/haematol.2016.152769","article-title":"Risk of Thrombosis According to Need of Phlebotomies in Patients with Polycythemia Vera Treated with Hydroxyurea","volume":"102","author":"Magro","year":"2017","journal-title":"Haematologica"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Parra-Izquierdo, I., Melrose, A.R., Pang, J., Lakshmanan, H.H.S., Reitsma, S.E., Vavilapalli, S.H., Larson, M.K., Shatzel, J.J., McCarty, O.J.T., and Aslan, J.E. (2021). Janus Kinase Inhibitors Ruxolitinib and Baricitinib Impair Glycoprotein-VI Mediated Platelet Function. Platelets, 1\u201312.","DOI":"10.1080\/09537104.2021.1934665"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e015616","DOI":"10.1161\/JAHA.119.015616","article-title":"Blockade of PAR-1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice","volume":"9","author":"Yokono","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/hep.20054","article-title":"PAR1 Antagonism Protects against Experimental Liver Fibrosis. Role of Proteinase Receptors in Stellate Cell Activation","volume":"39","author":"Fiorucci","year":"2004","journal-title":"Hepatology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"576","DOI":"10.2119\/molmed.2015.00094","article-title":"Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis","volume":"21","author":"Lin","year":"2015","journal-title":"Mol. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1042\/CS20200923","article-title":"The PAR-1 Antagonist Vorapaxar Ameliorates Kidney Injury and Tubulointerstitial Fibrosis","volume":"134","author":"Lok","year":"2020","journal-title":"Clin. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1093\/eurheartj\/ehz117","article-title":"Protease-Activated Receptor 2 Deficiency Mediates Cardiac Fibrosis and Diastolic Dysfunction","volume":"40","author":"Friebel","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/jcmm.12520","article-title":"Protease-Activated Receptor (PAR)-2 Is Required for PAR-1 Signalling in Pulmonary Fibrosis","volume":"19","author":"Lin","year":"2015","journal-title":"J. Cell. Mol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1160\/TH12-11-0854","article-title":"Protease-Activated Receptors (PAR)-1 and -3 Drive Epithelial-Mesenchymal Transition of Alveolar Epithelial Cells\u2013Potential Role in Lung Fibrosis","volume":"110","author":"Wygrecka","year":"2013","journal-title":"Thromb. Haemost."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1042\/bst0300194","article-title":"Coagulation Cascade Proteases and Tissue Fibrosis","volume":"30","author":"Chambers","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJMoa1109719","article-title":"Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes","volume":"366","author":"Tricoci","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1056\/NEJMoa1200933","article-title":"Vorapaxar in the Secondary Prevention of Atherothrombotic Events","volume":"366","author":"Morrow","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Li, S., Tarlac, V., and Hamilton, J.R. (2019). Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225629"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Rwibasira Rudinga, G., Khan, G., and Kong, Y. (2018). Protease-Activated Receptor 4 (PAR4): A Promising Target for Antiplatelet Therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020573"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"112893","DOI":"10.1016\/j.ejmech.2020.112893","article-title":"Protease Activated Receptor 4 (PAR4) Antagonists: Research Progress on Small Molecules in the Field of Antiplatelet Agents","volume":"209","author":"Liu","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1080\/09537104.2017.1282607","article-title":"Molecular Requirements Involving the Human Platelet Protease-Activated Receptor-4 Mechanism of Activation by Peptide Analogues of Its Tethered-Ligand","volume":"28","author":"Moschonas","year":"2017","journal-title":"Platelets"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nrd3615","article-title":"Targeting Proteinase-Activated Receptors: Therapeutic Potential and Challenges","volume":"11","author":"Ramachandran","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.thromres.2021.02.019","article-title":"Influence of PAR-1 in Patients with Non-Valvular Atrial Fibrillation: The Antiplatelet Effect of Dabigatran","volume":"201","author":"Oi","year":"2021","journal-title":"Thromb. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1124\/mol.114.096446","article-title":"Characterization of Thrombin-Bound Dabigatran Effects on Protease-Activated Receptor-1 Expression and Signaling In Vitro","volume":"88","author":"Chen","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1038\/s41375-021-01279-1","article-title":"Direct Oral Anticoagulants for Myeloproliferative Neoplasms: Results from an International Study on 442 Patients","volume":"35","author":"Barbui","year":"2021","journal-title":"Leukemia"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"13","DOI":"10.2119\/molmed.2016.00214","article-title":"Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice","volume":"23","author":"Shi","year":"2017","journal-title":"Mol. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"317","DOI":"10.7326\/M17-0028","article-title":"Risk for Arterial and Venous Thrombosis in Patients with Myeloproliferative Neoplasms","volume":"168","author":"Hultcrantz","year":"2018","journal-title":"Ann. Intern. Med."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"G\u0103man, M.-A., Cozma, M.-A., Dobric\u0103, E.-C., Cre\u021boiu, S.M., G\u0103man, A.M., and Diaconu, C.C. (2021). Liquid Biopsy and Potential Liquid Biopsy-Based Biomarkers in Philadelphia-Negative Classical Myeloproliferative Neoplasms: A Systematic Review. Life, 11.","DOI":"10.3390\/life11070677"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11343\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:19:27Z","timestamp":1760167167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11343"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,20]]},"references-count":108,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111343"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111343","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,20]]}}}