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Liu J, Chin-Yee B, Ho J, Lazo-Langner A, Chin-Yee IH, Iansavitchene A, Hsia CC. Diagnosis, management, and outcomes of drug-induced erythrocytosis: a systematic review. Blood Adv 2025; 9:2108-2118. [PMID: 39913688 DOI: 10.1182/bloodadvances.2024015410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/23/2025] [Indexed: 04/25/2025] Open
Abstract
ABSTRACT Secondary erythrocytosis refers to an elevation in hemoglobin or hematocrit due to elevated serum erythropoietin levels. Medications including testosterone and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are increasingly recognized as causes of secondary erythrocytosis. We conducted a systematic review to inform the clinical management of drug-induced erythrocytosis. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we performed a systematic literature search in MEDLINE, EMBASE, CENTRAL (all via Ovid), and Google Scholar. Of the 2036 articles screened for eligibility, 45 studies were included in our review, with 35 studies on testosterone and other androgen use, 5 studies on SGLT-2 inhibitors, 3 studies on antiangiogenic tyrosine kinase inhibitors (TKIs), 1 study on erythropoiesis-stimulating agents, and 1 study on a treatment regimen for multidrug-resistant tuberculosis. Cisgender and transgender men on prescription testosterone had erythrocytosis rates of up to 66.7%, with intramuscular formulations, higher doses, and older age associated with increased risk of erythrocytosis. Up to 2.7% of men on testosterone therapy developed thromboembolic events. Among individuals on SGLT-2 inhibitors, erythrocytosis rates ranged from 2.1% to 22%, with those who discontinued therapy demonstrating improvement or resolution of erythrocytosis. Thromboembolic events were reported in up to 10% of these individuals. Antiangiogenic TKIs were studied in patients with cancer, with erythrocytosis developing in up to 43.5% of patients. Drug-induced erythrocytosis is a heterogeneous condition for which there is no clear consensus among clinicians about its diagnosis and management. We offer recommendations for clinical practice within the scope of this systematic review, although further research is required.
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Affiliation(s)
- Jessica Liu
- Department of Medicine, London Health Sciences Centre, London, ON, Canada
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Benjamin Chin-Yee
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
- Department of History and Philosophy of Science, University of Cambridge, Cambridge, United Kingdom
| | - Jenny Ho
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
| | - Alejandro Lazo-Langner
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
| | - Ian H Chin-Yee
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
| | - Alla Iansavitchene
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Health Science Library, London Health Sciences Centre, London, ON, Canada
| | - Cyrus C Hsia
- Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- Division of Hematology, Department of Medicine, London Health Sciences Centre, London, ON, Canada
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Mahdi A, Rampotas A, Roberts P, Stokes J, Mahdi E, Witherall R, Mannari D, Ibrahim N, Naylor G, Garg M, Manjra I, Glancy P, Katis G, Bhagat S, Coppell J, McGregor A, Frewin R, Butt NM. Safety and Efficacy of Busulphan Based on Dosing Patterns in the Real-World Management of Myeloproliferative Neoplasms. EJHAEM 2025; 6:e1097. [PMID: 40110073 PMCID: PMC11920812 DOI: 10.1002/jha2.1097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 01/02/2025] [Indexed: 03/22/2025]
Abstract
Introduction Myeloproliferative neoplasms (MPNs), such as polycythaemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are primarily treated by managing blood counts to reduce the thrombotic risk using cytoreductive agents. Busulphan, an oral alkylating agent, has been historically used for MPN management due to its myelosuppressive effects, but concerns about its risk of leukaemic transformation have limited its use. Methods This real-world retrospective study evaluated the safety and efficacy of busulphan in 115 MPN patients across 13 UK hospitals. Responses in patients with ET and PV only were assessed using European LeukemiaNet (ELN) criteria. Results With a median age of 78 years, the overall response rate was 78.1%, with 29% of PV and 18% of ET patients achieving complete responses. Dosing regimens were similarly distributed between repeated single doses of busulphan (31%), courses of treatment lasting 1-4 weeks (30%) and continuous therapy for more than 4 weeks (35%). No cases of disease progression to acute leukaemia or myelofibrosis were recorded during the median follow-up of 23 months. Adverse events were infrequent, with fatigue and cytopaenia being the most common (4% each). Conclusion Busulphan demonstrated a favourable safety profile and is a viable cytoreductive option, particularly for elderly patients who are intolerant to hydroxycarbamide. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.
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Affiliation(s)
- Ali Mahdi
- Department of Haematology Aneurin Bevan University Health Board Newport UK
| | - Alexandros Rampotas
- Department of Haematology University College London Hospital NHS Foundation Trust London UK
| | - Patrick Roberts
- Department of Haematology Torbay and South Devon NHS Foundation Trust Torquay UK
| | - Joanna Stokes
- Department of Haematology Gloucestershire Hospitals NHS Trust Gloucester UK
| | - Eamon Mahdi
- Department of Haematology Aneurin Bevan University Health Board Newport UK
| | - Ruth Witherall
- Department of Haematology Royal Cornwall Hospital NHS Trust Truro UK
| | - Deepak Mannari
- Department of Haematology Musgrove Park Hospital NHS Trust Taunton UK
| | - Naheed Ibrahim
- Department of Haematology Aneurin Bevan University Health Board Newport UK
| | - Georgina Naylor
- Department of Haematology Derriford Hospital NHS Trust Plymouth UK
| | - Mamta Garg
- Department of Haematology Leicester Royal Infirmary NHS Trust Leicester UK
| | - Imran Manjra
- Department of Haematology Leicester Royal Infirmary NHS Trust Leicester UK
| | - Paula Glancy
- Department of Haematology Beatson West of Scotland Cancer Centre Glasgow UK
| | - George Katis
- Department of Haematology University College London Hospital NHS Foundation Trust London UK
| | - Sahil Bhagat
- Department of Haematology University Hospital of Wales Cardiff UK
| | - Jason Coppell
- Department of Haematology Royal Devon University Healthcare NHS Foundation Trust Exeter UK
| | - Andrew McGregor
- Department of Haematology the Newcastle Upon Tyne Hospitals NHS Foundation Trust Newcastle Upon Tyne UK
| | - Rebecca Frewin
- Department of Haematology Gloucestershire Hospitals NHS Trust Gloucester UK
| | - Nauman M Butt
- Department of Haematology Clatterbridge Cancer Centre NHS Trust Liverpool UK
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Bagnall B, Woodley C, Bains R, Gibson K, Nawaz A, Ryan J, McMullin MF. Exploring perceptions in the management and treatment of polycythaemia vera in the UK. Ann Hematol 2025; 104:1623-1631. [PMID: 40202537 DOI: 10.1007/s00277-025-06352-8] [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: 02/19/2025] [Accepted: 04/01/2025] [Indexed: 04/10/2025]
Abstract
Approximately 1140 people are diagnosed with polycythaemia vera (PV) annually in the United Kingdom (UK). Adherence to the British Society of Haematology (BSH) guidelines for PV diagnosis and management is not well understood. To explore UK's PV diagnosis, management practices and unmet needs. A structured survey, co-developed with a UK haematology consultant, an advanced nurse practitioner and a pharmacist, was completed by 57/332 invited healthcare practitioners from July to October 2023 through 1:1 interviews conducted by Novartis Medical Science Liaisons. Results were analysed descriptively. Most respondents (68%) follow the BSH 2018 guidelines for diagnosing PV. Treatment goals are to reduce thromboembolic event risk and control haematocrit and symptoms. Most patients (68%) were receiving cytoreductive therapy (typically first-line hydroxycarbamide); 28% received antiplatelet medication and/or venesection alone. Stable patients are usually monitored every 3 months through telephone (68%), increasing to monthly when uncontrolled, mainly in-person (54%). General practitioners (56%) manage cardiovascular risks, but there is doubt over referral response. All respondents monitor symptoms, with only 19% regularly using MPN10. The greatest educational need was identifying hydroxycarbamide resistance and intolerance (58%). This survey offers insights into therapeutic approaches and areas for improvement in the UK's PV clinical practice.
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Affiliation(s)
| | | | | | | | - Amir Nawaz
- Novartis Pharmaceuticals UK Ltd, London, UK
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Singh P, Millson C, Huang C, Driver RJ. Identifying haemochromatosis patients with C282Y homozygosity from inpatient electronic patient records in England using a novel algorithm: a retrospective observational study. BMJ Open 2025; 15:e089369. [PMID: 39965948 PMCID: PMC11836853 DOI: 10.1136/bmjopen-2024-089369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
INTRODUCTION Hereditary haemochromatosis (HH) is the most common genetic condition among populations of northern European ancestry, but it does not have a specific International Classification of Diseases 10th revision (ICD-10) diagnosis code. HH is commonly assigned the ICD-10 code E83.1 defined as 'disorders of iron metabolism'. However, the E83.1 diagnosis code is also applied to patients with transfusion-related iron overload and hyperferritinaemia from non-iron loading conditions. Venesection is the main treatment option for patients with HH and is assigned the Office of Population, Census and Surveys Classification of Interventions and Procedures, 4th revision (OPCS-4) code X36.2. We aimed to develop a novel algorithm to identify haemochromatosis patients with C282Y homozygosity from electronic patient records (EPR) using ICD-10 and OPCS-4 codes. METHODS The Hospital Episode Statistics Admitted Patient Care (APC) database was used to identify all patients with the ICD-10 code E83.1 from 1 April 2018 to 31 March 2023 in our NHS Trust. Case notes were reviewed to evaluate the presence of HH, genotype, medical history and associated procedures. Algorithms were generated using Stata MP V.18 by applying a combination of ICD-10 and OPCS-4 codes to all patients with the diagnosis code E83.1 including those without HH gene mutations. RESULTS A total of 9264 patient episodes were identified from the HES APC database corresponding to 787 unique patients: 479 (60.9%) C282Y homozygous, 107 (13.6%) C282Y/H63D compound heterozygotes, 42 (5.3%) other HH genetic mutations and 159 (20.2%) without any HH gene mutations. Six algorithms were developed to identify patients with HH within inpatient EPR, all of which showed improved positive predictive value (PPV) compared with the baseline cohort. The application of the OPCS-4 code for venesection (X36.2) in five of the algorithms resulted in large improvements in specificity and increased all their PPVs to >70%. Algorithms 4 and 6 had the best PPV at 74.3% and 74.4%, respectively, and included the removal of patients with ICD-10 codes associated with transfusion-related iron overload and other conditions treated with venesection. CONCLUSION These novel algorithms represent a more reliable method to detect haemochromatosis patients with C282Y homozygosity from EPR than the single ICD-10 code E83.1. It may be applied to large administrative datasets for investigation of HH in population studies.
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Affiliation(s)
- Prabhsimran Singh
- University of York, York, UK
- Department of Hepatology, York and Scarborough Teaching Hospitals NHS Foundation Trust, York, UK
- Hull York Medical School, York, UK
| | - Charles Millson
- Department of Hepatology, York and Scarborough Teaching Hospitals NHS Foundation Trust, York, UK
| | - Chao Huang
- Institute of Clinical and Applied Health Research, University of Hull, Hull, UK
| | - Robert J Driver
- Department of Hepatology, York and Scarborough Teaching Hospitals NHS Foundation Trust, York, UK
- Hull York Medical School, York, UK
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Anžej Doma S, Kraljić N, Kristan A, Debeljak N, Maver A, Pajič T, Preložnik Zupan I. Utility of next-generation sequencing in identifying congenital erythrocytosis in patients with idiopathic erythrocytosis. Front Med (Lausanne) 2024; 11:1440712. [PMID: 39309680 PMCID: PMC11412850 DOI: 10.3389/fmed.2024.1440712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 08/19/2024] [Indexed: 09/25/2024] Open
Abstract
Background Congenital erythrocytosis (CE) is increasingly recognized as the cause of erythrocytosis in patients in whom polycythemia vera and secondary acquired causes have been excluded. The aim of our study was to determine possible genetic background in patients with idiopathic erythrocytosis. Methods 40 patients with idiopathic erythrocytosis, referred to our institution in a 5-year period, were analyzed. We collected data on erythropoietin (Epo) levels, hemoglobin (Hgb), hematocrit (Hct), erythrocyte count, age, gender, past thrombotic events, concomitant diseases, and smoking status. CE was tested using next-generation sequencing (NGS), in the majority of patients also measurement of P50 and Hgb electrophoresis were performed. Patients with signs of iron overload were tested for genetic variants in the HFE gene. Results The median patient age at analysis was 46.5 years (range 22-73), with 37 out of 40 being males (93 %). The median Hgb, Hct and red blood cells count were 180 g/L, 0.51, 5.985 x 1012/L in men and 171 g/L, 0.50 and 5.68 x 1012/L in women, respectively. Epo levels were decreased in three, increased in one patient and within the normal range in the rest (median 7.55 mIU/mL; range 2.90-19.50). Eight patients (20 %) smoked. 32 (80 %) were treated with low-dose aspirin, and 20 (50 %) underwent at least one phlebotomy. Thromboembolic events were recorded in 2 patients (5 %). P50 was measured in 20 out of 40 patients, and it was above 24 mm Hg (3.12 kPa) in all of them. Hemoglobin electrophoresis was performed in 73 % of patients, with no abnormal Hgb detected. Variants in the HFE gene were found in 8 out of 40 patients (20 %), but in only one patient the results were associated with an increased risk for hemochromatosis. Although no pathogenic variants for CE were detected by NGS, two variants of uncertain significance, namely EGLN1 (NM_022051.2):c.1072C>T (p.(Pro358Ser)) and EGLN1 (NM_022051.2):c.1124A>G (p.(Glu375Gly)) were identified as strong etiologic candidates. Conclusion CE is an extremely rare condition. Genetic testing is advised in young individuals with a long-standing persistent erythrocytosis, possibly with a family history and after exclusion of more frequent secondary causes and polycytemia vera.
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Affiliation(s)
- Saša Anžej Doma
- Hematology Department, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nika Kraljić
- Hematology Department, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Aleša Kristan
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nataša Debeljak
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Aleš Maver
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tadej Pajič
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Clinical Biochemistry, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Irena Preložnik Zupan
- Hematology Department, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Borsani O, Varettoni M, Riccaboni G, Rumi E. Erythrocytosis in congenital heart defects: hints for diagnosis and therapy from a clinical case. Front Med (Lausanne) 2024; 11:1419092. [PMID: 39188884 PMCID: PMC11345742 DOI: 10.3389/fmed.2024.1419092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 05/30/2024] [Indexed: 08/28/2024] Open
Abstract
Erythrocytosis is one of the most common abnormalities that clinical hematologists, general practitioners, and internal medicine specialists could have to face off in their routine clinical practice. While diagnostic criteria for primary erythrocytosis (i.e., polycythemia vera) are well known and characterized, there are several causes of secondary erythrocytosis that should be kept in mind to avoid misdiagnosis. Congenital heart defects are rarely cause of secondary erythrocytosis as they are normally recognized and treated at an early stage. Eisenmenger syndrome is a complex clinical syndrome that arise as consequence of an untreated congenital heart defect associated with large intracardiac shunt. The clinical picture of this syndrome usually includes a severe erythrocytosis that could tempt clinicians to start an intensive phlebotomy (or venesection) program. However, clinicians should be aware that erythrocytosis in Eisenmenger syndrome is a compensatory mechanism aimed at improving blood oxygen-carrying capacity; accordingly, phlebotomies should be reserved for those cases complaining hyperviscosity symptoms. Here we present a case of an adult female patient with Eisenmenger syndrome that has been evaluated because of severe and persistent erythrocytosis. In this case we present a step-by-step approach by which clinical hematologist could proceed to reach the definitive diagnosis. We will also provide some hints that could help clinicians when choosing the best treatment strategy to avoid unnecessary and potentially harmful procedures.
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Affiliation(s)
- Oscar Borsani
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
- Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
| | - Marzia Varettoni
- Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
| | | | - Elisa Rumi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
- Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
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Boulnois L, Robles M, Maaziz N, Aral B, Gauthier M, Duchene F, Goujart MA, Gardie B, Girodon F. Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with EPOR primary familial polycythemia on the island of New Caledonia. Haematologica 2024; 109:2688-2692. [PMID: 38546672 PMCID: PMC11290533 DOI: 10.3324/haematol.2023.284658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 03/20/2024] [Indexed: 08/02/2024] Open
Abstract
Not available.
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Affiliation(s)
| | - Margot Robles
- Onco-Hématologie, Service de Médecine Interne, Maladies Infectieuses et Hématologie, CHT Gaston Bourret, Nouméa, Nouvelle-Calédonie
| | | | | | - Martin Gauthier
- Service d'Hématologie, Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France; Centre Hospitalier Jean Rougier, Cahors
| | - Francis Duchene
- Service de Médecine Interne, Hôpital Nord Franche Comté, Belfort Montbéliard
| | - Marie-Amélie Goujart
- Service d'Hématologie Biologique, Laboratoire de Biologie Médicale, CHT Gaston Bourret, Nouméa, Nouvelle-Calédonie
| | - Betty Gardie
- Université de Nantes, CNRS, INSERM, L'Institut du thorax, Nantes, France; Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Laboratoire d'Excellence GR-Ex
| | - François Girodon
- Pôle Biologie, CHU Dijon, France; Laboratoire d'Excellence GR-Ex, France; Inserm U1231, Université de Bourgogne, Dijon, France; Member of France Intergroupe Myeloprolifératifs (FIM).
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Ngo TQ, Scott MW, Sirdesai S, Hempton JL, Hodges GS, Campbell PJ. A comparison between erythrocytapheresis and venesection for the treatment of JAK2-mutated polycythaemia. Intern Med J 2024; 54:909-915. [PMID: 38145421 DOI: 10.1111/imj.16313] [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: 02/12/2023] [Accepted: 12/06/2023] [Indexed: 12/26/2023]
Abstract
BACKGROUND JAK2-mutated polycythaemia vera (PV) is associated with reduced survival because of thrombotic events and haematological disease transformation. Therapeutic venesection has traditionally been used to lower haematocrit, but the technique of erythrocytapheresis has emerged over the last decade. AIM To compare erythrocytapheresis with venesection as treatment for PV by assessing medical efficacy and financial viability. METHODS One hundred sixteen patients with PV who received red cell depletion therapy at Barwon Health between 2014 and 2021 were identified. The haematocrit drop after each session, interval between treatment times and number of sessions required to achieve a haematocrit <0.45 were compared with an independent t test. Thrombosis rates were compared with Pearson's chi-squared test. Cost-funding analysis was done by assessing the Weighted Inlier Equivalent Separation and National Weighted Activity Unit funding models. RESULTS Patients treated with erythrocytapheresis achieved a greater haematocrit drop each treatment session (0.075 vs 0.03, P < 0.01), required fewer sessions to achieve a haematocrit <0.45 (1 vs 4, P < 0.01) and experienced fewer thrombotic complications (8.7% vs 32.1%, P = 0.02) than those treated with venesection. Cost-funding analysis demonstrated that erythrocytapheresis was more financially viable with a surplus of AU$297 per session compared to a deficit of AU$176 with venesection. Even if funding for venesection is increased, the cost of erythrocytapheresis may be mitigated by a lower number of procedures required per year (3.8 vs 5.3, P < 0.01). CONCLUSIONS Erythrocytapheresis is more efficacious than venesection for the treatment of PV and is accompanied by rapid reductions in haematocrit and reduced thrombotic complications.
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Affiliation(s)
- Trung Q Ngo
- Andrew Love Cancer Centre, Barwon Health, Geelong, Victoria, Australia
| | - Matthew W Scott
- Geelong Clinical School, Deakin University, Geelong, Victoria, Australia
| | | | | | - Georgina S Hodges
- Andrew Love Cancer Centre, Barwon Health, Geelong, Victoria, Australia
| | - Philip J Campbell
- Andrew Love Cancer Centre, Barwon Health, Geelong, Victoria, Australia
- Geelong Clinical School, Deakin University, Geelong, Victoria, Australia
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Noye J, Beggs J, Mason J. Discrepant low von Willebrand factor activity results on the ACL TOP analyzer are frequent in unselected patients with myeloproliferative neoplasms and show no correlation with high-molecular-weight multimer loss or bleeding phenotype. J Thromb Haemost 2024; 22:965-974. [PMID: 38160725 DOI: 10.1016/j.jtha.2023.12.024] [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: 09/25/2023] [Revised: 12/09/2023] [Accepted: 12/11/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Bleeding complications are common in patients with myeloproliferative neoplasms (MPNs), with a subset developing acquired von Willebrand disease. Despite this association, a wide spectrum of von Willebrand factor (VWF) abnormalities are described, and the performance of modern assays remains unclear. OBJECTIVES To comprehensively describe the pattern of VWF laboratory abnormalities in the MPN population. METHODS We collected samples from 74 unselected clinic patients with MPNs to evaluate VWF quantitatively and qualitatively via multiple methods, correlating findings with a retrospective analysis of clinical bleeding data. VWF assays were performed on both ACL TOP (Instrumentation Laboratory) and Acustar (Instrumentation Laboratory) analyzers using HemosIL reagents (Instrumentation Laboratory), along with multimer analysis by gel electrophoresis. RESULTS Functional VWF measurements were not concordant between assays, with a median ACL TOP VWF glycoprotein IbR to antigen ratio (VWF:GPIbR/VWF:Ag) of 0.57 (IQR, 0.43-0.71) compared to a median Acustar VWF:GPIbR/VWF:Ag of 0.91 (IQR: 0.82-1.03;P < .001). The ACL TOP showed disproportionately lower results, with 73% of patients having a ratio <0.7. Despite this, no patient experienced loss of high-molecular-weight multimers by gel electrophoresis. An inverse relationship was observed between platelet count and functional ratios on both ACL TOP (R2 = 0.20; P < .001) and Acustar (R2 = 0.18; P = .0011) analyzers. While clinically significant bleeding events were relatively common (11% patients), there was no association with VWF assay abnormalities, and generally, an alternate cause(s) was identified. CONCLUSION Discrepancies in functional VWF assays are common in patients with MPN, particularly by ACL TOP VWF:GPIbR. Based on our limited series, a VWF functional to an antigenic ratio of <0.7 ("type 2 pattern") alone is poorly predictive of bleeding risk.
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Affiliation(s)
- Joseph Noye
- Department of Haematology, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
| | - Joanne Beggs
- Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Jane Mason
- Department of Haematology, Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Pathology Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; School of Medicine, University of Queensland, Brisbane, Queensland, Australia
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Wang Z, Mei Y, Yang Z, Gao Q, Xu H, Han Z, Hong Z. TNF-α is a predictive marker in distinguishing myeloproliferative neoplasm and idiopathic erythrocytosis/thrombocytosis: development and validation of a non-invasive diagnostic model. Front Oncol 2024; 14:1369346. [PMID: 38585007 PMCID: PMC10995358 DOI: 10.3389/fonc.2024.1369346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 03/12/2024] [Indexed: 04/09/2024] Open
Abstract
Purpose Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) exhibit phenotypic similarities with JAK/STAT-unmutated idiopathic erythrocytosis and thrombocytosis (IE/IT). We aimed to develop a clinical diagnostic model to discern MPN and IE/IT. Methods A retrospective study was performed on 77 MPN patients and 32 IE/IT patients in our center from January 2018 to December 2023. We investigated the role of hemogram, cytokine and spleen size in differentiating MPN and IE/IT among newly onset erythrocytosis and thrombocytosis patients. Independent influencing factors were integrated into a nomogram for individualized risk prediction. The calibration and discrimination ability of the model were evaluated by concordance index (C-index), calibration curve. Results MPN had significantly higher TNF-α level than IE/IT, and the TNF-α level is correlated with MF-grade. Multivariable analyses revealed that TNF-α, PLT count, age, size of spleen were independent diagnostic factors in differentiating MPN and IE/IT. Nomograms integrated the above 4 factors for differentiating MPN and IE/IT was internally validated and had good performance, the C-index of the model is 0.979. Conclusion The elevation of serum TNF-α in MPN patients is of diagnostic significance and is correlated with the severity of myelofibrosis. The nomogram incorporating TNF-α with age, PLT count and spleen size presents a noteworthy tool in the preliminary discrimination of MPN patients and those with idiopathic erythrocytosis or thrombocytosis. This highlights the potential of cytokines as biomarkers in hematologic disorders.
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Affiliation(s)
- Zhenhao Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yu Mei
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhuming Yang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiang Gao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hao Xu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhiqiang Han
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhenya Hong
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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11
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O'Neill C, O'Connell C. Idiopathic erythrocytosis: A diagnostic and management challenge with emerging areas for exploration. Br J Haematol 2024; 204:774-783. [PMID: 38262687 DOI: 10.1111/bjh.19287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 12/18/2023] [Accepted: 12/22/2023] [Indexed: 01/25/2024]
Abstract
Despite published algorithms for approaching the work-up of erythrocytosis, a significant proportion of patients are left with uncertainty as to its aetiology and prognosis. The term 'idiopathic erythrocytosis' (IE) is applied when known primary and secondary aetiologies have been ruled out. However, the assignment of secondary aetiologies is not always straightforward or evidence based, which can lead to misdiagnosis and heterogeneity in cohort studies. Furthermore, new studies have identified germline or somatic mutations that may affect prognosis. Epidemiological and cohort data are inconsistent as to whether IE increases the risk for complications such as arterial and venous thromboembolism, clonal transformation or comorbid conditions. Randomized trials assessing the role of phlebotomy for long-term management of IE have not been performed, so treatment remains a vexing problem for clinicians. Standardization of terminology and testing strategies, including comprehensive genetic screening in clinical research, are key to refining our understanding of IE.
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Affiliation(s)
- Caitlin O'Neill
- Jane Anne Nohl Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Casey O'Connell
- Jane Anne Nohl Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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12
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Robinson S, Ragheb M, Harrison C. How I treat myeloproliferative neoplasms in pregnancy. Blood 2024; 143:777-785. [PMID: 38145575 DOI: 10.1182/blood.2023020729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 12/27/2023] Open
Abstract
ABSTRACT Although myeloproliferative neoplasms (MPNs) are traditionally considered diseases of adults in their sixth or seventh decade, these conditions do occur in young patients; for example, for essential thrombocythemia, in particular, there is a second peak in women of reproductive age. Therefore, pregnancy is an uncommon but not rare occurrence and clinical challenge in some scenarios. Here, we discuss in detail our local approach to the management of pregnancy in patients with MPN while taking a case-based approach. We include relevant updates in the field and point to a future research strategy that should be internationally focused to obtain as much information in as short a time as possible.
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Affiliation(s)
- Susan Robinson
- Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, United Kingdom
| | - Monica Ragheb
- Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, United Kingdom
| | - Claire Harrison
- Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, United Kingdom
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13
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Elli EM, Mauri M, D'Aliberti D, Crespiatico I, Fontana D, Redaelli S, Pelucchi S, Spinelli S, Manghisi B, Cavalca F, Aroldi A, Ripamonti A, Ferrari S, Palamini S, Mottadelli F, Massimino L, Ramazzotti D, Cazzaniga G, Piperno A, Gambacorti-Passerini C, Piazza R. Idiopathic erythrocytosis: a germline disease? Clin Exp Med 2024; 24:11. [PMID: 38244120 PMCID: PMC10799805 DOI: 10.1007/s10238-023-01283-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/08/2023] [Indexed: 01/22/2024]
Abstract
Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.
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Affiliation(s)
- E M Elli
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy
| | - M Mauri
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - D D'Aliberti
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - I Crespiatico
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - D Fontana
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - S Redaelli
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - S Pelucchi
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - S Spinelli
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - B Manghisi
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - F Cavalca
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - A Aroldi
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - A Ripamonti
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - S Ferrari
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - S Palamini
- Tettamanti Research Center, IRCCS, San Gerardo dei Tintori, Monza, Italy
| | - F Mottadelli
- Monza and Brianza Foundation for the Child and his Mother (MBBM), IRCCS, San Gerardo dei Tintori, Monza, Italy
| | - L Massimino
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - D Ramazzotti
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - G Cazzaniga
- Tettamanti Research Center, IRCCS, San Gerardo dei Tintori, Monza, Italy
| | - A Piperno
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - C Gambacorti-Passerini
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy
| | - R Piazza
- Division of Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS, San Gerardo dei Tintori, Monza, Italy.
- Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy.
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14
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McLornan DP, Psaila B, Ewing J, Innes A, Arami S, Brady J, Butt NM, Cargo C, Cross NCP, Francis S, Frewin R, Garg M, Godfrey AL, Green A, Khan A, Knapper S, Lambert J, McGregor A, McMullin MF, Nangalia J, Neelakantan P, Woodley C, Mead A, Somervaille TCP, Harrison CN. The management of myelofibrosis: A British Society for Haematology Guideline. Br J Haematol 2024; 204:136-150. [PMID: 38037886 DOI: 10.1111/bjh.19186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/03/2023] [Accepted: 10/20/2023] [Indexed: 12/02/2023]
Affiliation(s)
- Donal P McLornan
- Department of Haematology, University College London Hospitals, London, UK
| | - Bethan Psaila
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Haematology, Churchill Hospital, Oxford University NHS Trust, Oxford, UK
| | - Joanne Ewing
- Department of Haematology, University Hospitals Birmingham Trust, London, UK
| | - Andrew Innes
- Department of Haematology, Imperial College, London, UK
| | - Siamak Arami
- Department of Haematology, London Northwest Healthcare University NHS Trust, London, UK
| | - Jessica Brady
- Department of Clinical Oncology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Nauman M Butt
- Department of Haematology, The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK
| | - Catherine Cargo
- Department of Haematology, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, UK
| | | | - Sebastian Francis
- Department of Haematology, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK
| | - Rebecca Frewin
- Department of Haematology, Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK
| | - Mamta Garg
- Department of Haematology, University Hospitals Leicester NHS Trust, Leicester, UK
| | - Anna L Godfrey
- Haematopathology & Oncology Diagnostics Service, Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Anna Green
- Department of Histopathology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Alesia Khan
- Department of Haematology, Leeds Teaching Hospitals NHS Foundation Trust, Leeds, UK
| | - Steve Knapper
- Department of Haematology, Cardiff University, Cardiff, UK
| | - Jonathan Lambert
- Department of Haematology, University College London Hospitals, London, UK
| | | | | | - Jyoti Nangalia
- Wellcome Sanger Institute, University of Cambridge, Cambridge, UK
| | - Pratap Neelakantan
- Department of Haematology, Royal Berkshire NHS Foundation Trust, London, UK
| | - Claire Woodley
- Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Adam Mead
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Department of Haematology, Churchill Hospital, Oxford University NHS Trust, Oxford, UK
| | - Tim C P Somervaille
- Cancer Research UK Manchester Institute & The Christie NHS Foundation Trust, Manchester, UK
| | - Claire N Harrison
- Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
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15
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Duminuco A, Harrington P, Harrison C, Curto-Garcia N. Polycythemia Vera: Barriers to and Strategies for Optimal Management. Blood Lymphat Cancer 2023; 13:77-90. [PMID: 38146420 PMCID: PMC10749566 DOI: 10.2147/blctt.s409443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 12/16/2023] [Indexed: 12/27/2023]
Abstract
Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms characterized by impaired quality of life and severe complications. Despite the increasingly in-depth knowledge of this condition, it necessitates a multifaceted management approach to mitigate symptoms and prevent thrombotic and hemorrhagic events, ensuring prolonged survival. The therapeutic landscape has been revolutionized in recent years, where venesection and hydroxycarbamide associated with antiplatelet therapy have a central role and are now accompanied by other drugs, such as interferon and Janus kinase inhibitors. Ongoing research and advancements in targeted therapies hold promise for further enhancing the therapeutic choice for PV management.
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Affiliation(s)
- Andrea Duminuco
- Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
- Haematology with BMT Unit, A.O.U. Policlinico “G.Rodolico-San Marco”, Catania, Italy
| | - Patrick Harrington
- Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
| | - Claire Harrison
- Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
| | - Natalia Curto-Garcia
- Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
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16
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Tang P, Wang H. Regulation of erythropoiesis: emerging concepts and therapeutic implications. Hematology 2023; 28:2250645. [PMID: 37639548 DOI: 10.1080/16078454.2023.2250645] [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: 04/19/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023] Open
Abstract
The process of erythropoiesis is complex and involves the transfer of cells from the yolk sac to the fetal hepar and, ultimately, to the bone marrow during embryonic development. Within the bone marrow, erythroid progenitor cells undergo several stages to generate reticulocytes that enter the bloodstream. Erythropoiesis is regulated by various factors, with erythropoietin (EPO) synthesized by the kidney being the promoting factor and hepcidin synthesized by the hepar inhibiting iron mobilization. Transcription factors, such as GATA and KLF, also play a crucial role in erythropoiesis. Disruption of any of these factors can lead to abnormal erythropoiesis, resulting in red cell excess, red cell deficiency, or abnormal morphological function. This review provides a general description of erythropoiesis, as well as its regulation, highlighting the significance of understanding the process for the diagnosis and treatment of various hematological disorders.
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Affiliation(s)
- Pu Tang
- Department of Hematology, General Hospital, Tianjin Medical University, Tianjin, People's Republic of China
| | - Huaquan Wang
- Department of Hematology, General Hospital, Tianjin Medical University, Tianjin, People's Republic of China
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17
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Anthony N, Khan I, Shah A, Tariq A, Khan M. Incidental Finding of Post-Transplant Erythrocytosis After Renal Transplantation in a Patient With Chronic Kidney Disease: A Case Report. Cureus 2023; 15:e51218. [PMID: 38283474 PMCID: PMC10821203 DOI: 10.7759/cureus.51218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2023] [Indexed: 01/30/2024] Open
Abstract
Renal transplant aims to provide a healthy substitute for the chronically damaged kidney while also correcting the anemia of chronic disease by producing erythropoietin for effective erythropoiesis. However, in a small number of renal transplant patients, the hematocrit continues to rise even after correction of the anemia, ultimately leading to abnormally increased hemoglobin and hematocrit. This condition is termed "post-transplant erythrocytosis" (PTE). We present a case of a 50-year-old male who was diabetic, positive for hepatitis B surface antigen, and negative for polymerase chain reaction. He presented with symptoms of acute hepatitis. During the work-up, PTE was diagnosed. Our case sheds light on a common complication of renal transplant known as PTE, its possible complications in the patient, and the necessary interventions to prevent untoward outcomes. PTE, although a less common complication of renal transplant, can become serious and potentially fatal due to its sequelae of thromboembolism. The complications can range from simple thrombophlebitis and thrombosis of digital and brachial arteries to more severe events such as pulmonary embolism or stroke and cardiovascular events. Regular post-transplant follow-ups with frequent bloodwork will aid in the early diagnosis of PTE, allowing for timely intervention with appropriate treatment options such as venesection or angiotensin receptor blockers (ARBs)/angiotensin-converting enzyme (ACE) inhibitors.
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Affiliation(s)
- Nouman Anthony
- General Medicine, Rehman Medical Institute, Peshawar, PAK
| | - Imran Khan
- Urology, Royal London Hospital, London, GBR
- Cardiothoracic Surgery, St. Bartholomew's Hospital, London, GBR
| | | | - Anum Tariq
- Nephrology, Rehman Medical Institute, Peshawar, PAK
| | - Mudassar Khan
- Emergency Medicine, Rehman Medical Institute, Peshawar, PAK
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18
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Benevolo G, Marchetti M, Melchio R, Beggiato E, Sartori C, Biolé CA, Rapezzi D, Bruno B, Milan A. Diagnosis and Management of Cardiovascular Risk in Patients with Polycythemia Vera. Vasc Health Risk Manag 2023; 19:765-778. [PMID: 38025519 PMCID: PMC10676644 DOI: 10.2147/vhrm.s429995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 11/04/2023] [Indexed: 12/01/2023] Open
Abstract
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV.
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Affiliation(s)
- Giulia Benevolo
- University Hematology Division, Città della Salute e della Scienza di Torino, Turin, Italy
| | - Monia Marchetti
- Hematology and Transplant Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Remo Melchio
- Division of Internal Medicine, A.O. S. Croce E Carle, Cuneo, Italy
| | - Eloise Beggiato
- University Hematology Division, Città della Salute e della Scienza di Torino, Turin, Italy
| | - Chiara Sartori
- Cardiology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | | | | | - Benedetto Bruno
- University Hematology Division, Città della Salute e della Scienza di Torino, Turin, Italy
- Department of Molecular Biotechnolgies and Medical Sciences, University of Turin, Turin, Italy
| | - Alberto Milan
- Department of Medical Sciences, University of Turin, Città della Salute e della Scienza di Torino, Turin, Italy
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19
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Liu A, Kremyanskaya M, Mehrazin R, Si Q, Robinson BD, Cushing MM, Hoffman R, Ginzburg YZ. Erythropoietin-secreting metanephric adenoma presenting as erythrocytosis. Am J Hematol 2023; 98:1808-1813. [PMID: 37528578 DOI: 10.1002/ajh.27047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/14/2023] [Accepted: 07/16/2023] [Indexed: 08/03/2023]
Affiliation(s)
- Angela Liu
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Marina Kremyanskaya
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Reza Mehrazin
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Qiusheng Si
- Pathology Department, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Brian D Robinson
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Melissa M Cushing
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Ronald Hoffman
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yelena Z Ginzburg
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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20
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Vermeersch G, Devos T, Devos H, Lambert F, Poppe B, Van Hecke S. Germline heterozygous SH2B3-mutations and (idiopathic) erythrocytosis: Detection of a previously undescribed mutation. EJHAEM 2023; 4:1143-1147. [PMID: 38024597 PMCID: PMC10660405 DOI: 10.1002/jha2.800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 09/16/2023] [Accepted: 09/20/2023] [Indexed: 12/01/2023]
Abstract
Erythrocytosis or polycythemia refers to a true or apparent increase in hemoglobin or hematocrit. When no etiology of erythrocytosis is identified, people are diagnosed with "idiopathic erythrocytosis" (IE). The identification of new contributing genes has recently improved the diagnostic workup of IE. As such mutations within the SH2B3 gene, which codes for the LNK protein and negatively regulates the JAK-STAT pathway, have been identified in cases diagnosed as IE. This reports describes the presence of a previously undescribed germline SH2B3 variant p.(Thr335ArgfsTer4) within IE and emphasizes the advantages of gene panel sequencing as second step in the diagnostic work-up.
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Affiliation(s)
- Gaël Vermeersch
- Department of HematologyUniversity Hospitals LeuvenLeuvenBelgium
- Department of HematologyAZ DamiaanOstendBelgium
| | - Timothy Devos
- Department of HematologyUniversity Hospitals LeuvenLeuvenBelgium
- Department of Microbiology and ImmunologyLaboratory of Molecular Immunology (Rega Institute), KU LeuvenLeuvenBelgium
| | - Helena Devos
- Department of Laboratory HematologyAZ Sint‐Jan Brugge‐Oostende AVBrugesBelgium
| | - Frédéric Lambert
- Center for Human Genetic, Molecular Hemato‐Oncology UnitUniLab Liège, Centre Hospitalier Universitaire de LiègeLiègeBelgium
| | - Bruce Poppe
- Center for Medical GeneticsGhent University HospitalGhentBelgium
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21
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Delamare M, Le Roy A, Pacault M, Schmitt L, Garrec C, Maaziz N, Myllykoski M, Rimbert A, Karaghiannis V, Aral B, Catherwood M, Airaud F, Mansour-Hendili L, Hoogewijs D, Peroni E, Idriss S, Lesieur V, Caillaud A, Si-Tayeb K, Chariau C, Gaignerie A, Rab M, Haferlach T, Meggendorfer M, Bézieau S, Benetti A, Casadevall N, Hirsch P, Rose C, Wemeau M, Galacteros F, Cassinat B, Bellosillo B, Bento C, Van Wijk R, Petrides PE, Randi ML, McMullin MF, Koivunen P, Girodon F, Gardie B. Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis. Haematologica 2023; 108:3068-3085. [PMID: 37317877 PMCID: PMC10620589 DOI: 10.3324/haematol.2023.282913] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 06/06/2023] [Indexed: 06/16/2023] Open
Abstract
Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study involving a collection of 2,160 patients with erythrocytosis sequenced in ten different laboratories. We focused our study on the EGLN1 gene and identified 39 germline missense variants including one gene deletion in 47 probands. EGLN1 encodes the PHD2 prolyl 4-hydroxylase, a major inhibitor of hypoxia-inducible factor. We performed a comprehensive study to evaluate the causal role of the identified PHD2 variants: (i) in silico studies of localization, conservation, and deleterious effects; (ii) analysis of hematologic parameters of carriers identified in the UK Biobank; (iii) functional studies of the protein activity and stability; and (iv) a comprehensive study of PHD2 splicing. Altogether, these studies allowed the classification of 16 pathogenic or likely pathogenic mutants in a total of 48 patients and relatives. The in silico studies extended to the variants described in the literature showed that a minority of PHD2 variants can be classified as pathogenic (36/96), without any differences from the variants of unknown significance regarding the severity of the developed disease (hematologic parameters and complications). Here, we demonstrated the great value of federating laboratories working on such rare disorders in order to implement the criteria required for genetic classification, a strategy that should be extended to all hereditary hematologic diseases.
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Affiliation(s)
- Marine Delamare
- Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Amandine Le Roy
- Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Mathilde Pacault
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Service de Génétique Médicale, CHU de Nantes, Nantes
| | - Loïc Schmitt
- Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Céline Garrec
- Service de Génétique Médicale, CHU de Nantes, Nantes
| | - Nada Maaziz
- Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon
| | - Matti Myllykoski
- Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland. 90014 Oulu
| | - Antoine Rimbert
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Valéna Karaghiannis
- Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Bernard Aral
- Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon
| | | | | | - Lamisse Mansour-Hendili
- Département de Biochimie-Biologie Moléculaire, Pharmacologie, Génétique Médicale AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Université Paris-Est Créteil, IMRB Equipe Pirenne, Laboratoire d'excellence LABEX GRex, Créteil
| | - David Hoogewijs
- Section of Medicine, Department of Endocrinology, Metabolism and Cardiovascular System, University of Fribourg, CH-1700 Fribourg, Switzerland; National Center of Competence in Research "Kidney.CH"
| | - Edoardo Peroni
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, 35128 Padova, Italy; Medical Genetics Unit, Mater Domini University Hospital, 88100 Catanzaro
| | - Salam Idriss
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Valentine Lesieur
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Amandine Caillaud
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Karim Si-Tayeb
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes
| | - Caroline Chariau
- Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, FR-44000, Nantes
| | - Anne Gaignerie
- Nantes Université, CHU Nantes, CNRS, Inserm, BioCore, FR-44000, Nantes
| | - Minke Rab
- Central Diagnostic Laboratory - Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht
| | | | | | - Stéphane Bézieau
- Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Service de Génétique Médicale, CHU de Nantes, Nantes
| | - Andrea Benetti
- Department of Medicine-DIMED, University of Padua, Via Giustiniani 2, 35128, Padua
| | - Nicole Casadevall
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique, 75012, Paris
| | - Pierre Hirsch
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique, 75012, Paris
| | - Christian Rose
- Service d'onco-hématologie, Saint-Vincent de Paul Hospital, Boulevard de Belfort, Université Catholique de Lille, Univ. Nord de France, F-59000 Lille
| | - Mathieu Wemeau
- Hematology Department, Claude Huriez Hospital, Lille Hospital, 59000 Lille
| | - Frédéric Galacteros
- Département de Biochimie-Biologie Moléculaire, Pharmacologie, Génétique Médicale AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France; Red Cell Disease Referral Center-UMGGR, AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil
| | - Bruno Cassinat
- Université Paris Cité, APHP, Hôpital Saint-Louis, Laboratoire de Biologie Cellulaire, Paris
| | | | - Celeste Bento
- Hematology Department, Centro Hospitalar e Universitário de Coimbra; CIAS, University of Coimbra
| | - Richard Van Wijk
- Central Diagnostic Laboratory - Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht
| | - Petro E Petrides
- Hematology Oncology Center and Ludwig-Maximilians-University Munich Medical School, Munich
| | - Maria Luigia Randi
- Department of Medicine-DIMED, University of Padua, Via Giustiniani 2, 35128, Padua
| | - Mary Frances McMullin
- Belfast Health and Social Care Trust, Belfast N.Ireland; Queen's University, Belfast, N. Ireland
| | - Peppi Koivunen
- Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, 90014 Oulu, Finland. 90014 Oulu
| | - François Girodon
- Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon, France; Inserm U1231, Université de Bourgogne, Dijon, France; Laboratoire d'Excellence GR-Ex
| | - Betty Gardie
- Ecole Pratique des Hautes Etudes, EPHE, Université PSL, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France; Laboratoire d'Excellence GR-Ex
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22
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Zhou M, Liu X, Li L. Secondary polycythaemia from chronic hypoxia is a risk for cerebral thrombosis: a case report. BMC Neurol 2023; 23:225. [PMID: 37296428 DOI: 10.1186/s12883-023-03277-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 06/06/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Secondary polycythemia is considered the usual complication of chronic hypoxia. It can theoretically increase the oxygen-carrying capacity, but this adaptive trait has a deleterious effect because the blood viscosity increases, which can induce significant morbidity and mortality, such as stroke and myocardial infarction. CASE PRESENTATION A 55-year-old man with a history of a congenitally small main pulmonary artery presented to the emergency department with sustained unsteady walking, dizziness and vertigo. Evaluation revealed elevated hemoglobin and superior posterior circulation cerebral artery thrombosis. The patient was treated with high flux inhalation of oxygen and anti-platelet aggregation. CONCLUSIONS The involvement of cerebral vessels has rarely been reported in chronic hypoxia cases. The present case is the first case of superior posterior circulation cerebral artery thrombosis due to chronic hypoxia in a patient with a congenitally small main pulmonary artery. This case demonstrates the importance of recognizing some chronic diseases that can lead to hypoxia and secondary polycythemia thereby leading to hypercoagulable state and subsequent thrombosis.
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Affiliation(s)
- Min Zhou
- Department of Neurology, Ningbo No. 2 Hospital, 41 Xi'bei Street, Ningbo, Zhejiang, China
| | - Xiaoxia Liu
- Department of Neurology, Ningbo No. 2 Hospital, 41 Xi'bei Street, Ningbo, Zhejiang, China
| | - Li Li
- Department of Neurology, Ningbo No. 2 Hospital, 41 Xi'bei Street, Ningbo, Zhejiang, China.
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23
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Gangat N, Szuber N, Tefferi A. JAK2 unmutated erythrocytosis: 2023 Update on diagnosis and management. Am J Hematol 2023; 98:965-981. [PMID: 36966432 DOI: 10.1002/ajh.26920] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/18/2023] [Accepted: 03/22/2023] [Indexed: 03/27/2023]
Abstract
DISEASE OVERVIEW JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities. DIAGNOSIS Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12-15) mutation screening. Initial assessment should also include gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list. Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity Hgb variants, 2,3-bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% Hgb saturation (P50). The latter include germline oxygen sensing pathway (HIF2A-PHD2-VHL) and other rare mutations. Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high-altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo-producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis stimulating agents, sodium-glucose cotransporter-2 inhibitors). Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation. MANAGEMENT Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non-clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low dose aspirin is often advised. FUTURE DIRECTIONS Advances in molecular hematology might result in better characterization of "idiopathic erythrocytosis" and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy.
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Affiliation(s)
- Naseema Gangat
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Natasha Szuber
- Department of Hematology, Université de Montréal, Montréal, Quebec, Canada
| | - Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
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24
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Maaziz N, Garrec C, Airaud F, Bobée V, Contentin N, Cayssials E, Rimbert A, Aral B, Bézieau S, Gardie B, Girodon F. Germline JAK2 E846D Substitution as the Cause of Erythrocytosis? Genes (Basel) 2023; 14:genes14051066. [PMID: 37239426 DOI: 10.3390/genes14051066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/01/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
The discovery in 2005 of the JAK2 V617F gain-of-function mutation in myeloproliferative neoplasms and more particularly in polycythemia vera has deeply changed the diagnostic and therapeutic approaches to polycythemia. More recently, the use of NGS in routine practice has revealed a large number of variants, although it is not always possible to classify them as pathogenic. This is notably the case for the JAK2 E846D variant for which for which questions remain unanswered. In a large French national cohort of 650 patients with well-characterized erythrocytosis, an isolated germline heterozygous JAK2 E846D substitution was observed in only two cases. For one of the patients, a family study could be performed, without segregation of the variant with the erythrocytosis phenotype. On the other hand, based on the large UK Biobank resource cohort including more than half a million UK participants, the JAK2 E846D variant was found in 760 individuals, associated with a moderate increase in hemoglobin and hematocrit values, but with no significant difference to the mean values of the rest of the studied population. Altogether, our data as well as UK Biobank cohort analyses suggest that the occurrence of an absolute polycythemia cannot be attributed to the sole demonstration of an isolated JAK2 E846D variant. However, it must be accompanied by other stimuli or favoring factors in order to generate absolute erythrocytosis.
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Affiliation(s)
- Nada Maaziz
- Laboratoire de Génétique Chromosomique et Moléculaire, Pôle Biologie, CHU de Dijon, 21000 Dijon, France
| | - Céline Garrec
- Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France
| | - Fabrice Airaud
- Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France
| | - Victor Bobée
- Service d'Hématologie Biologique, CHU de Rouen, 76000 Rouen, France
| | | | - Emilie Cayssials
- Service d'Oncologie Hématologique, CHU de Poitiers, 86000 Poitiers, France
| | - Antoine Rimbert
- l'Institut du Thorax, INSERM, Nantes Université, CHU Nantes, 44300 Nantes, France
| | - Bernard Aral
- Laboratoire de Génétique Chromosomique et Moléculaire, Pôle Biologie, CHU de Dijon, 21000 Dijon, France
| | - Stéphane Bézieau
- Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France
- l'Institut du Thorax, INSERM, Nantes Université, CHU Nantes, 44300 Nantes, France
| | - Betty Gardie
- l'Institut du Thorax, INSERM, Nantes Université, CHU Nantes, 44300 Nantes, France
- Ecole Pratique des Hautes Etudes, Université PSL, 75006 Paris, France
- Laboratory of Excellence GR-Ex, Imagine Institute, 75015 Paris, France
| | - François Girodon
- Laboratory of Excellence GR-Ex, Imagine Institute, 75015 Paris, France
- Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, 21000 Dijon, France
- Inserm U1231, Université de Bourgogne, 21000 Dijon, France
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25
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Babakhanlou R, Verstovsek S, Pemmaraju N, Rojas-Hernandez CM. Secondary erythrocytosis. Expert Rev Hematol 2023; 16:245-251. [PMID: 36927204 DOI: 10.1080/17474086.2023.2192475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
INTRODUCTION Erythrocytosis is associated with an elevation of the hemoglobin level above 16.5 g/dL in men and above 16 g/dL in women and an elevation of the hematocrit level above 49% in men and > 48% in women. In primary erythrocytosis, the defect is a clonal disorder in the myeloid compartment of the bone marrow, leading to an increased red cell production. Secondary erythrocytosis is the result of external stimuli to the bone marrow, leading to the production of red cells in excess. Secondary erythrocytosis is more common than primary erythrocytosis and has a broad differential diagnosis. AREAS COVERED This review will discuss secondary erythrocytosis, its causes, clinical presentation, and both diagnostic and therapeutic approaches. EXPERT OPINION Although secondary erythrocytosis is more common than PV, there are still challenges and difficulties associated with the distinction between these two conditions. Moreover, there is a paucity of data and guidance when it comes to the management of certain congenital and acquired conditions. A pragmatic approach is recommended in order to identify the cause for this condition. Treatment should be directed at the management of the underlying cause.
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Affiliation(s)
- Rodrick Babakhanlou
- Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Srdan Verstovsek
- Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Naveen Pemmaraju
- Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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26
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Ntounis T, Zioutos KA, Koutras A, Prokopakis I, Fasoulakis Z, Sapantzoglou I, Perros P, Samara AA, Spanoudakis E, Valsamaki A, Krouskou SE, Nikolettos K, Palios VC, Mousios P, Goula K, Konis K, Chionis A, Kontomanolis EN. Portal Vein Thrombosis after C-Section in a Patient with Polycythemia Vera (PV) Due to Pregnancy and Iron Deficiency Anemia (IDA). Clin Pract 2022; 12:1069-1077. [PMID: 36547117 PMCID: PMC9776423 DOI: 10.3390/clinpract12060109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Polycythemia vera (PV) is one of the three main classic disorders of Philadelphia-negative myeloproliferative neoplasms (MPNs), with the other two being essential thrombocythemia (ET) and primary myelofibrosis (PMF). PV may develop (15%) in women of childbearing age (15-45 years), with an anticipated rate of roughly 0.3 per 100,000 people, although maintaining a male to female ratio predominance of about 2:1 and a peak prevalence in the sixth and seventh decades of life. Without always being presented with its actual clinical manifestations due to pregnancy itself, and most commonly due to iron deficiency, PV can be frequently missed and therefore belatedly diagnosed. We describe the case of a primipara woman in her 40s, without risk factors for thrombosis, who developed a portal vein occlusion 1.5 month postpartum after C-section and who had a delayed diagnosis of PV.
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Affiliation(s)
- Thomas Ntounis
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Konstantinos A. Zioutos
- Department of Obstetrics and Gynecology-Kastoria General Hospital, Mavriotissis 33, 52100 Kastoria, Greece
| | - Antonios Koutras
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
- Correspondence:
| | - Ioannis Prokopakis
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Zacharias Fasoulakis
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Ioakeim Sapantzoglou
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Paraskevas Perros
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Lourou and Vasilissis Sofias Ave, 11528 Athens, Greece
| | - Athina A. Samara
- Department of Embryology, University General Hospital of Larissa, Mezourlo, 41110 Larissa, Greece
| | - Emmanouil Spanoudakis
- Department of Hematology, Democritus University of Thrace, University General Hospital of Alexandroupolis, 6th km Alexandroupolis–Makris, Dragana, 68100 Alexandroupolis, Greece
| | - Asimina Valsamaki
- Department of Internal Medicine, General Hospital of Larisa, Tsakalof 1, 41221 Larisa, Greece
| | - Sevasti-Effraimia Krouskou
- Department of Obstetrics and Gynecology, Democritus University of Thrace, 6th km Alexandroupolis–Makris, 68100 Alexandroupolis, Greece
| | - Konstantinos Nikolettos
- Department of Obstetrics and Gynecology, Democritus University of Thrace, 6th km Alexandroupolis–Makris, 68100 Alexandroupolis, Greece
| | | | - Paschalis Mousios
- Department of Obstetrics and Gynecology, University General Hospital of Larissa, Mezourlo, 41110 Larissa, Greece
| | - Kallirroi Goula
- Department of Pathology, Alexandra General Hospital of Athens, 11528 Athens, Greece
| | - Kyriakos Konis
- Department of Obstetrics and Gynecology, General Hospital of Arta, 47100 Arta, Greece
| | - Athanasios Chionis
- Department of Gynecology, Laiko General Hospital of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Emmanuel N. Kontomanolis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, 6th km Alexandroupolis–Makris, 68100 Alexandroupolis, Greece
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27
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[Chinese guideline for the diagnosis and treatment of polycythemia vera (2022)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2022; 43:537-541. [PMID: 36709129 PMCID: PMC9395570 DOI: 10.3760/cma.j.issn.0253-2727.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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28
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La enfermedad de Graves-Basedow: causa de policitemia en el adolescente. A propósito de un caso. Semergen 2022; 48:101809. [DOI: 10.1016/j.semerg.2022.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/01/2022] [Indexed: 11/22/2022]
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Rampotas A, Hargreaves R, McLornan DP. Challenges of diagnosing and managing pre-fibrotic myelofibrosis: A case-based and practical approach. Best Pract Res Clin Haematol 2022; 35:101378. [PMID: 36333067 DOI: 10.1016/j.beha.2022.101378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 08/19/2022] [Indexed: 11/02/2022]
Abstract
Pre-Fibrotic Myelofibrosis is a frequently under-recognised entity that has distinct features separate to those of both Essential Thrombocythaemia and overt Primary Myelofibrosis. Misdiagnosis is relatively common due to subtle differences in bone marrow trephine morphology and multidisciplinary approaches are required. The clinical phenotype and disease course is heterogeneous and hence management approaches tend to vary widely. Although patients may initially be asymptomatic, disease-related complications can include troublesome symptom burdens, increased incidence of both arterial and venous thromboses, haemorrhage, anaemia and an inherent risk of disease evolution to either overt myelofibrosis or blastic phase disease. Specific prognostic tools with high discriminatory power are lacking. Within this review we use case-based approaches to review the current literature, highlight challenges in both diagnostics and disease management and suggest contemporary approaches to improve patient outcomes.
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Affiliation(s)
- Alexandros Rampotas
- Department of Haematology, University College London Hospitals, 250 Euston Road, London, UK
| | - Rupen Hargreaves
- Department of Haematology, University College London Hospitals, 250 Euston Road, London, UK
| | - Donal P McLornan
- Department of Haematology, University College London Hospitals, 250 Euston Road, London, UK.
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30
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Chen R, Shi X, Wang L, Wang X, Wei J, Kang X, Du F, Gao S, Yang F, Jiang W. Essential thrombocythemia with CALR mutation and recurrent stroke: two case reports and literature review. Ther Adv Neurol Disord 2022; 15:17562864221092093. [PMID: 35498365 PMCID: PMC9052815 DOI: 10.1177/17562864221092093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
Cerebrovascular events, especially ischemic stroke, are common complications of
essential thrombocythemia (ET). Compared to JAK2V617 F mutation, CALR mutation
is considered as a lower risk factor of thrombosis in ET. Until now stroke in ET
with CALR mutation has rarely been reported. We retrospectively investigated
patients diagnosed with stroke and ET in Xijing hospital of Air Force Medical
University, from 2015 to 2021. Clinical characteristics (including medical
history, physical and auxiliary examination and prognosis) were recorded and
associated literature was reviewed. Among the 19 patients diagnosed with both
stroke and ET we retrieved, two cases were positive for CALR mutation. In case
1, a 71-year-old man developed the first ischemic event under the treatment of
anagrelide, followed by a hemorrhagic stroke after receiving aspirin and
clopidogrel for 4 months. Ischemic stroke reccurred and the neurological
function deteriorated progressively. In case 2, a 44-year-old man presented with
hypoxic-ischemic encephalopathy due to serious myocardial infarction and
subsequent brain imaging indicated three times of ischemic stroke events. The
patient gradually got improved through cytoreductive and antiplatelet therapy
and rehabilitation. Literature review showed that cerebrovascular event is the
most serious neurological complication of ET and may be the presenting symptom.
Most of reported cases with ET accompanied by stroke were positive for JAK2 V617
F mutation, but with rare CALR mutation. ET with CALR mutation can cause both
hemorrhagic and ischemic stroke. Identification of such rare causes of stroke is
of great importance to provide precise and individualized prevention and
therapy.
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Affiliation(s)
- Rong Chen
- Department of Neurology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xiaodan Shi
- Department of Neurology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Luojun Wang
- Department of Neurology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xuan Wang
- Department of Neurology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Jingya Wei
- Department of Neurology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xiaogang Kang
- Department of Neurology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Fang Du
- Department of Neurology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Shan Gao
- Department of Hematology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Fang Yang
- Department of Neurology, Xijing Hospital, Air Force Medical University, 127 Changle West Road, Xi’an 710032, Shaanxi Province, China
| | - Wen Jiang
- Department of Neurology, Xijing Hospital, Air Force Medical University, 127 Changle West Road, Xi’an 710032, Shaanxi Province, China
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31
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Treatment options and pregnancy management for patients with PV and ET. Int J Hematol 2022; 115:659-671. [PMID: 35394259 DOI: 10.1007/s12185-022-03336-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/20/2022] [Accepted: 03/21/2022] [Indexed: 10/18/2022]
Abstract
Polycythemia vera (PV) and essential thrombocythemia (ET) are the two most common subtypes of Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). PV results in erythrocytosis and ET in thrombocytosis. The discovery of JAK2 mutations in the majority of patients with MPN over the last 2 decades has led to the development of JAK inhibitors. Because PV and ET progress relatively slowly, the main treatment strategy for these two diseases is to prevent thrombotic complications. The first-line agent for both PV and ET is hydroxyurea, although some patients are intolerant or refractory to this compound and need other treatment options. Notably, hydroxyurea is contraindicated during pregnancy. In addition to JAK inhibitors, several new agents, such as HDAC inhibitors, LSD1 inhibitors, MDM2 inhibitors and hepcidin mimetics, have been developed as treatment options. Classical agents, such as busulfan and interferon, are still used to treat patients with PV or ET as well. Based on this context, treatment options and pregnancy management for patients with PV or ET are discussed in this review.
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Potential limitations of diagnostic standard codes to distinguish polycythemia vera and secondary erythrocytosis. Sci Rep 2022; 12:4674. [PMID: 35304527 PMCID: PMC8933419 DOI: 10.1038/s41598-022-08606-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/25/2022] [Indexed: 11/18/2022] Open
Abstract
Red cell overproduction is seen in polycythemia vera (PV), a bone marrow myeloproliferative neoplasm characterized by trilinear cell proliferation (WBC, platelets), as well as in secondary erythrocytosis (SE), a group of heterogeneous disorders characterized by elevated EPO gene transcription. We aimed to verify the concordance of the International Classification of Diseases (ICD) code-based diagnosis of “polycythemia” or “erythrocytosis” with the true clinical diagnosis of these conditions. We retrospectively reviewed the electronic medical records (January 1, 2005, to December 31, 2016) of adult patients with ICD codes of polycythemia and/or erythrocytosis who had testing done for the presence of the JAK2V617F mutation. We verified the accuracy of the ICD code-based diagnoses by meticulous chart review and established whether these patients fulfilled the criteria by the evaluating physician for PV or SE and according to the World Health Organization 2016 diagnostic guidelines. The reliability of ICD coding was calculated using Cohen's kappa. We identified and chart reviewed a total of 578 patient records. Remarkably, 11% of the patients had concurrent diagnosis codes for PV and SE and were unable to be classified appropriately without individual chart review. The ICD code-based diagnostic system led to misidentification in an important fraction of cases. This represents a problem for the detection of PV or SE cases by ICD-based registries and their derived studies. Research based exclusively on ICD codes could have a potential impact on patient care and public health, and limitations must be weighed when research findings are conveyed.
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Nurgat Z, Lawrence M. Management of Myeloproliferative Neoplasms (MPNs). J Oncol Pharm Pract 2022; 28:1400-1410. [PMID: 35296179 DOI: 10.1177/10781552221082293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE To provide up to date guidance, practice recommendations and highlight barriers to medication adherence in the long-term management of chronic myeloproliferative neoplasms (MPNs). AIM Current drug therapy for MPN is not curative and has not been shown to prolong survival. The main indication for treatment is the prevention of thrombosis and medication adherence remains a challenge in this group of patients. Identifying potentially modifiable barriers to medication adherence including primary nonadherence and non-persistent adherence enables timely interventions to be put in place and improve overall medication adherence. METHODS A systematic review of peer-reviewed literature and expert opinions was performed using electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) that were searched for articles reporting MPN and medication adherence. Discussions A case vignette is discussed throughout the article and expert opinion with international peer reviewed guidelines that are authored to support clinical decision making at the point of care were utilised. The evidence base was combined with more practical/clinical (data based) insight from real world clinical practice. Adoption of a broad range of digital health care activities and services in the health care system (telehealth applications) by the advanced practice providers (Non-Medical Prescribers-NMPs) in MPN clinics included medication prescribing and management, oral drug compliance and adherence evaluations, interventions, chronic care management, counselling and patient education on treatments. CONCLUSION Current drug therapy for MPN is neither curative nor has it been shown to prolong survival, and medication adherence remains a challenge in this group of patients. The longevity of the patients' disease course may contribute to the high risk of non-adherence in this patient cohort. Poor adherence to long-term therapies severely compromises the effectiveness of treatment. Adherence interventions should be tailored to the needs of the patient in order to achieve maximum impact. Interventions aimed at improving adherence provide the best experience and outcome for the patient and their families and can have a profound impact on the quality of life and mitigation of disease consequences.
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Affiliation(s)
- Zubeir Nurgat
- Lead Pharmacist, Haematology / Oncology & Clinical Trials, Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent, UK
| | - Myer Lawrence
- Lead Nurse Acute Oncology Service, East Suffolk and North Essex NHS Foundation Trust, Colchester General & Ipswich Hospital, England, UK
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34
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McLornan DP, Hargreaves R, Hernández-Boluda JC, Harrison CN. How I manage myeloproliferative neoplasm-unclassifiable: Practical approaches for 2022 and beyond. Br J Haematol 2022; 197:407-416. [PMID: 35191542 DOI: 10.1111/bjh.18087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/19/2022] [Accepted: 01/28/2022] [Indexed: 12/15/2022]
Abstract
Myeloproliferative neoplasm (MPN)-unclassifiable (MPN-U) or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. Disease incidence is difficult to define but likely represents close to 5% of all MPNs when strict World Health Organisation (WHO) criteria are applied. Dynamic review over time is required to assess if the disease can be re-classified into another MPN entity. A diagnosis of MPN-U leads to many challenges for both the patient and physician alike including lack of agreed monitoring and therapeutic guidelines, validated prognostic markers and licenced therapies coupled with exclusion from clinical trials. MPN-U has an inherent risk of an aggressive clinical course and transformation in some but who, and when to treat in the chronic phase, including identifying who may require more aggressive therapy at an earlier stage, remains elusive. Moreover, despite the significant thrombotic risk, there is no agreement on systematic primary thromboprophylaxis. We hereby provide a contemporary overview of MPN-U in addition to four illustrative cases providing our collective suggested approaches to clinical challenges.
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Affiliation(s)
- Donal P McLornan
- Department of Haematology, 4th Floor Southwark Wing, Guy's and St. Thomas' NHS Foundation Trust, Great Maze Pond, London, UK.,Department of Haematology, University College London Hospitals, London, UK
| | - Rupen Hargreaves
- Department of Haematology, University College London Hospitals, London, UK
| | | | - Claire N Harrison
- Department of Haematology, 4th Floor Southwark Wing, Guy's and St. Thomas' NHS Foundation Trust, Great Maze Pond, London, UK
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35
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Remenyi G, Bereczky Z, Gindele R, Ujfalusi A, Illes A, Udvardy M. rs779805 Von Hippel-Lindau Gene Polymorphism Induced/Related Polycythemia Entity, Clinical Features, Cancer Association, and Familiar Characteristics. Pathol Oncol Res 2021; 27:1609987. [PMID: 34899081 PMCID: PMC8660678 DOI: 10.3389/pore.2021.1609987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/03/2021] [Indexed: 11/13/2022]
Abstract
Increased red blood cell count may result from primary erythrocytosis (polycythemia vera), but it is often due to secondary causes with increased erythropoietin levels. Secondary erythrocytosis may also be congenital due to different gene mutations of hemoglobin, hemoglobin stabilization proteins, EPO receptors, or oxygen sensing pathways. Von Hippel- Lindau gene mutation causes altered tissue oxygen sensation in VHL disease, usually with normal hemoglobin. Germline VHL mutations associate with classical VHL disease and represent genetic susceptibility for pheochromocytoma. VHL polymorphisms are mostly considered an innocent phenomenon. Still, some data indicate that these polymorphisms are not always harmless and can occur with prostate, renal, and colon cancer or even with isolated erythrocytosis. Seventy-eight patients referred to our department with elevated hemoglobin were screened for VHL mutations. There were no classical somatic VHL mutations. However, we found heterozygous (GA) or homozygous (AA) rs779805 VHL c.-195G>A polymorphism accompanied by erythrocytosis. These patients are Jak-2 negative, with normal or elevated EPO levels, sometimes with family accumulations and often phlebotomy needs, and in some cases with malignancies in the family. No other cause of erythrocytosis was found. We use phlebotomy regularly, and for those with cardiovascular risk factors, we recommend aspirin.
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Affiliation(s)
- Gyula Remenyi
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsuzsanna Bereczky
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Réka Gindele
- Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Aniko Ujfalusi
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Arpad Illes
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Miklos Udvardy
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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36
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NGS Evaluation of a Bernese Cohort of Unexplained Erythrocytosis Patients. Genes (Basel) 2021; 12:genes12121951. [PMID: 34946900 PMCID: PMC8701725 DOI: 10.3390/genes12121951] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/23/2021] [Accepted: 12/01/2021] [Indexed: 01/06/2023] Open
Abstract
(1) Background: Clinical and molecular data on patients with unexplained erythrocyto-sis is sparse. We aimed to analyze the clinical and molecular features of patients with congenital erythrocytosis in our tertiary reference center. (2) Methods: In 34 patients with unexplained erythrocytosis, a 13-gene Next-Generation Sequencing erythrocytosis panel developed at our center was conducted. (3) Results: In 6/34 (18%) patients, eight different heterozygous gene variants were found. These patients were, therefore, diagnosed with congenital erythrocytosis. Two patients had two different gene variants each. All variants were characterized as variants of unknown significance as they had not previously been described in the literature. The rest of the patients (28/34, 82%) had no detected gene variants. (4) Conclusions: Our experience shows that the NGS panel can be helpful in determining the reasons for persistent, unexplained erythrocytosis. In our cohort of patients with erythrocytosis, we identified some, thus far unknown, gene variants which may explain the clinical picture. However, further investigations are needed to determine the relationship between the molecular findings and the phenotype.
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37
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Gangat N, Oliveira JL, Hoyer JD, Patnaik MM, Pardanani A, Tefferi A. High-oxygen-affinity hemoglobinopathy-associated erythrocytosis: Clinical outcomes and impact of therapy in 41 cases. Am J Hematol 2021; 96:1647-1654. [PMID: 34633117 DOI: 10.1002/ajh.26375] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 12/18/2022]
Abstract
We describe presenting features, treatment strategies, and follow-up events involving 41 patients (median age 39 years, range 1-81; 54% males) with high oxygen affinity (HOA) hemoglobinopathy-associated erythrocytosis, seen at our institution (1973-2020). Thirty-four (83%) patients carried β-chain (13 Malmo, 4 Olympia, 3 San Diego, 2 Wood) and 7 (17%) α-chain (4 Dallas and one each Columbia-Missouri, Jackson, and Wayne) variants. Median (range) hemoglobin (Hgb)/hematocrit (Hct), serum erythropoietin and p50 were 18 g/dL/52.9% (16-21.9/48-66), 10.4 mIU (4-36.3), and 20 mmHg (12-25), respectively. Family history was documented in 24 patients and history of thrombosis in two (5%). Treatment included phlebotomy in 23 and antiplatelet therapy in 21 patients. At a median follow-up of 10 years, 23 (56%) patients reported one or more symptoms that were thought to be related to their increased Hct while thrombosis was documented in 10 (24%) patients. Neither Hgb/Hct level nor active phlebotomy showed a significant correlation with either thrombotic or nonthrombotic symptoms (p > .1 in all instances). Among 23 pregnancies recorded, 78% resulted in live births and no fetal loss was attributed to erythrocytosis. The current study does not implicate Hgb/Hct level as a major contributor of morbidity in HOA hemoglobinopathy-associated erythrocytosis and suggests limited therapeutic value for phlebotomy.
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Affiliation(s)
- Naseema Gangat
- Division of Hematology, Department of Internal Medicine Mayo Clinic Rochester Minnesota USA
| | - Jennifer L. Oliveira
- Division of Hematopathology, Department of Laboratory Medicine Mayo Clinic Rochester Minnesota USA
| | - James D. Hoyer
- Division of Hematopathology, Department of Laboratory Medicine Mayo Clinic Rochester Minnesota USA
| | - Mrinal M. Patnaik
- Division of Hematology, Department of Internal Medicine Mayo Clinic Rochester Minnesota USA
| | - Animesh Pardanani
- Division of Hematology, Department of Internal Medicine Mayo Clinic Rochester Minnesota USA
| | - Ayalew Tefferi
- Division of Hematology, Department of Internal Medicine Mayo Clinic Rochester Minnesota USA
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38
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Janmohamed IK, Sondh RS, Ahmed H, Afzal MB, Tyson N, Harky A. Polycythaemia Vera and Coronary Artery Bypass Graft Surgery: A Systematic Review of the Literature. Heart Lung Circ 2021; 31:304-312. [PMID: 34794873 DOI: 10.1016/j.hlc.2021.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 09/15/2021] [Accepted: 10/14/2021] [Indexed: 12/01/2022]
Abstract
OBJECTIVES Polycythaemia vera (PV) is a condition that may potentially put patients undergoing cardiac surgery at an increased risk of bleeding and thrombosis; however, there is currently a paucity of literature regarding the management of these patients. We aim to examine the literature in this systematic review to indicate the interventions that may be considered to minimise complications. METHODS We conducted a literature search using keywords and MeSH terms to identify articles discussing PV and cardiac surgery. The studies were identified and qualitatively analysed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. RESULTS In total, 10 case reports representing 11 patients were identified for this systematic review and were included in qualitative analysis. 63.6% of patients had preoperative intermittent phlebotomy, and the majority of patients received postoperative therapy that involved one antiplatelet and one anticoagulant. Generous perioperative fluid management, phlebotomy, preservation of core body temperature, early extubation, monitoring of myocardial ischaemia, infarction and vascular events, intense chest physiotherapy and patient mobilisation are important to consider to reduce the risk of complications arising from surgery. CONCLUSION These considerations should be systematically discussed in a multidisciplinary team, where the acute surgical need can be balanced appropriately against the risk of haemorrhage and thrombosis.
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Affiliation(s)
| | - Rajan Singh Sondh
- St George's Hospital Medical School, University of London, London, UK
| | - Hasan Ahmed
- Imperial College London, Department of Medicine, London, UK
| | | | - Nathan Tyson
- Nottingham University Hospitals, Department of Cardiac Surgery, UK
| | - Amer Harky
- Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, UK.
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39
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Thomas S, Krishnan A. Platelet Heterogeneity in Myeloproliferative Neoplasms. Arterioscler Thromb Vasc Biol 2021; 41:2661-2670. [PMID: 34615371 PMCID: PMC8551046 DOI: 10.1161/atvbaha.121.316373] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/20/2021] [Indexed: 12/24/2022]
Abstract
Myeloproliferative neoplasms (MPNs) are a group of malignant disorders of the bone marrow where a dysregulated balance between proliferation and differentiation gives rise to abnormal numbers of mature blood cells. MPNs encompass a spectrum of disease entities with progressively more severe clinical features, including complications with thrombosis and hemostasis and an increased propensity for transformation to acute myeloid leukemia. There is an unmet clinical need for markers of disease progression. Our understanding of the precise mechanisms that influence pathogenesis and disease progression has been limited by access to disease-specific cells as biosources. Here, we review the landscape of MPN pathology and present blood platelets as potential candidates for disease-specific understanding. We conclude with our recent work discovering progressive platelet heterogeneity by subtype in a large clinical cohort of patients with MPN.
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Affiliation(s)
- Sally Thomas
- Department of Oncology and Metabolism, University of Sheffield and Department of Haematology, Royal Hallamshire Hospital, United Kingdom (S.T.)
| | - Anandi Krishnan
- Department of Pathology, Stanford University School of Medicine, CA (A.K.)
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40
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Cross NCP, Godfrey AL, Cargo C, Garg M, Mead AJ. The use of genetic tests to diagnose and manage patients with myeloproliferative and myeloproliferative/myelodysplastic neoplasms, and related disorders. Br J Haematol 2021; 195:338-351. [PMID: 34409596 DOI: 10.1111/bjh.17766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 07/28/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Nicholas C P Cross
- Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
- Faculty of Medicine, University of Southampton, Southampton, UK
| | - Anna L Godfrey
- Haematopathology & Oncology Diagnostics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Catherine Cargo
- Haematological Malignancy Diagnostic Service, Leeds Cancer Centre, St James's University Hospital, Leeds, UK
| | - Mamta Garg
- Leicester Royal Infirmary, Infirmary Square, Leicester, UK
| | - Adam J Mead
- MRC Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
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41
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Sassi H, Menif S, Ammar SB, Farrah A, Othmen HBH, Amouri H. JAK2 p.(V617F) mutation in Tunisian myeloproliferative neoplasms and its genotype-phenotype correlation. Pan Afr Med J 2021; 39:194. [PMID: 34603575 PMCID: PMC8464212 DOI: 10.11604/pamj.2021.39.194.28307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/07/2021] [Indexed: 11/11/2022] Open
Abstract
Myeloproliferative neoplasms (MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The relationship between JAK2 p.(V617F) mutation and MPNs was first described in 2005. The purpose of this study was to determine the prevalence of JAK2 p.(V617F) mutation in Tunisian patients assessed for MPNs and try to set a genotype-phenotype correlation. A retrospective study was conducted between January 2015 and April 2019. We collected the clinical data of all patients with MPNs suspicion or atypical splanchnic vein thrombosis (SVT). JAK2 p.(V617F) mutation was detected by allele specific real-time quantitative fluorescence PCR (AS-qPCR). We gathered 974 patients who underwent molecular analysis, 55.5% of them were male and 44.5% were female. The median age of all studied patients was 56 years. JAK2 p.(V617F) was found in 349 (35.8%) of total enrolled cases. It was reported in 44%, 37%, 29% and 25% of all patients diagnosed as having respectively ET, PV, PMF and atypical SVT. JAK2 p.(V617F) was negative in 62.2% of patients addressed for suspicion of PV. There was a significant positive correlation between the JAK2 p.(V617F) mutation status, age, gender, white blood cell counts and platelet counts. To our best knowledge, this is the first vast investigation of JAK2 p.(V617F) variant in Tunisia and North Africa with the lowest mutation rate in entire cohort and MPNs subgroups, underlying a specific presentation of this mutation. It is considered as an essential marker of MPNs’ diagnosis and prognosis and is associated with differences in the phenotype of these disorders, helpful for the follow-up of these patients.
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Affiliation(s)
- Hela Sassi
- Laboratory of Molecular and Cellular Hematology, Pasteur Institute of Tunis, University Tunis El Manar, 1002, Tunis, Tunisia.,Faculty of Medicine of Tunis, University Tunis El Manar, 1006, Tunis, Tunisia
| | - Samia Menif
- Laboratory of Molecular and Cellular Hematology, Pasteur Institute of Tunis, University Tunis El Manar, 1002, Tunis, Tunisia.,Faculty of Medicine of Tunis, University Tunis El Manar, 1006, Tunis, Tunisia
| | - Safa Ben Ammar
- Laboratory of Molecular and Cellular Hematology, Pasteur Institute of Tunis, University Tunis El Manar, 1002, Tunis, Tunisia.,Faculty of Medicine of Tunis, University Tunis El Manar, 1006, Tunis, Tunisia
| | - Ahlem Farrah
- Laboratory of Molecular and Cellular Hematology, Pasteur Institute of Tunis, University Tunis El Manar, 1002, Tunis, Tunisia
| | - Hend Ben Hadj Othmen
- Laboratory of Molecular and Cellular Hematology, Pasteur Institute of Tunis, University Tunis El Manar, 1002, Tunis, Tunisia
| | - Hassiba Amouri
- Laboratory of Molecular and Cellular Hematology, Pasteur Institute of Tunis, University Tunis El Manar, 1002, Tunis, Tunisia
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42
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Olivas-Martinez A, Corona-Rodarte E, Nuñez-Zuno A, Barrales-Benítez O, Oca DMMD, Mora JDDL, León-Aguilar D, Hernández-Juárez HE, Tuna-Aguilar E. Causes of erythrocytosis and its impact as a risk factor for thrombosis according to etiology: experience in a referral center in Mexico City. Blood Res 2021; 56:166-174. [PMID: 34462407 PMCID: PMC8478616 DOI: 10.5045/br.2021.2021111] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/23/2021] [Accepted: 07/30/2021] [Indexed: 01/14/2023] Open
Abstract
Background Thrombotic events are well documented in primary erythrocytosis, but it is uncertain if secondary etiologies increase the risk of thrombosis. This study aimed to determine the causes of erythrocytosis and to identify its impact as a risk factor for thrombosis. Methods Data were obtained from patients with erythrocytosis between 2000 and 2017 at a referral hospital in Mexico City. Erythrocytosis was defined according to the 2016 WHO classification. Time to thrombosis, major bleeding, or death were compared among groups of patients defined by the etiology of erythrocytosis using a Cox regression model, adjusting for cardiovascular risk factors. Results In total, 330 patients with erythrocytosis were studied. The main etiologies of erythrocytosis were obstructive sleep apnea (OSA) in 29%, polycythemia vera (PV) in 18%, and chronic lung disease (CLD) in 9.4% of the patients. The incidence rate of thrombosis was significantly higher in patients with PV and CLD than that in patients with OSA (incidence rates of 4.51 and 6.24 vs. 1.46 cases per 100 person-years, P=0.009), as well as the mortality rate (mortality rates of 2.72 and 2.43 vs. 0.17 cases per 100 person-years, P =0.003). Conclusion The risk of thrombosis in CLD with erythrocytosis was comparable to that in patients with PV. Further larger-scale studies are needed to confirm these findings and evaluate the benefits of preventive management of COPD with erythrocytosis similar to PV.
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Affiliation(s)
- Antonio Olivas-Martinez
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México.,Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Eduardo Corona-Rodarte
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Adrián Nuñez-Zuno
- Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, México
| | - Olga Barrales-Benítez
- Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - Jesús Delgado-de la Mora
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Diana León-Aguilar
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Hilda Elizeth Hernández-Juárez
- Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Elena Tuna-Aguilar
- Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Abstract
Venous thromboembolism (VTE) is increasingly recognised in primary and secondary care practice. The arrival of direct oral anticoagulants (DOACs) has made the management of VTE easier and more convenient. Some patients established on DOACs may need screening for underlying thrombophilias as certain thrombophilic conditions are known to confer a higher thrombosis risk, although the guidelines for when and how to test for a thrombophilia, especially in a patient taking a DOAC, are unclear. This literature review aims to examine when thrombophilia screening should take place in a patient already taking a DOAC, the effect of DOACs on thrombophilia tests, and analyse whether DOACs are safe and effective in both inherited and acquired thrombophilias.
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Affiliation(s)
- Jennifer Darlow
- Manchester Royal Infirmary, Manchester, UK; equal first authors.
| | - Holly Mould
- University of Manchester, Manchester, UK; equal first authors
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44
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Aylan Gelen S, Sarper N, Zengin E, Tahsin İ, Azizoğlu M. Clinical Characteristics of Pediatric Patients with Congenital Erythrocytosis: A Single-Center Study. Indian J Hematol Blood Transfus 2021; 38:366-372. [PMID: 35496967 PMCID: PMC9001768 DOI: 10.1007/s12288-021-01484-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 08/19/2021] [Indexed: 11/29/2022] Open
Abstract
Although congenital erythrocytosis (CE), an inherited disorder, impairs pediatric quality of life, physicians often overlook high hemoglobin (Hgb) levels and its symptoms due to lack of knowledge of age-adjusted pediatric Hgb levels and CE's rarity. In a retrospective, single-center study, data from hospital records of pediatric patients diagnosed with CE were evaluated. Twenty-six patients from 25 families (80.8% male) had been diagnosed with CE in 20 years, at a mean age of 14.9 ± 2.8 years (8.3-17.8) and with a mean Hgb level of 17.36 ± 1.44 g/dL (14.63-22.1). No serum erythropoietin levels exceeded the reference levels. Although the most common symptom was headache (85%), 38% of patients presented with at least one gastrointestinal symptom (e.g., nausea, vomiting, abdominal pain, and rectal bleeding), and 54% exhibited plethora. No patient had leukocytosis, thrombocytosis, JAK2 mutation; capillary oxygen saturation, venous blood gas analysis, and Hgb electrophoresis revealed no abnormalities. While 34.6% of patients had family histories of CE, 42.3% had 15-45-year-old relatives who had experienced myocardial infarction, stroke, and/or sudden death. Aspirin was routinely prescribed, and phlebotomy was performed when hyperviscosity symptoms were present. To detect CE, physicians should consider age-adjusted normal Hgb levels in children. Pediatric patients with CE may also present with gastrointestinal symptoms. Although no thrombotic episode occurred among the patients, their family histories included life-threatening thrombotic episodes, even in adolescents.
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Affiliation(s)
- Sema Aylan Gelen
- Division of Pediatric Hematology, Department of Pediatrics, Kocaeli University, Umuttepe, 41380 Kocaeli, Turkey
| | - Nazan Sarper
- Division of Pediatric Hematology, Department of Pediatrics, Kocaeli University, Umuttepe, 41380 Kocaeli, Turkey
| | - Emine Zengin
- Division of Pediatric Hematology, Department of Pediatrics, Kocaeli University, Umuttepe, 41380 Kocaeli, Turkey
| | - İnci Tahsin
- Division of Pediatric Hematology, Department of Pediatrics, Kocaeli University, Umuttepe, 41380 Kocaeli, Turkey
| | - Mehmet Azizoğlu
- Division of Pediatric Hematology, Department of Pediatrics, Kocaeli University, Umuttepe, 41380 Kocaeli, Turkey
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Mekraksakit P, Boonpheng B, Leelaviwat N, Duangkham S, Deb A, Kewcharoen J, Nugent K, Cheungpasitporn W. Risk factors and outcomes of post-transplant erythrocytosis among adult kidney transplant recipients: a systematic review and meta-analysis. Transpl Int 2021; 34:2071-2086. [PMID: 34412165 DOI: 10.1111/tri.14016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/05/2021] [Accepted: 08/02/2021] [Indexed: 11/28/2022]
Abstract
Post-transplant erythrocytosis (PTE) can occur in up to 10-16% after kidney transplant (KT). However, the post-transplant outcomes of recipients with PTE in the literature were conflicting. We performed systematic review and meta-analysis of published studies to evaluate risk factors of PTE as well as outcomes of recipients who developed PTE compared with controls. A literature search was conducted evaluating all literature from existence through February 2, 2021, using MEDLINE and EMBASE. Data from each study were combined using the random-effects model. (PROSPERO: CRD42021230377). Thirty-nine studies from July 1982 to January 2021 were included (7,099 KT recipients). The following factors were associated with PTE development: male gender (pooled RR = 1.62 [1.38, 1.91], I2 = 39%), deceased-donor KT (pooled RR = 1.18 [1.03, 1.35], I2 = 32%), history of smoking (pooled RR = 1.36 [1.11, 1.67], I2 = 13%), underlying polycystic kidney disease (PKD) (pooled RR=1.56 [1.21, 2.01], I2 =44%), and pretransplant dialysis (pooled RR=1.6 [1.02, 2.51], I2 =46%). However, PTE was not associated with outcomes of interest, including overall mortality, death-censored graft failure, and thromboembolism. Our meta-analysis demonstrates that male gender, deceased-donor KT, history of smoking, underlying PKD, and pretransplant dialysis were significantly associated with developing PTE. However, with proper management, PTE has no impact on prognosis of KT patients.
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Affiliation(s)
- Poemlarp Mekraksakit
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Boonphiphop Boonpheng
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Natnicha Leelaviwat
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Samapon Duangkham
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Anasua Deb
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Jakrin Kewcharoen
- Internal Medicine Residency Program, University of Hawaii, Honolulu, HI, USA
| | - Kenneth Nugent
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
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Hofstetter L, Rozen-Zvi B, Schechter A, Raanani P, Itzhaki O, Rahamimov R, Gafter-Gvili A. Post-transplantation erythrocytosis in kidney transplant recipients-A retrospective cohort study. Eur J Haematol 2021; 107:595-601. [PMID: 34370889 DOI: 10.1111/ejh.13696] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To characterize risk factors for the development of post-transplant erythrocytosis (PTE), and its long-term effect on mortality, graft failure, and thrombosis. METHODS Retrospective study including all kidney transplant recipients in Rabin Medical Center (RMC) during the years 2005-2014. The primary outcome was a composite outcome of all-cause mortality or graft failure at the end of follow-up. Secondary outcomes included death censored graft loss, venous thromboembolism, major adverse cardiovascular events, and mortality. A matched control group was also evaluated. Univariate and multivariate time-varying Cox model analyses were conducted for outcome evaluation. RESULTS A total of 1304 patients were included, 169 of whom were diagnosed with PTE (12.9%). PTE was associated with male gender, higher glomerular filtration rate (GFR), and polycystic kidney disease. PTE was found to be associated with a reduced risk of the primary outcome (HR 0.355, CI 95% 0.151-0.89, P = .027) in a univariate time-varying Cox analysis, but was not associated with the composite outcome in a multivariate analysis. There was no difference in the primary outcome when the PTE group was compared with the matched control. CONCLUSION PTE was not found to be associated with long-term outcomes of graft failure and poor survival.
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Affiliation(s)
- Liron Hofstetter
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Benaya Rozen-Zvi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Nephrology and Hypertension, Rabin Medical Center, Petah Tikva, Israel
| | - Amir Schechter
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Nephrology and Hypertension, Rabin Medical Center, Petah Tikva, Israel
| | - Pia Raanani
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oranit Itzhaki
- Medicine A, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
| | - Ruth Rahamimov
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Nephrology and Hypertension, Rabin Medical Center, Petah Tikva, Israel
| | - Anat Gafter-Gvili
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Medicine A, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
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McMullin MF. Genetic Background of Congenital Erythrocytosis. Genes (Basel) 2021; 12:genes12081151. [PMID: 34440325 PMCID: PMC8392557 DOI: 10.3390/genes12081151] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 01/14/2023] Open
Abstract
True erythrocytosis is present when the red cell mass is greater than 125% of predicted sex and body mass, which is reflected by elevated hemoglobin and hematocrit. Erythrocytosis can be primary or secondary and congenital or acquired. Congenital defects are often found in those diagnosed at a young age and with a family history of erythrocytosis. Primary congenital defects mainly include mutations in the Erythropoietin receptor gene but SH2B3 has also been implicated. Secondary congenital erythrocytosis can arise through a variety of genetic mechanisms, including mutations in the genes in the oxygen sensing pathway, with high oxygen affinity hemoglobin variants and mutations in other genes such as BPMG, where ultimately the production of erythropoietin is increased, resulting in erythrocytosis. Recently, mutations in PIEZ01 have been associated with erythrocytosis. In many cases, a genetic variant cannot be identified, leaving a group of patients with the label idiopathic erythrocytosis who should be the subject of future investigations. The clinical course in congenital erythrocytosis is hard to evaluate as these are rare cases. However, some of these patients may well present at a young age and with sometimes catastrophic thromboembolic events. There is little evidence to guide the management of congenital erythrocytosis but the use of venesection and low dose aspirin should be considered.
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Kristan A, Pajič T, Maver A, Režen T, Kunej T, Količ R, Vuga A, Fink M, Žula Š, Podgornik H, Anžej Doma S, Preložnik Zupan I, Rozman D, Debeljak N. Identification of Variants Associated With Rare Hematological Disorder Erythrocytosis Using Targeted Next-Generation Sequencing Analysis. Front Genet 2021; 12:689868. [PMID: 34349782 PMCID: PMC8327209 DOI: 10.3389/fgene.2021.689868] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/16/2021] [Indexed: 12/28/2022] Open
Abstract
An erythrocytosis is present when the red blood cell mass is increased, demonstrated as elevated hemoglobin and hematocrit in the laboratory evaluation. Congenital predispositions for erythrocytosis are rare, with germline variants in several genes involved in oxygen sensing (VHL, EGLN1, and EPAS1), signaling for hematopoietic cell maturation (EPOR and EPO), and oxygen transfer (HBB, HBA1, HBA2, and BPGM) that were already associated with the eight congenital types (ECYT1–8). Screening for variants in known congenital erythrocytosis genes with classical sequencing approach gives a correct diagnosis for only up to one-third of the patients. The genetic background of erythrocytosis is more heterogeneous, and additional genes involved in erythropoiesis and iron metabolism could have a putative effect on the development of erythrocytosis. This study aimed to detect variants in patients with yet unexplained erythrocytosis using the next-generation sequencing (NGS) approach, targeting genes associated with erythrocytosis and increased iron uptake and implementing the diagnostics of congenital erythrocytosis in Slovenia. Selected 25 patients with high hemoglobin, high hematocrit, and no acquired causes were screened for variants in the 39 candidate genes. We identified one pathogenic variant in EPAS1 gene and three novel variants with yet unknown significance in genes EPAS1, JAK2, and SH2B3. Interestingly, a high proportion of patients were heterozygous carriers for two variants in HFE gene, otherwise pathogenic for the condition of iron overload. The association between the HFE variants and the development of erythrocytosis is not clearly understood. With a targeted NGS approach, we determined an actual genetic cause for the erythrocytosis in one patient and contributed to better management of the disease for the patient and his family. The effect of variants of unknown significance on the enhanced production of red blood cells needs to be further explored with functional analysis. This study is of great significance for the improvement of diagnosis of Slovenian patients with unexplained erythrocytosis and future research on the etiology of this rare hematological disorder.
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Affiliation(s)
- Aleša Kristan
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tadej Pajič
- Department of Hematology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Clinical Biochemistry, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Aleš Maver
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tadeja Režen
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tanja Kunej
- Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Rok Količ
- Kemomed Research and Development, Kemomed Ltd., Ljubljana, Slovenia
| | - Andrej Vuga
- Kemomed Research and Development, Kemomed Ltd., Ljubljana, Slovenia
| | - Martina Fink
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.,Department of Hematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Špela Žula
- Department of Hematology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Helena Podgornik
- Department of Hematology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Saša Anžej Doma
- Department of Hematology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Irena Preložnik Zupan
- Department of Hematology, University Medical Centre Ljubljana, Ljubljana, Slovenia.,Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Damjana Rozman
- Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nataša Debeljak
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Vetluzhskaya M, Abramova A, Oganesyan K, Podzolkov V. Polycythemia vera as a rare cause of hypertension in a young man. BMJ Case Rep 2021; 14:14/6/e242008. [PMID: 34162611 DOI: 10.1136/bcr-2021-242008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Polycythemia vera (PV) is an orphan haematological disease and one of the most common myeloproliferative diseases, with the incidence rate of about 0.4-2.8 cases per 100 000 population per year. In patients, proliferation of all three haematopoietic lineages is observed, typically with the development of erythrocytosis. As a rule, PV occurs in patients aged 60-70 years, slightly more often in men. The main clinical signs of PV are weakness, significant burning sensation in fingers and palms due to the increased blood viscosity and microcirculation disorders, discomfort in the left hypochondrium due to splenomegaly at the background of extramedullary haematopoietic sites development, as well as gross vascular complications (thrombosis) of various localisation. Our clinical case represents a rare cardiac manifestation of the PV in a young man.
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Affiliation(s)
- Maria Vetluzhskaya
- Department of Faculty Therapy #2, I M Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Antonina Abramova
- Department of Faculty Therapy #2, I M Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Karine Oganesyan
- Internal Medicine Department of University Hospital #4, I M Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Valery Podzolkov
- Department of Faculty Therapy #2, I M Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
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Alzoubi B, Kharel A, Machhi R, Aziz F, Swanson KJ, Parajuli S. Post-transplant erythrocytosis after kidney transplantation: A review. World J Transplant 2021; 11:220-230. [PMID: 34164297 PMCID: PMC8218346 DOI: 10.5500/wjt.v11.i6.220] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023] Open
Abstract
Post-transplant erythrocytosis (PTE) is defined as persistently elevated hemoglobin > 17 g/dL or hematocrit levels > 51% following kidney transplantation, independent of duration. It is a relatively common complication within 8 months to 24 months post-transplantation, occurring in 8%-15% of kidney transplant recipients. Established PTE risk factors include male gender, normal hemoglobin/hematocrit pre-transplant (suggestive of robust native kidney erythropoietin production), renal artery stenosis, patients with a well-functioning graft, and dialysis before transplantation. Many factors play a role in the development of PTE, however, underlying endogenous erythropoietin secretion pre-and post-transplant is significant. Other contributory factors include the renin-angiotensin- aldosterone system, insulin-like growth factors, endogenous androgens, and local renal hypoxia. Most patients with PTE experience mild symptoms like malaise, headache, fatigue, and dizziness. While prior investigations showed an increased risk of thromboembolic events, more recent evidence tells a different story-that PTE perhaps has lessened risk of thromboembolic events or negative graft outcomes than previously thought. In the evaluation of PTE, it is important to exclude other causes of erythrocytosis including malignancy before treatment. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) are the mainstays of treatment. Increased ACE-I/ARB use has likely contributed to the falling incidence of erythrocytosis. In this review article, we summarize the current literature in the field of post-transplant erythrocytosis after kidney transplantation.
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Affiliation(s)
- Beyann Alzoubi
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53705, United States
| | - Abish Kharel
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53705, United States
| | - Rushad Machhi
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53705, United States
| | - Fahad Aziz
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53705, United States
| | - Kurtis J Swanson
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53705, United States
| | - Sandesh Parajuli
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Madison, Madison, WI 53705, United States
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