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King HL, Benedetti GB, Keller JJ, DeLoughery TG, Shatzel JJ, Martens KL. Dermatologic manifestations of hematologic disorders. Ann Hematol 2024; 103:3889-3903. [PMID: 38662204 DOI: 10.1007/s00277-024-05761-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/14/2024] [Indexed: 04/26/2024]
Abstract
Distinguishing key morphologic features and understanding the pathophysiology of common cutaneous manifestations of hematologic disorders is essential to ensure prompt and appropriate treatment. In fact, classic cutaneous signs may provide the first clue to the diagnosis of an underlying hematologic disease. Disorders of coagulation, vascular abnormalities, or cutaneous infiltration and deposition are responsible for the underlying pathophysiology of cutaneous manifestations in the majority of cases. Hematologists often feel ill-equipped in identifying morphologic changes in the skin. Thus, the purpose of this review is to provide a comprehensive overview of classic cutaneous manifestations and diagnostic considerations of the associated hematologic conditions. Though there is a specific focus on non-malignant disorders, those straddling the spectrum of malignancy are also discussed. In many disease states, the skin may serve as an important marker of an emerging hematologic disorder, so close collaboration and multidisciplinary input remain essential to provide optimal and timely care for these patients.
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Affiliation(s)
- Hannah L King
- Department of Medicine, Oregon Health & Science University, Portland, OR, USA
| | | | - Jesse J Keller
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Thomas G DeLoughery
- Division of Hematology and Medical Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road Mail Code: OC14HO, 97239, Portland, OR, USA
| | - Joseph J Shatzel
- Division of Hematology and Medical Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road Mail Code: OC14HO, 97239, Portland, OR, USA
| | - Kylee L Martens
- Division of Hematology and Medical Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road Mail Code: OC14HO, 97239, Portland, OR, USA.
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Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management. Am J Hematol 2024; 99:697-718. [PMID: 38269572 DOI: 10.1002/ajh.27216] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/26/2024]
Abstract
OVERVIEW Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia. DIAGNOSIS In addition to thrombocytosis (platelets ≥450 × 109 /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters. GENETICS Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-. SURVIVAL AND PROGNOSIS Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years. RISK FACTORS FOR THROMBOSIS Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation). MUTATIONS AND PROGNOSIS MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype. TREATMENT The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan. ADDITIONAL CONTENT The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Alessandro Maria Vannucchi
- CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
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3
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Caldito EG, Kaul S, Caldito NG, Piette W, Mehta S. Erythromelalgia. Part I: Pathogenesis, clinical features, evaluation, and complications. J Am Acad Dermatol 2024; 90:453-462. [PMID: 37364617 DOI: 10.1016/j.jaad.2023.02.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 01/27/2023] [Accepted: 02/12/2023] [Indexed: 06/28/2023]
Abstract
Erythromelalgia is a rare pain disorder that is underrecognized and difficult-to-treat. It is characterized by episodes of extremity erythema and pain that can be disabling; it may be genetic, related to an underlying systemic disease, or idiopathic. Considering the prominent cutaneous features characteristic of the condition, dermatologists can play an important role in early recognition and limitation of morbidity. The first article in this 2-part continuing medical education series reviews the epidemiology, pathogenesis, clinical manifestations, evaluation, and complications.
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Affiliation(s)
| | - Subuhi Kaul
- Division of Dermatology, John H Stroger Hospital of Cook County, Chicago, Illinois
| | | | - Warren Piette
- Division of Dermatology, John H Stroger Hospital of Cook County, Chicago, Illinois; Department of Dermatology, Rush University Medical Center, Chicago, Illinois
| | - Shilpa Mehta
- Division of Dermatology, John H Stroger Hospital of Cook County, Chicago, Illinois.
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Caldito EG, Caldito NG, Kaul S, Piette W, Mehta S. Erythromelalgia. Part II: Differential diagnoses and management. J Am Acad Dermatol 2024; 90:465-474. [PMID: 37364616 DOI: 10.1016/j.jaad.2023.02.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 06/28/2023]
Abstract
The management of erythromelalgia is challenging and requires multidisciplinary effort. Patient education is crucial as unsafe self-administered cooling techniques can lead to significant morbidity, including acral necrosis, infection, and amputation. The goal of management is pain control, reduction of flare frequency, and prevention of complications. This text is focused on the management of erythromelalgia and several other incompletely understood and under-recognized neurovascular disorders such as red scrotum syndrome, red ear syndrome, facial flushing, and complex regional pain syndrome.
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Affiliation(s)
| | | | - Subuhi Kaul
- Division of Dermatology, John H Stroger Hospital of Cook County, Chicago, Illinois
| | - Warren Piette
- Division of Dermatology, John H Stroger Hospital of Cook County, Chicago, Illinois; Department of Dermatology, Rush University Medical Center, Chicago, Illinois
| | - Shilpa Mehta
- Division of Dermatology, John H Stroger Hospital of Cook County, Chicago, Illinois.
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Kuipers RS, Kok L, Virmani R, Tefferi A. Essential thrombocytosis: diagnosis, differential diagnosis, complications and treatment considerations of relevance for a cardiologist. Neth Heart J 2023; 31:371-378. [PMID: 36757576 PMCID: PMC10516821 DOI: 10.1007/s12471-023-01757-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2022] [Indexed: 02/10/2023] Open
Abstract
Essential thrombocytosis (ET) is a rare haematological malignancy, with an incidence rate of 1.5-2.5/100,000 per year. For many patients with ET the first manifestation of their underlying disease is a thrombotic or haemorrhagic complication. A recent retrospective study revealed an incidence rate of at least 2.1% in people under 40 years presenting with an acute coronary syndrome, although the diagnosis was initially missed in all cases. Thus, cardiologists face a much higher than average incidence rate of ET in their daily practice, but seem insufficiently aware of the disease. The current review summarises symptoms, (differential) diagnosis, complications and treatment considerations of ET of relevance for a cardiologist. Typical symptoms, besides thrombosis and haemorrhage, include erythromelalgia and aquagenic pruritus, while platelets > 450 × 109/l are a diagnostic for ET once other myeloproliferative neoplasms, secondary and spurious thrombocytosis have been excluded. With regard to treatment, timing of revascularisation depends on the presence of ischaemia and concurrent platelet counts. In the presence of ischaemia, revascularisation should not be delayed and adequate platelet counts can be achieved by platelet apheresis. In the absence of ischaemia, revascularisation can be delayed until adequate platelet counts have been achieved by cytoreductive therapies. Cardiologists should be aware of/screen for possible ET.
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Affiliation(s)
- R S Kuipers
- OLVG Heart Centre, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
- Department of Cardiology, Dijklander Hospital, Purmerend/Hoorn, The Netherlands.
| | - L Kok
- OLVG Heart Centre, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
- Department of Cardiology, Spaarne Hospital, Haarlem, The Netherlands
| | - R Virmani
- CVPath Institute, Gaithersburg, MD, USA
| | - A Tefferi
- Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, MN, USA
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Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol 2023; 98:1465-1487. [PMID: 37357958 DOI: 10.1002/ajh.27002] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 06/27/2023]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis; other features include leukocytosis, thrombocytosis, splenomegaly, pruritus, constitutional symptoms, microcirculatory disturbances, and increased risk of thrombosis and progression into myelofibrosis (post-PV MF) or acute myeloid leukemia (AML). DIAGNOSIS A working diagnosis is considered in the presence of a JAK2 mutation associated with hemoglobin/hematocrit levels of >16.5 g/dL/49% in men or 16 g/dL/48% in women; morphologic confirmation by bone marrow examination is advised but not mandated. CYTOGENETICS Abnormal karyotype is seen in 15%-20% of patients with the most frequent sole abnormalities being +9 (5%), loss of chromosome Y (4%), +8 (3%), and 20q- (3%). MUTATIONS Over 50% of patients harbor DNA sequence variants/mutations other than JAK2, with the most frequent being TET2 (18%) and ASXL1 (15%). Prognostically adverse mutations include SRSF2, IDH2, RUNX1, and U2AF1, with a combined incidence of 5%-10%. SURVIVAL AND PROGNOSIS Median survival is ⁓15 years but exceeds 35 years for patients aged ≤40 years. Risk factors for survival include older age, leukocytosis, abnormal karyotype, and the presence of adverse mutations. Twenty-year risk for thrombosis, post-PV MF, or AML are ⁓26%, 16% and 4%, respectively. RISK FACTORS FOR THROMBOSIS Two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). Additional predictors for arterial thrombosis include cardiovascular risk factors and for venous thrombosis higher absolute neutrophil count and JAK2V617F allele burden. TREATMENT Current goal of therapy is to prevent thrombosis. Periodic phlebotomy, with a hematocrit target of <45%, combined with once- or twice-daily aspirin (81 mg) therapy, absent contraindications, is the backbone of treatment in all patients, regardless of risk category. Cytoreductive therapy is reserved for high-risk disease with first-line drugs of choice being hydroxyurea and pegylated interferon-α and second-line busulfan and ruxolitinib. In addition, systemic anticoagulation is advised in patients with venous thrombosis history. ADDITIONAL TREATMENT CONSIDERATIONS At the present time, we do not consider a drug-induced reduction in JAK2V617F allele burden, which is often incomplete and seen not only with peg-IFN but also with ruxolitinib and busulfan, as an indicator of disease-modifying activity, unless accompanied by cytogenetic and independently-verified morphologic remission. Accordingly, we do not use the specific parameter to influence treatment choices. The current review also includes specific treatment strategies in the context of pregnancy, splanchnic vein thrombosis, pruritus, perioperative care, and post-PV MF.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
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Michelerio A, Tomasini C, Arbustini E, Vassallo C. Clinical Challenges in Primary Erythromelalgia: a Real-Life Experience from a Single Center and a Diagnostic-Therapeutic Flow-Chart Proposal. Dermatol Pract Concept 2023; 13:e2023191. [PMID: 37557164 PMCID: PMC10412061 DOI: 10.5826/dpc.1303a191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2023] [Indexed: 08/11/2023] Open
Abstract
INTRODUCTION Primary erythromelalgia (EM) is a rare clinical syndrome characterized by recurrent erythema, burning pain and warmth of the extremities. The symptoms greatly compromise the patients' quality of life leading to severe disability. SCN9A mutations can be the cause of the disease. Dermatologists are often the specialists these patients turn to for assistance. OBJECTIVES To describe the demographic and clinical characteristics of patients with primary EM, to assess the presence and mutation types in the SCN9A gene, to evaluate the effectiveness of several therapeutic approaches, and to propose a diagnostic algorithm with therapeutic implications. METHODS A monocentric retrospective study using the database of patients with a discharge diagnosis of primary EM of our Center. Demographic, clinical, instrumental and laboratory data of patients were reviewed. RESULTS Eleven female patients (age range 16 to 57) were selected. All patients were affected in both the lower and upper extremities. Follow-up ranged from 2 to 9 years. Four patients had four different heterozygous variants of the SCN9A gene. Two patients, although genetically negative, had a suggestive family history. A variety of medications were tried in all our patients to alleviate symptoms, but their efficacy was variable, partial and/or transitory. The most effective therapies were antihistamines, venlafaxine, and mexiletine. CONCLUSIONS The diagnosis and treatment of EM remain challenging. Patients with this condition display a wide spectrum of clinical manifestations and severity, as well as a paucity of resources and structures to support them. Mutations in the SCN9A gene are not always detected.
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Affiliation(s)
- Andrea Michelerio
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Dermatology Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Carlo Tomasini
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Dermatology Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Eloisa Arbustini
- Centre for Inherited Cardiovascular Diseases, IRCCS Policlinico San Matteo, Pavia, Italy
| | - Camilla Vassallo
- Dermatology Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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8
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol 2020; 95:1599-1613. [PMID: 32974939 DOI: 10.1002/ajh.26008] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 12/25/2022]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus and risk of leukemic or fibrotic transformation. DIAGNOSIS Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR or MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. SURVIVAL Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. THROMBOSIS RISK In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). RISK-ADAPTED THERAPY The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily or twice-daily aspirin (81 mg), in the absence of contraindications. Very low risk ET might not require therapy while aspirin therapy is advised for low risk disease. Cytoreductive therapy is recommended for high-risk ET and PV, but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. NEW TREATMENT DIRECTIONS Controlled studies are needed to confirm the clinical outcome value of twice-daily vs once-daily aspirin dosing and the therapeutic role of pegylated interferons and direct oral anticoagulants.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine Mayo Clinic Rochester Minnesota
| | - Tiziano Barbui
- Research Foundation Papa Giovanni XXIII Hospital Bergamo Italy
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Iurlo A, Cattaneo D, Bucelli C, Baldini L. New Perspectives on Polycythemia Vera: From Diagnosis to Therapy. Int J Mol Sci 2020; 21:ijms21165805. [PMID: 32823537 PMCID: PMC7461104 DOI: 10.3390/ijms21165805] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/09/2020] [Accepted: 08/10/2020] [Indexed: 12/15/2022] Open
Abstract
Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called “masked PV”, as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients’ prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors.
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Affiliation(s)
- Alessandra Iurlo
- Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (D.C.); (C.B.); (L.B.)
- Correspondence: ; Tel.: +39-02-5503-3463; Fax: +39-02-5503-4105
| | - Daniele Cattaneo
- Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (D.C.); (C.B.); (L.B.)
| | - Cristina Bucelli
- Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (D.C.); (C.B.); (L.B.)
| | - Luca Baldini
- Hematology Division, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (D.C.); (C.B.); (L.B.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
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10
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Mornet C, Galinat H, Mingant F, Ianotto JC, Lippert E. [Thrombosis and platelet dysfunction in myeloproliferative neoplasms]. Rev Med Interne 2020; 41:319-324. [PMID: 32008800 DOI: 10.1016/j.revmed.2019.12.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 12/23/2019] [Indexed: 12/15/2022]
Abstract
Myeloproliferative neoplasms are acquired hematological malignancies, mainly affecting the adult and whose morbidity and mortality stems from haemostasis disorders. The most frequently encountered complications include thrombosis, affecting preferentially the arterial territory, but also atypical locations such as splanchnic vein thrombosis. The pathophysiology of these thromboses is complex and involves different actors: blood cells, endothelium and flow conditions. Numerous studies have been conducted to identify risk factors for thrombosis. To date, only two risk factors have been validated through prospective studies (age over 60 years old, history of thrombotic events) and allow classification of patients as "low risk" and "high risk" as the basis for current treatment recommendations. Haemorrhagic manifestations, less frequent than thrombosis, are mainly related to an alteration of primary haemostasis and are therefore manifested by mucocutaneous bleeding. In these patients, platelet dysfunctions and/or acquired Willebrand syndromes can be found. The pathophysiology of thrombosis and platelet dysfunction during myeloproliferative neoplasms remains to date partially unknown. In this review, we offer to focus on physiopathological mechanisms as well as the latest advances in their understanding.
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Affiliation(s)
- C Mornet
- Hématologie biologique, CHU de Brest, Brest, France
| | - H Galinat
- Hématologie biologique, CHU de Brest, Brest, France
| | - F Mingant
- Hématologie biologique, CHU de Brest, Brest, France
| | - J C Ianotto
- Hématologie clinique et thérapie cellulaire, CHU de Brest, Brest, France
| | - E Lippert
- Hématologie biologique, CHU de Brest, Brest, France; Inserm, EFS, UMR 1078, GGB, Université Brest, Brest, France.
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11
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Hybiak J, Broniarek I, Kiryczyński G, Los LD, Rosik J, Machaj F, Sławiński H, Jankowska K, Urasińska E. Aspirin and its pleiotropic application. Eur J Pharmacol 2019; 866:172762. [PMID: 31669590 DOI: 10.1016/j.ejphar.2019.172762] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/21/2019] [Accepted: 10/25/2019] [Indexed: 12/31/2022]
Abstract
Aspirin (acetylsalicylic acid), the oldest synthetic drug, was originally used as an anti-inflammatory medication. Being an irreversible inhibitor of COX (prostaglandin-endoperoxide synthase) enzymes that produce precursors for prostaglandins and thromboxanes, it has gradually found several other applications. Sometimes these applications are unrelated to its original purpose for example its use as an anticoagulant. Applications such as these have opened opportunities for new treatments. In this case, it has been tested in patients with cardiovascular disease to reduce the risk of myocardial infarct. Its function as an anticoagulant has also been explored in the prophylaxis and treatment of pre-eclampsia, where due to its anti-inflammatory properties, aspirin intake may be used to reduce the risk of colorectal cancer. It is important to always consider both the risks and benefits of aspirin's application. This is especially important for proposed use in the prevention and treatment of neurologic ailments like Alzheimer's disease, or in the prophylaxis of myocardial infarct. In such cases, the decision if aspirin should be applied, and at what dose may be guided by specific molecular markers. In this revived paper, the pleiotropic application of aspirin is summarized.
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Affiliation(s)
- Jolanta Hybiak
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland.
| | - Izabela Broniarek
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University Poznan, Poland
| | - Gerard Kiryczyński
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Laura D Los
- Faculty of Science, University of Manitoba, Winnipeg, Canada
| | - Jakub Rosik
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Filip Machaj
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Hubert Sławiński
- Wellcome Centre for Human Genetics, University of Oxford, United Kingdom
| | - Kornelia Jankowska
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland
| | - Elżbieta Urasińska
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland
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12
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Cuthbert D, Stein BL. Polycythemia Vera-Associated Complications: Pathogenesis, Clinical Manifestations, And Effects On Outcomes. J Blood Med 2019; 10:359-371. [PMID: 31695542 PMCID: PMC6805785 DOI: 10.2147/jbm.s189922] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 09/18/2019] [Indexed: 12/13/2022] Open
Abstract
Polycythemia vera is a Philadelphia-negative chronic myeloproliferative neoplasm, characterized by erythrocytosis, which is unique, compared to essential thrombocytosis and primary myelofibrosis. Though longevity can usually be expected, vascular morbidity is associated with this condition, as well as a propensity to evolve into myelofibrosis (post-PV MF) and acute myeloid leukemia. In addition, patients can have a pronounced symptom burden. Herein, contributors to the symptomatic burden, as well as the thrombotic and transformative tendencies are reviewed. From a symptom perspective, some are explained by cytokine release, others by microvascular complications, whereas certain symptoms can herald disease evolution. Thrombosis has multifactorial contributors, including but not limited to gender, and inflammatory stress; investigators have recently hypothesized that microparticles and Neutrophil Extracellular Trap Formations may add to thrombotic burden. Finally, we examine the progression to post-PV MF as well as leukemic transformation, highlighting well-established risk factors including age and leukocytosis, certain treatments, and the presence of “non-driver” mutations.
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Affiliation(s)
- Danielle Cuthbert
- McGaw Medical Center of Northwestern University, Department of Internal Medicine, Chicago, IL 60611, USA
| | - Brady Lee Stein
- Northwestern University Feinberg School of Medicine, Division of Hematology/Oncology, Department of Medicine, Chicago, IL 60611, USA
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Mann N, King T, Murphy R. Review of primary and secondary erythromelalgia. Clin Exp Dermatol 2019; 44:477-482. [PMID: 30609105 DOI: 10.1111/ced.13891] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2018] [Indexed: 01/15/2023]
Abstract
Erythromelalgia is a condition characterized by episodic pain, erythema and temperature of the extremities, which is relieved by cooling and aggravated by warming. It is useful to review this topic in light of recent discoveries of the genetic mutations that now define primary erythromelalgia, as opposed to secondary erythromelalgia, which is often associated with underlying medical disorders.
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Affiliation(s)
- N Mann
- Department of Dermatology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - T King
- Department of Dermatology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - R Murphy
- Department of Dermatology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol 2019; 94:133-143. [PMID: 30281843 DOI: 10.1002/ajh.25303] [Citation(s) in RCA: 147] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 12/15/2022]
Abstract
Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR, or myeloproliferative leukemia mutations. In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Survival: Median survivals are 14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET. Risk of thrombosis is higher in JAK2-mutated ET. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. Thrombosis Risk: In PV, 2 risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors); in ET, 4 risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). Risk-Adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once- or twice-daily aspirin (81 mg), in the absence of contraindications. Very low-risk ET might not require therapy while aspirin therapy is advised for low-risk disease. Cytoreductive therapy is recommended for high-risk ET and PV but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital; Bergamo Italy
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15
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De Stefano V, Carobbio A, Di Lazzaro V, Guglielmelli P, Iurlo A, Finazzi MC, Rumi E, Cervantes F, Elli EM, Randi ML, Griesshammer M, Palandri F, Bonifacio M, Hernandez-Boluda JC, Cacciola R, Miroslava P, Carli G, Beggiato E, Ellis MH, Musolino C, Gaidano G, Rapezzi D, Tieghi A, Lunghi F, Loscocco GG, Cattaneo D, Cortelezzi A, Betti S, Rossi E, Finazzi G, Censori B, Cazzola M, Bellini M, Arellano-Rodrigo E, Bertozzi I, Sadjadian P, Vianelli N, Scaffidi L, Gomez M, Cacciola E, Vannucchi AM, Barbui T. Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms. Blood Cancer J 2018. [PMID: 29535299 PMCID: PMC5849668 DOI: 10.1038/s41408-018-0048-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.
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Affiliation(s)
- Valerio De Stefano
- Institute of Hematology, Catholic University, Fondazione Policlinico Universitario A. Gemelli, Roma, Italy
| | | | - Vincenzo Di Lazzaro
- Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Biomedico di Roma, Rome, Italy
| | - Paola Guglielmelli
- CRIMM-Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, and Departmentt Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Alessandra Iurlo
- Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, and University of Milan, Milan, Italy
| | | | - Elisa Rumi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Elena Maria Elli
- Hematology Division, Ospedale San Gerardo, ASST Monza, Monza, Italy
| | | | - Martin Griesshammer
- University Clinic for Hematology and Oncology Minden, University of Bochum, Bochum, Germany
| | - Francesca Palandri
- Institute of Hematology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, Bologna, Italy
| | | | | | - Rossella Cacciola
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Palova Miroslava
- Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
| | - Giuseppe Carli
- Hematology Department, Ospedale San Bortolo, Vicenza, Italy
| | - Eloise Beggiato
- Unit of Hematology, Department of Oncology, University of Torino, Torino, Italy
| | - Martin H Ellis
- Hematology Institute and Blood Bank, Meir Medical Center, Kfar Saba, and Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel
| | - Caterina Musolino
- Division of Hematology, Dipartimento di Patologia Umana dell'Adulto e dell'Età Evolutiva, Policlinico G Martino, University of Messina, Messina, Italy
| | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Davide Rapezzi
- S.C. Ematologia, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
| | - Alessia Tieghi
- Divisione di Ematologia, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
| | - Francesca Lunghi
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy
| | - Giuseppe Gaetano Loscocco
- CRIMM-Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, and Departmentt Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Daniele Cattaneo
- Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, and University of Milan, Milan, Italy
| | - Agostino Cortelezzi
- Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, and University of Milan, Milan, Italy
| | - Silvia Betti
- Institute of Hematology, Catholic University, Fondazione Policlinico Universitario A. Gemelli, Roma, Italy
| | - Elena Rossi
- Institute of Hematology, Catholic University, Fondazione Policlinico Universitario A. Gemelli, Roma, Italy
| | - Guido Finazzi
- Hematology Division, Papa Giovanni XXIII hospital, Bergamo, Italy
| | - Bruno Censori
- Neurology Division, Papa Giovanni XXIII hospital, Bergamo, Italy
| | - Mario Cazzola
- Department of Molecular Medicine, University of Pavia, Pavia, Italy.,Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Marta Bellini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | | | - Irene Bertozzi
- Department of Medicine - DIMED, University of Padua, Padova, Italy
| | - Parvis Sadjadian
- University Clinic for Hematology and Oncology Minden, University of Bochum, Bochum, Germany
| | - Nicola Vianelli
- Institute of Hematology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Luigi Scaffidi
- Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
| | - Montse Gomez
- Hematology Department, Hospital Clínico Universitario, Valencia, Spain
| | - Emma Cacciola
- Department of Medical, Surgical and Advanced Technologies Sciences "G.F. Ingrassia", University of Catania, Catania, Italy
| | - Alessandro M Vannucchi
- CRIMM-Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, and Departmentt Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Tiziano Barbui
- FROM Research Foundation, Papa Giovanni XXIII hospital, Bergamo, Italy.
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Abstract
Erythromelalgia is a rare syndrome characterized by the intermittent or, less commonly, by the permanent occurrence of extremely painful hyperperfused skin areas mainly located in the distal extremities. Primary erythromelalgia is nowadays considered to be a genetically determined neuropathic disorder affecting SCN9A, SCN10A, and SCN11A coding for NaV1.7, NaV1.8, and NaV1.9 neuronal sodium channels. Secondary forms might be associated with myeloproliferative disorders, connective tissue disease, cancer, infections, and poisoning. Between the pain episodes, the affected skin areas are usually asymptomatic, but there are patients with typical features of acrocyanosis and/or Raynaud's phenomenon preceding or occurring in between the episodes of erythromelalgia. Diagnosis is made by ascertaining the typical clinical features. Thereafter, the differentiation between primary and secondary forms should be made. Genetic testing is recommended, especially in premature cases and in cases of family clustering in specialized genetic institutions after genetic counselling. Multimodal therapeutic intervention aims toward attenuation of pain and improvement of the patient's quality of life. For this purpose, a wide variety of nonpharmacological approaches and pharmacological substances for topical and systemic use have been proposed, which are usually applied individually in a step-by-step approach. Prognosis mainly depends on the underlying condition and the ability of the patients and their relatives to cope with the disease.
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Affiliation(s)
| | | | - Jutta Gisela Richter
- 2 Poliklinik, Funktionsbereich und Hiller Forschungszentrum für Rheumatologie, Medizinische Fakultät, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
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Michelerio A, Derlino F, Brazzelli V, Vassallo C. Secondary erythromelalgia: a tryptophan dietary supplement-induced case associated with elevated 5-hydroxyindoleacetic acid (5HIAA) urinary levels. Int J Dermatol 2017; 57:83-85. [PMID: 29152720 DOI: 10.1111/ijd.13760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 08/10/2017] [Accepted: 08/22/2017] [Indexed: 11/29/2022]
Affiliation(s)
- Andrea Michelerio
- Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Federica Derlino
- Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Valeria Brazzelli
- Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Camilla Vassallo
- Department of Clinical-Surgical, Diagnostic and Pediatric Science, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
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Michiels JJ. Aspirin cures erythromelalgia and cerebrovascular disturbances in JAK2-thrombocythemia through platelet-cycloxygenase inhibition. World J Hematol 2017; 6:32-54. [DOI: 10.5315/wjh.v6.i3.32] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 04/27/2017] [Accepted: 07/17/2017] [Indexed: 02/05/2023] Open
Abstract
Hypersensitive (sticky) platelets in JAK2-mutated essential thrombocythemia (ET) and polycythemia vera (PV) with thrombocythemia spontaneously activate at high shear in arterioles, secrete their inflammatory prostaglandin endoperoxides and induce platelet-mediated arteriolar fibromuscular intimal proliferation. Constitutively activated JAK2 mutated hypersensitive (sticky) platelets spontaneously aggregate at high shear in the endarteriolar circulation as the cause of aspirin responsive erythromelalgia and platelet arterial thrombophilia in JAK2-mutated thrombocythemia patients. Increased production of prostglandin endoperoxides E2 and thromboxane A2 released by activated sticky platelets in arterioles account for redness warmth and swelling of erythromelalgia and platelet derived growth factor can readily explain the arteriolar fibromuscular intimal proliferation. Von Willebrand factor (VWF) platelet rich occlusive thrombi in arterioles are the underlying pathobiology of erythromelalgic acrocyanosis, migraine-like transient cerebral attacks (MIAs), acute coronary syndromes and abdominal microvscular ischemic events. Irreversible platelet cyco-oxygenase inhibition by aspirin cures the erythromelalgia, MIAs and microvascular events, corrects shortened platelet survival to normal, and returns increased plasma levels of beta-TG, platelet factor 4, thrombomoduline and urinary thromboxane B2 excretion to normal in symptomatic JAK2-thrombocythemia patients. In vivo activation of sticky platelets and VWF-platelet aggregates account for endothelial cell activation to secrete thrombomoduline and sVCAM followed by occlusion of arterioles by VWF-rich platelet thrombi in patients with erythromelalgic thrombotic thrombocythemia (ETT) in ET and PV patients. ETT is complicated by spontaneous hemorrhagic thrombocythemia (HT) or paradoxical ETT/HT due to acquired von Willebrand disease type 2A at platelet counts above 1000 × 109/L and disappears by cytoreduction of platelets to normal (< 400 × 109/L).
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20
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 2017; 92:94-108. [PMID: 27991718 DOI: 10.1002/ajh.24607] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 11/11/2016] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant. SURVIVAL AND LEUKEMIC/FIBROTIC TRANSFORMATION Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2. THROMBOSIS RISK STRATIFICATION Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history, JAK2/MPL un-mutated), low risk (age ≤60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. RISK-ADAPTED THERAPY The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high-risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high-risk ET patients but it is not mandatory for intermediate-risk patients. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota USA
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital; Bergamo Italy
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21
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Michiels JJ. Aspirin responsive erythromelalgia in JAK2-thrombocythemia and incurable inherited erythrothermalgia in neuropathic Nav1.7 sodium channelopathy: from Mitchell 1878 to Michiels 2017. Expert Opin Orphan Drugs 2016. [DOI: 10.1080/21678707.2017.1270822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Jan Jacques Michiels
- Department of Hematology & Coagulation, Academic Hospital Dijkzigt and Erasmus University, Rotterdam, The Netherlands
- Department of Blood and Coagulation Disorders, University Hospital Antwerp, Edegem, Belgium
- Blood, Coagulation and Vascular Medicine Research Center, Goodheart Institute & Foundation in Nature Medicine & Health, Freedom of Science and Education, European Free University, Erasmus Tower, Rotterdam
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22
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Affiliation(s)
- Jill JF Belch
- Ninewells Hospital and Medical School, Dundee, Scotland
| | - Iain R Mackay
- Ninewells Hospital and Medical School, Dundee, Scotland
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23
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[Erythromelalgia: Diagnosis and therapeutic approach]. Rev Med Interne 2016; 38:176-180. [PMID: 27639908 DOI: 10.1016/j.revmed.2016.08.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 08/10/2016] [Indexed: 12/29/2022]
Abstract
Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is considered in its primary form as an autosomal dominant neuropathy related to mutations of SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection. Primary familial erythromelalgia include genetics and sporadic forms associated with small fibers neuropathy. Aspirin is a useful treatment of erythromelagia associated with myeloproliferative disorders. Treatment of primary erythromelalgia is difficult, individualized, with sodium channel blockers such as lidocaine, carbamazepine and mexiletine.
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24
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Jain A, Gupta N, Singh T, Agarwal S. A Study of Haemostatic Parameters in Patients of Chronic Myeloid Leukaemia. J Clin Diagn Res 2016; 10:OC19-23. [PMID: 27630882 DOI: 10.7860/jcdr/2016/19185.8135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 03/20/2016] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Chronic Myeloid Leukaemia (CML) is characterized by derangement of various components of the haemostatic system resulting in thrombo-haemorrhagic complications. Although less common than other myeloproliferative neoplasms, derangement of various components of the haemostatic system is observed in CML. Haemostatic abnormalities have been described in relation to hyperleucostasis and drugs used to treat CML. However, the correlation between haemostatic derangements and phase of CML is unclear in the literature. AIM The purpose of this cross-sectional study was to assay various haemostatic parameters in patients of CML receiving Imatinib and to determine any correlation between them and phases of disease as well as the status of remission. MATERIALS AND METHODS The study included 30 patients with CML (17 males, 13 females, mean age of 35.53 ± 8.92 years) receiving imatinib mesylate. Haemostatic parameters including platelet counts, Prothrombin Time (PT), activated Partial Thromboplastin Time (APTT), fibrinogen, D-dimers and Factor VIII levels were assayed for all patients using standard methods. Bcr-abl gene product (quantitative) was determined on the peripheral blood by reverse transcriptase polymerase chain reaction (RT-PCR). Patients were grouped into phases of disease (chronic, accelerated and blast) and their response to imatinib was determined in the form of remission (clinical, haematological and molecular). Correlations were drawn between them using spearman's coefficient. RESULTS A significant positive correlation was found between PT (p=0.002), fibrinogen (p=0.011), D-dimers (p=0.050), Factor VIII levels (p=0.006) with the phase of CML and a significant negative correlation was observed between PT (p=0.003, 0.006), fibrinogen (p=0.010, 0.005), D-dimers (p=0.035, 0.017), Factor VIII levels (p=0.005, 0.001) and clinical and haematological remission respectively. No significant correlation of platelet counts and APTT was seen with the phase of CML or remission status. CONCLUSION Haemostatic system is significantly disturbed in CML and correlate positively with the progression of the disease. Imatinib treatment leads to improvement in some of these parameters.
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Affiliation(s)
- Ankur Jain
- Postgraduate Student, Department of Medicine, Maulana Azad Medical College , Delhi, India
| | - Naresh Gupta
- Professor and Head, Department of Medicine, Maulana Azad Medical College , Delhi, India
| | - Tejinder Singh
- Professor, Department of Pathology, Maulana Azad Medical College , Delhi, India
| | - Sunita Agarwal
- Associate Professor, Department of Medicine, Maulana Azad Medical College , Delhi, India
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Hou JL, Onajin O, Gangat N, Davis MDP, Wolanskyj AP. Erythromelalgia in patients with essential thrombocythemia and polycythemia vera. Leuk Lymphoma 2016; 58:715-717. [DOI: 10.1080/10428194.2016.1205740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Jennifer L. Hou
- Mayo Medical School, Mayo Clinic College of Medicine, Rochester, MN, USA
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Sakamoto Y, Nito C, Abe A, Nogami A, Sato T, Sawada K, Hokama H, Yamada M, Hijikata N, Kumagai T, Ishiwata A, Nagayama H, Kimura K. Aspirin, but not clopidogrel, ameliorates vasomotor symptoms due to essential thrombocythemia: A case report. J Neurol Sci 2016; 365:74-5. [PMID: 27206879 DOI: 10.1016/j.jns.2016.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 03/31/2016] [Accepted: 04/11/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Yuki Sakamoto
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
| | - Chikako Nito
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Arata Abe
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akane Nogami
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Takahiro Sato
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Kazutaka Sawada
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hiroyuki Hokama
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Mai Yamada
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Nanako Hijikata
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Tomoaki Kumagai
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akiko Ishiwata
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Hiroshi Nagayama
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Kazumi Kimura
- Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
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Myocardial infarction as a thrombotic complication of essential thrombocythemia and polycythemia vera. Anatol J Cardiol 2016; 16:397-402. [PMID: 27182615 PMCID: PMC5331370 DOI: 10.14744/anatoljcardiol.2015.6125] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE Detailed analyses of clinical characteristics of myocardial infarction (MI) as an essential thrombocythemia (ET)- and polycythemia vera (PV)-related complication have been so far presented mostly as case reports. Therefore, the aim of this retrospective analysis was to evaluate the main cardiological and hematological characteristics for better understanding myocardial complications in ET/PV. METHODS A retrospective analysis was carried out involving 263 patients diagnosed with ET or PV (155/108) between 1998 and 2014. Fourteen patients suffered MI during the hematological follow-up. Their clinical characteristics were compared to 162 patients (97 ET and 65 PV patients) who did not exhibit any major thrombotic complications (MI, stroke/transient ischemic attack, and venous events) before or after hematological diagnosis of ET/PV. RESULTS Fourteen MI events occurred among the 263 patients (5.3%). Vascular risk factors were found in 92.9% (13/14) of analyzed cases. In all, 71.4% of the MI complications developed within 12 months after the diagnosis of ET/PV. The coronary angiography findings revealed ST-elevation MI in four cases and non-ST-elevation MI in 10. Significant stenosis of coronary arteries requiring percutaneous coronary intervention with a stent implantation was present in seven cases, while three had complex stenoses or previous grafts/stents. All of them had undergone coronary artery bypass graft operations. CONCLUSION The results of the present study suggest that early detection and consideration of individual management of vascular risk factors in ET/PV patients are also important. Furthermore, a better theoretic understanding of platelet activation and role of leukocytes in myeloproliferative neoplasm-related thrombosis could open new perspectives in thrombosis prediction and prevention.
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Abstract
Aspirin has been one of the oldest drugs in the field of medicine, with a wide range of applications. In dermatology, aspirin has shown benefit in a variety of disorders. Recently, reduction of melanoma risk with aspirin has been demonstrated. Although an analgesic to begin with, aspirin has come a long way; after cardiology, it is now found to be useful even in dermatology.
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Affiliation(s)
- Aditya Kumar Bubna
- Department of Dermatology, Sri Ramachandra University, Chennai, Tamil Nadu, India
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Cozzani E, Iurlo A, Merlo G, Cattaneo D, Burlando M, Pierri I, Gugliotta L, Parodi A. Essential Thrombocythemia: The Dermatologic Point of View. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2015; 15:739-47. [PMID: 26432058 DOI: 10.1016/j.clml.2015.08.086] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 08/18/2015] [Accepted: 08/24/2015] [Indexed: 12/12/2022]
Abstract
Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increase in blood platelets and dominated by a predisposition to vascular events. Cutaneous manifestations can complicate its course. itching has been the most common symptom reported; however, the percentage has ranged from 3% to 46%, depending on the survey. Erythromelalgia is found in 6% of cases, and livedo reticularis, minor bleeding, acrocyanosis, and Raynaud's phenomenon are rare manifestations. It is important to recognize and treat these events, because they can affect patients' quality of life and could worsen the prognosis. In addition to skin involvement as a possible sign of ET, the treatment of ET can be associated with cutaneous complications. Hydroxycarbamide, interferon-alfa, and anagrelide can induce different skin lesions. Hydroxycarbamide has been associated with major complications, including painful leg ulcers and actinic keratoses. Minor events include alopecia and hyperpigmentation. Xerosis, pruritus, and photosensitivity are some of the complications reported by patients treated with interferon-alfa. Anagrelide has proved to be associated with fewer dermatologic effects, only detected in single cases. Knowledge of the ET cutaneous manifestations, together with the clinical examination findings, can result in an earlier diagnosis and the start of effective treatment.
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Affiliation(s)
- Emanuele Cozzani
- Di. S. Sal. Section of Dermatology, IRCCS Azienda Ospedaliera Universitaria, San Martino-IST, Genoa, Italy.
| | - Alessandra Iurlo
- Oncohematology Division, Oncohematology Unit of the Elderly, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy
| | - Giulia Merlo
- Di. S. Sal. Section of Dermatology, IRCCS Azienda Ospedaliera Universitaria, San Martino-IST, Genoa, Italy
| | - Daniele Cattaneo
- Oncohematology Division, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation, Milan, Italy
| | - Martina Burlando
- Di. S. Sal. Section of Dermatology, IRCCS Azienda Ospedaliera Universitaria, San Martino-IST, Genoa, Italy
| | - Ivana Pierri
- Department of Hematology and Oncology, IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy
| | - Luigi Gugliotta
- Institute of Hematology "L. e A. Seragnoli", S. Orsola Malpighi University Hospital, Bologna, Italy
| | - Aurora Parodi
- Di. S. Sal. Section of Dermatology, IRCCS Azienda Ospedaliera Universitaria, San Martino-IST, Genoa, Italy
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Michiels JJ, Valster F, Wielenga J, Schelfout K, Raeve HD. European vs 2015-World Health Organization clinical molecular and pathological classification of myeloproliferative neoplasms. World J Hematol 2015; 4:16-53. [DOI: 10.5315/wjh.v4.i3.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 11/15/2014] [Accepted: 04/30/2015] [Indexed: 02/05/2023] Open
Abstract
The BCR/ABL fusion gene or the Ph1-chromosome in the t(9;22)(q34;q11) exerts a high tyrokinase acticity, which is the cause of chronic myeloid leukemia (CML). The 1990 Hannover Bone Marrow Classification separated CML from the myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV) and chronic megakaryocytic granulocytic myeloproliferation (CMGM). The 2006-2008 European Clinical Molecular and Pathological (ECMP) criteria discovered 3 variants of thrombocythemia: ET with features of PV (prodromal PV), “true” ET and ET associated with CMGM. The 2008 World Health Organization (WHO)-ECMP and 2014 WHO-CMP classifications defined three phenotypes of JAK2V617F mutated ET: normocellular ET (WHO-ET), hypercelluar ET due to increased erythropoiesis (prodromal PV) and ET with hypercellular megakaryocytic-granulocytic myeloproliferation. The JAK2V617F mutation load in heterozygous WHO-ET is low and associated with normal life expectance. The hetero/homozygous JAK2V617F mutation load in PV and myelofibrosis is related to myeloproliferative neoplasm (MPN) disease burden in terms of symptomatic splenomegaly, constitutional symptoms, bone marrow hypercellularity and myelofibrosis. JAK2 exon 12 mutated MPN presents as idiopathic eryhrocythemia and early stage PV. According to 2014 WHO-CMP criteria JAK2 wild type MPL515 mutated ET is the second distinct thrombocythemia featured by clustered giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow consistent with the diagnosis of “true” ET. JAK2/MPL wild type, calreticulin mutated hypercellular ET appears to be the third distinct thrombocythemia characterized by clustered larged immature dysmorphic megakaryocytes and bulky (bulbous) hyperchromatic nuclei consistent with CMGM or primary megakaryocytic granulocytic myeloproliferation.
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Michiels JJ. Myeloproliferative and thrombotic burden and treatment outcome of thrombocythemia and polycythemia patients. World J Crit Care Med 2015; 4:230-9. [PMID: 26261774 PMCID: PMC4524819 DOI: 10.5492/wjccm.v4.i3.230] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 06/10/2015] [Accepted: 07/11/2015] [Indexed: 02/07/2023] Open
Abstract
Prospective studies indicate that the risk of microvascular and major thrombosis in untreated thrombocythemia in various myeloproliferative neoplasms (MPN-T) is not age dependent and causally related to platelet-mediated thrombosis in early, intermediate and advanced stages of thrombocythemia in MPN-T. If left untreated both microvascular and major thrombosis frequently do occur in MPN-T, but can easily be cured and prevented by low dose aspirin as platelet counts are above 350 × 10(9)/L. The thrombotic risk stratification in the retrospective Bergamo study has been performed in 100 essential thrombocythemia (ET) patients not treated with aspirin thereby overlooking the discovery in 1985 of aspirin responsive platelet-mediated arteriolar and arterial thrombotic tendency in MPN-T disease of ET and polycythemia vera (PV) patients. The Bergamo definition of high thrombotic risk and its persistence in the 2012 International Prognostic Score for ET is based on statistic mystification and not applicable for low and intermediate MPN-T disease burden in ET and PV patients on aspirin. With the advent of molecular screening of MPN patients, MPN-T disease associated with significant leukocytosis, thrombocytosis, constitutional symptoms and/or moderate splenomegaly are candidates for low dose peglyated interferon (Pegasys(R), 45 μg/mL once per week or every two weeks) as the first line myeloreductive treatment option in JAK2(V617F) mutated MPN-T disease in ET and PV patients. If non-responsive to or side effects induced by IFN, hydroxyurea is the second line myelosuppressive treatment option in JAK2(V617F) mutated ET and PV patients with increased MPN-T disease burden.
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Schwarz J, Ovesná P, Černá O, Kissová J, Soukupová JM, Brychtová Y, Doubek M, Červinek L, Cmunt E, Dulíček P, Campr V, Křen L, Penka M. Thrombosis in thrombocythemic Ph‐ myeloproliferations is associated with higher platelet count prior to the event: results of analyses of prothrombotic risk factors from a registry of patients treated with anagrelide. Eur J Haematol 2015; 96:98-106. [DOI: 10.1111/ejh.12554] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2015] [Indexed: 02/02/2023]
Affiliation(s)
- Jiří Schwarz
- Institute of Hematology and Blood Transfusion Prague Czech Republic
- Institute of Clinical and Experimental Hematology 1st Medical Faculty Charles University Prague Czech Republic
| | - Petra Ovesná
- Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic
| | - Olga Černá
- Internal Hematology Clinic Faculty Hospital Královské Vinohrady Prague Czech Republic
| | - Jarmila Kissová
- Department of Clinical Hematology Faculty Hospital Brno Masaryk University Brno Czech Republic
| | | | - Yvona Brychtová
- Department of Internal Medicine – Hematology and Oncology Faculty Hospital Brno Masaryk University Brno Czech Republic
| | - Michael Doubek
- Department of Internal Medicine – Hematology and Oncology Faculty Hospital Brno Masaryk University Brno Czech Republic
| | - Libor Červinek
- Department of Internal Medicine – Hematology and Oncology Faculty Hospital Brno Masaryk University Brno Czech Republic
| | - Eduard Cmunt
- Department of Clinical Hematology of the 1st Department of Internal Medicine 1st Medical Faculty Charles University Prague Czech Republic
| | - Petr Dulíček
- 4th Department of Internal Medicine – Hematology Faculty Hospital Charles University Hradec Králové Czech Republic
| | - Vít Campr
- Institute of Hematology and Blood Transfusion Prague Czech Republic
- Institute of Pathological Anatomy 2nd Medical Faculty Faculty Hospital Motol Charles University Prague Czech Republic
| | - Leoš Křen
- Department of Pathology Faculty Hospital Brno Masaryk University Brno Czech Republic
| | - Miroslav Penka
- Department of Clinical Hematology Faculty Hospital Brno Masaryk University Brno Czech Republic
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Liu T, Zhang Y, Lin H, Lv X, Xiao J, Zeng W, Gu Y, Rutherford S, Tong S, Ma W. A large temperature fluctuation may trigger an epidemic erythromelalgia outbreak in China. Sci Rep 2015; 5:9525. [PMID: 25820221 PMCID: PMC4377627 DOI: 10.1038/srep09525] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 03/06/2015] [Indexed: 01/14/2023] Open
Abstract
Although erythromelalgia (EM) has been documented in the literature for almost 150 years, it is still poorly understood. To overcome this limitation, we examined the spatial distribution of epidemic EM, and explored the association between temperature fluctuation and epidemic EM outbreaks in China. We searched all peer-reviewed literature on primary epidemic EM outbreaks in China. A two-stage model was used to characterize the relationship between temperature fluctuation and epidemic EM outbreaks. We observed that epidemic EM outbreaks were reported from 13 provinces during 1960-2014 and they mainly occurred between February and March in southern China. The majority of EM cases were middle school students, with a higher incidence rate in female and resident students. The major clinical characteristics of EM cases included burning, sharp, tingling and/or stinging pain in toes, soles and/or dorsum of feet, fever, erythema and swelling. A large "V"-shaped fluctuation of daily average temperature (TM) observed during the epidemic EM outbreaks was significantly associated with the number of daily EM cases (β = 1.22, 95%CI: 0.66 ~ 1.79), which indicated that this "V"-shaped fluctuation of TM probably triggered the epidemic EM outbreaks.
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Affiliation(s)
- Tao Liu
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China
- Environment and Health, Guangdong Provincial Key Medical Discipline of Twelfth Five-Year Plan, Guangzhou, 511430, China
| | - Yonghui Zhang
- Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China
| | - Hualiang Lin
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China
- Environment and Health, Guangdong Provincial Key Medical Discipline of Twelfth Five-Year Plan, Guangzhou, 511430, China
| | - Xiaojuan Lv
- Southern Medical University, Guangzhou, 510515, China
| | - Jianpeng Xiao
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China
- Environment and Health, Guangdong Provincial Key Medical Discipline of Twelfth Five-Year Plan, Guangzhou, 511430, China
| | - Weilin Zeng
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China
- Environment and Health, Guangdong Provincial Key Medical Discipline of Twelfth Five-Year Plan, Guangzhou, 511430, China
| | - Yuzhou Gu
- Jinan University, Guangzhou, 510632, China
| | - Shannon Rutherford
- Centre for Environment and Population Health, Griffith University, Brisbane, 4111, Australia
| | - Shilu Tong
- Queensland University of Technology, Brisbane, Australia
| | - Wenjun Ma
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou, 511430, China
- Environment and Health, Guangdong Provincial Key Medical Discipline of Twelfth Five-Year Plan, Guangzhou, 511430, China
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Vianello F, Cella G, Osto E, Ballin A, Famoso G, Tellatin S, Iliceto S, Cucchini U, Saggiorato G, Omenetto E, Tona F. Coronary microvascular dysfunction due to essential thrombocythemia and policythemia vera: the missing piece in the puzzle of their increased cardiovascular risk? Am J Hematol 2015; 90:109-13. [PMID: 25352381 DOI: 10.1002/ajh.23881] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 10/24/2014] [Indexed: 01/14/2023]
Abstract
Myeloproliferative neoplasms are most commonly associated with venous thrombosis. Up to 60% of patients experience a thrombotic event in their lifetimes, including stroke or myocardial infarction. It is unclear whether pathogenetic factors linking essential thrombocythemia (ET) and polycythemia vera (PV) to thrombotic complications do play a role in the risk of coronary artery disease (CAD). We aimed to assess coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic patients with ET and PV. Fifty-two patients with ET (M/F 13/39, age 61 ± 7 years) and 22 patients with PV (M/F 13/9, age 60.4 ± 13 years) without clinical evidence of heart disease, and 50 controls matched for age and gender were studied. None had CAD. All control subjects were asymptomatic with no history of heart disease. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. In patients with ET and PV, CFR was lower than in controls (2.9 ± 0.94 and 2.2 ± 0.7 vs. 3.8 ± 0.7, P < 0.004 and P < 0.0001 respectively). The prevalence of CFR ≤ 2.5 was higher in patients with ET (20 cases, 38.5%) and PV (15 cases, 68.2%) compared with controls (4.1%) (P < 0.0001). Severe CFR (CFR < 2) impairment was found in eight patients with ET (15.4%), in nine patients with PV (40.9%), and in none of control subjects. The mutation of JAK2 gene was associated with abnormal CFR. Asymptomatic patients with ET and PV have coronary microvascular dysfunction in the absence of clinical conditions suggesting CAD.
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Affiliation(s)
| | - Giuseppe Cella
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Elena Osto
- Cardiovascular Center; University Hospital and Cardiovascular Research; Institute of Physiology; Zurich Switzerland
| | - Andrea Ballin
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Giulia Famoso
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Sara Tellatin
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Sabino Iliceto
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Umberto Cucchini
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Graziella Saggiorato
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Elisabetta Omenetto
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
| | - Francesco Tona
- Department of Cardiac; Thoracic and Vascular Sciences; University Hospital; Padua Italy
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90:162-73. [PMID: 25611051 DOI: 10.1002/ajh.23895] [Citation(s) in RCA: 146] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 11/05/2014] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ∼14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life-expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. RISK-ADAPTED THERAPY The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low-dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota
| | - Tiziano Barbui
- Research Foundation; Papa Giovanni XXIII Hospital; Bergamo Italy
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JAK2 V617F, MPL, and CALR Mutations in Essential Thrombocythaemia and Major Thrombotic Complications: A Single-Institute Retrospective Analysis. Pathol Oncol Res 2015; 21:751-8. [DOI: 10.1007/s12253-014-9885-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 12/22/2014] [Indexed: 02/02/2023]
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Michiels JJ, Berneman Z, Gadisseur A, Lam KH, De Raeve H, Schroyens W. Aspirin-responsive, migraine-like transient cerebral and ocular ischemic attacks and erythromelalgia in JAK2-positive essential thrombocythemia and polycythemia vera. Acta Haematol 2014; 133:56-63. [PMID: 25116182 DOI: 10.1159/000360388] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 02/04/2014] [Indexed: 01/03/2023]
Abstract
Migraine-like cerebral transient ischemic attacks (MIAs) and ocular ischemic manifestations were the main presenting features in 10 JAK2(V617F)-positive patients studied, with essential thrombocythemia (ET) in 6 and polycythemia vera (PV) in 4. Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures. MIAs were frequently preceded or followed by ocular ischemic events of blurred vision, scotomas, transient flashing of the eyes, and sudden transient partial blindness preceded or followed erythromelalgia in the toes or fingers. The time lapse between the first symptoms of aspirin-responsive MIAs and the diagnosis of ET in 5 patients ranged from 4 to 12 years. At the time of erythromelalgia and MIAs, shortened platelet survival, an increase in the levels of the platelet activation markers β-thromboglobulin and platelet factor 4 and also in urinary thromboxane B2 were clearly indicative of the spontaneous in vivo platelet activation of constitutively JAK2(V617F)-activated thrombocythemic platelets. Aspirin relieves the peripheral, cerebral and ocular ischemic disturbances by irreversible inhibition of platelet cyclo-oxygenase (COX-1) activity and aggregation ex vivo. Vitamin K antagonist, dipyridamole, ticlopidine, sulfinpyrazone and sodium salicylate have no effect on platelet COX-1 activity and are ineffective in the treatment of thrombocythemia-specific manifestations of erythromelalgia and atypical MIAs. If not treated with aspirin, ET and PV patients are at a high risk of major arterial thrombosis including stroke, myocardial infarction and digital gangrene.
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Michiels JJ, Berneman Z, Schroyens W, De Raeve H. Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond. Acta Haematol 2014; 133:36-51. [PMID: 25116092 DOI: 10.1159/000358580] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 01/10/2014] [Indexed: 12/23/2022]
Abstract
The Polycythemia Vera Study Group (PVSG) and WHO classifications distinguished the Philadelphia (Ph(1)) chromosome-positive chronic myeloid leukemia from the Ph(1)-negative myeloproliferative neoplasms (MPN) essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) or primary megakaryocytic granulocytic myeloproliferation (PMGM). Half of PVSG/WHO-defined ET patients show low serum erythropoietin levels and carry the JAK2(V617F) mutation, indicating prodromal PV. The positive predictive value of a JAK2(V617F) PCR test is 95% for the diagnosis of PV, and about 50% for ET and MF. The WHO-defined JAK2(V617F)-positive ET comprises three ET phenotypes at clinical and bone marrow level when the integrated WHO and European Clinical, Molecular and Pathological (ECMP) criteria are applied: normocellular ET (WHO-ET), hypercellular ET due to increased erythropoiesis (prodromal PV) and hypercellular ET associated with megakaryocytic granulocytic myeloproliferation (EMGM). Four main molecular types of clonal MPN can be distinguished: JAK2(V617F)-positive ET and PV; JAK2 wild-type ET carrying the MPL(515); mutations in the calreticulin (CALR) gene in JAK2/MPL wild-type ET and MF, and a small proportion of JAK2/MPL/CALR wild-type ET and MF patients. The JAK2(V617F) mutation load is low in heterozygous normocellular WHO-ET. The JAK2(V617F) mutation load in hetero-/homozygous PV and EMGM is clearly related to MPN disease burden in terms of splenomegaly, constitutional symptoms and fibrosis. The JAK2 wild-type ET carrying the MPL(515) mutation is featured by clustered small and giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow (WHO-ET), and lacks features of PV. JAK2/MPL wild-type, CALR mutated hypercellular ET associated with PMGM is featured by dense clustered large immature dysmorphic megakaryocytes and bulky (cloud-like) hyperchromatic nuclei, which are never seen in WHO-ECMP-defined JAK2(V617F) mutated ET, EMGM and PV, and neither in JAK2 wild-type ET carrying the MPL(515) mutation. Two thirds of JAK2/MPL wild-type ET and MF patients carry one of the CALR mutations as the cause of the third distinct MPN entity. WHO-ECMP criteria are recommended to diagnose, classify and stage the broad spectrum of MPN of various molecular etiologies.
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Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 2013; 88:507-16. [PMID: 23695894 DOI: 10.1002/ajh.23417] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 02/13/2013] [Indexed: 12/13/2022]
Abstract
DISEASE OVERVIEW Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus and a small risk of disease progression into acute myeloid leukemia or myelofibrosis. DIAGNOSIS Almost all patients with PV harbor a JAK2 mutation. When PV is suspected, the presence of a JAK2 mutation highly suggests the diagnosis and its absence, combined with normal or increased serum erythropoietin level, excludes the diagnosis. Differential diagnosis of ET should include reactive thrombocytosis, chronic myeloid leukemia, prefibrotic myelofibrosis and RARS-T (refractory anemia with ring sideroblasts associated with marked thrombocytosis). A JAK2 mutation is found in 50-70% of patients with ET, myelofibrosis or RARS-T and is capable of distinguishing reactive from clonal thrombocytosis. RISK STRATIFICATION Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data considers JAK2V617F and cardiovascular (CV) risk factors as additional risk factors for thrombosis. Presence of extreme thrombocytosis (platelet count >1,000 × 10(9) /L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include advanced age, leukocytosis, and history of thrombosis. RISK-ADAPTED THERAPY Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is <1%/1% in ET and <3%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications. In low risk patients, this is effectively and safely accomplished by the use of low-dose aspirin in both PV and ET and phlebotomy (hematocrit target of <45%) in PV. In high risk patients, treatment with hydroxyurea is additionally recommended, although not mandated in older patients without JAK2V617F or CV risk factors. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures. Screening for clinically significant AvWS is recommended before administrating aspirin in the presence of extreme thrombocytosis.
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Affiliation(s)
- Ayalew Tefferi
- Department of Medicine; Division of Hematology, Mayo Clinic; Rochester; Minnesota
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Abstract
Abstract
Persistently enhanced platelet activation has been characterized in polycythemia vera (PV) and essential thrombocythemia (ET) and shown to contribute to a higher risk of both arterial and venous thrombotic complications. The incidence of major bleeding complications is also somewhat higher in PV and ET than in the general population. Although its efficacy and safety was assessed in just 1 relatively small trial in PV, low-dose aspirin is currently recommended in practically all PV and ET patients. Although for most patients with a thrombosis history the benefit/risk profile of antiplatelet therapy is likely to be favorable, in those with no such history this balance will depend critically on the level of thrombotic and hemorrhagic risks of the individual patient. Recent evidence for a chemopreventive effect of low-dose aspirin may tilt the balance of benefits and harm in favor of using aspirin more broadly, but the potential for additional benefits needs regulatory scrutiny and novel treatment guidelines. A clear pharmacodynamic rationale and analytical tools are available for a personalized approach to antiplatelet therapy in ET, and an improved regimen of low-dose aspirin therapy should be tested in a properly sized randomized trial.
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Thrombocytosis and Essential Thrombocythemia. Platelets 2013. [DOI: 10.1016/b978-0-12-387837-3.00049-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Kremyanskaya M, Mascarenhas J, Hoffman R. Why Does My Patient Have Erythrocytosis? Hematol Oncol Clin North Am 2012; 26:267-83, vii-viii. [DOI: 10.1016/j.hoc.2012.02.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol 2012; 87:285-93. [PMID: 22331582 DOI: 10.1002/ajh.23135] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute myeloid leukemia or myelofibrosis. DIAGNOSIS Almost all patients with PV harbor a JAK2 mutation. When PV is suspected, the presence of a JAK2 mutation confirms the diagnosis and its absence, combined with normal or increased serum erythropoietin level, excludes the diagnosis. Differential diagnosis of ET had to include chronic myelogenous leukemia and prefibrotic myelofibrosis. A JAK2 mutation is found in approximately 60% of patients with ET. RISK STRATIFICATION Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Presence of extreme thrombocytosis (platelet count >1,000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include advanced age, leukocytosis, and history of thrombosis. RISK-ADAPTED THERAPY Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is <1%/1% in ET and <3%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications and this is effectively and safely accomplished by the use of low-dose aspirin (PV and ET), phlebotomy (PV) and hydroxyurea (high risk PV and ET). Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures. Screening for clinically significant AvWS is recommended before administrating aspirin in the presence of extreme thrombocytosis.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Park HJ, Ranganathan P. Neoplastic and Paraneoplastic Vasculitis, Vasculopathy, and Hypercoagulability. Rheum Dis Clin North Am 2011; 37:593-606. [DOI: 10.1016/j.rdc.2011.09.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Thrombocytosis: diagnostic evaluation, thrombotic risk stratification, and risk-based management strategies. THROMBOSIS 2011; 2011:536062. [PMID: 22084665 PMCID: PMC3200282 DOI: 10.1155/2011/536062] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 03/17/2011] [Indexed: 12/11/2022]
Abstract
Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The differential diagnosis for thrombocytosis is broad and the diagnostic process can be challenging. Thrombocytosis can be spurious, attributed to a reactive process or due to clonal disorder. This distinction is important as it carries implications for evaluation, prognosis, and treatment. Clonal thrombocytosis associated with the myeloproliferative neoplasms, especially essential thrombocythemia and polycythemia vera, carries a unique prognostic profile, with a markedly increased risk of thrombosis. This risk is the driving factor behind treatment strategies in these disorders. Clinical trials utilizing targeted therapies in thrombocytosis are ongoing with new therapeutic targets waiting to be explored. This paper will outline the mechanisms underlying thrombocytosis, the diagnostic evaluation of thrombocytosis, complications of thrombocytosis with a special focus on thrombotic risk as well as treatment options for clonal processes leading to thrombocytosis, including essential thrombocythemia and polycythemia vera.
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Tefferi A. Annual Clinical Updates in Hematological Malignancies: a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86:292-301. [PMID: 21351120 DOI: 10.1002/ajh.21946] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute leukemia or myelofibrosis. DIAGNOSIS Diagnosis is based on JAK2 mutation status (PV and ET), serum erythropoietin (Epo) level (PV), and bone marrow histopathology (ET). The presence of a JAK2 mutation and subnormal serum Epo level confirm a diagnosis of PV. Differential diagnosis in ET should include chronic myelogenous leukemia and prefibrotic myelofibrosis. RISK STRATIFICATION Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications: high-risk-age > 60 years or presence of thrombosis history; low-risk-absence of both of these two risk factors. Presence of extreme thrombocytosis (platelet count > 1,000 x 10⁹/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include age > 60 years, leukocytosis, history of thrombosis, and anemia. RISK-ADAPTED THERAPY Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is < 1%/1% in ET and < 5%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications and this is effectively and safely accomplished by the use of low-dose aspirin (PV and ET), phlebotomy (PV), and hydroxyurea (high risk PV and ET). Treatment with busulfan or interferon-a is usually effective in hydroxyurea failures.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
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Papadakis E, Hoffman R, Brenner B. Thrombohemorrhagic complications of myeloproliferative disorders. Blood Rev 2010; 24:227-32. [DOI: 10.1016/j.blre.2010.08.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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