|
1
|
Ishida T. A Case of Essential Thrombocythemia Treated for Epileptic Peri-Ictal Psychiatric Symptoms Resulting in Appropriate Palliative Care. Cureus 2025; 17:e76710. [PMID: 39897264 PMCID: PMC11785351 DOI: 10.7759/cureus.76710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2024] [Indexed: 02/04/2025] Open
Abstract
Myeloproliferative neoplasms are diseases characterized by excessive proliferation of myeloid cells in the bone marrow. Essential thrombocythemia (ET) is a myeloproliferative neoplasm that causes platelet proliferation. Although the prognosis for ET has improved because of cytoreductive therapies, some patients can still experience complications including bone marrow fibrosis or acquired von Willebrand disease. A 79-year-old man with a history of hyperthrombocytosis was admitted for rehabilitation after prolonged hospitalization. His treatment included hydroxyurea, which was discontinued because of side effects, and anagrelide, which was unsuccessful in controlling his platelet count. The patient showed generalized convulsions and psychiatric symptoms such as irritability. Based on his clinical symptoms and electroencephalography, he was diagnosed with peri-seizure psychiatric symptoms. Lacosamide was administered to control the seizures. He eventually died of hemorrhagic shock because of ET. However, appropriate epilepsy care improved his psychiatric symptoms and quality of life. The patient was classified as having ET with a high risk of both thrombosis and a poor prognosis because of his age, history of thrombosis, elevated white blood cell count, and JAK2 mutation. In epilepsy care, both convulsive seizures and psychiatric symptoms are important therapeutic targets. Lacosamide, which can be administered orally or intravenously and has a low risk of side effects, was chosen for the present patient. There have been no reports of epileptic seizures associated with ET in palliative medicine. Therefore, this case report is novel and useful for psychiatrists engaged in palliative care medicine and liaison consultation psychiatry.
Collapse
Affiliation(s)
- Tetsuro Ishida
- Department of Psychiatry, Shiroishi Tomo Mental Clinic, Sapporo, JPN
- Department of Neuropsychiatry, School of Medicine, Sapporo Medical University, Sapporo, JPN
| |
Collapse
|
|
2
|
Si Y, Wang J, Hambly BD, Wang Y, Zhang Y, Bao S. Essential thrombocytosis transformed AML with TP53 mutations and its clinical implications. Discov Oncol 2024; 15:786. [PMID: 39692923 DOI: 10.1007/s12672-024-01665-y] [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] [Received: 05/07/2024] [Accepted: 12/03/2024] [Indexed: 12/19/2024] Open
Abstract
Essential thrombocytosis (ET) is a chronic myeloproliferative neoplasm. There is a rare possibility of its transformation from ET into acute myeloid leukemia (AML). While the TP53 mutation is a well-known risk factor for AML, limited research exists regarding ET patients who develop AML with TP53 mutations. Among three ET transformed AML patients, two exhibited TP53 mutations, with an increased number of AML cells. Conversely, the third ET patient who transformed to AML without TP53 mutations had a lower burden of AML cells. The patients with TP53 mutations had shorter survival times compared to that without mutations, in response to decitabine treatment. In contrast, the patient with ET transformed AML without TP53 mutations showed a better response to decitabine. The ET transformed AML without TP53 mutations patient exhibited a survival period exceeding 20 months. ET patients who develop AML with a high allelic burden of TP53 mutations may experience a more aggressive disease progression and severe complications compared to AML patient without TP53 mutations. Our report sheds light on the distinct clinical presentations of ET patients who develop AML, characterized by different TP53 mutations and varying therapeutic outcomes when treated with decitabine. However, further studies that include a larger quantity of samples are needed to elucidate the precise underlying molecular mechanisms involved in this process.
Collapse
Affiliation(s)
- Yang Si
- Department of Hematology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiyuan Wang
- Department of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Brett D Hambly
- Centre for Healthy Futures, Torrens University Australia, Sydney, NSW, Australia
| | - Yuli Wang
- Department of Hematology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Yanfang Zhang
- Department of Hematology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Shisan Bao
- Department of Hematology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
| |
Collapse
|
|
3
|
Rocca B, Tosetto A, Petrucci G, Rossi E, Betti S, Soldati D, Iurlo A, Cattaneo D, Bucelli C, Dragani A, Di Ianni M, Ranalli P, Palandri F, Vianelli N, Beggiato E, Lanzarone G, Ruggeri M, Carli G, Elli EM, Renso R, Randi ML, Bertozzi I, Loscocco GG, Ricco A, Specchia G, Vannucchi AM, Rodeghiero F, De Stefano V, Patrono C. Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial. Am J Hematol 2024; 99:1462-1474. [PMID: 38877813 DOI: 10.1002/ajh.27418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/25/2024] [Accepted: 05/29/2024] [Indexed: 06/16/2024]
Abstract
Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.
Collapse
Affiliation(s)
- Bianca Rocca
- Department of Safety and Bioethics, Section of Pharmacology, Catholic University School of Medicine, Rome, Italy
- Department NeuroFarBa, University of Florence, Florence, Italy
| | | | - Giovanna Petrucci
- Department of Safety and Bioethics, Section of Pharmacology, Catholic University School of Medicine, Rome, Italy
- Department of Radiological and Hematological Sciences, Section of Hematology, Catholic University School of Medicine, Roma, Italy
| | - Elena Rossi
- Department of Radiological and Hematological Sciences, Section of Hematology, Catholic University School of Medicine, Roma, Italy
- Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Silvia Betti
- Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Denise Soldati
- Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Alessandra Iurlo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Daniele Cattaneo
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milano, Italy
| | - Cristina Bucelli
- Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Alfredo Dragani
- Hematology Unit, Department of Oncology and Hematology, Ospedale Civile "Santo Spirito", Pescara, Italy
| | - Mauro Di Ianni
- Hematology Unit, Department of Oncology and Hematology, Ospedale Civile "Santo Spirito", Pescara, Italy
- Department of Medicine and Aging Sciences, "G. D'Annunzio" University, Chieti, Italy
| | - Paola Ranalli
- Hematology Unit, Department of Oncology and Hematology, Ospedale Civile "Santo Spirito", Pescara, Italy
- Department of Medicine and Aging Sciences, "G. D'Annunzio" University, Chieti, Italy
| | - Francesca Palandri
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Nicola Vianelli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Eloise Beggiato
- Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
| | - Giuseppe Lanzarone
- Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy
| | - Marco Ruggeri
- Hematology Department, San Bortolo Hospital, Vicenza, Italy
| | - Giuseppe Carli
- Hematology Department, San Bortolo Hospital, Vicenza, Italy
| | - Elena Maria Elli
- Division of Haematology and Bone Marrow Transplantation Unit, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy
| | - Rossella Renso
- Division of Haematology and Bone Marrow Transplantation Unit, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy
| | | | - Irene Bertozzi
- Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Giuseppe Gaetano Loscocco
- Department of Experimental and Clinical Medicine, CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
| | - Alessandra Ricco
- Unit of Hematology and Stem Cell Transplantation, AOU Consorziale Policlinico, Bari, Italy
| | | | - Alessandro M Vannucchi
- Department of Experimental and Clinical Medicine, CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
| | - Francesco Rodeghiero
- Hematology Project Foundation, Affiliated to the Department of Hematology, San Bortolo Hospital, Vicenza, Italy
| | - Valerio De Stefano
- Department of Radiological and Hematological Sciences, Section of Hematology, Catholic University School of Medicine, Roma, Italy
- Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Italy
| | - Carlo Patrono
- Department of Safety and Bioethics, Section of Pharmacology, Catholic University School of Medicine, Rome, Italy
- Center of Excellence on Aging, "G. D'Annunzio" University School of Medicine, Chieti, Italy
| |
Collapse
|
|
4
|
Guleken Z, Ceylan Z, Aday A, Bayrak AG, Hindilerden İY, Nalçacı M, Jakubczyk P, Jakubczyk D, Depciuch J. Application of Fourier Transform InfraRed spectroscopy of machine learning with Support Vector Machine and principal components analysis to detect biochemical changes in dried serum of patients with primary myelofibrosis. Biochim Biophys Acta Gen Subj 2023; 1867:130438. [PMID: 37516257 DOI: 10.1016/j.bbagen.2023.130438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/24/2023] [Accepted: 07/24/2023] [Indexed: 07/31/2023]
Abstract
Primary myelofibrosis (PM) is a myeloproliferative neoplasm characterized by stem cell-derived clonal neoplasms. Several factors are involved in diagnosing PM, including physical examination, peripheral blood findings, bone marrow morphology, cytogenetics, and molecular markers. Commonly gene mutations are used. Also, these gene mutations exist in other diseases, such as polycythemia vera and essential thrombocythemia. Hence, understanding the molecular mechanism and finding disease-related biomarker characteristics only for PM is crucial for the treatment and survival rate. For this purpose, blood samples of PM (n = 85) vs. healthy controls (n = 45) were collected for biochemical analysis, and, for the first time, Fourier Transform InfraRed (FTIR) spectroscopy measurement of dried PM and healthy patients' blood serum was analyzed. A Support Vector Machine (SVM) model with optimized hyperparameters was constructed using the grid search (GS) method. Then, the FTIR spectra of the biomolecular components of blood serum from PM patients were compared to those from healthy individuals using Principal Components Analysis (PCA). Also, an analysis of the rate of change of FTIR spectra absorption was studied. The results showed that PM patients have higher amounts of phospholipids and proteins and a lower amount of H-O=H vibrations which was visible. The PCA results indicated that it is possible to differentiate between dried blood serum samples collected from PM patients and healthy individuals. The Grid Search Support Vector Machine (GS-SVM) model showed that the prediction accuracy ranged from 0.923 to 1.00 depending on the FTIR range analyzed. Furthermore, it was shown that the ratio between α-helix and β-sheet structures in proteins is 1.5 times higher in PM than in control people. The vibrations associated with the CO bond and the amide III region of proteins showed the highest probability value, indicating that these spectral features were significantly altered in PM patients compared to healthy ones' spectra. The results indicate that the FTIR spectroscope may be used as a technique helpful in PM diagnostics. The study also presents preliminary results from the first prospective clinical validation study.
Collapse
Affiliation(s)
- Zozan Guleken
- Gaziantep University of Islam Science and Technology, Faculty of Medicine, Department of Physiology, Küçükkızılhisar, 27220 Şahinbey/Gaziantep, Turkey (b)Medical College of Rzeszow University, Rzeszów, Poland; Medical College of Rzeszow University, Rzeszów, Poland.
| | - Zeynep Ceylan
- Samsun University, Faculty of Engineering, Department of Industrial Engineering, Samsun, Turkey
| | - Aynur Aday
- Istanbul University, Faculty of Medicine, Department of Internal Medicine, Division of Medical Genetics, Istanbul, Turkey
| | - Ayşe Gül Bayrak
- Istanbul University, Faculty of Medicine, Department of Internal Medicine, Division of Medical Genetics, Istanbul, Turkey
| | - İpek Yönal Hindilerden
- Istanbul University Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Istanbul, Turkey
| | - Meliha Nalçacı
- Istanbul University Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Istanbul, Turkey
| | | | - Dorota Jakubczyk
- Faculty of Mathematics and Applied Physics, Rzeszow University of Technology, Powstancow Warszawy 12, PL-35959 Rzeszow, Poland
| | - Joanna Depciuch
- Institute of Nuclear Physics, PAS, 31342 Krakow, Poland; Department of Biochemistry and Molecular Biology, Medical University of Lublin, 20-093 Lublin, Poland.
| |
Collapse
|
|
5
|
Ciarambino T, Crispino P, Minervini G, Giordano M. Cerebral Sinus Vein Thrombosis and Gender: A Not Entirely Casual Relationship. Biomedicines 2023; 11:1280. [PMID: 37238951 PMCID: PMC10216036 DOI: 10.3390/biomedicines11051280] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/13/2023] [Accepted: 04/22/2023] [Indexed: 05/28/2023] Open
Abstract
Cerebral sinus venous thrombosis (CSVT) is a relatively rare acute disorder of cerebral circulation, but it can potentially be associated with serious sequelae and a poor prognosis. The neurological manifestations associated with it are often not adequately taken into consideration given the extreme variability and nuances of its clinical presentation and given the need for radiological methods suitable for this type of diagnosis. CSVT is usually more common in women, but so far there are little data available in the literature on sex-specific characteristics regarding this pathology. CSVT is the result of multiple conditions and is therefore to be considered a multifactorial disease where at least one risk factor is present in over 80% of cases. From the literature, we learn that congenital or acquired prothrombotic states are to be considered extremely associated with the occurrence of an acute episode of CSVT and its recurrences. It is, therefore, necessary to fully know the origins and natural history of CSVT, in order to implement the diagnostic and therapeutic pathways of these neurological manifestations. In this report, we summarize the main causes of CSVT considering the possible influence of gender, bearing in mind that most of the causes listed above are pathological conditions closely linked to the female sex.
Collapse
Affiliation(s)
- Tiziana Ciarambino
- Internal Medicine Department, Hospital of Marcianise, ASL Caserta, 81024 Caserta, Italy
| | - Pietro Crispino
- Internal Medicine Department, Hospital of Latina, ASL Latina, 04100 Latina, Italy
| | - Giovanni Minervini
- Emergency Department, Hospital of Lagonegro, AOR San Carlo, 85042 Lagonegro, Italy
| | - Mauro Giordano
- Advanced Medical and Surgical Sciences Department, University of Campania, L. Vanvitelli, 81100 Naples, Italy
| |
Collapse
|
|
6
|
Abstract
The Philadelphia-negative myeloproliferative neoplasms (MPNs)-essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), are characterized by a propensity for thrombotic events and variable risks for transformation to MF (for ET and PV) and acute leukemia. Leukocytosis, which serves a minor criterion for the diagnosis of MF, is present in a significant portion of patients with MPNs. The relation and impact of leukocytosis on disease course and outcomes of patients with MPNs has been studied in multiple, large retrospective and prospective studies. Despite this, the association of leukocytosis and thrombosis, fibrosis and leukemic transformation remains unclear. This article details the published investigations regarding the impact of leukocytosis in MPNs and explores the changing role of leukocytosis in disease prognostication as increasing emphasis is placed on molecular and genetic studies.
Collapse
Affiliation(s)
- Alexander Coltoff
- Department of Hematology/Oncology, Medical University of South Carolina, Charleston, SC, USA
| |
Collapse
|
|
7
|
Furuya C, Hashimoto Y, Morishita S, Inano T, Ochiai T, Shirane S, Edahiro Y, Araki M, Ando M, Komatsu N. Reevaluation of cardiovascular risk factors for thrombotic events in 580 Japanese patients with essential thrombocythemia. J Thromb Thrombolysis 2023; 55:263-272. [PMID: 36484956 DOI: 10.1007/s11239-022-02751-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2022] [Indexed: 12/13/2022]
Abstract
Risk-adapted therapy is recommended to prevent thrombosis in essential thrombocythemia (ET) patients. An advanced age, a history of thrombosis, and the presence of the JAK2V617F mutation are well-defined risk factors for thrombosis in ET; however, the impact of cardiovascular risk (CVR) factors on thrombosis in ET remains elusive. Therefore, we herein investigated the impact of CVR factors on thrombosis in 580 ET patients who met the 2017 World Health Organization Classification diagnostic criteria. A univariate analysis identified hypertriglyceridemia and multiple CVR factors as strong risk factors for thrombosis (hazard ratio [HR] 3.530, 95% confidence interval [CI] 1.630-7.643, P = 0.001 and HR 3.368, 95% CI 1.284-8.833, P = 0.014, respectively) and hyper-LDL cholesterolemia as a potential risk factor (HR 2.191, 95% CI 0.966-4.971, P = 0.061). A multivariate analysis revealed that hypertriglyceridemia was an independent risk factor for thrombosis (HR 3.364, 95% CI 1.541-7.346, P = 0.002). Furthermore, poor thrombosis-free survival was observed in patients with a serum triglyceride level ≥ 1.2 mmol/L (HR = 2.592, P = 0.026 vs. < 1.2 mmol/L) or two or more CVR factors (P = 0.011 vs. no CVR factors and P = 0.005 vs. one CVR factor). These results revealed the impact of CVR factors on thrombosis in ET. Since CVR factors are manageable, lifestyle interventions, such as the control of serum triglyceride levels, may effectively prevent thrombosis in ET patients.
Collapse
Affiliation(s)
- Chiho Furuya
- Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yoshinori Hashimoto
- Department of Hematology, Tottori Prefectural Central Hospital, 730 Ezu, Tottori City, Tottori, 680-0901, Japan.,Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Soji Morishita
- Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Laboratory for the Development of Therapies Against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tadaaki Inano
- Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomonori Ochiai
- Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Laboratory for the Development of Therapies Against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Shuichi Shirane
- Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Laboratory for the Development of Therapies Against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yoko Edahiro
- Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Laboratory for the Development of Therapies Against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Marito Araki
- Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Laboratory for the Development of Therapies Against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Miki Ando
- Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Norio Komatsu
- Department of Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. .,Department of Advanced Hematology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. .,Laboratory for the Development of Therapies Against MPN, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. .,PharmaEssentia Japan KK, 1-3-13 Motoakasaka, Minato-ku, Tokyo, 107-0051, Japan.
| |
Collapse
|
|
8
|
Puglianini OC, Peker D, Zhang L, Papadantonakis N. Essential Thrombocythemia and Post-Essential Thrombocythemia Myelofibrosis: Updates on Diagnosis, Clinical Aspects, and Management. Lab Med 2023; 54:13-22. [PMID: 35960786 DOI: 10.1093/labmed/lmac074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Although several decades have passed since the description of myeloproliferative neoplasms (MPN), many aspects of their pathophysiology have not been elucidated. In this review, we discuss the mutational landscape of patients with essential thrombocythemia (ET), prognostic scores and salient pathology, and clinical points. We discuss also the diagnostic challenges of differentiating ET from prefibrotic MF. We then focus on post-essential thrombocythemia myelofibrosis (post-ET MF), a rare subset of MPN that is usually studied in conjunction with post-polycythemia vera MF. The transition of ET to post-ET MF is not well studied on a molecular level, and we present available data. Patients with secondary MF could benefit from allogenic hematopoietic stem cell transplantation, and we present available data focusing on post-ET MF.
Collapse
Affiliation(s)
- Omar Castaneda Puglianini
- H. Lee Moffitt Cancer Center & Research Institute, Department of Blood & Marrow Transplant & Cellular Immunotherapy, Tampa, FL, USA
- Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Deniz Peker
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Linsheng Zhang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Nikolaos Papadantonakis
- Winship Cancer Institute of Emory University, Department of Hematology and Medical Oncology, Atlanta, GA, USA
| |
Collapse
|
|
9
|
Mustafa AHM, Krämer OH. Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer. Pharmacol Rev 2023; 75:35-61. [PMID: 36752816 DOI: 10.1124/pharmrev.122.000612] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 07/08/2022] [Accepted: 08/15/2022] [Indexed: 12/13/2022] Open
Abstract
Hyperactivated Janus kinase (JAK) signaling is an appreciated drug target in human cancers. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the efficacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades. Like JAKs, epigenetic modifiers of the histone deacetylase (HDAC) family regulate the growth and development of cells and are often dysregulated in cancer cells. The notion that inhibitors of histone deacetylases (HDACi) abrogate oncogenic JAK-dependent signaling cascades illustrates an intricate crosstalk between JAKs and HDACs. Here, we summarize how structurally divergent, broad-acting as well as isoenzyme-specific HDACi, hybrid fusion pharmacophores containing JAKi and HDACi, and proteolysis targeting chimeras for JAKs inactivate the four JAK proteins JAK1, JAK2, JAK3, and tyrosine kinase-2. These agents suppress aberrant JAK activity through specific transcription-dependent processes and mechanisms that alter the phosphorylation and stability of JAKs. Pharmacological inhibition of HDACs abrogates allosteric activation of JAKs, overcomes limitations of ATP-competitive type 1 and type 2 JAKi, and interacts favorably with JAKi. Since such findings were collected in cultured cells, experimental animals, and cancer patients, we condense preclinical and translational relevance. We also discuss how future research on acetylation-dependent mechanisms that regulate JAKs might allow the rational design of improved treatments for cancer patients. SIGNIFICANCE STATEMENT: Reversible lysine-ɛ-N acetylation and deacetylation cycles control phosphorylation-dependent Janus kinase-signal transducer and activator of transcription signaling. The intricate crosstalk between these fundamental molecular mechanisms provides opportunities for pharmacological intervention strategies with modern small molecule inhibitors. This could help patients suffering from cancer.
Collapse
Affiliation(s)
- Al-Hassan M Mustafa
- Department of Toxicology, University Medical Center, Mainz, Germany (A.-H.M.M., O.H.K.) and Department of Zoology, Faculty of Science, Aswan University, Aswan, Egypt (A.-H.M.M.)
| | - Oliver H Krämer
- Department of Toxicology, University Medical Center, Mainz, Germany (A.-H.M.M., O.H.K.) and Department of Zoology, Faculty of Science, Aswan University, Aswan, Egypt (A.-H.M.M.)
| |
Collapse
|
|
10
|
Pirciulescu N, Gaman MA, Mihailescu M, Constantin C, Dragomir M, Dobrea C, Costache S, Ursuleac I, Coriu D, Crisan AM. Essential Thrombocythemia: One-Center Data in a Changing Disease. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:1798. [PMID: 36557000 PMCID: PMC9782858 DOI: 10.3390/medicina58121798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Introduction: Essential thrombocythemia is a chronic myeloproliferative neoplasm associated with thrombo-hemorrhagic events and the progression to myelofibrosis or acute myeloid leukemia. The purpose of this article is to present real-world data on ET cases diagnosed and managed between 1998 and 2020 in the largest, tertiary hematology reference center in Romania and to evaluate the impact of thrombotic events on survival. Methods: A real-world, retrospective cohort-type study was conducted. We collected and statistically analyzed data from 168 patients who met the 2016 WHO diagnostic criteria for ET and who were managed between 1998 and 2020 in our center. Results: The median age at diagnosis of ET was 51.8 years, with a female predominance (66.07%). The JAK2V617F mutation was detected in 60.71% of patients. Leukocytosis at diagnosis was associated with a higher risk of thrombosis, and JAK2V617F-positive cases exhibited a 1.5-fold higher risk of developing thrombotic events. The average survival in ET with major thrombosis was 14.5 years versus 20.6 years in ET cases without major thrombosis. Other predictors of survival were high-risk IPSET score and age >60 years. Conclusions: Romanian patients diagnosed with ET are generally younger than 60 years and are predominantly female. The occurrence of thrombotic events was influenced by gender, leukocyte count at diagnosis and JAK2V617F positivity. Survival was impacted by age, the presence of JAK2V617F mutation, hypertension, major thrombotic complications and IPSET score. Notably, these findings warrant careful interpretation and further confirmation in the setting of prospective studies.
Collapse
Affiliation(s)
- Nicoleta Pirciulescu
- Department of Clinical Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Mihnea-Alexandru Gaman
- Department of Clinical Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Marina Mihailescu
- Department of Clinical Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Cristina Constantin
- Department of Clinical Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Mihaela Dragomir
- Department of Molecular Biology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Camelia Dobrea
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Hematopathology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Simona Costache
- Department of Cytomorphology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Iulia Ursuleac
- Department of Clinical Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Daniel Coriu
- Department of Clinical Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Ana Manuela Crisan
- Department of Clinical Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| |
Collapse
|
|
11
|
Muacevic A, Adler JR, Verbeek EC, van de Wetering M, Voogel AJ, Oosterom L, Herrman JPR, Kuipers RS. Essential Thrombocytosis in Patients <40 Years Old With Acute Coronary Syndromes: A Not So Uncommon Underlying Diagnosis Often Overlooked. Cureus 2022; 14:e32638. [PMID: 36654555 PMCID: PMC9842111 DOI: 10.7759/cureus.32638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND In patients under <40 years, traditional cardiovascular (CV)-risk factors are a less likely cause of acute coronary syndromes (ACS) compared to older counterparts. AIMS To estimate the prevalence of essential thrombocytosis (ET), a hematological disorder and less-prevalent risk factor, in young patients presenting with ACS. METHODS We constructed a retrospective database of all patients <40 years (n=271) that had consecutively undergone coronary angiography (CAG) after their first ACS within our hospital within the last ten years (2010-2020) and had known thrombocyte counts (n=241). Patients with thrombocytes >450x10*9/L were screened for this hematological disorder. RESULTS In our database, we identified 15 subjects with thrombocytosis. One was previously known as ET. Of the remaining 14 patients, five were considered reactive/secondary thrombocytosis, and four were lost to follow-up, four were eventually diagnosed with ET, one remains uncertain. The diagnosis was newly established before the initiation of this study in two patients (average delay: six years). Two patients were identified as a result of this study. Conclusion: With a prevalence of at least 2.1%, ET appears not uncommon in patients <40 years with ACS. Moreover, screening patients with ACS and elevated thrombocytes yielded a novel diagnosis of ET in 27% of patients. The diagnosis was initially missed in all cases. Since the timing of revascularization should be adjusted to thrombocyte count/initiation of ET therapy to prevent thrombotic complications, cardiologists should know, recognize and screen for this pathology in ACS-patients, notably in those with absent traditional CV-risk factors: an 'ACS-protocol' aimed at less-prevalent risk factors could support this.
Collapse
|
|
12
|
Christensen SF, Svingel LS, Kjærsgaard A, Stenling A, Darvalics B, Paulsson B, Andersen CL, Christiansen CF, Stentoft J, Starklint J, Severinsen MT, Clausen MB, Hilsøe MH, Hasselbalch HC, Frederiksen H, Mikkelsen EM, Bak M. Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study. Eur J Haematol 2022; 109:526-541. [PMID: 35900040 PMCID: PMC9804288 DOI: 10.1111/ejh.13841] [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: 04/26/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 01/05/2023]
Abstract
Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.
Collapse
Affiliation(s)
| | - Lise Skovgaard Svingel
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | - Anders Kjærsgaard
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | | | - Bianka Darvalics
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | | | - Christen Lykkegaard Andersen
- Department of HematologyCopenhagen University HospitalRigshospitaletDenmark,The Research Unit for General Practice and Section of General Practice, Department of Public HealthUniversity of CopenhagenCopenhagenDenmark
| | - Christian Fynbo Christiansen
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | - Jesper Stentoft
- Department of HematologyAarhus University HospitalAarhusDenmark
| | - Jørn Starklint
- Department of HematologyHolstebro HospitalHolstebroDenmark
| | | | - Mette Borg Clausen
- Department of HematologyCopenhagen University HospitalRigshospitaletDenmark
| | | | | | | | - Ellen Margrethe Mikkelsen
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | - Marie Bak
- Department of HematologyZealand University HospitalRoskildeDenmark,Department of HematologyCopenhagen University HospitalRigshospitaletDenmark
| |
Collapse
|
|
13
|
Singh K, V. P, Ahuja A, Somasundarum V, Mishra K, Chatterjee T. Correlation of Thrombosis and Clinicohematological Parameters with JAK2V617F Mutation in Philadelphia-Negative CMPNs: A Study from India. J Lab Physicians 2022; 14:394-397. [DOI: 10.1055/s-0042-1757230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Abstract
Objective Philadelphia-negative chronic myeloproliferative neoplasms (CMPNs), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by the presence of JAK2V617F (exon 14) mutation, and this occurs in 90 to 95% cases of PV and 50 to 60% cases of ET and PMF. Still, this is a matter of debate regarding the correlation of this mutation with thrombosis and clinicohematological parameters in CMPNs. So, we conducted this study to ascertain the association of JAK2V617F mutation with thrombotic complications and clinicohematological parameters of these patients.
Materials and Methods This prospective and retrospective study was conducted during 2018 to 2019 at the Department of Laboratory Sciences and Molecular Medicine of a tertiary care hospital, and 160 CMPN patients were enrolled. Complete hemogram was done and DNA was extracted, followed by real-time qualitative polymerase chain reaction to check for JAK2V617F mutation. This mutation was then correlated with complications, mainly thrombosis, hematological parameters, and clinical parameters such as age and splenomegaly.
Results Among 160 CMPN patients, 60 were females and 100 were males, with male to female ratio of 1:0.6, and age range of 27 to 85 years. Total 91 (56.9%) patients were JAK2V617F positive and the remaining 69 (43.1%) were negative for this mutation. We observed statistically significant correlation of leukocyte count, splenomegaly, and thrombosis in JAK2V617F-mutated patients as compared to unmutated patients.
Conclusion This study emphasizes the importance of JAK2V617F mutation in CMPNs and stresses on its association with clinical, hematological phenotype, and thrombotic complications, which may open new horizons in prognostication and management protocol.
Collapse
Affiliation(s)
- Kanwaljeet Singh
- Department of Laboratory Sciences and Molecular Medicine, Army Hospital (R&R), Delhi Cantt, India
| | - Pradeep V.
- Department of Laboratory Sciences and Molecular Medicine, Army Hospital (R&R), Delhi Cantt, India
| | - Ankur Ahuja
- Department of Laboratory Sciences and Molecular Medicine, Army Hospital (R&R), Delhi Cantt, India
| | - Venkatesan Somasundarum
- Department of Laboratory Sciences and Molecular Medicine, Army Hospital (R&R), Delhi Cantt, India
| | - Kundan Mishra
- Department of Laboratory Sciences and Molecular Medicine, Army Hospital (R&R), Delhi Cantt, India
| | - Tathagat Chatterjee
- Department of Laboratory Sciences and Molecular Medicine, Army Hospital (R&R), Delhi Cantt, India
| |
Collapse
|
|
14
|
Tsuboi Y, Sakamoto T, Makishima K, Suehara Y, Hattori K, Kurita N, Yokoyama Y, Kato T, Nishikii H, Obara N, Matsumura F, Matsuoka R, Chiba S, Sakata-Yanagimoto M. Triple-negative Thrombocythemia and Subsequent Acute Lymphoblastic Leukemia with Additional Somatic Mutations. Intern Med 2022; 62:1527-1530. [PMID: 36104197 DOI: 10.2169/internalmedicine.0269-22] [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: 11/06/2022] Open
Abstract
Triple-negative essential thrombocythemia (ET) is a condition in which mutations in JAK2, CALR and MPL are all negative. Transformation to acute myeloid leukemia may occur during the course of ET, while B-acute lymphoblastic leukemia (B-ALL) is rare. We experienced a case diagnosed as B-ALL during the course of triple-negative ET. Notably, cytoreduction was required for the excessive increase in blood cells during the bone marrow recovery period after chemotherapies. Whole-exome sequencing identified 17 somatic mutations: 9 were identified in both ET and B-ALL samples, while 8 were specific to B-ALL, suggesting that these 8 might have caused the transformation.
Collapse
Affiliation(s)
- Yuri Tsuboi
- Department of Hematology, University of Tsukuba Hospital, Japan
| | - Tatsuhiro Sakamoto
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | - Kenichi Makishima
- Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan
| | | | - Keiichiro Hattori
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | - Naoki Kurita
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | - Yasuhisa Yokoyama
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | - Takayasu Kato
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | - Hidekazu Nishikii
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | - Naoshi Obara
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | | | - Ryota Matsuoka
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Japan
| | - Shigeru Chiba
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
| | - Mamiko Sakata-Yanagimoto
- Department of Hematology, University of Tsukuba Hospital, Japan
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Japan
- Division of Advanced Hemato-Oncology, Transborder Medical Research Center, Japan
| |
Collapse
|
|
15
|
Real world study of children and young adults with myeloproliferative neoplasms identifying risks and unmet needs. Blood Adv 2022; 6:5171-5183. [PMID: 35802458 PMCID: PMC9631631 DOI: 10.1182/bloodadvances.2022007201] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 06/06/2022] [Indexed: 11/21/2022] Open
Abstract
In a contemporary cohort of 444 young MPN patients, risks of thrombosis, hemorrhage, and transformation were 1% pt/y. Current risk scores had no utility. Uniquely, we identify that splenomegaly and hyperviscosity symptoms predict thrombosis and transformation. Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.
Collapse
|
|
16
|
Nicol C, Ajzenberg N, Lacut K, Couturaud F, Pan-Petesch B, Lippert E, Ianotto JC. Hemorrhages in polycythemia vera and essential thrombocythemia: epidemiology, description, and risk factors, learnings from a large cohort. Thromb Haemost 2022; 122:1712-1722. [PMID: 35545123 DOI: 10.1055/a-1849-8477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND The management of myeloproliferative neoplasms (MPN) is based on the reduction of thrombosis risk. The incidence, impact, and risk factors of bleedings have been less studied. METHOD All patients with polycythemia vera (n=339) or essential thrombocythemia (n=528) treated in our center are included in OBENE cohort (NCT02897297). Major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) occurring after diagnosis were included, except after leukemic transformation. RESULTS With a median follow-up of 8.3 years, incidence of hemorrhages was 1.85% patient/year, with an incidence of MB of 0.95% patient/year. The 10-year bleeding-free survival was 89%. The most frequent locations were digestive tractus, "mouth, nose and throat" and muscular hematoma. The case fatality rate of MB was 25%. The proportion of potentially avoidable iatrogenic bleeding was remarkable (17.6%). In multivariable analysis, eight risk factors of bleeding were identified: leukocytes >20 giga/l at diagnosis (HR=5.13 95%CI [1.77;14.86]), secondary hemopathies (HR=2.99 95%CI [1.27;7.04]), aspirin use at diagnosis (HR=2.11 95%CI [1.24;3.6]), platelet count >1000 giga/l at diagnosis (HR=1.93, 95%CI [1.11;3.36]), history of hemorrhage (HR=1.82 95%CI [1.03;3.24]), secondary cancers (HR=1.71 95%CI [1.01;2.89]), atrial fibrillation (HR=1.66, 95%CI [1.01;2.72]) and male gender (HR=1.54, 95%CI [1.02-2.33]). The majority of patients taking hydroxyurea displayed a non-macrocytic median corpuscular value in the months preceding bleeding (51.4%). DISCUSSION The morbidity and mortality of bleedings in MPN should not be underestimated, and some patients could beneficiate from cytoreduction in order to reducing bleeding risk. Iatrogenic bleedings represent a substantial proportion of bleeding and could be better prevented.
Collapse
Affiliation(s)
| | | | - Karine Lacut
- CIC1412, Inserm, Brest, France.,EA 3878, Brest University, Brest, France
| | - Francis Couturaud
- Department of internal medicine and chest diseases, Brest University Hospital Centre, Brest, France
| | | | - Eric Lippert
- Laboratoire d'Hématologie, CHU de Brest, Brest, France.,Equipe ECLA, INSERM U1078, France
| | | |
Collapse
|
|
17
|
Goulart H, Mascarenhas J, Tremblay D. Low-risk polycythemia vera and essential thrombocythemia: management considerations and future directions. Ann Hematol 2022; 101:935-951. [PMID: 35344066 DOI: 10.1007/s00277-022-04826-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/21/2022] [Indexed: 01/06/2023]
Abstract
Thrombotic events are a distinctive feature of the myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and essential thrombocythemia (ET). Patients with these MPNs may also experience a poor quality of life secondary to symptom burden, as well as progression of disease to acute leukemia or myelofibrosis. Over the years, various risk stratification methods have evolved in order to attempt to predict thrombotic risk, which is the largest contributor of morbidity and mortality in these patients. More than half of PV and ET patients are low- or intermediate-risk disease status at the time of diagnosis. While therapeutic development is presently focused on high-risk patients, there is a paucity of therapies, outside of aspirin and therapeutic phlebotomy, which can reduce the thrombotic risk or delay disease progression in low-risk patients. In this review, we first describe the various complications that patients with PV and ET experience, and then detail our evolving understanding of risk stratification in these diseases. We then highlight the available evidence on the management of low-risk PV and ET and include a description of novel therapies currently under investigation in this space. We conclude with recommendations for future directions to advance our understanding and improve the treatment of low-risk PV and ET.
Collapse
Affiliation(s)
- Hannah Goulart
- Division of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - John Mascarenhas
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, 10029, USA
| | - Douglas Tremblay
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, 10029, USA.
| |
Collapse
|
|
18
|
Analysis of factors associated with the development of myelofibrosis in polycythemia vera and essential thrombocythemia patients: a single-center experience. J Hematop 2022. [DOI: 10.1007/s12308-022-00488-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
|
|
19
|
Song IC, Yeon SH, Lee MW, Ryu H, Lee HJ, Yun HJ, Kim SY, Jo DY. Myelofibrotic and leukemic transformation in 2016 WHO-defined Philadelphia-negative myeloproliferative neoplasm. Blood Res 2022; 57:59-68. [PMID: 35256550 PMCID: PMC8958372 DOI: 10.5045/br.2021.2021209] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 02/05/2022] [Accepted: 02/07/2022] [Indexed: 12/05/2022] Open
Abstract
Background Information on myelofibrotic and leukemic transformations in Korean Philadelphia chromosome-negative myeloproliferative neoplasms (Ph‒ MPNs) is limited. Methods This study retrospectively analyzed transformations in patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV) prefibrotic/early primary myelofibrosis (pre-PMF), or overt primary myelofibrosis (PMF) based on the 2016 World Health Organization criteria between January 1996 and December 2020 at Chungam National University Hospital, Daejeon, Korea. Results A total of 351 patients (144 with ET, 131 with PV, 45 with pre-PMF, and 31 with PMF; 204 men and 147 women) with a median age of 64 years (range, 15‒91 years) were followed for a median of 4.6 years (range, 0.2‒24.8 years). The 10-year incidence of overt myelofibrosis was higher in pre-PMF than in ET (31.3% and 13.7%, respectively; P=0.031) and PV (12.2%; P=0.003). The 10-year incidence of leukemic transformation was significantly higher in PMF than in ET (40.0% and 7.9%, respectively; P=0.046), pre-PMF (4.7%; P=0.048), and PV (3.2%; P=0.031). The 5-year incidence of leukemic transformation was higher in patients with secondary myelofibrosis (SMF) than in those with PMF (19.0% and 11.4%, respectively; P=0.040). The 5-year overall survival of patients with SMF was significantly worse than that of patients with pre-PMF (74% and 93%, respectively; P=0.027) but did not differ from that of patients with PMF (57%; P=0.744). Conclusion The rates and clinical courses of myelofibrotic and leukemic transformations in Korean patients with Ph‒ MPN did not differ from those in Western populations.
Collapse
Affiliation(s)
- Ik-Chan Song
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Sang Hoon Yeon
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Myung-Won Lee
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Hyewon Ryu
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Hyo-Jin Lee
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Hwan-Jung Yun
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Seon Young Kim
- Department of Laboratory Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Deog-Yeon Jo
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| |
Collapse
|
|
20
|
Papageorgiou L, Elalamy I, Vandreden P, Gerotziafas GT. Thrombotic and Hemorrhagic Issues Associated with Myeloproliferative Neoplasms. Clin Appl Thromb Hemost 2022; 28:10760296221097969. [PMID: 35733370 PMCID: PMC9234921 DOI: 10.1177/10760296221097969] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Thrombotic and hemorrhagic complications are related to a significant rate of
morbidity and mortality in patients with myeloproliferative neoplasms (MPNs),
they are therefore called “thrombohemorrhagic” syndromes. Several clinical
factors, such as age and presence of cardiovascular comorbidities are
responsible for thrombotic complications. High blood counts, platelet
alterations, presence of JAK2 mutation and possibly of other CHIP mutations such
as TET2, DNMT3A, and ASXL1, procoagulant microparticles, NETs formation,
endothelial activation and neo-angiogenesis are some of the parameters
accounting for hypercoagulability in patients with myeloproliferative neoplasms.
Bleeding complications emerge as a result of platelet exhaustion. They can be
also linked to a functional deficiency of von Willebrand factor, when platelet
counts rise above 1000G/L. The mainstay of management consists on preventing
hemostatic complications, by antiplatelet and/or anticoagulant treatment and
myelosuppressive agents in high-risk patients.Circumstances related to a high
thrombohemorrhagic risk, such as pregnancy and the perioperative period, prompt
for specific management with regards to anticoagulation and myelosuppression
treatment type. In order to apply a patient-specific treatment strategy, there
is a need for a risk score assessment tool encompassing clinical parameters and
hemostasis biomarkers.
Collapse
Affiliation(s)
- Loula Papageorgiou
- Hrombosis Center, 432215Service d'Hématologie Biologique Hôpital Tenon, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris, Faculté de Médecine Sorbonne Université, Paris, France.,Faculty of Medicine, Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Sorbonne University, Paris, France
| | - Ismail Elalamy
- Hrombosis Center, 432215Service d'Hématologie Biologique Hôpital Tenon, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris, Faculté de Médecine Sorbonne Université, Paris, France.,Faculty of Medicine, Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Sorbonne University, Paris, France.,The First I.M. Sechenov Moscow State Medical University, Moscow, Russia
| | - Patrick Vandreden
- Faculty of Medicine, Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Sorbonne University, Paris, France.,Clinical Research Department, Diagnostica Stago, Gennevilliers, France
| | - Grigoris T Gerotziafas
- Hrombosis Center, 432215Service d'Hématologie Biologique Hôpital Tenon, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris, Faculté de Médecine Sorbonne Université, Paris, France.,Faculty of Medicine, Research Group "Cancer, Haemostasis and Angiogenesis", INSERM U938, Centre de Recherche Saint-Antoine, Institut Universitaire de Cancérologie, Sorbonne University, Paris, France
| |
Collapse
|
|
21
|
Hamid MAB, Sehbai AS, Tariq S. Ischemic Stroke in a Young Man: Unraveling the Domain of Myeloproliferative Disorders. Cureus 2021; 13:e16495. [PMID: 34430110 PMCID: PMC8373526 DOI: 10.7759/cureus.16495] [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] [Accepted: 07/19/2021] [Indexed: 11/05/2022] Open
Abstract
Ischemic stroke is a rare phenomenon in young adults. A complete workup for hypercoagulable and myeloproliferative disorders is a cornerstone of evaluation. Essential thrombocytosis is a chronic myeloproliferative disorder that primarily involves platelets. It may remain undiagnosed in patients and subsequently present in the form of ischemic stroke. The management of this disorder is complex and often involves cytoreduction therapies. The initiation of these drugs in such patients may lead to unnecessary adverse effects and complications. This case report is an attempt to highlight an underappreciated cause of stroke when assessing young individuals.
Collapse
Affiliation(s)
| | - Aasim S Sehbai
- Hematology and Oncology, Alabama Cancer Care, Anniston, USA
| | - Shahan Tariq
- Hematology and Oncology, Alabama Cancer Care, Anniston, USA
| |
Collapse
|
|
22
|
Late excess mortality in essential thrombocythemia: a population-based study in the Netherlands, 2001-2018. Leukemia 2021; 36:275-278. [PMID: 34363011 DOI: 10.1038/s41375-021-01372-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/16/2021] [Accepted: 07/27/2021] [Indexed: 11/09/2022]
|
|
23
|
Al-Qadi M, LeVarge B, Ford HJ. Epidemiology, Pathogenesis, and Clinical Approach in Group 5 Pulmonary Hypertension. Front Med (Lausanne) 2021; 7:616720. [PMID: 33842491 PMCID: PMC8026868 DOI: 10.3389/fmed.2020.616720] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/17/2020] [Indexed: 01/19/2023] Open
Abstract
Pulmonary hypertension (PH) is recognized to be associated with a number of comorbid conditions. Based on these associations, PH is classified into 5 groups, considering common pathophysiologic drivers of disease, histopathologic features, clinical manifestations and course, and response to PH therapy. However, in some of these associated conditions, these characteristics are less well-understood. These include, among others, conditions commonly encountered in clinical practice such as sarcoidosis, sickle cell disease, myeloproliferative disorders, and chronic kidney disease/end stage renal disease. PH in these contexts presents a significant challenge to clinicians with respect to disease management. The most recent updated clinical classification schemata from the 6th World Symposium on PH classifies such entities in Group 5, highlighting the often unclear and/or multifactorial nature of PH. An in-depth review of the state of the science of Group 5 PH with respect to epidemiology, pathogenesis, and management is provided. Where applicable, future directions with respect to research needed to enhance understanding of the clinical course of these entities is also discussed.
Collapse
Affiliation(s)
- Mazen Al-Qadi
- Division of Pulmonary and Critical Care Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Barbara LeVarge
- Division of Pulmonary and Critical Care Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - H James Ford
- Division of Pulmonary and Critical Care Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| |
Collapse
|
|
24
|
Handlos Grauslund J, Holmström MO, Jørgensen NG, Klausen U, Weis-Banke SE, El Fassi D, Schöllkopf C, Clausen MB, Gjerdrum LMR, Breinholt MF, Kjeldsen JW, Hansen M, Koschmieder S, Chatain N, Novotny GW, Petersen J, Kjær L, Skov V, Met Ö, Svane IM, Hasselbalch HC, Andersen MH. Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms. Front Oncol 2021; 11:637420. [PMID: 33718228 PMCID: PMC7952976 DOI: 10.3389/fonc.2021.637420] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
Background The calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR-mutant MPN. Methods The safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALRmut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446). Results Patients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines. Conclusion Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response.
Collapse
Affiliation(s)
- Jacob Handlos Grauslund
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Morten Orebo Holmström
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Nicolai Grønne Jørgensen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Uffe Klausen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Stine Emilie Weis-Banke
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Daniel El Fassi
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.,Department of Medicine, Copenhagen University, Copenhagen, Denmark
| | - Claudia Schöllkopf
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | - Mette Borg Clausen
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | | | | | - Julie Westerlin Kjeldsen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Morten Hansen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Nicolas Chatain
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Guy Wayne Novotny
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | - Jesper Petersen
- Department of Hematology, Copenhagen University Hospital, Herlev, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Özcan Met
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.,Institute for Immunology and Microbiology, Copenhagen University, Copenhagen, Denmark
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | | | - Mads Hald Andersen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.,Institute for Immunology and Microbiology, Copenhagen University, Copenhagen, Denmark
| |
Collapse
|
|
25
|
Shallis RM, Zeidan AM, Wang R, Podoltsev NA. Epidemiology of the Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms. Hematol Oncol Clin North Am 2021; 35:177-189. [PMID: 33641862 DOI: 10.1016/j.hoc.2020.11.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) comprise the BCR-ABL-negative classical myeloproliferative neoplasms (MPNs). These clonal myeloid diseases are principally driven by well-described molecular events; however, factors leading to their acquisition are not well understood. Beyond increasing age, male sex, and race/ethnicity differences, few consistent risk factors for the MPNs are known. PV and ET have an incidence of 0.5 to 4.0 and 1.1 to 2.0 cases per 100,000 person-years, respectively, and predict similar survival. PMF, which has an incidence of about 0.3 to 2.0 cases per 100,000 person-years, is associated with the shortest survival of the MPNs.
Collapse
Affiliation(s)
- Rory M Shallis
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine and Yale Cancer Center, 333 Cedar Street, P.O. Box 208028, New Haven, CT 06520-8028, USA
| | - Amer M Zeidan
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine and Yale Cancer Center, 333 Cedar Street, P.O. Box 208028, New Haven, CT 06520-8028, USA
| | - Rong Wang
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, 333 Cedar Street, P.O. Box 208028, New Haven, CT 06520-8028, USA
| | - Nikolai A Podoltsev
- Section of Hematology, Department of Internal Medicine, Yale University School of Medicine and Yale Cancer Center, 333 Cedar Street, P.O. Box 208028, New Haven, CT 06520-8028, USA.
| |
Collapse
|
|
26
|
Accurso V, Santoro M, Mancuso S, Napolitano M, Carlisi M, Mattana M, Russo C, Di Stefano A, Sirocchi D, Siragusa S. The Essential Thrombocythemia in 2020: What We Know and Where We Still Have to Dig Deep. Clin Med Insights Blood Disord 2020; 13:2634853520978210. [PMID: 33447121 PMCID: PMC7780200 DOI: 10.1177/2634853520978210] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 11/12/2020] [Indexed: 01/08/2023]
Abstract
The Essential Thrombocythemia is a Chronic Philadelphia-negative Myeloproliferative Neoplasm characterized by a survival curve that is only slightly worse than that of age- and sex-adjusted healthy population. The criteria for diagnosis were reviewed in 2016 by WHO. The incidence varies from 0.2 to 2.5:100 000 people per year, with a prevalence of 38 to 57 cases per 100 000 people. The main characteristics of ET are the marked thrombocytosis and the high frequency of thrombosis. The spectrum of symptoms is quite wide, but fatigue results to be the most frequent. Thrombosis is frequently observed, often occurring before or at the time of diagnosis. The classification of thrombotic risk has undergone several revisions. Recently, the revised-IPSET-t has distinguished 4 risk classes, from very low risk to high risk. Driver mutations seem to influence thrombotic risk and prognosis, while the role of sub-driver mutations still remains uncertain. Antiplatelet therapy is recommended in all patients aged ⩾ 60 years and in those with a positive history of thrombosis or with cardiovascular risk factors, while cytoreductive therapy with hydroxyurea or interferon is reserved for high-risk patients.
Collapse
Affiliation(s)
- Vincenzo Accurso
- Hematology Division University Hospital Policlinico “Paolo Giaccone”, Palermo, Italy
| | - Marco Santoro
- Department of Surgical, Oncological and Stomatological Disciplines, University of Palermo, Palermo, Italy
| | - Salvatrice Mancuso
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), Hematology Unit, University of Palermo, Palermo, Italy
| | - Mariasanta Napolitano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), Hematology Unit, University of Palermo, Palermo, Italy
| | - Melania Carlisi
- Hematology Division University Hospital Policlinico “Paolo Giaccone”, Palermo, Italy
| | - Marta Mattana
- Hematology Division University Hospital Policlinico “Paolo Giaccone”, Palermo, Italy
| | - Chiara Russo
- Hematology Division University Hospital Policlinico “Paolo Giaccone”, Palermo, Italy
| | - Alessandro Di Stefano
- Hematology Division University Hospital Policlinico “Paolo Giaccone”, Palermo, Italy
| | - Davide Sirocchi
- Hematology Division University Hospital Policlinico “Paolo Giaccone”, Palermo, Italy
| | - Sergio Siragusa
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), Hematology Unit, University of Palermo, Palermo, Italy
| |
Collapse
|
|
27
|
Moon KC, Gim JA, Kim DS, Choi CW, Yoon J, Yoon SY. Total Platelet Transcriptomics and Its Network Analysis by RNA-Seq and miRNA-Seq and PCA Application in Essential Thrombocythaemia. Acta Haematol 2020; 144:337-344. [PMID: 33227791 DOI: 10.1159/000510459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 07/26/2020] [Indexed: 11/19/2022]
Abstract
Differentiating the aetiology of thrombocytosis is limited yet crucial in patients with essential thrombocythaemia (ET). MicroRNAs (miRNAs) regulate haematopoiesis and lineage commitment; aberrant expression of miRNAs plays an important role in myeloproliferative neoplasms. However, the miRNA profile has been poorly explored in ET patients compared to patients with reactive thrombocytosis (RT). A total of 9 samples, including 5 ET patient samples, 2 RT patient samples, and 2 healthy control samples, were analysed in this study. We produced 81.43 million reads from transcripts and 59.60 million reads from small RNAs. We generated a comprehensive miRNA-mRNA regulatory network and identified unique 14 miRNA expression patterns associated with ET. Among the 14 miRNAs, miR-1268a was downregulated in ET and showed an inverse correlation with its 8 putative target genes, including genes associated with thrombus formation and platelet activation (CDH6, EHD2, FUT1, KIF26A, LINC00346, PTPRN, SERF1A, and SLC6A9). Principal component analysis (PCA) showed ET and non-ET groups well clustered in space, suggesting each group had a distinctive expression pattern of mRNAs and miRNAs. These results suggest that the significant dysregulation of miR-1268a and its 8 target genes could be a unique expression of platelet mi-RNAs and miRNA/mRNA regulatory network in ET patients.
Collapse
Affiliation(s)
- Kyung Chul Moon
- Department of Laboratory Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jeong-An Gim
- Medical Science Research Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Dae Sik Kim
- Division of Oncology and Hematology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Chul Won Choi
- Division of Oncology and Hematology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Jung Yoon
- Department of Laboratory Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soo-Young Yoon
- Department of Laboratory Medicine, Korea University College of Medicine, Seoul, Republic of Korea,
| |
Collapse
|
|
28
|
Nicol C, Lacut K, Pan-Petesch B, Lippert E, Ianotto JC. Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature. Thromb Haemost 2020; 121:553-564. [PMID: 33186994 DOI: 10.1055/s-0040-1720979] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially CALR-mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.
Collapse
Affiliation(s)
- Christophe Nicol
- Service d'Hématologie Clinique, Institut de Cancéro-Hématologie, CHRU de Brest, Bretagne, France
| | - Karine Lacut
- Département de Médecine Interne et Pneumologie, CHRU de Brest, Bretagne, France.,GETBO, Groupe d'Etude de la Thrombose de Bretagne Occidentale, CHRU de Brest, Brest, Bretagne, France
| | - Brigitte Pan-Petesch
- Service d'Hématologie Clinique, Institut de Cancéro-Hématologie, CHRU de Brest, Bretagne, France.,GETBO, Groupe d'Etude de la Thrombose de Bretagne Occidentale, CHRU de Brest, Brest, Bretagne, France
| | - Eric Lippert
- Laboratoire d'Hématologie, CHRU de Brest, Bretagne, France.,FIM, France Intergroupe des Néoplasies Myéloprolifératives, France
| | - Jean-Christophe Ianotto
- Service d'Hématologie Clinique, Institut de Cancéro-Hématologie, CHRU de Brest, Bretagne, France.,GETBO, Groupe d'Etude de la Thrombose de Bretagne Occidentale, CHRU de Brest, Brest, Bretagne, France.,FIM, France Intergroupe des Néoplasies Myéloprolifératives, France
| |
Collapse
|
|
29
|
Gotic M, Egyed M, Gercheva L, Warzocha K, Kvasnicka HM, Achenbach H, Wu J. Cardiovascular Safety of Anagrelide Hydrochloride versus Hydroxyurea in Essential Thrombocythaemia. Cardiovasc Toxicol 2020; 21:236-247. [PMID: 33123978 PMCID: PMC7847982 DOI: 10.1007/s12012-020-09615-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 10/16/2020] [Indexed: 11/30/2022]
Abstract
Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac safety, efficacy and tolerability of first-line treatment with anagrelide or hydroxyurea in high-risk ET patients for up to 3 years. Eligible patients aged ≥ 18 years with a diagnosis of high-risk ET confirmed by bone marrow biopsy within 6 months of randomisation received anagrelide (n = 75) or hydroxyurea (n = 74), administered twice daily. Treatment dose for either compound was titrated to the lowest dose needed to achieve a response. Planned primary outcome measures were change in left ventricular ejection fraction from baseline over time and platelet count at Month 6. Planned secondary outcome measures were platelet count change from baseline at Months 3 and 36; percentage of patients with complete or partial response; time to complete or partial response; number of patients with thrombohaemorrhagic events; and changes in white blood cell count or red blood cell count over time. Neither treatment altered cardiac function. There were no significant differences in adverse events between treatment groups, and no reports of malignant transformation. The incidence of disease-related thrombotic or haemorrhagic events was numerically higher in anagrelide-treated patients. Both treatments controlled platelet counts at 6 months, with the majority of patients experiencing complete or partial responses. In conclusion, these results suggest that long-term treatment with anagrelide is not associated with adverse effects on cardiac function. This is one of the few studies using left ventricular ejection fraction assessment and central biopsy reading to confirm the diagnosis of ET. Trial registration number: Clinicaltrials.gov NCT00202644
Collapse
Affiliation(s)
- Mirjana Gotic
- Clinic for Hematology Clinical Centre of Serbia Belgrade, Medical Faculty, University of Belgrade, Koste Todorovica 2, 11000, Belgrade, Serbia.
| | - Miklos Egyed
- Somogy Megyei Kaposi Mór Oktató Kórház, Kaposvár, 7400, Hungary
| | - Liana Gercheva
- Clinic of Hematology, University Hospital St. Marina, 9010, Varna, Bulgaria
| | - Krzysztof Warzocha
- Institute of Hematology and Transfusion Medicine, Department of Haematology, 00-791, Warsaw, Poland
| | - Hans Michael Kvasnicka
- Institute of Pathology, University Clinic Wuppertal, University of Witten / Herdecke, Wuppertal, Germany
| | - Heinrich Achenbach
- Research & Development, Shire International GmbH (a Member of the Takeda Group of Companies), 6300, Zug, Switzerland
| | - Jingyang Wu
- Research & Development, Shire (a Member of the Takeda Group of Companies), Lexington, MA, 02421, USA
| |
Collapse
|
|
30
|
Enomoto M, Kinoshita T, Kondo Y, Suzuki T, Asai T. Cardiac Surgery Using Hypothermic Circulatory Arrest in a Case of Essential Thrombocythemia. Ann Thorac Cardiovasc Surg 2020; 26:290-293. [PMID: 29925725 PMCID: PMC7641890 DOI: 10.5761/atcs.cr.17-00241] [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] [Indexed: 12/02/2022] Open
Abstract
We present the case of a 61-year-old patient with a history of essential thrombocythemia (ET) who was diagnosed as having aortic valve stenosis and dilatation of his ascending aorta. His aortic valve and ascending aorta were replaced under hypothermic circulatory arrest (HCA). No clear guideline exists for preoperative, perioperative, and postoperative management of cardiac surgery using HCA for ET patients. After performing risk assessment, we prescribed preoperative aspirin therapy and postoperative care was planned as usual for cardiovascular surgery in our establishment. Unexpectedly, activated clotting time did not exceed 400 seconds, but the course of treatment was otherwise uneventful.
Collapse
Affiliation(s)
- Masahide Enomoto
- Department of Cardiovascular Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Takeshi Kinoshita
- Department of Cardiovascular Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yasuo Kondo
- Department of Cardiovascular Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Tomoaki Suzuki
- Department of Cardiovascular Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Tohru Asai
- Department of Cardiovascular Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| |
Collapse
|
|
31
|
Leukocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis. Blood Adv 2020; 3:1729-1737. [PMID: 31175128 DOI: 10.1182/bloodadvances.2019000211] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/02/2019] [Indexed: 12/21/2022] Open
Abstract
In the last years, a growing amount of evidence has been produced regarding the role of leukocytosis as a risk factor for thrombosis in patients with myeloproliferative neoplasms, predominantly in polycythemia vera (PV) and essential thrombocythemia (ET). Results from epidemiologic studies on this issue, however, are inconclusive. We conducted a systematic review and meta-analysis of articles published in the last 12 years addressing the issue, according to a predefined protocol. Forty-one articles analyzing >30 000 patients met our inclusion criteria and were deemed of acceptable methodologic quality. In addition to data on thrombosis, data were collected on bleeding, hematologic evolution, secondary cancer, and death. The relative risk (RR) of thrombosis in the presence of leukocytosis was 1.59 (95% CI, 1.40-1.80), mainly accounted for by ET (RR, 1.65; 95% CI, 1.43-1.91) and arterial thrombosis (RR, 1.45; 95% CI, 1.13-1.86) subgroups; the effect was not significant in venous thrombosis alone. Sensitivity analyses considering recurrent events as well as white blood cell estimates adjusted or unadjusted for confounding factors confirmed the primary results. In addition, the pooled RR of studies that tested white blood cell counts in time-dependent models suggested a causative effect of leukocytes in the mechanism that triggers thrombosis. The effect of leukocytosis on bleeding (RR, 1.87; 95% CI, 1.26-2.77) and death (RR, 1.89; 95% CI, 1.59-2.23) was confirmed, whereas conclusions on hematologic evolutions and solid tumors were uncertain. To confirm the accuracy of these results, an investigation on individual patient data in a large collective archive of homogeneous patients is warranted.
Collapse
|
|
32
|
Essential thrombocythemia: a hemostatic view of thrombogenic risk factors and prognosis. Mol Biol Rep 2020; 47:4767-4778. [PMID: 32472297 DOI: 10.1007/s11033-020-05536-x] [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: 03/25/2020] [Accepted: 05/15/2020] [Indexed: 01/03/2023]
Abstract
Essential thrombocythemia (ET) is a classical myeloproliferative neoplasm that is susceptible to hypercoagulable state due to impaired hemostatic system, so that thrombotic complications are the leading cause of mortality in ET patients. The content used in this article has been obtained by the PubMed database and Google Scholar search engine from English-language articles (2000-2019) using the following keywords: "Essential thrombocythemia," "Thrombosis," "Risk factors" and "Hemostasis. In this neoplasm, the count and activity of cells such as platelets, leukocytes, endothelial cells, as well as erythrocytes are increased, which can increase the risk of thrombosis through rising intercellular interactions, expression of surface markers, and stimulation of platelet aggregation. In addition to these factors, genetic polymorphisms in hematopoietic stem cells (HSCs), including mutations in JAK2, CALR, MPL, or genetic abnormalities in other genes associated with the hemostatic system may be associated with increased risk of thrombotic events. Moreover, disruption of coagulant factors can pave the way for thrombogeneration. Therefore, the identification of markers related to cell activation, genetic abnormalities, or alternation in the coagulant system can be used together as diagnostic and prognostic markers for the occurrence of thrombosis among ET patients. Thus, because thrombotic complications are the main factors of mortality in ET patients, a hemostatic viewpoint and risk assessment of cellular, genetic, and coagulation factors can have prognostic value and contribute to the choice of effective treatment and prevention of thrombosis.
Collapse
|
|
33
|
Epidemiology of the classical myeloproliferative neoplasms: The four corners of an expansive and complex map. Blood Rev 2020; 42:100706. [PMID: 32517877 DOI: 10.1016/j.blre.2020.100706] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 03/02/2020] [Accepted: 05/08/2020] [Indexed: 12/15/2022]
Abstract
The classical myeloproliferative neoplasms (MPNs), specifically chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), represent clonal myeloid disorders whose pathogenesis is driven by well-defined molecular abnormalities. In this comprehensive review, we summarize the epidemiological literature and present our own analysis of the most recent the Surveillance, Epidemiology, and End Results (SEER) program data through 2016. Older age and male gender are known risk factors for MPNs, but the potential etiological role of other variables is less established. The incidences of CML, PV, and ET are relatively similar at 1.0-2.0 per 100,000 person-years in the United States, while PMF is rarer with an incidence of 0.3 per 100,000 person-years. The availability of tyrosine kinase inhibitor therapy has dramatically improved CML patient outcomes and yield a life expectancy similar to the general population. Patients with PV or ET have better survival than PMF patients.
Collapse
|
|
34
|
Inhibitors of the blood coagulation process in patients with essential thrombocythemia. Blood Coagul Fibrinolysis 2020; 31:219-224. [PMID: 32108679 DOI: 10.1097/mbc.0000000000000903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
: The aim of the study was to assess the activity of protein C, protein S and tissue factor pathway inhibitor in relation to the risk factors for thrombotic complications in patients with essential thrombocythemia.The study group consisted of 45 newly diagnosed patients with essential thrombocythemia. Protein S activity was determined by chromogenic method. Activities of protein C and tissue factor pathway inhibitor (TFPI) were determined using ELISAs.Significantly lower protein C and protein S activity but higher TFPI activity were found in patients with ET in comparison with the control group. TFPI activity was higher in women as compared to men, and in patients over 60 years of age compared with patients below 60 years of age. TFPI activity was higher in patients with leukocytes count at least 11 g/l than in patients with leukocytes count below 11 g/l and the difference almost reached statistical significance. Significantly lower protein C activity was found in patients with the JAK2V617F mutation, in comparison with essential thrombocythemia patients JAK2V617F (-).The reduced protein C and protein S activity may be one of the pathogenic factors of increased prothrombotic state in essential thrombocythemia patients. The decreased protein C activity in patients with the JAK2 V617F mutation seems to confirm the significant role of this mutation in the pathogenesis of thrombotic complications in essential thrombocythemia patients. Significantly increased TFPI activity in essential thrombocythemia patients above 60 years of age and with leukocyte count above 11 g/l expresses the activation of the compensatory mechanism for increased prothrombotic activity.
Collapse
|
|
35
|
Soucy-Giguère MC, Turgeon PY, Sénéchal M. What cardiologists should know about essential thrombocythemia and acute myocardial infarction: report of two cases and advanced heart failure therapies considerations. Int Med Case Rep J 2019; 12:253-259. [PMID: 31496834 PMCID: PMC6690852 DOI: 10.2147/imcrj.s217568] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 07/09/2019] [Indexed: 11/23/2022] Open
Abstract
We present the cases of two young male patients aged 22 and 31 without prior medical history nor cardiovascular risk factors, who presented to the hospital with large anterior ST-elevation myocardial infarction (STEMI). Urgent coronary angiography revealed acute thrombotic occlusion of the proximal left anterior descending artery in both patients. Persistent thrombocytosis was noted and subsequent investigations led to the diagnosis of essential thrombocythemia (ET) with positive JAK2-V617F mutation. Myocardial infarction as a first clinical manifestation of ET is rare but must be considered in patients without cardiovascular risk factors who show persistent thrombocytosis. In young patients without risk factors, there may be great delays before the diagnosis of STEMI is made. Longer time to revascularization of extensive STEMI is associated with adverse outcomes and cardiogenic shock which can lead to advanced therapies like heart transplant and left ventricular assist device (LVAD). Considering the favorable long-term prognosis of patients with ET, advanced therapies may be a valuable option in the presence of severe left ventricular dysfunction.
Collapse
Affiliation(s)
- Marie-Camille Soucy-Giguère
- Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
| | - Pierre Yves Turgeon
- Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
| | - Mario Sénéchal
- Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
| |
Collapse
|
|
36
|
Tanashyan MM, Melikyan AL, Kuznetsova PI, Raskurazhev AA, Shabalina AA, Konovalov RN. [Brain MRI-findings in Ph - negative myeloproliferative disorders]. TERAPEVT ARKH 2019; 91:29-34. [PMID: 32598733 DOI: 10.26442/00403660.2019.07.000329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Indexed: 11/22/2022]
Abstract
Myeloproliferative disorders (MPD) are accompanied by a high proportion of thrombotic complications, which may lead to cerebrovascular disease (CVD). AIM To describe MRI-findings in patients with Ph - negative MPD and evaluate any cerebrovascular disease. MATERIALS AND METHODS We included 104 patients with Ph - negative MPD (age varied between 20 and 58) with clinical correlates of cerebrovascular pathology. RESULTS Brain MRI showed post - stroke lesions in 20% of patients (7 hemispheric infarcts due to thrombotic occlusion of one of the large cerebral arteries, 14 - cortical infarcts). 37 patients (36%) had vascular cerebral lesions. Cerebral venous sinus thrombosis occurred in 5 patients - in 7% (n=3) of patients with polycythemia vera and 5% (n=2) - in patients with essential thrombocythemia. The incidence of vascular cerebral lesions was associated with higher levels of the following: erythrocyte, platelet count, fibrinogen, and with the decrease in fibrinolytic activity, as well. CONCLUSION The pioneering results of the study include the description and analysis of brain MRI-findings in patients with Ph - negative MPD. The underlying mechanisms of cerebrovascular pathology in these patients are associated with certain blood alterations (particularly, hemorheology) which present a major risk factor.
Collapse
|
|
37
|
Melikyan AL, Subortseva IN, Koloshejnova EA, Gilyazitdinova EA, Shashkina KS, Gorgidze LA, Tratsevskaya ZV, Margolin OV. [Clinical features and diagnosis of Ph - negative myeloproliferative neoplasms occurring in conjunction with the antiphospholipid syndrome]. TERAPEVT ARKH 2019; 91:93-99. [PMID: 32598741 DOI: 10.26442/00403660.2019.07.000324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Indexed: 02/02/2023]
Abstract
Thrombosis is a serious and extremely dangerous disease that has a negative impact on the quality and longevity. Antiphospholipid syndrome (APS) is a pathology characterized by recurring venous, arterial, microvasculature thrombosis, pregnancy pathology with loss of the fetus and the synthesis of antiphospholipid antibodies. A high risk of thrombotic complications is also observed in patients with myeloproliferative neoplasms (MPN). This article presents a description of three clinical cases of Ph - negative myeloproliferative diseases, occurring in conjunction with APS. In all cases, recurrent thrombosis allowed to suspect the presence of two diseases - MPN and APS.
Collapse
|
|
38
|
Lally J, Boasman K, Brown L, Martinelli V, Cappuccio I, Sovani V, Marinaccio C, Crispino JD, Graham C, Rinaldi C. GATA-1: A potential novel biomarker for the differentiation of essential thrombocythemia and myelofibrosis. J Thromb Haemost 2019; 17:896-900. [PMID: 30889303 DOI: 10.1111/jth.14433] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 03/08/2019] [Indexed: 11/30/2022]
Abstract
Essentials The BCR-ABL negative myeloproliferative neoplasms are subjected to unknown phenotypic modifiers. GATA-1 is upregulated in ET patients, regardless of treatment regimen or mutational status. Myelofibrosis (MF) megakaryocytes displayed decreased GATA-1 staining. GATA-1 may have utility as a diagnostic marker in ET and in its differential diagnosis from MF. ABSTRACT: Background The BCR-ABL-negative myeloproliferative neoplasms, i.e., polycythemia vera, essential thrombocythemia (ET), and myelofibrosis (MF), are characterized by mutations in JAK2, CALR, or MPL. However, an as yet unknown factor drives the precise disease phenotype. The hematopoietic transcription factor GATA-1 and its downstream targets NFE2 and FLI1 are responsible for determining erythroid and megakaryocyte lineages during hematopoietic stem cell differentiation. Previous studies have demonstrated a low level of GATA-1 expression in megakaryocytes from patients with MF. Objectives and methods The expression of GATA-1, NFE2 and FLI1 was studied for changes in the peripheral blood (PB) of ET patients. Peripheral blood samples were obtained from 36 ET patients, 14 MF patients, and seven healthy control donors. Total RNA from PB mononuclear cells (PBMCs) was extracted, and quantitative polymerase chain reaction was used to determine relative changes in gene expression. Protein levels of GATA-1 were also determined in bone marrow sections from ET and MF patients. Results GATA-1 mRNA was upregulated in ET patients, regardless of treatment regimen or mutational status. FLI1 expression was significantly downregulated, whereas NFE2 expression was unaffected by changes in GATA-1 mRNA levels. Megakaryocytes from ET patients showed increased protein levels of GATA-1 as compared with those from MF patients. Conclusions Our results confirmed, in PB, our previous data demonstrating elevated levels of GATA-1 mRNA in total bone marrow of ET patients. GATA-1 mRNA levels are independent of cytoreductive therapies, and may have utility as a diagnostic marker in ET and in its differential diagnosis from MF.
Collapse
Affiliation(s)
- James Lally
- School of Life Sciences, University of Lincoln, Lincoln, UK
| | | | - Lilia Brown
- School of Life Sciences, University of Lincoln, Lincoln, UK
| | | | | | - Vishaka Sovani
- Histopathology Department, Nottingham University Hospital, Nottingham, UK
| | - Christian Marinaccio
- Northwestern University, Department of Medicine, Hematology/Oncology, Chicago, IL, USA
| | - John D Crispino
- Northwestern University, Department of Medicine, Hematology/Oncology, Chicago, IL, USA
| | - Ciaren Graham
- School of Biological Sciences, Queen's University Belfast, Belfast, UK
| | - Ciro Rinaldi
- School of Life Sciences, University of Lincoln, Lincoln, UK
| |
Collapse
|
|
39
|
Tavares RS, Nonino A, Pagnano KBB, Nascimento ACKVD, Conchon M, Fogliatto LM, Funke VAM, Bendit I, Clementino NCD, Chauffaille MDLLF, Bernardo WM, Santos FPDS. Guideline on myeloproliferative neoplasms: Associacão Brasileira de Hematologia, Hemoterapia e Terapia Cellular: Project guidelines: Associação Médica Brasileira - 2019. Hematol Transfus Cell Ther 2019; 41 Suppl 1:1-73. [PMID: 31248788 PMCID: PMC6630088 DOI: 10.1016/j.htct.2019.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 03/20/2019] [Indexed: 12/22/2022] Open
Affiliation(s)
| | - Alexandre Nonino
- Instituto Hospital de Base do Distrito Federal (IHBDF), Brasília, DF, Brazil
| | | | | | | | | | | | - Israel Bendit
- Hospital Das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | | | | | - Wanderley Marques Bernardo
- Hospital Das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil; Associação Médica Brasileira (AMB), São Paulo, SP, Brazil
| | | |
Collapse
|
|
40
|
Szuber N, Mudireddy M, Nicolosi M, Penna D, Vallapureddy RR, Lasho TL, Finke C, Begna KH, Elliott MA, Hook CC, Wolanskyj AP, Patnaik MM, Hanson CA, Ketterling RP, Sirhan S, Pardanani A, Gangat N, Busque L, Tefferi A. 3023 Mayo Clinic Patients With Myeloproliferative Neoplasms: Risk-Stratified Comparison of Survival and Outcomes Data Among Disease Subgroups. Mayo Clin Proc 2019; 94:599-610. [PMID: 30824279 DOI: 10.1016/j.mayocp.2018.08.022] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/16/2018] [Accepted: 08/06/2018] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To document the Mayo Clinic decades-long experience with myeloproliferative neoplasms (MPNs) and provide mature risk-stratified survival data and disease complication estimates. PATIENTS AND METHODS All Mayo Clinic patients with World Health Organization-defined MPNs constituted the core study group and included those with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). RESULTS A total of 3023 consecutive patients (median age, 62 years; range, 18-96 years) were considered: 665 PV, 1076 ET, and 1282 PMF. From October 27, 1967, through December 29, 2017, 1631 deaths (54%), 183 leukemic transformations (6%), 244 fibrotic progressions (14%), and 516 thrombotic events (17%) were recorded. Median overall survival (OS) was 18 years for ET, 15 years for PV, and 4.4 years for PMF (P<.05 for all intergroup comparisons). Inferior survival was documented in patients with ET diagnosed more recently (post-1990) (P<.001), whereas survival data were time independent in PV and PMF. After conventional risk stratification, OS in low-risk ET and low-risk PV were superimposed (P=.89) but each differed significantly from that of age- and sex-matched controls (P<.001). Leukemia-free survival was similar for ET and PV (P=.22) and significantly worse with PMF (P<.001). Compared with ET, PV was associated with higher risk of fibrotic progression (P<.001). Thrombosis risk after diagnosis was highest in PV and lowest in PMF (P=.002 for PV vs ET; P=.56 for ET vs PMF; and P=.001 for PV vs PMF). CONCLUSION This study provides the most mature survival and outcomes data in MPNs and highlights MPN subgroup risk categorization as key in appraising disease natural history. The OS was only marginally better in ET compared with PV, and PV displayed a higher risk of thrombosis and fibrotic progression.
Collapse
Affiliation(s)
- Natasha Szuber
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Mythri Mudireddy
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Maura Nicolosi
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Domenico Penna
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Rangit R Vallapureddy
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Terra L Lasho
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Christy Finke
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Kebede H Begna
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Michelle A Elliott
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - C Christopher Hook
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Alexandra P Wolanskyj
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Mrinal M Patnaik
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Curtis A Hanson
- Division of Hematopathology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Rhett P Ketterling
- Division of Laboratory Genetics and Genomics, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Shireen Sirhan
- Division of Hematology, Jewish General Hospital, Montréal, Québec, Canada; Chronic Myeloid Leukemia and Myeloproliferative Neoplasms Quebec Research Group
| | - Animesh Pardanani
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Naseema Gangat
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | - Lambert Busque
- Chronic Myeloid Leukemia and Myeloproliferative Neoplasms Quebec Research Group; Department of Laboratory Hematology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec, Canada
| | - Ayalew Tefferi
- Division of Hematology, Department of Internal and Laboratory Medicine, Mayo Clinic, Rochester, MN.
| |
Collapse
|
|
41
|
Rungjirajittranon T, Owattanapanich W, Ungprasert P, Siritanaratkul N, Ruchutrakool T. A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms. BMC Cancer 2019; 19:184. [PMID: 30819138 PMCID: PMC6393965 DOI: 10.1186/s12885-019-5387-9] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 02/19/2019] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Philadelphia (Ph) chromosome-negative myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematopoietic stem cell clonal diseases. Most patients with MPN are asymptomatic at diagnosis although some of them suffer from constitutional symptoms. Thrombosis and bleeding can also be one of the initial manifestations although the reported prevalence varied considerably across the studies. This systematic review and meta-analysis was conducted with the aims to better understand the prevalence and characteristics of thrombosis and bleeding among patients with newly-diagnosed MPN. METHODS Using a search strategy that included the terms for myeloproliferative neoplasms, thrombosis, and bleeding, two investigators independently searched for published articles indexed in the MEDLINE and EMBASE databases from inception to August 2018. The pooled prevalence was calculated using the DerSimonian-Laird random-effects model with a double arcsine transformation. RESULTS A total of 29 cohort studies (8 prospective and 21 retrospective) with 13,436 patients with MPN were included into this meta-analysis. At diagnosis, the pooled prevalence of overall thrombosis among patients with MPN was 20.0% (95% CI, 16.6-23.8%; I2 96%), with the pooled prevalence of arterial thrombosis of 16.2% (95% CI, 13.0-20.0%; I2 95%) and the pooled prevalence of venous thrombosis of 6.2% (95% CI, 4.9-7.8%; I2 89%). Common thrombotic events included cerebrovascular disease/transient ischemic attack, coronary heart disease, and deep venous thrombosis. The pooled prevalence of hemorrhagic complications among patients who were newly diagnosed with MPN patients was 6.2% (95% CI, 5.0-7.8%; I2 85%). Common sites of bleeding included gastrointestinal, mucosal, and cutaneous bleeding. CONCLUSIONS Thrombosis and bleeding are common initial manifestations of MPN. Investigations for MPN should be considered for patients who present with unexplained thrombosis or abnormal bleeding.
Collapse
Affiliation(s)
| | - Weerapat Owattanapanich
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok, 10700 Thailand
| | - Patompong Ungprasert
- Clinical Epidemiology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700 Thailand
| | - Noppadol Siritanaratkul
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok, 10700 Thailand
| | - Theera Ruchutrakool
- Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok, 10700 Thailand
| |
Collapse
|
|
42
|
Mora B, Passamonti F. Developments in diagnosis and treatment of essential thrombocythemia. Expert Rev Hematol 2019; 12:159-171. [PMID: 30793984 DOI: 10.1080/17474086.2019.1585239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by thrombocytosis, increased risk of thrombotic/hemorrhagic events and clonal evolution into blast phase or myelofibrosis. Areas covered: The authors will discuss biology, diagnosis, prognosis, therapy, and outcome of ET. An accurate molecular-morphologic assessment is necessary in order to properly establish diagnosis and prognosis of ET. Stratification for thrombosis prediction is essential, and IPSET-t model is widely applied. The current treatment strategy is directed to lower the rate of vascular events using cytoreduction in patients at high risk. Prophylactic low dose aspirin indication is more uncertain. To date, therapies for patients who are resistant or intolerant to first-line treatments are scarce. Overall, life expectancy indicates an indolent disease, but IPSET model helps in predicting survival at the time of diagnosis. Expert opinion: Challenging for the future will be to share criteria for ET diagnosis with the community. New insights into the molecular pathogenesis of the disease will improve the prediction of clonal evolution and outcome, and lead to the use of disease-modifying treatments.
Collapse
Affiliation(s)
- Barbara Mora
- a Ospedale di Circolo , ASST Sette Laghi, Hematology , Varese , Italy
| | - Francesco Passamonti
- a Ospedale di Circolo , ASST Sette Laghi, Hematology , Varese , Italy.,b Department of Medicine and Surgery , Universita degli Studi dell'Insubria , Varese , Italy
| |
Collapse
|
|
43
|
A Rare Case of Triple-Negative Essential Thrombocythemia in a Young Postsplenectomy Patient: A Diagnostic Challenge. Case Rep Hematol 2018; 2018:9079462. [PMID: 30647982 PMCID: PMC6311807 DOI: 10.1155/2018/9079462] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 10/04/2018] [Accepted: 10/29/2018] [Indexed: 01/11/2023] Open
Abstract
The distinction between primary and reactive thrombocytosis by bone marrow histology is very important. Reactive thrombocytosis, the most common cause of thrombocytosis, can be expected in postsplenectomy states; however, close hematological evaluation of prolonged thrombocytosis is essential to identify patients who may have an underlying myeloproliferative neoplasm. We report a 37-year-old woman who was found to have portal, mesenteric, and splenic vein thrombosis with thrombocytosis, two months after she had a splenectomy for spontaneous splenic rupture. Other reactive conditions and myeloproliferative neoplasms (MPN) were excluded, and subsequently, the diagnosis of triple-negative essential thrombocythemia (ET) was established by bone marrow histology. This case of primary thrombocythemia following splenectomy in a young patient illustrates some of the diagnostic difficulties associated with postsplenectomy thrombocytosis. Continuing reports of anecdotal experiences in managing similar complex scenarios is essential and remains the only reference for clinicians facing these rare conditions.
Collapse
|
|
44
|
ERSOY E, SOYALTIN UE, PEKER A, ÇOLAK A, CEYLAN C, AKAR H. Ischemia-Modified Albumin Levels in Patients With Essential Thrombocytosis. KONURALP TIP DERGISI 2018. [DOI: 10.18521/ktd.376723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
|
|
45
|
Azevedo AP, Silva SN, Reichert A, Lima F, Júnior E, Rueff J. Effects of polymorphic DNA genes involved in BER and caspase pathways on the clinical outcome of myeloproliferative neoplasms under treatment with hydroxyurea. Mol Med Rep 2018; 18:5243-5255. [PMID: 30320340 DOI: 10.3892/mmr.2018.9535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 06/01/2018] [Indexed: 11/06/2022] Open
Abstract
Several single nucleotide polymorphisms (SNPs) influencing DNA repair capacity and apoptotic status may confer genetic predisposition to Philadelphia‑chromosome negative myeloproliferative neoplasms (PN‑MPNs), and influence therapeutic response and the clinical course. In the present study, whether SNPs in genes involved in apoptosis and the base excision repair (BER) pathway was evaluated. In addition, some known risk factors in PN‑MPNs that may influence survival and therapeutic response to hydroxyurea (HU) were analyzed, taking into account three items: Disease progression, predisposition to new non‑myeloid neoplasms and thrombotic events. The present study involved a total of 133 Caucasian Portuguese PN‑MPNs patients treated with HU, whereby 17 cases showed progression to myelofibrosis/leukemia, 11 developed new non‑myeloid neoplasms and 22 presented with thrombotic events. Progression to secondary myelofibrosis/leukemia is influenced by exposure to cytoreductive agents, and caspase and BER polymorphisms {globally, CASP8 3'untranslated region [odds ratio (OR)=0.24; 95% confidence interval (CI), 0.08‑0.69], XRCC1 Arg194Trp [OR=3.58; 95% CI, 0.98‑13.01]; for essential thrombocythemia patients CASP9 Arg173His [OR=11.27; 95% CI, 1.13‑112.28], APEX1 Asp148Glu [OR=0.28; 95% CI, 0.74‑1.03], and XRCC1 Arg194Trp [OR=6.60; 95% CI, 1.60‑27.06]}. Moreover, globally caspase and BER polymorphisms influenced the development of new nonmyeloid malignancies [CASP8 Asp270His (OR=5.90; 95% CI, 1.42‑24.62) and XRCC1 Arg399Gln (OR=0.27; 95% CI, 0.07‑1.03)]. On the other hand, only the BER pathway had a role in the presence of thrombotic events [XRCC1 Gln399Arg (OR=0.35; 95% CI, 0.14‑0.88)]. JAK2 mutation had no influence on these complications. Larger studies are required to confirm these results, and to provide conclusive evidence of association between these and other variants with PN‑MPNs therapeutic response and clinical evolution. However, this study may allow the development of drugs more directly targeted to the pathophysiology of the disease, with high efficacy, fewer adverse effects, contributing to compliance of patients with treatments. The clinical indication for classical drugs, including HU, may be guided by variant genes, which may provide additional beneficial effects.
Collapse
Affiliation(s)
- Ana P Azevedo
- Centre for Toxicogenomics and Human Health (Toxomics), Genetics, Oncology and Human Toxicology, NOVA Medical School/Faculty of Medical Sciences, Universidade Nova de Lisboa, 1150‑082 Lisbon, Portugal
| | - Susana N Silva
- Centre for Toxicogenomics and Human Health (Toxomics), Genetics, Oncology and Human Toxicology, NOVA Medical School/Faculty of Medical Sciences, Universidade Nova de Lisboa, 1150‑082 Lisbon, Portugal
| | - Alice Reichert
- Department of Clinical Haematology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449‑005 Lisbon, Portugal
| | - Fernando Lima
- Department of Clinical Haematology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449‑005 Lisbon, Portugal
| | - Esmeraldina Júnior
- Department of Clinical Pathology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449‑005 Lisbon, Portugal
| | - José Rueff
- Centre for Toxicogenomics and Human Health (Toxomics), Genetics, Oncology and Human Toxicology, NOVA Medical School/Faculty of Medical Sciences, Universidade Nova de Lisboa, 1150‑082 Lisbon, Portugal
| |
Collapse
|
|
46
|
Fowlkes S, Murray C, Fulford A, De Gelder T, Siddiq N. Myeloproliferative neoplasms (MPNs) - Part 1: An overview of the diagnosis and treatment of the "classical" MPNs. Can Oncol Nurs J 2018; 28:262-268. [PMID: 31148835 DOI: 10.5737/23688076284262268] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Myeloproliferative neoplasms (MPNs) are rare, yet potentially life-threatening, disorders caused by overproliferation of bone marrow stem cells. The symptom burden experienced by patients with the BCR-ABL1-negative MPNs (also referred to as the classical MPNs, i.e., essential thrombocythemia [ET], polycythemia vera [PV] and myelofibrosis [MF]) can be significant and can negatively impact quality of life (QOL). Since patients with these MPNs can live for several years, thereby requiring long-term treatment and follow-up, nurses play an essential role in communicating with these patients, assessing their symptoms, and educating them on treatments and self-management strategies that can reduce their symptom burden. This article, which is the first of a two-part series, was developed to provide nurses and other healthcare professionals with a review of the diagnosis and treatment of the most common classical MPNs. The second article in this series (also available in this issue) will provide nurses with practical guidance for managing the symptom burden associated with MPNs in order to help enhance the overall health and well-being of patients living with these disorders.
Collapse
Affiliation(s)
- Sabrina Fowlkes
- Chronic Myelogenous Leukemia/Myeloproliferative Neoplasms, Jewish General Hospital, Montreal, Quebec
| | - Cindy Murray
- Malignant Hematology, UHN Princess Margaret Cancer Centre, Toronto, Ontario
| | - Adrienne Fulford
- Hematology Oncology, London Health Sciences Centre, London, Ontario
| | - Tammy De Gelder
- Hamilton Health Sciences, Juravinski Hospital and Cancer Centre, Hamilton, Ontario
| | - Nancy Siddiq
- Clinical Nurse Specialist for Myeloproliferative Neoplasms (MPN), Princess Margaret Cancer Centre, Toronto, Ontario
| |
Collapse
|
|
47
|
Yildiz A, Güryildirim M, Pepeler MS, Yazol M, Oktar SÖ, Acar K. Assessment of Endothelial Dysfunction With Flow-Mediated Dilatation in Myeloproliferative Disorders. Clin Appl Thromb Hemost 2018; 24:1102-1108. [PMID: 29683036 PMCID: PMC6714746 DOI: 10.1177/1076029618766260] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Thrombosis is the most important cardiovascular complication of classical myeloproliferative disorders (MPDs). Endothelial dysfunction (ED) is known to play a major role in the mechanism of thrombophilia in MPDs. METHODS Endothelial dysfunction and its associations with other parameters were investigated. A total of 18 patients with polycythemia vera (PV), 24 with essential thrombocytosis (ET), 7 with primary myelofibrosis (PMF), and 30 healthy patients as a control group were included in the study. To assess the ED, flow-mediated dilatation (FMD) measurements were used. RESULTS The FMD (%) result showing ED was determined as 9.9 (0.0-21.6) in the patients with PV, 7.3 (0.0-30.5) in patients with ET, 7.5 (0.0-18.0) in patients with PMF, and 13.9 (6.2-26.7) in the control group. The FMD (%) was markedly impaired in all patients with MPD compared to the control patients (7.8 [0.0-30.5] vs 13.9 [6.15-26.8], P = .02). According to the disease subtypes, FMD (%) was significantly lower in the ET group than in the control group ( P = .01). CONCLUSION Endothelial function was assessed in patients with MPD having FMD and was determined to demonstrate ED. Lower FMD was associated with older age, leukocytosis, thrombocytosis, and thrombosis history.
Collapse
Affiliation(s)
- Abdulkerim Yildiz
- Faculty of Medicine, Department of Internal Medicine, Gazi University, Ankara, Turkey
| | - Melike Güryildirim
- Faculty of Medicine, Department of Radiology, Gazi University, Ankara, Turkey
| | | | - Merve Yazol
- Faculty of Medicine, Department of Radiology, Gazi University, Ankara, Turkey
| | - Suna Özhan Oktar
- Faculty of Medicine, Department of Radiology, Gazi University, Ankara, Turkey
| | - Kadir Acar
- Faculty of Medicine, Department of Hematology, Gazi University, Ankara, Turkey
| |
Collapse
|
|
48
|
Singh K, Sazawal S, Chhikara S, Mahapatra M, Saxena R. Association of JAK2V617F mutation with thrombosis in Indian patients with Philadelphia negative chronic myeloproliferative neoplasms. INDIAN J PATHOL MICR 2018; 61:371-374. [PMID: 30004057 DOI: 10.4103/ijpm.ijpm_781_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background : It is still a matter of debate regarding the association of JAK2V617F mutation with thrombosis in BCR-ABL negative CMPN patients. The role of JAK2V617F mutation in increasing the thrombotic risk in CMPNs is yet unequivocal. Aims : To clarify the contribution of JAK2V617F mutation in thrombosis in CMPN patients. Settings and Design This retrospective study was done to evaluate role of JAK2V617F mutation in thrombosis in CMPNs. Materials and Methods 65 CMPN patients (PV, ET and PMF) were analyzed for JAK2V617F mutation using ARMS-PCR and detailed history of thrombosis was recorded in these patients. Statistical Analysis P values were 2 tailed, and statistical significance was set at P < 0.05. Results : 46/65 were males and 19/65 were females [M: F: 2.4:1] with median age 46 years [range, 14-80 years]. Patients had median Hb 15.6 g/dl [range, 5.1-20.3], median TLC 10.7 × 109/l [range 2.4-216] and platelet count 360 × 109/l [range, 20-1859]. 32 were JAK2V617F positive and 33 were negative for this mutation. On comparing the prevalence of thrombosis in JAK2V617F positive patients with JAK2V617F negative patients, we observed that 20/32 (62.5%) JAK2V617F positive patients had thrombosis as compared to 16/33 (48%) in JAK2V617F negative patients (P = 0.04). We observed significant association of JAK2V617F mutation with thrombosis, however no association of this mutation with thrombosis was observed among the JAK2V617F negative patients. Conclusion Our study suggests that JAK2V617F mutation may increase the risk of thrombosis in CMPNs. This finding could lead to risk stratification, setting up the treatment strategy in CMPNs.
Collapse
Affiliation(s)
- Kanwaljeet Singh
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Sudha Sazawal
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Sunita Chhikara
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Manoranjan Mahapatra
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Renu Saxena
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
49
|
Pedersen KM, Zangger G, Brochmann N, Grønfeldt BM, Zwisler AD, Hasselbalch HC, Tang LH. The effectiveness of exercise-based rehabilitation to patients with myeloproliferative neoplasms-An explorative study. Eur J Cancer Care (Engl) 2018; 27:e12865. [DOI: 10.1111/ecc.12865] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/26/2018] [Accepted: 04/21/2018] [Indexed: 02/03/2023]
Affiliation(s)
- Kasper Mønsted Pedersen
- Department of Hematology; Zealand University Hospital; University of Copenhagen; Roskilde Denmark
| | - Graziella Zangger
- Danish Knowledge Centre for Rehabilitation and Palliative Care; University of Southern Denmark; Nyborg Denmark
| | - Nana Brochmann
- Department of Hematology; Zealand University Hospital; University of Copenhagen; Roskilde Denmark
| | - Birk Mygind Grønfeldt
- Danish Knowledge Centre for Rehabilitation and Palliative Care; University of Southern Denmark; Nyborg Denmark
| | - Ann-Dorthe Zwisler
- Danish Knowledge Centre for Rehabilitation and Palliative Care; University of Southern Denmark; Nyborg Denmark
| | - Hans Carl Hasselbalch
- Department of Hematology; Zealand University Hospital; University of Copenhagen; Roskilde Denmark
| | - Lars Hermann Tang
- Danish Knowledge Centre for Rehabilitation and Palliative Care; University of Southern Denmark; Nyborg Denmark
- Bachelor’s Degree Program in Physiotherapy; Department of Rehabilitation and Nutrition; Faculty of Health and Technology; Metropolitan University College; Copenhagen Denmark
| |
Collapse
|
|
50
|
Abstract
INTRODUCTION The outlook for patients with myeloproliferative neoplasms, particularly myelofibrosis, has improved in recent years, with greater understanding of the pathogenesis and the subsequent development of a plethora of new agents. Areas covered: This article will discuss some of the advances in the field in recent years and explore in greater detail some of the most advanced emerging agents as well as those with greatest potential. An extensive literature review has been performed to identify recent clinical trials and any relevant pre-clinical work. Expert commentary: Important discoveries regarding molecular pathogenesis have led to advances in diagnostic algorithms, prognosis and ultimately also treatment strategies. However, the therapeutic armamentarium for MPN is still largely inadequate to cope with significant challenges including normalization of life span, reduction of cardiovascular complications, prevention of hematological progression and improved quality of life. Sadly, no currently available drugs have shown clear evidence of disease-modifying activity and results of early phase I and II clinical trials have been quite disappointing to date, with toxicities sometimes limiting and a lack of meaningful biological surrogate end points.
Collapse
Affiliation(s)
- Patrick M Harrington
- a Department of Haematology , Guys and St Thomas' NHS Foundation Trust , London , UK
| | - Claire N Harrison
- a Department of Haematology , Guys and St Thomas' NHS Foundation Trust , London , UK
| |
Collapse
|