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Manganas K, Bemplidakis T, Papachristou K, Angelara M, Karamanakos G. Multiple Aneurysms and Thrombotic Events as Initial Manifestations of Primary Myelofibrosis: A Case Report. Cureus 2025; 17:e79519. [PMID: 40135024 PMCID: PMC11936429 DOI: 10.7759/cureus.79519] [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: 02/23/2025] [Indexed: 03/27/2025] Open
Abstract
This case report presents a 66-year-old male who developed deep venous thrombosis (DVT), pulmonary embolism (PE), and a ruptured iliac aneurysm as initial manifestations of primary myelofibrosis (PMF). Due to the presence of pre-existing aneurysms in combination with anticoagulation therapy, the patient experienced a retroperitoneal hematoma, necessitating temporary cessation of treatment. Genetic testing revealed a JAK2 V617F mutation and bone marrow biopsy confirmed PMF. The patient's recovery was uneventful, with hematological parameters stabilized upon discharge. The case emphasizes the importance of considering myeloproliferative neoplasms (MPNs) in the differential diagnosis of unexplained thrombotic events. JAK2 mutations are linked to thrombotic complications and aneurysm formation, highlighting the need for vigilant monitoring. It is also important that MPNs may not initially be evident in a complete blood count, while coexisting conditions, such as β-thalassemia trait in this patient's case, can alter the blood count findings.
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Affiliation(s)
- Konstantinos Manganas
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens, GRC
| | | | - Klairi Papachristou
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens, GRC
| | - Maria Angelara
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens, GRC
| | - George Karamanakos
- First Department of Propaedeutic and Internal Medicine, Laiko General Hospital, Athens, GRC
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Gurban P, Mambet C, Botezatu A, Necula LG, Matei L, Neagu AI, Pitica IM, Dragu LD, Nastasie Schulman A, Ataman M, Nedeianu S, Chivu‐Economescu M, Bleotu C, Anton G, Diaconu CC. Increased mRNA expression for serotonin receptor 1B (HTR1B) is associated with thrombosis in BCR::ABL1-negative myeloproliferative neoplasms. J Cell Mol Med 2024; 28:e70024. [PMID: 39183370 PMCID: PMC11345121 DOI: 10.1111/jcmm.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/08/2024] [Accepted: 08/11/2024] [Indexed: 08/27/2024] Open
Abstract
BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal haematopoietic stem cell disorders characterized by specific driver mutations and an increased risk of both macrothrombosis and microthrombosis. Serotonin receptor type 1B (HTR1B) was found to be expressed by various solid tumours, and also primary bone marrow mononuclear cells from myelodysplastic neoplasm and acute myeloid leukaemia patients, representing a potential therapeutic target. In this study we assessed for the first time the expression levels of HTR1B mRNA in the peripheral blood mononuclear cells (PBMC) of 85 newly diagnosed MPN patients, consisting of 28 polycythemia vera, 25 essential thrombocythemia and 32 primary myelofibrosis cases. Levels of HTR1B expression between MPN subtypes and control group were not significantly different. However, at clinical data examination, it was observed that MPN patients with a recent history of major thrombosis and/or signs of impaired microcirculation exhibited significantly higher HTR1B expression levels compared to non-thrombotic MPNs and control group. Moreover, thrombotic MPN patients had significantly higher HTR1B expression than patients with recent thrombosis and absence of MPN diagnostic criteria. These findings suggest that increased levels of HTR1B expression in PBMC might be associated with thrombosis in MPN patients, but larger studies are needed for confirmation, including testing of the receptor protein expression level.
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Affiliation(s)
- Petruta Gurban
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
- Cytogenomic Medical LaboratoryBucharestRomania
| | - Cristina Mambet
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
- Department of Radiology, Oncology, and Hematology, Faculty of MedicineCarol Davila University of Medicine and PharmacyBucharestRomania
- Hematology DepartmentEmergency University Clinical HospitalBucharestRomania
| | - Anca Botezatu
- Molecular Virology DepartmentStefan S. Nicolau Institute of Virology, Romanian AcademyBucharestRomania
| | - Laura G. Necula
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Lilia Matei
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Ana Iulia Neagu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
- Department of Infectious Diseases, Epidemiology, Microbiology, Parasitology, Virology, Diabetes, Endocrinology, Faculty of MedicineCarol Davila University of Medicine and PharmacyBucharestRomania
| | - Ioana Madalina Pitica
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Laura Denisa Dragu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Alina Nastasie Schulman
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Marius Ataman
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Saviana Nedeianu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Mihaela Chivu‐Economescu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Coralia Bleotu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
| | - Gabriela Anton
- Molecular Virology DepartmentStefan S. Nicolau Institute of Virology, Romanian AcademyBucharestRomania
| | - Carmen Cristina Diaconu
- Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of VirologyRomanian AcademyBucharestRomania
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Chen Y, Kong BB, Yin H, Liu H, Wu S, Xu T. Acute upper gastrointestinal bleeding due to portal hypertension in a patient with primary myelofibrosis: A case report. World J Clin Cases 2024; 12:2621-2626. [PMID: 38817215 PMCID: PMC11135446 DOI: 10.12998/wjcc.v12.i15.2621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/10/2024] [Accepted: 04/07/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND Acute upper gastrointestinal bleeding is a common medical emergency that has a 10% hospital mortality rate. According to the etiology, this disease can be divided into acute varicose veins and nonvaricose veins. Bleeding from esophageal varices is a life-threatening complication of portal hypertension. Portal hypertension is a clinical syndrome defined as a portal venous pressure that exceeds 10 mmHg. Cirrhosis is the most common cause of portal hypertension, and thrombosis of the portal system not associated with liver cirrhosis is the second most common cause of portal hypertension in the Western world. Primary myeloproliferative disorders are the main cause of portal venous thrombosis, and somatic mutations in the Janus kinase 2 gene (JAK2 V617F) can be found in approximately 90% of polycythemia vera, 50% of essential thrombocyrosis and 50% of primary myelofibrosis. CASE SUMMARY We present a rare case of primary myelofibrosis with gastrointestinal bleeding as the primary manifestation that presented as portal-superior-splenic mesenteric vein thrombosis. Peripheral blood tests revealed the presence of the JAK2 V617F mutation. Bone marrow biopsy ultimately confirmed the diagnosis of myelofibrosis (MF-2 grade). CONCLUSION In patients with acute esophageal variceal bleeding due to portal hypertension and vein thrombosis without cirrhosis, the possibility of myeloproliferative neoplasms should be considered, and the JAK2 mutation test should be performed.
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Affiliation(s)
- Yu Chen
- Department of Emergency, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Bing-Bing Kong
- Department of Emergency, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - He Yin
- Department of Emergency, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Hao Liu
- Department of Pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Sheng Wu
- Department of Emergency, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Ting Xu
- Department of Emergency, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
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Cohen O, Caiano LM, Levy-Mendelovich S. Cancer-associated splanchnic vein thrombosis: Clinical implications and management considerations. Thromb Res 2024; 234:75-85. [PMID: 38183815 DOI: 10.1016/j.thromres.2023.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/13/2023] [Accepted: 12/19/2023] [Indexed: 01/08/2024]
Abstract
Splanchnic vein thrombosis (SVT), a thrombosis which involves the portal, mesenteric, and splenic veins, and the Budd-Chiari syndrome, represents an uncommon type of venous thromboembolism (VTE). Like with deep vein thrombosis of the lower extremities and pulmonary embolism, ample evidence suggests a significant association between SVT and cancer, particularly intra-abdominal solid malignancies (e.g. hepatobiliary and pancreatic cancers) and myeloproliferative neoplasms (MPN). Clinical symptoms of SVT in cancer patients can be ambiguous, and frequently attributed to the primary cancer itself. Alternatively, SVT may be asymptomatic and detected incidentally during cancer staging or follow-up evaluations. SVT can also precede the diagnosis of cancer and has been associated with poorer outcomes in patients with liver or pancreatic cancers. Therefore, an unprovoked SVT warrants a thorough evaluation for an underlying malignancy or MPN. Cancer-associated SVT carries a high risk of VTE extension, recurrence and bleeding. Extended anticoagulant treatment is often required in the absence of a high bleeding risk. Guidelines suggest treatment with either low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs), although available data on the safety and effectiveness of DOACs in these patients is limited. This comprehensive review outlines the epidemiology, pathogenesis, risk factors, and diagnosis of cancer-associated SVT and underscores the importance of comprehensive patient evaluation and evidence-based management.
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Affiliation(s)
- Omri Cohen
- National Hemophilia Center, Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel-Hashomer, Israel; School of Medicine, Tel Aviv University, Israel; Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Lucia Maria Caiano
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Sarina Levy-Mendelovich
- National Hemophilia Center, Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel-Hashomer, Israel; School of Medicine, Tel Aviv University, Israel
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Orion D, Itsekson-Hayosh Z, Peretz S, Mendel R, Yaniv G, Attia M, Grizim-Merkel D. Janus Kinase-2 V617F Mutation and Antiphospholipid Syndrome in Cerebral Sinus Venous Thrombosis: Natural History and Retrospective Bicenter Analysis. Front Neurol 2022; 13:783795. [PMID: 35493844 PMCID: PMC9046649 DOI: 10.3389/fneur.2022.783795] [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: 09/27/2021] [Accepted: 03/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background Cerebral sinus venous thrombosis (CSVT) is a rare neurovascular entity, usually associated with acquired or genetic hypercoagulable states. In up to 30% of the cases it remains idiopathic. Bone marrow proliferation disorders that are associated with Janus Kinase 2 V617F mutation (JAK-2) are known causes of the systemic and cerebral thrombosis—at times despite normal blood counts—for which hematologic treatment exists. However, JAK-2 prevalence in the CSVT cases is not clear. Methods In this retrospective analysis, data of 236 patients with CSVT admitted to two tertiary centers between 2010 and 2020 were analyzed, with emphasis on laboratory and imaging data and clinical and interventional outcomes. Results A total of 236 patients were included in the analysis. The patients' median age was 42 years and the average age was 44 years (±19 years), with 59% female patients. JAK-2 positivity rate was 18% (among 77 patients tested for the mutation). Patients with normal blood counts on presentation comprised 36% of the JAK-2 positive cases. Other hypercoagulability states were also investigated, with the antiphospholipid syndrome (APLA) showing the highest prevalence (11%) followed by other etiologies including oral contraceptive use, Factor V Leiden, prothrombin mutation, and malignancy. Selected JAK-2, APLA, and prothrombin mutation cases showed a more severe clinical course. Conclusion JAK-2 mutation is underdiagnosed and its screening may be warranted in the cases of idiopathic CSVT, even despite normal blood counts, to allow disease-modifying treatment and blood cell count monitoring. JAK-2, APLA, and prothrombin mutation may be associated with a more complicated clinical course.
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Affiliation(s)
- David Orion
- Department of Stroke and Neurovascular Disorders, Chaim Sheba Medical Center, Ramat Gan, Israel
- Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ze'ev Itsekson-Hayosh
- Department of Stroke and Neurovascular Disorders, Chaim Sheba Medical Center, Ramat Gan, Israel
- Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- *Correspondence: Ze'ev Itsekson-Hayosh
| | - Shlomi Peretz
- Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Rabin Medical Center, Petah Tiqwa, Israel
| | - Rom Mendel
- Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Neurology, Rabin Medical Center, Petah Tiqwa, Israel
| | - Gal Yaniv
- Department of Radiology, Interventional Neuroradiology and Radiology Units, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Moshe Attia
- Department of Neurosurgery, Sheba Medical Center, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Drorit Grizim-Merkel
- Hematology Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Krishnan A, Thomas S. Toward platelet transcriptomics in cancer diagnosis, prognosis and therapy. Br J Cancer 2022; 126:316-322. [PMID: 34811507 PMCID: PMC8810955 DOI: 10.1038/s41416-021-01627-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 10/26/2021] [Accepted: 11/02/2021] [Indexed: 12/29/2022] Open
Abstract
Widespread adoption of next-generation techniques such as RNA-sequencing (RNA-seq) has enabled research examining the transcriptome of anucleate blood platelets in health and disease, thus revealing a rich platelet transcriptomic signature that is reprogrammed in response to disease. Platelet signatures not only capture information from parent megakaryocytes and progenitor hematopoietic stem cells but also the bone marrow microenvironment, and underlying disease states. In cancer, the substantive body of research in patients with solid tumours has identified distinct signatures in 'tumour-educated platelets', reflecting influences of the tumour, stroma and vasculature on splicing, sequestration of tumour-derived RNAs, and potentially cytokine and microvesicle influences on megakaryocytes. More recently, platelet RNA expression has emerged as a highly sensitive approach to profiling chronic progressive haematologic malignancies, where the combination of large data cohorts and machine-learning algorithms enables precise feature selection and potential prognostication. Despite these advances, however, our ability to translate platelet transcriptomics toward clinical diagnostic and prognostic efforts remains limited. In this Perspective, we present a few actionable steps for our basic, translational and clinical research communities in advancing the utility of the platelet transcriptome as a highly sensitive biomarker in cancer and collectively enable efforts toward clinical translation and patient benefit.
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Affiliation(s)
- Anandi Krishnan
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
| | - Sally Thomas
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, UK
- Department of Haematology, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
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Burattini M, Falsetti L, Potente E, Rinaldi C, Bartolini M, Buratti L, Silvestrini M, Viticchi G. Ischemic stroke as a presenting manifestation of polycythemia vera: a narrative review. Rev Neurosci 2021; 33:303-311. [PMID: 34508650 DOI: 10.1515/revneuro-2021-0066] [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: 05/13/2021] [Accepted: 08/19/2021] [Indexed: 11/15/2022]
Abstract
Polycythemia vera (PV) is a myeloproliferative disorder associated with an increased risk of cerebrovascular diseases. In this narrative review, we aimed to analyze the relationships between acute ischemic stroke and PV. We conducted a PubMed/Medline and Web of Sciences Database search using MeSH major terms. We found 75 articles and finally considered 12 case reports and 11 cohort studies. The ischemic stroke resulted as the first manifestation of PV in up to 16.2% of cases; the cumulative rate of cerebrovascular events was up to 5.5 per 100 persons per year and stroke accounted for 8.8% of all PV-related deaths; age, mutations, and a previous history of thrombosis were the main risk factors. The best approach to reduce stroke recurrence risk is unclear, even if some evidence suggests a potential role of lowering hematocrit below 45%. Ischemic stroke represents one of the most common PV manifestations but, despite their relationship, patients with both diseases have a very heterogeneous clinical course and management. PV-related strokes often remain underdiagnosed, especially for the low prevalence of PV. An early diagnosis could lead to prompt treatment with phlebotomy, cytoreduction, and low-dose aspirin to decrease the risk of recurrences. Clinicians should be aware of PV as a risk factor for stroke when approaching the differential diagnosis of cryptogenic strokes. An early diagnosis could positively influence patients' management and clinical outcomes. Further studies are required to evaluate the role of PV treatments in the prevention of cerebrovascular disease.
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Affiliation(s)
- Marco Burattini
- Neurological Clinic, Marche Polytechnic University, via Conca n.1, 60020, Ancona, Italy
| | - Lorenzo Falsetti
- Internal and Subintensive Medicine, Ospedali Riuniti Ancona, via Conca n.1, 60020, Ancona, Italy
| | - Eleonora Potente
- Neurological Clinic, Marche Polytechnic University, via Conca n.1, 60020, Ancona, Italy
| | - Claudia Rinaldi
- Neurological Clinic, Marche Polytechnic University, via Conca n.1, 60020, Ancona, Italy
| | - Marco Bartolini
- Neurological Clinic, Marche Polytechnic University, via Conca n.1, 60020, Ancona, Italy
| | - Laura Buratti
- Neurological Clinic, Marche Polytechnic University, via Conca n.1, 60020, Ancona, Italy
| | - Mauro Silvestrini
- Neurological Clinic, Marche Polytechnic University, via Conca n.1, 60020, Ancona, Italy
| | - Giovanna Viticchi
- Neurological Clinic, Marche Polytechnic University, via Conca n.1, 60020, Ancona, Italy
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Cao YY, Cao J, Bi ZJ, Xu SB, Liu CC. Hemorrhagic transformation after acute ischemic stroke caused by polycythemia vera: Report of two case. World J Clin Cases 2021; 9:7551-7557. [PMID: 34616825 PMCID: PMC8464450 DOI: 10.12998/wjcc.v9.i25.7551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 07/12/2021] [Accepted: 07/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by an increase in red blood cells in the peripheral blood. Previous work has reported the occurrence of thrombosis or hemorrhage arising in the cerebral vasculature secondary to PV. However, hemorrhagic transformation after PV-associated acute ischemic stroke has not been previously described.
CASE SUMMARY We herein present two cases of PV where hemorrhagic transformation occurred after an acute ischemic stroke. Case 1 was a 57-year-old woman with a history of hypertension who was admitted for left-sided weakness. Case 2 was a 68-year-old man who was admitted for a 10-d sudden left arm weakness. Imaging examinations for the two patients revealed hemorrhagic transformation after acute ischemic stroke. Both patients had JAK-2-V617F mutation and received antiplatelet therapy. Both of them had a good prognosis during the follow-up.
CONCLUSION This report suggested that hemorrhagic transformation may occur in acute ischemic stroke caused by PV. Antiplatelet drugs do not seem to influence the long-term outcomes in such patients. Future research should focus on establishing a standard antiplatelet treatment strategy for this condition.
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Affiliation(s)
- Ya-Yun Cao
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
| | - Jie Cao
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Zhua-Jin Bi
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Sha-Bei Xu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Chen-Chen Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
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Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R. The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. Eur Heart J 2021; 42:4389-4400. [PMID: 34343257 DOI: 10.1093/eurheartj/ehab447] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/21/2021] [Accepted: 07/31/2021] [Indexed: 01/07/2023] Open
Abstract
Inflammation contributes centrally to cardiovascular diseases, and anti-inflammatory treatments can reduce cardiovascular events. The JAK-STAT pathway is an emerging target in inflammation, mainly in rheumatoid arthritis (RA) and chronic myeloproliferative neoplasms (MPNs), disorders that heighten cardiovascular risk. The aim of this study was to review the international literature on the relationship between dysregulation of the JAK-STAT pathway in RA/MPNs and cardiovascular risk and on the potential cardiovascular effects of JAK-STAT inhibitors. The JAK-STAT pathway sustains inflammatory and thrombotic events in autoimmune disorders such as RA and MPNs. Here, an imbalance exists between pro- and anti-inflammatory cytokines [increased levels of interleukin (IL)-6, IL-1-β, tumour necrosis factor-α, decreased levels of IL-10] and the over-expression of some prothrombotic proteins, such as protein kinase Cε, on the surface of activated platelets. This pathway also operates in atherosclerotic cardiovascular disease. JAK-STAT inhibitors may reduce cardiovascular events and related deaths in such conditions, but the potential of these agents requires more studies, especially with regard to cardiovascular safety, and particularly for potential prothrombotic effects. JAK-STAT inhibitors merit consideration to curb heightened cardiovascular risk in patients with RA and MPNs, with rigorous assessment of the potential benefits and risks.
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Affiliation(s)
- Chiara Baldini
- Division of Rheumatology, University of Pisa and Pisa University Hospital, Via Paradisa, 2, Pisa 56124, Italy
| | - Francesca Romana Moriconi
- Division of Rheumatology, University of Pisa and Pisa University Hospital, Via Paradisa, 2, Pisa 56124, Italy.,Division of Cardiology, University of Pisa and Pisa University Hospital, Via Paradisa, 2, Pisa 56124, Italy
| | - Sara Galimberti
- Division of Hematology, University of Pisa and Pisa University Hospital, Via Paradisa, 2, Pisa 56124, Italy
| | - Peter Libby
- Cardiovascular Division, Brigham and Women's Hospital-Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Raffaele De Caterina
- Division of Cardiology, University of Pisa and Pisa University Hospital, Via Paradisa, 2, Pisa 56124, Italy
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SICA A, SAGNELLI C, SAGNELLI E, FIORELLI A, CASALE B. Recurrent thrombosis: a case report of young patient JAK2+ without myeloproliferative disease and other risk factors. The role of sport activity. ACTA PHLEBOLOGICA 2021; 21. [DOI: 10.23736/s1593-232x.20.00475-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
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11
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Veninga A, De Simone I, Heemskerk JWM, Cate HT, van der Meijden PEJ. Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding. Haematologica 2020; 105:2020-2031. [PMID: 32554558 PMCID: PMC7395290 DOI: 10.3324/haematol.2019.235994] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022] Open
Abstract
Platelets are key elements in thrombosis, particularly in atherosclerosis-associated arterial thrombosis (atherothrombosis), and hemostasis. Megakaryocytes in the bone marrow, differentiated from hematopoietic stem cells are generally considered as a uniform source of platelets. However, recent insights into the causes of malignancies, including essential thrombocytosis, indicate that not only inherited but also somatic mutations in hematopoietic cells are linked to quantitative or qualitative platelet abnormalities. In particular cases, these form the basis of thrombo-hemorrhagic complications regularly observed in patient groups. This has led to the concept of clonal hematopoiesis of indeterminate potential (CHIP), defined as somatic mutations caused by clonal expansion of mutant hematopoietic cells without evident disease. This concept also provides clues regarding the importance of platelet function in relation to cardiovascular disease. In this summative review, we present an overview of genes associated with clonal hematopoiesis and altered platelet production and/or functionality, like mutations in JAK2 We consider how reported CHIP genes can influence the risk of cardiovascular disease, by exploring the consequences for platelet function related to (athero)thrombosis, or the risk of bleeding. More insight into the functional consequences of the CHIP mutations may favor personalized risk assessment, not only with regard to malignancies but also in relation to thrombotic vascular disease.
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Affiliation(s)
- Alicia Veninga
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht
| | - Ilaria De Simone
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht
| | - Johan W M Heemskerk
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht
| | - Hugo Ten Cate
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht.,Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht.,Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Paola E J van der Meijden
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht .,Thrombosis Expertise Center, Heart and Vascular Center, Maastricht University Medical Center, Maastricht
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Maze D, Kazi S, Gupta V, Malinowski AK, Fazelzad R, Shah PS, Shehata N. Association of Treatments for Myeloproliferative Neoplasms During Pregnancy With Birth Rates and Maternal Outcomes: A Systematic Review and Meta-analysis. JAMA Netw Open 2019; 2:e1912666. [PMID: 31584685 PMCID: PMC6784750 DOI: 10.1001/jamanetworkopen.2019.12666] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 08/16/2019] [Indexed: 12/15/2022] Open
Abstract
Importance Myeloproliferative neoplasms (MPNs) are increasingly being identified in women of childbearing potential. Pregnancy in women with MPNs is associated with maternal thrombosis, hemorrhage, and placental dysfunction leading to fetal growth restriction or loss. Objective To evaluate the association between the use of aspirin, heparin, interferon, or combinations and live birth rate and adverse maternal outcomes in pregnant women with MPNs. Data Sources Systematic searches of MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and the MEDLINE Epub Ahead of Print and In-Process and Other Non-Indexed Citations from inception to July 19, 2018, with no language restrictions, was conducted. Key search terms included myeloproliferative disorders, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Study Selection A study was eligible if it included pregnant patients with MPNs; interventions included aspirin, heparin, and/or interferon; there was a comparison group in which patients did not receive the intervention; the study reported on at least 1 of the study outcomes; and it was a randomized, case-control, or cohort study or series of at least 10 pregnancies. Data were extracted in duplicate; 0.5% of identified studies met selection criteria. Data Extraction and Synthesis The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and reported in accordance with Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using the Mantel-Haenszel approach. Main Outcomes and Measures Outcomes were the number of live births and maternal complications, specifically, arterial or venous thrombosis, hemorrhage, and preeclampsia. Results Twenty-two studies reporting on 1210 pregnancies were included. The live birth rate was 71.3% (95% CI, 65.1%-77.6%). Use of aspirin (11 studies, 227 patients; unadjusted odds ratio, 8.6; 95% CI, 4.0-18.1) and interferon (6 studies, 90 patients; unadjusted odds ratio, 9.7; 95% CI, 2.3-41.0) were associated with higher odds of live birth. Addition of heparin to aspirin was not associated with higher odds of live birth (6 studies, 96 patients; unadjusted odds ratio, 2.1; 95% CI, 0.5-9.0). The most common adverse maternal event was preeclampsia, with an incidence of 3.1% (95% CI, 1.7%-4.5%). Conclusions and Relevance Most studies reported on pregnancy with essential thrombocythemia. Few studies reported on pregnancy with polycythemia vera and none with myelofibrosis met the inclusion criteria. Most studies were retrospective and early pregnancy losses may have been underreported. Moderate-quality evidence suggests that aspirin or interferon is associated with higher odds of live birth in pregnant women with MPN.
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Affiliation(s)
- Dawn Maze
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
- University of Toronto, Toronto, Ontario, Canada
| | - Sajida Kazi
- University of Toronto, Toronto, Ontario, Canada
- Division of Hematology, University Health Network, Toronto, Ontario, Canada
| | - Vikas Gupta
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
- University of Toronto, Toronto, Ontario, Canada
| | - Ann Kinga Malinowski
- University of Toronto, Toronto, Ontario, Canada
- Division of Maternal–Fetal Medicine, Department of Obstetrics & Gynaecology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Rouhi Fazelzad
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
- University of Toronto, Toronto, Ontario, Canada
| | - Prakesh S. Shah
- University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Nadine Shehata
- University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
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Rotta Detto Loria J, Rawluk J, Krauss T, Bode C, Moser M, Helbing T. Acute transmural myocardial infarction by coronary embolism in a patient with JAK2 V617F-positive essential thrombocythemia. Hamostaseologie 2017; 99:16-12-0046. [PMID: 28692109 DOI: 10.5482/hamo-16-12-0046] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 04/06/2017] [Indexed: 12/17/2022] Open
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Dambrauskienė R, Gerbutavičius R, Ugenskienė R, Jankauskaitė R, Savukaitytė A, Šimoliūnienė R, Rudžianskienė M, Gerbutavičienė R, Juozaitytė E. Genetic Polymorphisms of Hemostatic Factors and Thrombotic Risk in Non BCR- ABL Myeloproliferative Neoplasms: A Pilot Study. Balkan J Med Genet 2017; 20:35-42. [PMID: 28924539 PMCID: PMC5596820 DOI: 10.1515/bjmg-2017-0005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The most important complications of Philadelphianegagive (non BCR-ABL) myeloproliferative neoplasms (MPNs) are vascular events. Our aim was to evaluate the effects of single nucleotide polymorphisms (SNPs), platelet glycoproteins (GPs) (Ia/IIa, Ibα, IIb/IIIa and VI), von Willebrand factor (vWF), coagulation factor VII (FVII), β-fibrinogen, and the risk of thrombosis in patients with non BCR-ABL MPNs at the Lithuanian University of Health Sciences. Kaunas, Lithuania. Genotyping was done for 108 patients. The TT genotype of the GP Ia/IIa c.807C>T polymorphism was more frequently found in the group of MPN patients with arterial thrombosis compared to MPN patients who were thrombosis-free [26.5 vs. 11.5%, p = 0.049; odds ratio (OR) 2.68; 95% confidence interval (95% CI) 1.01-7.38]. The CT genotype of the β-fibrinogen c.-148C>T polymorphism occurred more frequently in MPN patients with arterial, and total thrombosis compared to the wild or homozygous genotype (57.7 vs. 40.0 vs. 12.5%; p = 0.027), (64.7 vs. 44.4 vs. 25%; p = 0.032), respectively. The carrier state for the c.-323P10 variant of FVII SNP (summation of P10/10 and P0/10) was more frequent in MPN patients with thrombosis compared to the wild-type genotype carriers (71.4 vs. 43.4%; p = 0.049; OR 3.26; 95% CI 1.01-11.31). The coexistence of heterozygous β-fibrinogen c.-148C>T and FVII c.-323P0/10 SNP, increased the risk of arterial thrombosis (21.1 vs. 3.7%, p = 0.008; OR 6.93; 95% CI 1.38-34.80). The TT genotype of GP Ia/IIa c.807C>T, the CT genotype of β-fibrinogen c.-148C>T and FVII c.-323P0/10 SNP could be associated with risk of thrombosis in MPN patients.
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Affiliation(s)
- R Dambrauskienė
- Department of Oncology and Hematology, Institute of Oncology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - R Gerbutavičius
- Department of Oncology and Hematology, Institute of Oncology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - R Ugenskienė
- Lithuanian University of Health Sciences, Institute of Oncology, Oncology Research Laboratory, Kaunas, Lithuania
| | - R Jankauskaitė
- Lithuanian University of Health Sciences, Institute of Oncology, Oncology Research Laboratory, Kaunas, Lithuania
| | - A Savukaitytė
- Lithuanian University of Health Sciences, Institute of Oncology, Oncology Research Laboratory, Kaunas, Lithuania
| | - R Šimoliūnienė
- Department of Physics, Mathematics and Biophysics, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - M Rudžianskienė
- Department of Oncology and Hematology, Institute of Oncology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - R Gerbutavičienė
- Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - E Juozaitytė
- Department of Oncology and Hematology, Institute of Oncology, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Cerebrovascular events as presenting manifestations of Myeloproliferative Neoplasm. Rev Neurol (Paris) 2016; 172:703-708. [DOI: 10.1016/j.neurol.2016.09.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 06/17/2016] [Accepted: 09/27/2016] [Indexed: 12/17/2022]
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Sivakumaran Y, Freeman A. Refractory Arterial Insufficiency Associated with Janus Kinase 2 Positive Essential Thrombocythaemia. Ann Vasc Surg 2016; 38:317.e13-317.e16. [PMID: 27531097 DOI: 10.1016/j.avsg.2016.05.117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 05/01/2016] [Accepted: 05/20/2016] [Indexed: 10/21/2022]
Abstract
Essential thrombocythaemia (ET) is one of the severe rare clonal haematologic stem cell disorders that encompass myeloproliferative neoplasms. ET has a well-described association with peripheral arterial thrombosis, which presents a challenging clinical presentation. Further understanding into the underlying pathophysiology of thrombosis in ET has been made following the identification of the Janus Kinase 2 (JAK2) mutation, which is thought to confer a prothrombotic phenotype. Here we present a case of refractory arterial insufficiency associated with JAK2-positive ET.
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Affiliation(s)
| | - Anthony Freeman
- Department of Surgery, Bankstown-Lidcombe Hospital, Sydney, NSW, Australia; Division of Surgery, Concord Hospital Clinical School, University of Sydney, Sydney, NSW, Australia
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Bai J, Ai L, Zhang L, Yang FC, Zhou Y, Xue Y. Incidence and risk factors for myelofibrotic transformation among 272 Chinese patients with JAK2-mutated polycythemia vera. Am J Hematol 2015; 90:1116-21. [PMID: 26370613 DOI: 10.1002/ajh.24191] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 09/05/2015] [Accepted: 09/10/2015] [Indexed: 01/30/2023]
Abstract
Post-polycythemia vera myelofibrosis (post-PV MF) is a critical hematologic evolution of polycythemia vera (PV). The main purpose of the present study was to identify the possible risk factors for the occurrence and prognosis of post-PV MF in Chinese patients with PV. A cohort of 272 Chinese PV patients with JAK2(V617F) or exon12 mutation was retrospectively analyzed. Of the 272 patients with PV, 63 developed post-PV MF. Platelet count >550 × 10(9) /L and splenomegaly were identified as independent risk factors for post-PV MF. The median duration of survival for post-PV MF patients was 8 years. Anemia and age >65 years at diagnosis of post-PV MF were identified as significant predictors for the poor prognosis of post-PV MF. In conclusion, platelet counts and splenomegaly were significant predictors for the transformation to post-PV MF, while anemia (hemoglobin levels <100 g/L) and age>65 years were significant predictors for poor prognosis of post-PV MF in Chinese PV patients with JAK2(V617F) or exon12 mutation.
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Affiliation(s)
- Jie Bai
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Limei Ai
- Department of Hematology; The First Affiliated Hospital of Liaoning Medical University; Jinzhou People's Republic of China
| | - Lei Zhang
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Feng-Chun Yang
- Department of Biochemistry and Molecular Biology; Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine; Miami Florida
| | - Yuan Zhou
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
| | - Yanping Xue
- State Key Laboratory of Experimental Hematology; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Tianjin People's Republic of China
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JAK2V617F: Is It Sufficient as a Single Player in Splanchnic Venous Thrombosis? Case Rep Hematol 2015; 2015:373490. [PMID: 25878908 PMCID: PMC4387965 DOI: 10.1155/2015/373490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/12/2015] [Accepted: 03/12/2015] [Indexed: 12/12/2022] Open
Abstract
Splanchnic venous thrombosis (SVT) includes thrombosis of the hepatic, portal, and mesenteric venous system. Myeloproliferative neoplasms (MPNs) are important factors of SVT in adults. Addition of JAK2V617F mutation in WHO criteria for diagnosis of MPNs has made this test a useful tool for diagnosis. JAK2 is an intracytoplasmic tyrosine kinase that plays a critical role in signal transduction from multiple hematopoietic factor receptors. The mutation is found frequently in patients with SVT; many such patients have no other manifestations of an MPN. Although the correlation of JAK2V617F mutation with thrombotic risk in MPNs has been shown in many studies, the impact of presence of additional thrombophilic factors in these cases is yet not known. As the management of MPNs remains highly dependent on the patient's thrombotic risk, it is important to assess the thrombotic risk factors in detail. Here, we report two cases of JAK2V617F positive MPN who also had other thrombophilic conditions and presented with recurrent thrombosis.
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