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Xu DG, Tan J. Interplay of genetic and clinical factors in cancer-associated thrombosis: Deciphering the prothrombotic landscape of colorectal cancer. World J Gastroenterol 2025; 31:103901. [PMID: 40248375 PMCID: PMC12001197 DOI: 10.3748/wjg.v31.i14.103901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/03/2025] [Accepted: 03/25/2025] [Indexed: 04/11/2025] Open
Abstract
Colorectal cancer (CRC), the third most prevalent cancer globally, exhibits a notable association with venous thromboembolism (VTE), significantly impacting patient morbidity and mortality. We delve into the complex pathogenesis of cancer-associated thrombosis (CAT) in CRC, highlighting the interplay of clinical risk factors and tumor-specific mechanisms. Our comprehensive review synthesizes the current understanding of CRC's pro-thrombotic tendencies, examining both general clinical factors (e.g., age, gender, obesity, prior VTE history) and tumor-specific aspects (e.g., tumor location, stage, targeted therapies). Key findings illustrate how CRC cells themselves actively contribute to coagulation cascade activation through various procoagulant elements such as tissue factor, cancer procoagulant, and extracellular vesicles. We also explore how CRC influences host cells to adopt a procoagulant phenotype, thereby exacerbating thrombotic risks. This review underscores the role of genetic mutations in CRC (e.g., KRAS, p53) in modulating coagulation-related protein expression and thrombosis risks. An in-depth understanding of the genetic landscape specific to CRC subtypes is essential for developing targeted anticoagulation strategies and could significantly advance thrombosis prevention while improving the overall management of patients with CRC. This highlights the urgent need for precision in addressing CAT within clinical settings.
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Affiliation(s)
- Duo-Gang Xu
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, China
| | - Jing Tan
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, China
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2
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Kristiansen MH, Larsen MK, Massarenti L, Skov V, Kjær L, Enevold C, Ostrowski SR, Nielsen CH, Hasselbalch HC, Wienecke T. Thromboinflammation in ischemic cerebrovascular patients with the JAK2V617F mutation. Thromb Res 2025; 245:109236. [PMID: 39652998 DOI: 10.1016/j.thromres.2024.109236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/23/2024] [Accepted: 12/03/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND The JAK2V617F mutation is a driver of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) and is also implicated in cardiovascular diseases. Thrombosis in MPN involves JAK2V617F-associated platelet activation and endothelial dysfunction, all potentially influenced by chronic inflammation. Whether the mutation affects thromboinflammatory markers similarly in non-MPN patients remains unclear. METHOD We conducted a study involving 63 ischemic cerebrovascular patients with the JAK2V617F mutation, matched with 63 patients without the mutation. Serum samples were analyzed for 12 thromboinflammatory markers during the acute phase and at three months follow-up. RESULTS Overall, there was no significant difference in thromboinflammatory markers between cases and controls. However, subgroup analysis of patients with a JAK2V617F allele burden ≥1 % (n = 15) showed higher levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) at baseline (p = 0.018), and elevated Interleukin-10 (IL-10) (p = 0.004) and Tumor Necrosis Factor α (TNF-α) (p = 0.018) at follow-up compared to controls. Regression analysis revealed an association between higher JAK2V617F allele burden and increased VCAM-1 at baseline (p < 0.001), and higher VCAM-1 (p = 0.012), IL-10 (p = 0.003), and TNF-α (p = 0.034) at follow-up. CONCLUSION In ischemic cerebrovascular patients, the JAK2V617F mutation is associated with elevated markers of endothelial dysfunction and chronic inflammation. This underscores the role of inflammation in thrombosis driven by the JAK2V617F mutation.
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Affiliation(s)
- Marie Hvelplund Kristiansen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Neurology, Zealand University Hospital, Roskilde, Denmark.
| | - Morten Kranker Larsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Laura Massarenti
- Section for Oral Biology and Immunopathology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Christian Enevold
- Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sisse Rye Ostrowski
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Claus Henrik Nielsen
- Section for Oral Biology and Immunopathology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Hans Carl Hasselbalch
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Troels Wienecke
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Neurology, Zealand University Hospital, Roskilde, Denmark
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Malte AL, Højbjerg JA, Larsen JB. Platelet Parameters as Biomarkers for Thrombosis Risk in Cancer: A Systematic Review and Meta-analysis. Semin Thromb Hemost 2024; 50:360-383. [PMID: 36921613 DOI: 10.1055/s-0043-1764381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Cancer-associated thrombosis (CAT) is a major cause of both morbidity and mortality in cancer patients. Platelet count has been investigated as a predictor of CAT in various settings while knowledge on platelet activation parameters is sparse. This report provides a systematic review and meta-analysis on available literature on associations between platelet count and/or function and arterial and venous thrombosis in adult cancer patients. The review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. PubMed and Embase were searched up to March 2022. The National Heart, Lung, and Blood Institute's tools were used for quality assessment. In total, 100 studies were included which investigated the association between CAT and platelet count (n = 90), platelet indices (n = 19), and platelet function/activation markers (n = 13) in patients with solid cancers (n = 61), hematological cancers (n = 17), or mixed cancer types (n = 22). Eighty-one studies had venous thrombosis as their outcome measure, while 4 had arterial thrombosis and 15 studies had both. We found significantly elevated odds ratio of 1.50 (95% confidence interval: 1.19-1.88) for thrombosis with higher platelet counts. We saw a tendency toward an association between markers of platelet activation in forms of mean platelet volume and soluble P selectin and both arterial and venous thrombosis. Only one study investigated dynamic platelet function using flow cytometry. In conclusion, platelet count is associated with CAT across different cancer types and settings. Platelet function or activation marker analysis may be valuable in assisting thrombosis risk assessment in cancer patients but is sparsely investigated so far.
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Affiliation(s)
- Anne Lind Malte
- Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Johanne Andersen Højbjerg
- Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Julie Brogaard Larsen
- Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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4
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Aydın N, Tufek M. The effect of polycythemia vera on choroidal thickness and retrobulbar blood flow. Photodiagnosis Photodyn Ther 2024; 45:103985. [PMID: 38246214 DOI: 10.1016/j.pdpdt.2024.103985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 01/10/2024] [Accepted: 01/17/2024] [Indexed: 01/23/2024]
Abstract
BACKGROUND To evaluate the choroidal thickness and retrobulbar hemodynamic parameters in polycythemia vera (PV) patients in comparison with healthy individuals, and to investigate the relationship of these values with blood hematocrit levels. METHODS This prospective study included the 35 eyes of 35 PV patients and the 30 eyes of 30 healthy individuals. Choroidal thickness was measured at the subfoveal area and at 500 µm intervals nasal and temporal to the fovea up to a distance of 1500 µm. Color Doppler ultrasonography (CDU) was used to evaluate the retrobulbar vessels. Complete blood count values were recorded. RESULTS Choroidal thickness was found to be significantly lower in the PV group than in the control group at the subfoveal, nasal 500, and temporal 500 and 1000 µm measurement points (p = 0.01, p = 0.011, p = 0.04, p = 0.045, respectively). The central retinal artery (CRA) peak systolic velocity (PSV) and end diastolic velocity (EDV) values and the ophthalmic artery (OA) PSV value were significantly lower in the PV group than in the control group (p < 0.001, p < 0.001, p = 0.019, respectively). No significant difference was present between the groups in terms of CRA and OA resistive index (RI) and pulsatile index (PI) values (p = 0.388, p = 0.564, p = 0.897, p = 0.693, respectively). A negative correlation was found between the blood hematocrit levels and the subfoveal, nasal 500 µm, and temporal 500 µm choroidal thickness measurements and the CRA PSV and EDV and the OA PSV values. CONCLUSIONS PV may cause microvascular changes and lead to ocular vascular complications by affecting the choroidal and retrobulbar blood flow.
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Affiliation(s)
- Nihat Aydın
- Department of Ophthalmology, Amasya University, Sabuncuoglu Serefeddin Training and Research Hospital, Amasya, Turkey
| | - Melek Tufek
- Department of Ophthalmology, Amasya University, Sabuncuoglu Serefeddin Training and Research Hospital, Amasya, Turkey.
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Severino P, D'Amato A, Prosperi S, Myftari V, Colombo L, Tomarelli E, Piccialuti A, Di Pietro G, Birtolo LI, Maestrini V, Badagliacca R, Sardella G, Fedele F, Vizza CD, Mancone M. Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA): Focus on Coronary Microvascular Dysfunction and Genetic Susceptibility. J Clin Med 2023; 12:jcm12103586. [PMID: 37240691 DOI: 10.3390/jcm12103586] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/14/2023] [Accepted: 05/18/2023] [Indexed: 05/28/2023] Open
Abstract
Among the most common causes of death worldwide, ischemic heart disease (IHD) is recognized to rank first. Even if atherosclerotic disease of the epicardial arteries is known as the leading cause of IHD, the presence of myocardial infarction with non-obstructive coronary artery disease (MINOCA) is increasingly recognized. Notwithstanding the increasing interest, MINOCA remains a puzzling clinical entity that can be classified by distinguishing different underlying mechanisms, which can be divided into atherosclerotic and non-atherosclerotic. In particular, coronary microvascular dysfunction (CMD), classifiable in non-atherosclerotic mechanisms, is a leading factor for the pathophysiology and prognosis of patients with MINOCA. Genetic susceptibility may have a role in primum movens in CMD. However, few results have been obtained for understanding the genetic mechanisms underlying CMD. Future studies are essential in order to find a deeper understanding of the role of multiple genetic variants in the genesis of microcirculation dysfunction. Progress in research would allow early identification of high-risk patients and the development of pharmacological, patient-tailored strategies. The aim of this review is to revise the pathophysiology and underlying mechanisms of MINOCA, focusing on CMD and actual knowledge about genetic predisposition to it.
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Affiliation(s)
- Paolo Severino
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Andrea D'Amato
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Silvia Prosperi
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Vincenzo Myftari
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Lorenzo Colombo
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Elisa Tomarelli
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Alice Piccialuti
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Gianluca Di Pietro
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Lucia Ilaria Birtolo
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Viviana Maestrini
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Roberto Badagliacca
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Gennaro Sardella
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Francesco Fedele
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Carmine Dario Vizza
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
| | - Massimo Mancone
- Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, 00161 Rome, Italy
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Aoyama R, Kubota Y, Tara S, Wakita S, Yamaguchi H, Shimizu W, Takano H. Vascular Endothelial Dysfunction in Myeloproliferative Neoplasms and Gene Mutations. Int Heart J 2022; 63:661-668. [PMID: 35831151 DOI: 10.1536/ihj.22-003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Essential thrombocythemia (ET) and polycythemia vera (PV), are common Philadelphia-negative myeloproliferative neoplasms (MPN). Patients with MPN have a high rate of cardiovascular complications and often have acquired JAK2V617F and CALR genetic mutations. In this study, we aimed to analyze vascular endothelial function in patients with MPN.We evaluated 27 outpatients, including 10 patients diagnosed with MPN, flow-mediated dilatation (FMD), and nitroglycerin-mediated dilation (NMD), between September 2014 and August 2016. We measured serum adiponectin, which protects vascular endothelial function, and serum asymmetric dimethyl arginine (ADMA), which inhibits the production of adiponectin. The presence or absence of JAK2V617F and CALR mutations was evaluated in patients with MPN.Venous thrombosis was observed more frequently in patients with MPN than in those without. Seven MPN patients were diagnosed with PV, and 3 MPN patients were diagnosed with ET. JAK2V617F and CALR mutations were found in 5 and 3 MPN patients, respectively. FMD was significantly lower in JAK2V617F-positive MPN patients than in JAK2V617F-negative MPN patients, although NMD, adiponectin, and ADMA were similar in both groups. Adiponectin levels were higher and ADMA levels were lower in CALR-positive MPN patients than in CALR-negative MPN patients. There was no difference in FMD and NMD prevalence between the 2 groups. Furthermore, we had 3 representative MPN patients who were complicated with coronary spasm, possibly caused by MPN-related endothelial dysfunction.We found that patients with MPN presented with endothelial dysfunction, which was related to the presence of genetic mutations and was sometimes associated with cardiovascular disease.
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Affiliation(s)
- Rie Aoyama
- Department of Cardiovascular Medicine, Nippon Medical School.,Division of Cardiology, Heart and Vascular Institute, Funabashi Municipal Medical Center
| | - Yoshiaki Kubota
- Department of Cardiovascular Medicine, Nippon Medical School
| | - Shuhei Tara
- Department of Cardiovascular Medicine, Nippon Medical School
| | | | | | - Wataru Shimizu
- Department of Cardiovascular Medicine, Nippon Medical School
| | - Hitoshi Takano
- Department of Cardiovascular Medicine, Nippon Medical School
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Tanashyan M, Shabalina A, Roitman E. Microrheological disorders in patients with polycythemia vera suffered acute ischemic stroke. Mol Cell Biochem 2022; 477:989-994. [PMID: 34984595 DOI: 10.1007/s11010-021-04352-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/23/2021] [Indexed: 11/27/2022]
Abstract
The relevance of the study is determined by the fact that the combination of cerebrovascular disorders and myeloproliferative diseases requires the search for a predictive biomarker to improve outcomes. The aim of this article was to explore the meanings of microrheological disorders in patients with polycythemia vera (PV) who suffered an acute ischemic stroke (AIS). The study was carried out at the Research center of Neurology. We studied microrheological properties in 181 patients (aged 42-75 years). From the AIS developed in 68 (38%) patients with PV; 59 (32%) patients with AIS were without PV; 54 (30%) patients with PV did not suffer AIS. Microrheological disorders, first of all, the red blood cells (RBC) deformability correlated to AIS severity and its features in comorbid patients. The RBC deformability was dependent on the allelic load of the V617F mutation in the JAK2 gene. Additionally, it was found that RBC deformability perform diagnostic value in the acute phase of ischemic stroke as well as get predictive value for thrombotic complications development within 2 years after AIS in such patients. We suppose that in patients with PV an ischemic stroke and thrombosis would directly depend on the success of PV treatment. In turn, RBC deformability is applicable for some predictive models to late thrombosis development.
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Affiliation(s)
- Marine Tanashyan
- Department of Neurological No. 1, Research Center of Neurology, 80 Volokolamskoye Shosse, 125367, Moscow, Russian Federation
| | - Alla Shabalina
- Laboratory of Hemorheology, Hemostasis and Pharmacokinetics with Clinical Laboratory Diagnostics, Research Center of Neurology, 80 Volokolamskoye Shosse, 125367, Moscow, Russian Federation
| | - Eugene Roitman
- Laboratory of Hemorheology, Hemostasis and Pharmacokinetics with Clinical Laboratory Diagnostics, Research Center of Neurology, 80 Volokolamskoye Shosse, 125367, Moscow, Russian Federation.
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8
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Giordano G, Napolitano M, Cellurale M, Di Carlo P, Musuraca G, Micucci G, Lucchesi A. Circulating Endothelial Cell Levels Correlate with Treatment Outcomes of Splanchnic Vein Thrombosis in Patients with Chronic Myeloproliferative Neoplasms. J Pers Med 2022; 12:364. [PMID: 35330364 PMCID: PMC8954048 DOI: 10.3390/jpm12030364] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/12/2022] [Accepted: 02/24/2022] [Indexed: 02/05/2023] Open
Abstract
Circulating endothelial cells (CECs) are viable, apoptotic or necrotic cells, identified by CD 146 surface antigen expression, considered a biomarker of thrombotic risk, given their active role in inflammatory, procoagulant and immune processes of the vascular compartment. Growing evidence establishes that CECs are also involved in the pathogenesis of several hematological and solid malignancies. The primary aim of this study was to verify if CEC levels could predict both the course and treatment responses of splanchnic vein thrombosis (SVT), either in patients affected by myeloproliferative neoplasms (MPNs) or liver disease. Thus, a retrospective multicenter study was performed; fifteen patients receiving anticoagulant oral treatment with vitamin k antagonists (VKA) for SVT were evaluated. Nine patients were affected by MPN, and all of them received cytoreduction in addition to anticoagulant therapy; four of these patients had primary myelofibrosis (PMF) and were treated with ruxolitinib (RUX), and one patient with primary myelofibrosis, two patients with essential thrombocythemia (ET), and two patients with polycythemia vera (PV) were treated with hydroxyurea (HU). Six patients affected by liver diseases (three with liver cirrhosis and three with hepatocellular carcinoma) were included as the control group. CECs were assayed by flow cytometry on peripheral blood at specific time points, for up to six months after enrollment. The CEC levels were related to C-reactive protein (CRP) levels, splenic volume reduction, and thrombus recanalization, mainly in MPN patients. In patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC), for which the mechanism of SVT development is quite different, the relationship between CEC and SV reduction was absent. In conclusion, the CEC levels showed a significant correlation with the extent of venous thrombosis and endothelial cell damage in myeloproliferative neoplasm patients with splanchnic vein thrombosis. Although preliminary, these results show how monitoring CEC levels during cytoreductive and anticoagulant treatments may be useful to improve SVT outcome in MPN patients.
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Affiliation(s)
- Giulio Giordano
- Internal Medicine Division, Hematology Service, Regional Hospital “A. Cardarelli”, 86100 Campobasso, Italy; (G.G.); (M.C.)
| | - Mariasanta Napolitano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties and Haematology Unit, University Hospital “P. Giaccone”, 90127 Palermo, Italy;
| | - Michele Cellurale
- Internal Medicine Division, Hematology Service, Regional Hospital “A. Cardarelli”, 86100 Campobasso, Italy; (G.G.); (M.C.)
| | - Paola Di Carlo
- Department of Health Promotion, Mother, and Child Care, Internal Medicine and Medical Specialties and Infectious Disease Unit, University Hospital “P. Giaccone”, 90127 Palermo, Italy;
| | - Gerardo Musuraca
- Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Giorgia Micucci
- Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Alessandro Lucchesi
- Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
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9
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Thrombosis in myeloproliferative neoplasms: A clinical and pathophysiological perspective. THROMBOSIS UPDATE 2021. [DOI: 10.1016/j.tru.2021.100081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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10
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Šefer D, Miljić P, Kraguljac-Kurtović N, Bižić-Radulović S, Bogdanović A, Knežević V, Marković D, Beleslin-Čokić B, Novaković I, Marinković J, Leković D, Gotić M, Čokić V. Correlation between leukocyte-platelet aggregates and thrombosis in myeloproliferative neoplasms. Int J Lab Hematol 2021; 44:302-312. [PMID: 34755461 DOI: 10.1111/ijlh.13754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/14/2021] [Accepted: 10/21/2021] [Indexed: 01/31/2023]
Abstract
INTRODUCTION The impact of activated blood and endothelial cells on the thrombosis in myeloproliferative neoplasms (MPN) has not yet been clarified. We prospectively analyzed correlation between circulating leukocyte-platelet aggregates and soluble selectins to thrombosis occurrence in MPN, in the context of standard and cardiovascular risk factors, and different clinical and biological characteristics. METHODS Flow cytometric analysis of neutrophil-platelet (Neu-Plt) and monocyte-platelet (Mo-Plt) aggregates in peripheral blood, as well as quantification of soluble E-/L-/P-selectins by enzyme immunoassay, was performed on 95 newly diagnosed MPN patients. RESULTS During the follow-up, thrombosis occurred in 12.6% MPN patients (arterial 9.4%, venous 3.2%), with a mean time of 39 months. The overall incidence rate of main thrombotic events was 4.36 per 100 patient-years. The incidence of arterial hypertension (HTA) was significantly higher in patients with thrombosis, compared to those without thrombosis (P < .05). The level of soluble P-selectin was significantly higher in patients with thrombosis compared to those without thrombosis (346.89 ng/mL vs 286.39 ng/mL, P = .034). The mean level of Neu-Plt (26.7% vs 22.4%) and Mo-Plt (17.8% vs 12.3%) aggregates did not differ significantly between the groups with and without thrombosis. A multivariate COX proportional hazard regression model confirmed an independent predictive significance of Mo-Plt aggregates (HR = 1.561, 95% CI: 1.007-2.420, P = .046), as well as the cumulative effect of Mo-Plt aggregates and HTA (HR = 1.975, 95%CI: 1.215-3.212, P = .006) for thrombosis occurrence. CONCLUSION Monocyte-platelet aggregates represent an independent risk factor for thrombosis occurrence, further on supported by HTA.
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Affiliation(s)
- Dijana Šefer
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Predrag Miljić
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia.,Medical School, University of Belgrade, Belgrade, Serbia
| | - Nada Kraguljac-Kurtović
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Sandra Bižić-Radulović
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Andrija Bogdanović
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia.,Medical School, University of Belgrade, Belgrade, Serbia
| | - Vesna Knežević
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Dragana Marković
- Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - Bojana Beleslin-Čokić
- Clinic of Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center of Serbia, Belgrade, Serbia
| | - Ivana Novaković
- Institute for Human Genetics, Medical School, University of Belgrade, Belgrade, Serbia
| | - Jelena Marinković
- Institute for Medical Statistics and informatics, Medical School, University of Belgrade, Belgrade, Serbia
| | - Danijela Leković
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia.,Medical School, University of Belgrade, Belgrade, Serbia
| | - Mirjana Gotić
- Outpatient Clinic and Diagnostic Department, Clinic of Hematology, University Clinical Center of Serbia, Belgrade, Serbia.,Medical School, University of Belgrade, Belgrade, Serbia
| | - Vladan Čokić
- Institute for Medical Research, University of Belgrade, Belgrade, Serbia
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Subotički T, Mitrović Ajtić O, Djikić D, Kovačić M, Santibanez JF, Tošić M, Čokić VP. Nitric Oxide Mediation in Hydroxyurea and Nitric Oxide Metabolites' Inhibition of Erythroid Progenitor Growth. Biomolecules 2021; 11:1562. [PMID: 34827560 PMCID: PMC8616001 DOI: 10.3390/biom11111562] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/12/2021] [Accepted: 10/15/2021] [Indexed: 11/16/2022] Open
Abstract
In several systems, hydroxyurea has been shown to trigger nitric oxide (NO) release or activation of NO synthase (NOS). To elucidate this duality in its pharmacological effects, during myelosuppression, we individually examined hydroxyurea's (NO releasing agent) and NO metabolites' (stable NO degradation products) effects on erythroid colony growth and NOS/NO levels in mice using NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO). Hydroxyurea and nitrite/nitrate decreased the bone marrow cellularity that was blocked by PTIO only for the NO metabolites. Hydroxyurea inhibition of colony-forming unit-erythroid (CFU-E) formation and reticulocytes was reversed by PTIO. Moreover, hydroxyurea, through a negative feedback mechanism, reduced inducible NOS (iNOS) expressing cells in CFU-E, also prevented by PTIO. Nitrate inhibition of burst-forming units-erythroid (BFU-E) colony growth was blocked by PTIO, but not in mature CFU-E. The presented results reveal that NO release and/or production mediates the hydroxyurea inhibition of mature erythroid colony growth and the frequency of iNOS immunoreactive CFU-E.
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Affiliation(s)
- Tijana Subotički
- Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia; (T.S.); (O.M.A.); (D.D.); (M.K.); (J.F.S.); (M.T.)
| | - Olivera Mitrović Ajtić
- Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia; (T.S.); (O.M.A.); (D.D.); (M.K.); (J.F.S.); (M.T.)
| | - Dragoslava Djikić
- Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia; (T.S.); (O.M.A.); (D.D.); (M.K.); (J.F.S.); (M.T.)
| | - Marijana Kovačić
- Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia; (T.S.); (O.M.A.); (D.D.); (M.K.); (J.F.S.); (M.T.)
| | - Juan F. Santibanez
- Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia; (T.S.); (O.M.A.); (D.D.); (M.K.); (J.F.S.); (M.T.)
- Centro Integrativo de Biología y Química Aplicada, Universidad Bernardo O’Higgins, Santiago 8370993, Chile
| | - Milica Tošić
- Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia; (T.S.); (O.M.A.); (D.D.); (M.K.); (J.F.S.); (M.T.)
| | - Vladan P. Čokić
- Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia; (T.S.); (O.M.A.); (D.D.); (M.K.); (J.F.S.); (M.T.)
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12
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Sukrisman L. Soluble P-selectin and correlation with Prothrombin Fragment 1 + 2 in myeloid malignancies in Cipto Mangunkusumo general hospital. Thromb J 2021; 19:51. [PMID: 34330290 PMCID: PMC8325311 DOI: 10.1186/s12959-021-00307-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/20/2021] [Indexed: 11/17/2022] Open
Abstract
Background Myeloid cells express microparticles that could increase the expression of adhesion molecules including P-selectin. We aimed to evaluate the level of soluble P-selectin (sP-selectin) and prothrombin fragment 1 + 2 (F1 + 2), and to determine correlation of sP-selectin with leukocyte count and F1 + 2 levels in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patients. Methods Patients with newly diagnosed AML (n = 25), CML (n = 13), and controls (n = 17) were recruited in this study. The diagnosis of AML and CML is based on 2001 WHO and/or FAB criteria. Levels of sP-selectin and F1 + 2 were determined using enzyme-linked immunosorbent assay kits (Behring ELISA Processor-III® and Behring Enzygnost F1 + 2). Results sP-selectin was significantly elevated in CML patients compared to AML patients (p = 0.001). Levels of F1 + 2 in AML and CML patients were significantly increased in comparison to controls (p < 0.001 and p = 0.043). Levels of sP-selectin were significantly correlated to leukocyte count (r = 0.437; p = 0.029) and F1 + 2 (r = 0.436; p = 0.029) in AML patients. Conclusions AML and CML patients had an increased tendency to thrombosis. While CML patients had higher platelet and/or endothelial activation, hypercoagulable state are more pronounced in AML patients.
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Affiliation(s)
- Lugyanti Sukrisman
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo General Hospital, Jakarta, Indonesia.
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13
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Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth. Genes (Basel) 2021; 12:genes12081145. [PMID: 34440315 PMCID: PMC8391407 DOI: 10.3390/genes12081145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 11/29/2022] Open
Abstract
Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ- and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity.
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14
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Guy A, Poisson J, James C. Pathogenesis of cardiovascular events in BCR-ABL1-negative myeloproliferative neoplasms. Leukemia 2021; 35:935-955. [PMID: 33658660 DOI: 10.1038/s41375-021-01170-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 01/11/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
Thrombosis, both in arterial and venous territories, is the major complication of myeloproliferative neoplasms and is responsible for a high rate of morbidity and mortality. The currently accepted risk factors are an age over 60 years and a history of thrombosis. However, many complex mechanisms contribute to this increased prothrombotic risk, with involvement of all blood cell types, plasmatic factors, and endothelial cells. Besides, some cardiovascular events may originate from arterial vasospasm that could contribute to thrombotic complications. In this review, we discuss recent results obtained in mouse models in the light of data obtained from clinical studies. We emphasize on actors of thrombosis that are currently not targeted with current therapeutics but could be promising targets, i.e, neutrophil extracellular traps and vascular reactivity.
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Affiliation(s)
- Alexandre Guy
- UMR1034, Inserm, Biology of Cardiovascular Diseases, University of Bordeaux, Pessac, France.,Department of Biomedicine, University Hospital Basel, Basel, Switzerland
| | - Johanne Poisson
- Inserm, Centre de recherche sur l'inflammation, University of Paris, Paris, France.,Geriatrics Department, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Chloe James
- UMR1034, Inserm, Biology of Cardiovascular Diseases, University of Bordeaux, Pessac, France. .,Laboratoire d'Hématologie, CHU de Bordeaux, Pessac, France.
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15
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Tanaka R, Gatate Y, Sujino Y, Todo M, Ohta A, Shimizu Y, Watanabe A, Naganuma K, Muramatsu T, Fukushima K, Nakano S. Acute Myocardial Infarction in an Adolescent Receiving Anagrelide for Essential Thrombocythemia with Underlying Persistent Coronary Endothelial Dysfunction. Int Heart J 2020; 61:1289-1293. [PMID: 33191357 DOI: 10.1536/ihj.20-377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterized by the overproduction of platelets and a marked increase in the numbers of mature megakaryocytes present in the bone marrow. Thrombohemorrhagic disorders are major morbidities of ET, especially those with mutations in the gene encoding Janus kinase 2 (JAK2). In this study, we report the case of an 18-year-old patient with ET carrying JAK2 mutation who developed acute ST-elevation myocardial infarction (STEMI) 5 months after a commencement of anagrelide. Coronary endothelial dysfunction confirmed by positive acetylcholine provocation test lasted a year after the occurrence of STEMI. Furthermore, intracoronary imaging using optical coherence tomography demonstrated non-atheromatous intimal fibrosis possibly due to chronic endothelial damage. The coronary pathologies reflected chronic change potentially associated with properties of ET and JAK2 mutation in addition to hyperviscosity. These observations suggest that the side effect of anagrelide in our patient was considered causative, while underlying chronic endothelial dysfunction and adverse endothelial remodeling may be predisposing factors to his fatal cardiovascular events.
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Affiliation(s)
- Ryuhei Tanaka
- Department of Pediatric Hematology/Oncology, Saitama Medical University International Medical Center
| | - Yodo Gatate
- Department of Cardiology, Saitama Medical University International Medical Center
| | - Yasumori Sujino
- Department of Cardiology, Saitama Medical University International Medical Center
| | - Maki Todo
- Department of Pharmacy, Saitama Medical University International Medical Center
| | - Atsuhiko Ohta
- Department of Pediatric Hematology/Oncology, Saitama Medical University International Medical Center
| | - Yuki Shimizu
- Department of Pediatric Hematology/Oncology, Saitama Medical University International Medical Center
| | - Atsuko Watanabe
- Department of Pediatric Hematology/Oncology, Saitama Medical University International Medical Center
| | - Ken Naganuma
- Department of Pediatric Hematology/Oncology, Saitama Medical University International Medical Center
| | - Toshihiro Muramatsu
- Department of Cardiology, Saitama Medical University International Medical Center
| | - Kenji Fukushima
- Department of Nuclear Medicine, Saitama Medical University International Medical Center
| | - Shintaro Nakano
- Department of Cardiology, Saitama Medical University International Medical Center
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16
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Hauschner H, Bokstad Horev M, Misgav M, Nagar M, Seligsohn U, Rosenberg N, Koren‐Michowitz M. Platelets from Calreticulin mutated essential thrombocythemia patients are less reactive than JAK2 V617F mutated platelets. Am J Hematol 2020; 95:379-386. [PMID: 31868244 DOI: 10.1002/ajh.25713] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 12/13/2019] [Accepted: 12/20/2019] [Indexed: 01/09/2023]
Abstract
Both JAK2V617F and calreticulin (CALR) mutated essential thrombocythemia (ET) patients have different clinical characteristics, with lower thrombosis risk in patients with CALR mutations. To elucidate the mechanism for this lower risk we studied platelet function in ET patients with either JAK2V617F or a CALR mutation. Platelet activation state was similar in ET and healthy controls at baseline using P-selectin and PAC1 flow cytometry analysis. However, CALR mutated platelets were significantly less activated following ADP stimulation, compared to control or JAK2 mutated platelets (P < .001). In live-cell imaging of platelet attachment to immobilized fibrinogen by Interference Reflection Microscopy (IRM), the number of attached CALR mutated platelets was lower compared to control and JAK2 mutated platelets, with lower fractions of platelets achieving the fully spread state (90%, 78% and 54% of adherent cells for control, JAK2 and CALR mutated subjects, respectively). Compared to controls, ET patients, regardless of the mutation type, had increased numbers of immature platelets (IP) and leukocyte platelet aggregates (LPA), as well as plasma sP-selectin. These were all correlated with the platelet count and not to the state of platelet activation. We also found that intracellular free Ca2+ was increased in resting ET compared to control platelets. Note, CALR had a more dispersed localization in activated ET platelets compared to healthy controls, and mutated CALR interact physically with TpoR in CALR mutated platelets. We hypothesize that defects in platelet activation and spreading in CALR mutated patients can explain, at least in part, the lower thrombotic tendency in CALR mutated ET patients.
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Affiliation(s)
- Hagit Hauschner
- Scientific Equipment Center, The Mina & Everard Goodman Faculty of Life Sciences Bar‐Ilan University Ramat‐Gan Israel
| | - Melanie Bokstad Horev
- Department of Molecular Cell Biology The Weizmann Institute of Science Rehovot Israel
| | - Modi Misgav
- Sackler Faculty of Medicine Tel Aviv University Tel‐Aviv Israel
- The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center Tel Hashomer Israel
| | - Meital Nagar
- Molecular Hematology Laboratory Sheba Medical Center Tel Hashomer Israel
| | - Uri Seligsohn
- Sackler Faculty of Medicine Tel Aviv University Tel‐Aviv Israel
- The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center Tel Hashomer Israel
| | - Nurit Rosenberg
- Sackler Faculty of Medicine Tel Aviv University Tel‐Aviv Israel
- The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center Tel Hashomer Israel
| | - Maya Koren‐Michowitz
- Sackler Faculty of Medicine Tel Aviv University Tel‐Aviv Israel
- Department of Hematology Shamir Medical Center (Assaf Harofeh) Zerifin Israel
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17
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Mornet C, Galinat H, Mingant F, Ianotto JC, Lippert E. [Thrombosis and platelet dysfunction in myeloproliferative neoplasms]. Rev Med Interne 2020; 41:319-324. [PMID: 32008800 DOI: 10.1016/j.revmed.2019.12.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/23/2019] [Indexed: 12/15/2022]
Abstract
Myeloproliferative neoplasms are acquired hematological malignancies, mainly affecting the adult and whose morbidity and mortality stems from haemostasis disorders. The most frequently encountered complications include thrombosis, affecting preferentially the arterial territory, but also atypical locations such as splanchnic vein thrombosis. The pathophysiology of these thromboses is complex and involves different actors: blood cells, endothelium and flow conditions. Numerous studies have been conducted to identify risk factors for thrombosis. To date, only two risk factors have been validated through prospective studies (age over 60 years old, history of thrombotic events) and allow classification of patients as "low risk" and "high risk" as the basis for current treatment recommendations. Haemorrhagic manifestations, less frequent than thrombosis, are mainly related to an alteration of primary haemostasis and are therefore manifested by mucocutaneous bleeding. In these patients, platelet dysfunctions and/or acquired Willebrand syndromes can be found. The pathophysiology of thrombosis and platelet dysfunction during myeloproliferative neoplasms remains to date partially unknown. In this review, we offer to focus on physiopathological mechanisms as well as the latest advances in their understanding.
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Affiliation(s)
- C Mornet
- Hématologie biologique, CHU de Brest, Brest, France
| | - H Galinat
- Hématologie biologique, CHU de Brest, Brest, France
| | - F Mingant
- Hématologie biologique, CHU de Brest, Brest, France
| | - J C Ianotto
- Hématologie clinique et thérapie cellulaire, CHU de Brest, Brest, France
| | - E Lippert
- Hématologie biologique, CHU de Brest, Brest, France; Inserm, EFS, UMR 1078, GGB, Université Brest, Brest, France.
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18
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Guy A, James C. [Pathogenesis of thrombosis in JAK2V617F myeloproliferative neoplasms]. Med Sci (Paris) 2019; 35:651-658. [PMID: 31532377 DOI: 10.1051/medsci/2019133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BCR-ABL negative myeloproliferative neoplasms are acquired hematologic diseases characterized by blood cell proliferation and that include polycythemia vera (PV), essential thrombocytemia (ET) and primary myelofibrosis (PMF). Occurring of venous and arterial thrombosis is the main complication of these diseases. Risk factors for thrombosis are individuals older than 60 and history of thrombosis. The mechanisms leading to thrombosis are complex and involve several blood compartments, plasmatic factors and endothelial cells. Over the last years, new actors of thrombosis have been discovered.
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Affiliation(s)
- Alexandre Guy
- CHU de Bordeaux, Laboratoire d'hématologie, 1, avenue de Magellan, F-33600, Pessac, France. - Univ. Bordeaux, Inserm, UMR 1034, Biologie des maladies cardio-vasculaires, 1, avenue de Magellan, F-33600, Pessac, France
| | - Chloé James
- CHU de Bordeaux, Laboratoire d'hématologie, 1, avenue de Magellan, F-33600, Pessac, France. - Univ. Bordeaux, Inserm, UMR 1034, Biologie des maladies cardio-vasculaires, 1, avenue de Magellan, F-33600, Pessac, France
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19
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Visweshwar N, Jaglal M, Sokol L, Djulbegovic B. Hematological Malignancies and Arterial Thromboembolism. Indian J Hematol Blood Transfus 2019; 35:611-624. [PMID: 31741612 PMCID: PMC6825093 DOI: 10.1007/s12288-019-01085-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 01/21/2019] [Indexed: 01/10/2023] Open
Abstract
Established guidelines exist for prevention and treatment of venous thromboembolism in hematological malignancies, but none for arterial thromboembolism. However, arterial and venous thromboembolism share the same provoking features—including altered procoagulant factors and defective fibrinolytic system. The morbidity for arterial thromboembolism is increasing in hematological malignancies, with the advent of immunomodulatory and targeted therapy. However, survival rate for hematological malignancy is improving. Consequently, as patients with hematological malignancies live longer, comorbidities including diabetes, hypertension and dyslipidemia, may accentuate arterial thrombosis. Thus far, the scientific literature on prophylaxis and treatment for arterial thromboembolism in hematological malignancies is limited. This review highlights the pathogenesis, incidence and clinical features of arterial thromboembolism in hematological malignancies.
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Affiliation(s)
- Nathan Visweshwar
- 1Division of Hematology, University of South Florida, Tampa, FL 33612 USA
| | - Michael Jaglal
- 2Division of Medical Oncology, Moffitt Cancer Center, Tampa, FL 35316 USA
| | - Lubomir Sokol
- 2Division of Medical Oncology, Moffitt Cancer Center, Tampa, FL 35316 USA
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20
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Abstract
Thrombosis is a major cause of morbidity and mortality in cancer patients. The pathogenesis of blood coagulation activation in oncological patients is complex and involves both clinical and biological factors. Abnormalities in one or more coagulation test are common in cancer patients, even without thrombotic manifestations, indicating an ongoing hypercoagulable condition. Moreover, venous thromboembolism (VTE) can be the first symptom of an occult malignancy in an otherwise healthy individual. The levels of laboratory markers of activation of blood coagulation parallel the development of malignancy, being the coagulant mechanisms important for both thrombogenesis and tumor progression. Besides general clinical risk factors for VTE, also disease-specific clinical factors, i.e., type and stage of the tumor, and anticancer therapies increase the thrombotic risk in these patients. Furthermore, biological factors, including the cancer cell-specific prothrombotic properties together with the host cell inflammatory response to the tumor, are relevant as well as unique players in the pathogenesis of the cancer-associated hypercoagulability. Cancer cells produce and release procoagulant and fibrinolytic proteins, inflammatory cytokines, and procoagulant microparticles. They also express adhesion molecules binding to the receptors of host vascular cells (i.e., endothelial cells, platelets, and leukocytes), thereby stimulating the prothrombotic properties of these normal cells, including the shed of cell-specific microparticles and neutrophil extracellular traps. Of interest, several genes responsible for the cellular neoplastic transformation drive the programs of hemostatic properties expressed by cancer tissues. A better understanding of such mechanisms will help the development of novel strategies to prevent and treat the Trousseau's syndrome (i.e., cancer-associated thrombosis).
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Affiliation(s)
- Anna Falanga
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy.
- University of Milan Bicocca, School of Medicine and Surgery, Monza, Italy.
| | - Francesca Schieppati
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - Laura Russo
- Department of Transfusion Medicine and Hematology, Hospital Papa Giovanni XXIII, Bergamo, Italy
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21
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De Stefano V, Carobbio A, Di Lazzaro V, Guglielmelli P, Iurlo A, Finazzi MC, Rumi E, Cervantes F, Elli EM, Randi ML, Griesshammer M, Palandri F, Bonifacio M, Hernandez-Boluda JC, Cacciola R, Miroslava P, Carli G, Beggiato E, Ellis MH, Musolino C, Gaidano G, Rapezzi D, Tieghi A, Lunghi F, Loscocco GG, Cattaneo D, Cortelezzi A, Betti S, Rossi E, Finazzi G, Censori B, Cazzola M, Bellini M, Arellano-Rodrigo E, Bertozzi I, Sadjadian P, Vianelli N, Scaffidi L, Gomez M, Cacciola E, Vannucchi AM, Barbui T. Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms. Blood Cancer J 2018. [PMID: 29535299 PMCID: PMC5849668 DOI: 10.1038/s41408-018-0048-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.
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Affiliation(s)
- Valerio De Stefano
- Institute of Hematology, Catholic University, Fondazione Policlinico Universitario A. Gemelli, Roma, Italy
| | | | - Vincenzo Di Lazzaro
- Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Biomedico di Roma, Rome, Italy
| | - Paola Guglielmelli
- CRIMM-Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, and Departmentt Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Alessandra Iurlo
- Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, and University of Milan, Milan, Italy
| | | | - Elisa Rumi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Elena Maria Elli
- Hematology Division, Ospedale San Gerardo, ASST Monza, Monza, Italy
| | | | - Martin Griesshammer
- University Clinic for Hematology and Oncology Minden, University of Bochum, Bochum, Germany
| | - Francesca Palandri
- Institute of Hematology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, Bologna, Italy
| | | | | | - Rossella Cacciola
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Palova Miroslava
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
| | - Giuseppe Carli
- Hematology Department, Ospedale San Bortolo, Vicenza, Italy
| | - Eloise Beggiato
- Unit of Hematology, Department of Oncology, University of Torino, Torino, Italy
| | - Martin H Ellis
- Hematology Institute and Blood Bank, Meir Medical Center, Kfar Saba, and Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel
| | - Caterina Musolino
- Division of Hematology, Dipartimento di Patologia Umana dell'Adulto e dell'Età Evolutiva, Policlinico G Martino, University of Messina, Messina, Italy
| | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Davide Rapezzi
- S.C. Ematologia, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Alessia Tieghi
- Divisione di Ematologia, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - Francesca Lunghi
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
| | - Giuseppe Gaetano Loscocco
- CRIMM-Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, and Departmentt Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Daniele Cattaneo
- Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, and University of Milan, Milan, Italy
| | - Agostino Cortelezzi
- Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, and University of Milan, Milan, Italy
| | - Silvia Betti
- Institute of Hematology, Catholic University, Fondazione Policlinico Universitario A. Gemelli, Roma, Italy
| | - Elena Rossi
- Institute of Hematology, Catholic University, Fondazione Policlinico Universitario A. Gemelli, Roma, Italy
| | - Guido Finazzi
- Hematology Division, Papa Giovanni XXIII hospital, Bergamo, Italy
| | - Bruno Censori
- Neurology Division, Papa Giovanni XXIII hospital, Bergamo, Italy
| | - Mario Cazzola
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Marta Bellini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | | | - Irene Bertozzi
- Department of Medicine - DIMED, University of Padua, Padova, Italy
| | - Parvis Sadjadian
- University Clinic for Hematology and Oncology Minden, University of Bochum, Bochum, Germany
| | - Nicola Vianelli
- Institute of Hematology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Luigi Scaffidi
- Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
| | - Montse Gomez
- Hematology Department, Hospital Clínico Universitario, Valencia, Spain
| | - Emma Cacciola
- Department of Medical, Surgical and Advanced Technologies Sciences "G.F. Ingrassia", University of Catania, Catania, Italy
| | - Alessandro M Vannucchi
- CRIMM-Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, and Departmentt Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Tiziano Barbui
- FROM Research Foundation, Papa Giovanni XXIII hospital, Bergamo, Italy.
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Bak M, Sørensen TL, Flachs EM, Zwisler AD, Juel K, Frederiksen H, Hasselbalch HC. Age-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms. JAMA Ophthalmol 2017; 135:835-843. [PMID: 28655032 DOI: 10.1001/jamaophthalmol.2017.2011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Importance It has been suggested that systemic inflammation increases the risk of age-related macular degeneration (AMD). Given that chronic immune modulation is present in patients with myeloproliferative neoplasms (MPNs), the risk of AMD in these patients may be increased. Objective To compare the risk of AMD in patients with MPNs with the risk of AMD in matched controls from the general population. Design, Setting, and Participants A nationwide population-based cohort study using Danish registers was conducted of all patients in Denmark who received a diagnosis between January 1, 1994, and December 31, 2013, of essential thrombocythemia, polycythemia vera, myelofibrosis, or unclassifiable MPNs. For each patient, 10 age- and sex-matched controls were included. All patients without prior AMD were followed up from the date of diagnosis (or corresponding entry date for the controls) until the first AMD diagnosis, death or emigration, or December 31, 2013, whichever occurred first. Data analysis was performed from April 1, 2015, to October 31, 2016. Main Outcomes and Measures Incidence of AMD recorded in specialized hospital-based care. The rates and absolute risk of AMD were calculated. Using Cox proportional hazards regression models, smoking and risk-time adjusted hazard ratios (HRs) between patients and controls were calculated. In addition, HRs of neovascular AMD after 2006 were calculated since antivascular endothelial growth factor treatment was introduced nationwide at hospitals thereafter. Results A total of 7958 patients with MPNs (4279 women [53.8%] and 3679 men [46.2%]; mean [SD] age at diagnosis, 66.4 [14.3] years) were included in the study. The rate of AMD per 1000 person-years at risk was 5.2 (95% CI, 4.6-5.9) for patients with MPNs (2628 with essential thrombocythemia, 3063 with polycythemia vera, 547 with myelofibrosis, and 1720 with unclassifiable MPNs) and 4.3 (95% CI, 4.1-4.4) for the 77 445 controls, while the 10-year risk of AMD was 2.4% (95% CI, 2.1%-2.8%) for patients with MPNs and 2.3% (95% CI, 2.2%-2.4%) for the controls. The risk of AMD was increased overall for patients with MPNs (adjusted HR, 1.3; 95% CI, 1.1-1.5), with adjusted HRs for the subtypes of 1.2 (95% CI, 1.0-1.6) for essential thrombocythemia, 1.4 (95% CI, 1.2-1.7) for polycythemia vera, 1.7 (95% CI, 0.8-4.0) for myelofibrosis, and 1.5 (95% CI, 1.1-2.1) for unclassifiable MPNs. In addition, patients with MPNs had a higher risk of neovascular AMD (adjusted HR, 1.4; 95% CI, 1.2-1.6). Conclusions and Relevance Our results suggest that patients with MPNs are at increased risk of AMD, supporting the possibility that systemic inflammation is involved in the pathogenesis of AMD.
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Affiliation(s)
- Marie Bak
- Department of Haematology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
| | - Torben Lykke Sørensen
- Department of Ophthalmology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
| | - Esben Meulengracht Flachs
- Department of Occupational and Environmental Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Ann-Dorthe Zwisler
- Danish Knowledge Centre for Rehabilitation and Palliative Care, University of Southern Denmark and Odense University Hospital, Odense, Denmark
| | - Knud Juel
- National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark
| | - Henrik Frederiksen
- Department of Haematology, Odense University Hospital, Odense, Denmark.,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Hans Carl Hasselbalch
- Department of Haematology, Zealand University Hospital, University of Copenhagen, Roskilde, Denmark
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Piccin A, Steurer M, Feistritzer C, Murphy C, Eakins E, Van Schilfgaarde M, Corvetta D, Di Pierro AM, Pusceddu I, Marcheselli L, Gambato R, Langes M, Veneri D, Perbellini O, Pacquola E, Gottardi M, Gherlinzoni F, Mega A, Tauber M, Mazzoleni G, Piva E, Plebani M, Krampera M, Gastl G. Observational retrospective study of vascular modulator changes during treatment in essential thrombocythemia. Transl Res 2017; 184:21-34. [PMID: 28259616 DOI: 10.1016/j.trsl.2017.02.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 02/06/2017] [Accepted: 02/07/2017] [Indexed: 02/07/2023]
Abstract
Essential thrombocythemia (ET) patients are at risk of developing thrombotic events. Qualitative platelet (PLT) abnormalities and activation of endothelial cells (ECs) and PLTs are thought to be involved. Microparticles (MPs) can originate from PLTs (PMPs), ECs (EMPs), or red cells (RMPs). Previous studies have indicated that MPs contribute to ET pathophysiology. Endothelial modulators (eg, nitric oxide [NO], adrenomedullin [ADM], and endothelin-1 [ET-1]) are also involved in the pathophysiology of this condition. We hypothesized that treatments for reducing PLT count might also indirectly affect MP generation and endothelial activity by altering endothelial modulator production. The rationale of this study was that hydroxyurea (HU), a cytostatic drug largely used in ET, induces the production of a potent vasoactive agent NO in ECs. An observational retrospective study was designed to investigate the relationship between MPs, NO, ADM, and ET-1 in ET patients on treatment with HU, anagrelide (ANA), aspirin (ASA), and a group of patients before treatment. A total of 63 patients with ET diagnosis: 18 on HU + ASA, 15 on ANA + ASA, 19 on ASA only, and 11 untreated patients, and 18 healthy controls were included in this study. Blood samples were analyzed for MP (absolute total values) and functional markers (percentage values) by flow cytometry. PLT-derived MPs were studied using CD61, CD62P, CD36, and CD63, whereas endothelial-derived MPs were studied using CD105, CD62E, and CD144. Endothelial modulator markers (NO, ADM, and ET-1) were measured by ELISA. Total MP count was higher in the group treated with ANA + ASA (P < 0.01). MP markers modified in ET patients returned to levels of healthy controls following treatment, in particular, in patients on ANA treatment. NO and ADM values were higher in the HU group (P < 0.001). HU and ANA treatment also affected MP production in a cell origin-specific manner. HU and ANA, although acting via different pathways, have similar final effects. For instance, HU causes vasodilatation by increasing NO and ADM levels, whereas ANA impairs vasoconstriction by reducing ET-1. In conclusion, therapy with HU cytostatic drugs and ANA can reduce PLT count in ET, and also affect endothelial modulatory agents, with HU sustaining vasodilation and prothrombotic MP concentration, whereas ANA decreases vasoconstriction.
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Affiliation(s)
- Andrea Piccin
- Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria; Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy; Irish Blood Transfusion Service, Dublin, Ireland; IMREST Interdisciplinary Medical Research Center South Tyrol, Italy.
| | - Michael Steurer
- Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria
| | - Clemens Feistritzer
- Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Elva Eakins
- Irish Blood Transfusion Service, Dublin, Ireland
| | | | - Daisy Corvetta
- Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy; IMREST Interdisciplinary Medical Research Center South Tyrol, Italy
| | - Angela Maria Di Pierro
- IMREST Interdisciplinary Medical Research Center South Tyrol, Italy; Central Laboratory, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy
| | - Irene Pusceddu
- IMREST Interdisciplinary Medical Research Center South Tyrol, Italy; Central Laboratory, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy
| | - Luigi Marcheselli
- Department of Diagnostic, Medicine University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto Gambato
- Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy
| | - Martin Langes
- Department of Haematology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy
| | - Dino Veneri
- Department of Haematology, University of Medicine, Verona, Italy
| | - Omar Perbellini
- Department of Haematology, University of Medicine, Verona, Italy
| | - Enrica Pacquola
- Department of Haematology, Cà Foncello Hospital, Treviso, Italy
| | | | | | - Andrea Mega
- IMREST Interdisciplinary Medical Research Center South Tyrol, Italy; Department of Gastroenterology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy
| | - Martina Tauber
- Department of Pathology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy
| | - Guido Mazzoleni
- Department of Pathology, San Maurizio Regional Hospital, Bolzano/Bozen, South Tyrol, Italy
| | - Elisa Piva
- Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
| | - Mario Plebani
- Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
| | - Mauro Krampera
- Department of Haematology, University of Medicine, Verona, Italy
| | - Günther Gastl
- Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria
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Geddings JE, Hisada Y, Boulaftali Y, Getz TM, Whelihan M, Fuentes R, Dee R, Cooley BC, Key NS, Wolberg AS, Bergmeier W, Mackman N. Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice. J Thromb Haemost 2016; 14:153-66. [PMID: 26516108 PMCID: PMC4715578 DOI: 10.1111/jth.13181] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 10/22/2015] [Indexed: 02/06/2023]
Abstract
UNLABELLED ESSENTIALS: Cancer patients have a high rate of venous thrombosis (VT) but the underlying mechanisms are unknown. Tumor-derived, tissue factor-positive microvesicles in platelet activation in vitro and in vivo were studied. Tumor-derived, tissue factor-positive microvesicles enhanced VT in mice. Platelets may contribute to VT in some cancer patients, and this could be prevented with antiplatelet drugs. BACKGROUND Cancer patients have an approximately 4-fold increased risk of venous thromboembolism (VTE) compared with the general population, and cancer patients with VTE have reduced survival. Tumor cells constitutively release small membrane vesicles called microvesicles (MVs) that may contribute to thrombosis in cancer patients. Clinical studies have shown that levels of circulating tumor-derived, tissue factor-positive (TF(+) ) MVs in pancreatic cancer patients are associated with VTE. Objectives We tested the hypothesis that TF(+) tumor-derived MVs (TMVs) activate platelets in vitro and in mice. MATERIALS AND METHODS We selected two human pancreatic adenocarcinoma cell lines expressing high (BxPc-3) and low (L3.6pl) levels of TF as models to study the effect of TF(+) TMVs on platelets and thrombosis. RESULTS AND CONCLUSIONS We found that both types of TF(+) TMVs activated human platelets and induced aggregation in vitro in a TF and thrombin-dependent manner. Further, injection of BxPc-3 TF(+) TMVs triggered platelet activation in vivo and enhanced thrombosis in two mouse models of venous thrombosis in a TF-dependent manner. Importantly, BxPc-3 TF(+) TMV-enhanced thrombosis was reduced in Par4-deficient mice and in wild-type mice treated with clopidogrel, suggesting that platelet activation was required for enhanced thrombosis. These studies suggest that TF(+) TMV-induced platelet activation contributes to thrombosis in cancer patients.
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Affiliation(s)
- Julia E. Geddings
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Yohei Hisada
- Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Yacine Boulaftali
- Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Todd M. Getz
- Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Matthew Whelihan
- Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Rudy Fuentes
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Rachel Dee
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Brian C. Cooley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Nigel S. Key
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
- Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Alisa S. Wolberg
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Wolfgang Bergmeier
- Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Nigel Mackman
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
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Gumiero D, Di Gennaro L, Nicolazzi MA, Landolfi R. Hydroxyurea-mediated release of nitric oxide in myeloproliferative neoplasms patients: Effects on platelet-leukocyte interaction. J Clin Pharmacol 2015; 55:1125-30. [PMID: 25998252 DOI: 10.1002/jcph.548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 05/13/2015] [Indexed: 11/11/2022]
Affiliation(s)
- Daniela Gumiero
- Department of Medical Sciences, Institute of Internal Medicine and Geriatrics, Haemostasis Research Center, Catholic University School of Medicine, Rome, Italy
| | - Leonardo Di Gennaro
- Department of Medical Sciences, Institute of Internal Medicine and Geriatrics, Haemostasis Research Center, Catholic University School of Medicine, Rome, Italy
| | - Maria Anna Nicolazzi
- Department of Medical Sciences, Institute of Internal Medicine and Geriatrics, Haemostasis Research Center, Catholic University School of Medicine, Rome, Italy
| | - Raffaele Landolfi
- Department of Medical Sciences, Institute of Internal Medicine and Geriatrics, Haemostasis Research Center, Catholic University School of Medicine, Rome, Italy
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Kreher S, Ochsenreither S, Trappe RU, Pabinger I, Bergmann F, Petrides PE, Koschmieder S, Matzdorff A, Tiede A, Griesshammer M, Riess H. Prophylaxis and management of venous thromboembolism in patients with myeloproliferative neoplasms: consensus statement of the Haemostasis Working Party of the German Society of Hematology and Oncology (DGHO), the Austrian Society of Hematology and Oncology (ÖGHO) and Society of Thrombosis and Haemostasis Research (GTH e.V.). Ann Hematol 2014; 93:1953-63. [PMID: 25307456 DOI: 10.1007/s00277-014-2224-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 09/25/2014] [Indexed: 01/28/2023]
Abstract
Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) like polycythemia vera and essential thrombocythemia are at increased risk of arterial and venous thrombosis. Strategies of prevention may consist of platelet aggregation inhibitors and/or cytoreductive agents depending on the underlying disease and the individual risk. Clinical evidence for management of acute venous thromboembolic events in MPN patients is limited. Modality and duration of therapeutic anticoagulation after venous thrombosis has to be evaluated critically with special regard to the increased risk for spontaneous bleeding events associated with the underlying diseases. Both for therapy of the acute event and for secondary prophylaxis, low-molecular-weight heparins should preferentially be used. A prolongation of the therapeutic anticoagulation beyond the usual 3 to 6 months can only be recommended in high-risk settings and after careful evaluation of potential risks and benefits for the individual patient. New direct oral anticoagulants (NOAC) should not preferentially be used due to lack of clinical experience in patients with MPN and potential drug interactions (e.g. with JAK inhibitors). Consequent treatment of the underlying myeloproliferative disease and periodical evaluation of the response to therapy is crucial for optimal secondary prophylaxis of thromboembolic events in those patients.
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Affiliation(s)
- Stephan Kreher
- Department of Hematology and Oncology, Charite Berlin, Berlin, Hindenburgdamm 30, 12200, Berlin, Germany,
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Hasselbalch HC. The platelet–cancer loop in myeloproliferative cancer. Is thrombocythemia an enhancer of cancer invasiveness and metastasis in essential thrombocythemia, polycythemia vera and myelofibrosis? Leuk Res 2014; 38:1230-6. [DOI: 10.1016/j.leukres.2014.07.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 06/26/2014] [Accepted: 07/14/2014] [Indexed: 02/08/2023]
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Abstract
A high risk of arterial and venous thrombosis is the hallmark of chronic myeloproliferative neoplasms (MPNs), particularly polycythemia vera (PV) and essential thrombocythemia (ET). Clinical aspects, pathogenesis and management of thrombosis in MPN resemble those of other paradigmatic vascular diseases. The occurrence of venous thrombosis in atypical sites, such as the splanchnic district, and the involvement of plasmatic prothrombotic factors, including an acquired resistance to activated protein C, both link MPN to inherited thrombophilia. Anticoagulants are the drugs of choice for these complications. The pathogenic role of leukocytes and inflammation, and the high mortality rate from arterial occlusions are common features of MPN and atherosclerosis. The efficacy and safety of aspirin in reducing deaths and major thrombosis in PV have been demonstrated in a randomized clinical trial. Finally, the Virchow's triad of impaired blood cells, endothelium and blood flow is shared both by MPN and thrombosis in solid cancer. Phlebotomy and myelosuppressive agents are the current therapeutic options for correcting these abnormalities and reducing thrombosis in this special vascular disease represented by MPN.
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Affiliation(s)
- Guido Finazzi
- Division of Hematology, Ospedale Papa Giovanni XXIII, Piazza OMS, 1, 24127, Bergamo, BG, Italy,
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Torres C, Fonseca AM, Leander M, Matos R, Morais S, Campos M, Lima M. Circulating endothelial cells in patients with venous thromboembolism and myeloproliferative neoplasms. PLoS One 2013; 8:e81574. [PMID: 24339944 PMCID: PMC3855326 DOI: 10.1371/journal.pone.0081574] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 10/15/2013] [Indexed: 11/25/2022] Open
Abstract
Background Circulating endothelial cells (CEC) may be a biomarker of vascular injury and pro-thrombotic tendency, while circulating endothelial progenitor cells (CEP) may be an indicator for angiogenesis and vascular remodelling. However, there is not a universally accepted standardized protocol to identify and quantify these cells and its clinical relevancy remains to be established. Objectives To quantify CEC and CEP in patients with venous thromboembolism (VTE) and with myeloproliferative neoplasms (MPN), to characterize the CEC for the expression of activation (CD54, CD62E) and procoagulant (CD142) markers and to investigate whether they correlate with other clinical and laboratory data. Patients and Methods Sixteen patients with VTE, 17 patients with MPN and 20 healthy individuals were studied. The CEC and CEP were quantified and characterized in the blood using flow cytometry, and the demographic, clinical and laboratory data were obtained from hospital records. Results We found the CEC counts were higher in both patient groups as compared to controls, whereas increased numbers of CEP were found only in patients with MPN. In addition, all disease groups had higher numbers of CD62E+ CEC as compared to controls, whereas only patients with VTE had increased numbers of CD142+ and CD54+ CEC. Moreover, the numbers of total and CD62+ CEC correlated positively with the white blood cells (WBC) counts in both groups of patients, while the numbers of CEP correlated positively with the WBC counts only in patients with MPN. In addition, in patients with VTE a positive correlation was found between the numbers of CD54+ CEC and the antithrombin levels, as well as between the CD142+ CEC counts and the number of thrombotic events. Conclusions Our study suggests that CEC counts may reveal endothelial injury in patients with VTE and MPN and that CEC may express different activation-related phenotypes depending on the disease status.
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Affiliation(s)
- Cláudia Torres
- Laboratório de Citometria, Serviço de Hematologia Clínica, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal
- Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS/UP), Porto, Portugal
- * E-mail: (ML); (CT)
| | - Ana Mafalda Fonseca
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal
| | - Magdalena Leander
- Laboratório de Citometria, Serviço de Hematologia Clínica, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal
- Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS/UP), Porto, Portugal
| | - Rui Matos
- Secção de Trombose e Hemostase, Serviço de Hematologia Clínica, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal
| | - Sara Morais
- Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS/UP), Porto, Portugal
- Secção de Trombose e Hemostase, Serviço de Hematologia Clínica, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal
| | - Manuel Campos
- Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS/UP), Porto, Portugal
- Secção de Trombose e Hemostase, Serviço de Hematologia Clínica, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal
| | - Margarida Lima
- Laboratório de Citometria, Serviço de Hematologia Clínica, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Porto, Portugal
- Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto (ICBAS/UP), Porto, Portugal
- * E-mail: (ML); (CT)
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Rusak T, Misztal T, Piszcz J, Tomasiak M. Nitric oxide scavenging by cell-free hemoglobin may be a primary factor determining hypertension in polycythemic patients. Free Radic Res 2013; 48:230-8. [PMID: 24180690 DOI: 10.3109/10715762.2013.860225] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
We tested the hypothesis that hypertension associated with polycythemia vera (PV) may be related to hemoglobin released from erythrocytes (cell-free hemoglobin, fHb). We assessed hematocrit, mean arterial pressure (MAP), blood viscosity, and the level of fHb and nitrite/nitrate (NOx) in the plasma of 73 PV patients and 38 healthy controls. The effect of isovolemic erythrocytapheresis (ECP) on the considered parameters was also studied. From the whole group of PV patients a subset of subjects with normal (normotensive patients, n = 16) and elevated MAP (hypertensive patients, n = 57) can be subtracted. It was found that in comparison with healthy controls, PV patients have significantly (p ≤ 0.01) elevated Hct (0.567 vs. 0.422), blood viscosity (5.45 vs. 3.56 cP), MAP (106.8 vs. 93.8 mmHg), plasma fHb (9.7 vs. 2.8 mg/dL), and NOx levels (34.1 vs. 27.5 μM). Compared with normotensive patients, hypertensive PV patients demonstrated a higher rise in fHb (10.2 vs. 8.0) and plasma NOx levels (35.8 vs. 31.0). In PV patients, fHb positively correlates with MAP (r = 0.489), NOx levels (r = 0.461), hematocrit (r = 0.428), and viscosity (r = 0.393). Blood viscosity positively correlated with hematocrit (r = 0.894), but not with other considered parameters. In PV patients MAP poorly correlated with hematocrit, whereas the correlation between MAP and NOx altered from - 0.325 (healthy control) to + 0.268 (PV patients). ECP procedure was associated with a significant (p < 0.01) reduction of hematocrit, fHb, blood viscosity, and MAP. In the normotensive subgroup of PV patients the ECP procedure did not affect MAP. It can be concluded that accelerated scavenging of nitric oxide by fHb rather than high Hct may be a key factor determining the development of hypertension in PV patients.
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Affiliation(s)
- T Rusak
- Department of Physical Chemistry, Medical University of Bialystok , Bialystok , Poland
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Abstract
OBJECTIVE Haemoglobin is a potential nitric oxide (NO) scavenger. Haemoglobin is associated with blood viscosity and the red blood cell free layer width of microvessels that impact on shear stress in the microcirculation. We hypothesized that haemoglobin modulates retinal vascular function. METHODS In 139 nondiabetic male patients with haemoglobin levels within the normal range, the vasodilatatory response of retinal capillary blood flow (RCF) to flicker light exposure and the vasoconstrictor response of RCF to infusion of NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) were assessed. The latter, because of the selective nature of L-NMMA, reflects a parameter of basal NO activity of retinal vasculature. Examinations of retinal parameters were performed noninvasively and in vivo using scanning laser Doppler flowmetry. RESULTS Patients with haemoglobin greater or equal the median revealed reduced increase of RCF to flicker light exposure (2.83 ± 12 vs. 9.52 ± 14 (%), P adjusted = 0.002), and greater decrease of RCF to L-NMMA infusion (-7.35 ± 13 vs. -0.92 ± 14 (%), P adjusted = 0.008), compared with patients with haemoglobin below the median. Haemoglobin was negatively related to the percentage change of RCF to flicker light exposure (r = -0.249, P = 0.004) and to L-NMMA infusion (r = -0.201, P = 0.018). In multiple linear regression analysis haemoglobin was an independent determinant of the percentage change of RCF to flicker light exposure (model 1: ß = -0.278, P = 0.003 and model 2: ß = -0.283, P = 0.002) and to L-NMMA infusion (model 1: ß = -0.256, P = 0.005 and model 2: ß = -0.269, P = 0.004). CONCLUSION Haemoglobin emerged as an independent determinant of vascular function in the human retinal vascular bed.
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Sekhar M, McVinnie K, Burroughs AK. Splanchnic vein thrombosis in myeloproliferative neoplasms. Br J Haematol 2013; 162:730-47. [PMID: 23855810 DOI: 10.1111/bjh.12461] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Splanchnic vein thrombosis (SVT) is one of the most important complications of myeloproliferative neoplasms (MPN). Although MPN are common causes of SVT, the pathophysiological mechanisms underlying this predisposition, their epidemiology and natural history are not fully understood. Studies have concentrated on the generalized prothrombotic environment generated by MPN and their relationship with abnormal blood counts, thereby furthering our knowledge of arterial and venous thrombosis in this population. In contrast, there are few studies that have specifically addressed SVT in the context of MPN. Recent research has demonstrated in patients with MPN the existence of factors increasing the risk of SVT such as the presence of the JAK2 V617F mutation and its 46/1 haplotype. Features unique to the circulating blood cells, splanchnic vasculature and surrounding micro-environment in patients with MPN have been described. There are also abnormalities in local haemodynamics, haemostatic molecules, the spleen, and splanchnic endothelial and endothelial progenitor cells. This review considers these important advances and discusses the contribution of individual anomalies that lead to the development of SVT in both the pre-neoplastic and overt stage of MPN. Clinical issues relating to epidemiology, recurrence and survival in these patients have also been reviewed and their results discussed.
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Affiliation(s)
- Mallika Sekhar
- Department of Haematology, Royal Free Hospital, London, UK
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Abstract
Major causes of morbidity and mortality in myeloproliferative neoplasms are represented by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. The pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes but also qualitative modifications that characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a "high risk" or "low risk". Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk polycythemia vera patients, only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve the management of thrombosis is a challenge for future studies.
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Casini A, Fontana P, Lecompte TP. Thrombotic complications of myeloproliferative neoplasms: risk assessment and risk-guided management. J Thromb Haemost 2013; 11:1215-27. [PMID: 23601811 DOI: 10.1111/jth.12265] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Indexed: 12/29/2022]
Abstract
Philadelphia-negative myeloproliferative neoplasms are considered to be acquired thrombophilic states. Thromboses, both arterial and venous (not rarely in unusual sites), are often the initial events leading to the diagnosis. After diagnosis, the yearly incidence of thrombotic events is highly variable, and ranges from approximately 1% to 10%. The identification of patients at risk who may benefit from antithrombotic therapy remains a challenge, and it is currently based on age and history of thrombotic events. However, the predictive value of these clinical characteristics is rather limited. Few prospective studies and even fewer interventional randomized studies are available, and there are no studies designed to formally validate the use of risk stratification. The implementation of laboratory parameters such as leukocytosis and/or the JAK2 V617F mutation into a scoring system may be of interest. The mechanisms at work leading to thrombosis remain largely speculative, but are likely to be complex and multifactorial, with a prominent role of cell-cell interactions, mostly owing to qualitative changes. The long-term treatment options to prevent thrombosis are, schematically, aspirin alone as primary prevention for the low-risk patients, and cytoreduction combined with aspirin for the other patients. In very low-risk young essential thrombocythemia patients, abstention can even be considered. The optimal duration of anticoagulation after a thrombotic event is not established. All antithrombotic therapies should be balanced with the hemorrhagic risk, which can also be increased in these patients.
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Affiliation(s)
- A Casini
- Division of Angiology and Hemostasis, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland
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Michiels JJ, Ten Kate FWJ, Koudstaal PJ, Van Genderen PJJ. Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera. World J Hematol 2013; 2:20-43. [DOI: 10.5315/wjh.v2.i2.20] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 01/06/2013] [Indexed: 02/05/2023] Open
Abstract
Essential thrombocythemia (ET) and polycythemia vera (PV) frequently present with erythromelalgia and acrocyanotic complications, migraine-like microvascular cerebral and ocular transient ischemic attacks (MIAs) and/or acute coronary disease. The spectrum of MIAs in ET range from poorly localized symptoms of transient unsteadiness, dysarthria and scintillating scotoma to focal symptoms of transient monocular blindness, transient mono- or hemiparesis or both. The attacks all have a sudden onset, occur sequentially rather than simultaneously, last for a few seconds to several minutes and are usually associated with a dull, pulsatile or migraine-like headache. Increased hematocrit and blood viscosity in PV patients aggravate the microvascular ischemic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Phlebotomy to correct hematocrit to normal in PV significantly reduces major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated erythromelalgia and MIAs. Complete long-term relief of the erythromelalgic microvascular disturbances, MIAs and major thrombosis in ET and PV patients can be obtained with low dose aspirin and platelet reduction to normal, but not with anticoagulation. Skin punch biopsies from the erythromelalgic area show fibromuscular intimal proliferation of arterioles complicated by occlusive platelet-rich thrombi leading to acrocyanotic ischemia. Symptomatic ET patients with erythromelalgic microvascular disturbances have shortened platelet survival, increased platelet activation markers β-thromboglobulin (β-TG), platelet factor 4 (PF4) and thrombomoduline (TM), increased urinary thromboxane B2 (TXB2) excretion, and no activation of the coagulation markers thrombin fragments F1+2 and fibrin degradation products. Inhibition of platelet cyclooxygenase (COX1) by aspirin is followed by the disappearance and no recurrence of microvascular disturbances, increase in platelet number, correction of the shortened platelet survival times to normal, and reduction of increased plasma levels of β-TG, PF4, TM and urinary TXB2 excretion to normal. These results indicate that platelet-mediated fibromuscular intimal proliferation and platelet-rich thrombi in the peripheral, cerebral and coronary end-arterial microvasculature are responsible for the erythromelalgic ischemic complications, MIAs and splanchnic vein thrombosis. Baseline platelet P-selectin levels and arachidonic acid induced COX1 mediated platelet activation showed a highly significant increase of platelet P-selectin expression (not seen in ADP and collagen stimulated platelets), which was significantly higher in JAK2V617F mutated compared to JAK2 wild type ET.
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Abstract
Abstract
Thrombosis is a leading cause of morbidity and mortality in patients with Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), particularly polycythemia vera and essential thrombocythemia. Mechanisms involved in the pathogenesis of the acquired thrombophilic state associated with these diseases include abnormalities of MPN clone–derived blood cells, which display prothrombotic features, and abnormalities of normal vascular cells, which become procoagulant in response to inflammatory stimuli. Ultimately, the release into the blood of elevated levels of procoagulant microparticles by platelets and vascular cells and the increase in the global thrombin generation due to an acquired activated protein C resistance result in a highly prothrombotic scenario in patients with polycythemia vera and essential thrombocythemia. The acquired point mutation in the pseudokinase domain of JAK2 (JAK2V617F) in these disorders is variably associated with thrombosis and, more consistently, with elevations in WBC counts and alterations in biomarkers of blood-clotting abnormalities. The predictive value of these biomarkers for thrombosis remains to be established to identify subsets of patients at elevated risk who may benefit from prophylaxis with antithrombotic drugs.
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Abstract
Headache is frequently reported as one of the neurological manifestations of essential thrombocythaemia (ET) and other myeloproliferative neoplasms. It is associated with considerable morbidity; yet, it is a frequently under-recognised symptom. In patients with ET, headaches may be attributable to the disease, to the prescribed ET treatment, or unrelated to ET. The majority of headaches in ET are self-limiting and can be managed with standard headache therapies such as paracetamol, but it is vital that the clinician managing these conditions is able to recognise the headaches with a more sinister pathology. In this article, we will review the incidence and management of headaches in ET, whether they are primarily related to the disease or a result of its treatment. Identification of specific headache types in patients with ET may enable physicians to employ the most effective headache medication. This would enhance the patient-physician relationship, increasing patient compliance and thus reducing the risk of adverse outcomes.
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Affiliation(s)
- R Frewin
- Pathology Department, Gloucester Royal Hospital, Gloucester, UK.
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Panova-Noeva M, Marchetti M, Spronk HM, Russo L, Diani E, Finazzi G, Salmoiraghi S, Rambaldi A, Barbui T, Ten Cate H, Falanga A. Platelet-induced thrombin generation by the calibrated automated thrombogram assay is increased in patients with essential thrombocythemia and polycythemia vera. Am J Hematol 2011; 86:337-42. [PMID: 21442635 DOI: 10.1002/ajh.21974] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The platelet contribution to the thrombophilic state of patients with myeloproliferative neoplasms (MPNs), i.e., essential thrombocythemia (ET) and polycythemia vera (PV), remains uncertain. In this study we aimed to characterize the thrombin generation (TG) potential expressed by platelets from these subjects, compare it to normal platelets, and identify what factors might be responsible for platelet TG. In a group of 140 MPN patients (80 ET and 60 PV) and 72 healthy subjects, we measured the global procoagulant potential of platelet-rich plasma (PRP) utilizing the TG assay by the calibrated automated thrombogram (CAT). To characterize the procoagulant contribution of platelets in PRP, the TG of both isolated platelets and platelet-poor plasma was measured, and the platelet surface expression of TF was determined. Finally, the activation status of platelets was assessed by the levels of P-selectin expressed on platelet surface. MPN patients had significantly increased PRP and isolated platelet TG potential compared to controls. This was associated to the occurrence of platelet activation. Patients carriers of the JAK2V617F mutation showed the highest values of TG and platelet surface TF and P-selectin. Platelet TG potential was significantly lower in hydroxyurea(HU) compared to non-HU-treated patients and was lowest in HU-treated JAK2V617F carriers. In subjects not receiving HU, platelet TG significantly increased by JAK2V617F allele burden increment (P < 0.05).This study demonstrates a platelet-dependent form of hypercoagulability in MPN patients, particularly in those carriers of the JAK2V617F mutation. The cytoreductive therapy with HU significantly affects this prothrombotic phenotype.
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Affiliation(s)
- Marina Panova-Noeva
- Division of Immunohematology and Transfusion Medicine, Ospedali Riuniti di Bergamo, Largo Barozzi 1, Bergamo, Italy
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