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Wen S, Zhang W, Fei Y, Guan K, Zhao H, Song P, Ye X, Pan Y. Risk factors for ischemic stroke in patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. J Clin Neurosci 2024; 125:159-166. [PMID: 38815302 DOI: 10.1016/j.jocn.2024.05.025] [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: 12/27/2023] [Revised: 05/14/2024] [Accepted: 05/21/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs) are linked with various complications, notably ischemic stroke. The study aims to identify risk factors for ischemic stroke in Ph-negative MPNs patients. METHODS Patients were categorized into two groups based on whether they had experienced ischemic stroke. Subsequently, an analysis of demographics, biochemical makers, and genetic mutations (JAK2V617F and CALR mutations), was conducted to identify potential associations with an elevated risk of ischemic stroke in individuals with Ph-negative MPNs. RESULTS A total of 185 patients diagnosed with Ph-negative MPNs participated in the study, including 82 with essential thrombocythemia (ET), 78 with polycythemia vera (PV), and 25 with primary myelofibrosis (PMF). Among these, 57 patients (30.8 %) had a history of ischemic stroke. Independent risk factors associated with ischemic stroke in Ph-negative MPNs patients included hypertension (OR = 5.076) and smoking (OR = 5.426). Among ET patients, smoking (OR = 4.114) and an elevated percentage of neutrophils (OR = 1.080) were both positively correlated with ischemic stroke incidence. For PV patients, hypertension (OR = 4.647), smoking (OR = 6.065), and an increased percentage of lymphocytes (OR = 1.039) were independently associated with ischemic stroke. Regardless of the presence of the JAK2V617F mutation, hypertension was the sole positively and independently associated risk factor for ischemic stroke. The odds ratios for patients with the JAK2V617F mutation was 3.103, while for those without the mutation, it was 11.25. CONCLUSIONS Hypertension was a more substantial factor associated with an increased incidence of ischemic stroke in Ph-negative MPNs patients.
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Affiliation(s)
- Shirong Wen
- Department of Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Wenxiao Zhang
- Department of Neurology, Zhuhai People's Hospital (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, China
| | - Yiping Fei
- Department of Hematology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Ke Guan
- Department of Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Hui Zhao
- Department of Hematology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Peng Song
- Department of Hematology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Xiangmei Ye
- Department of Hematology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Yujun Pan
- Department of Neurology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
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Enblom-Larsson A, Renlund H, Andréasson B, Holmberg H, Liljeholm M, Själander A. Thromboembolic events, major bleeding and mortality in essential thrombocythaemia and polycythaemia vera-A matched nationwide population-based study. Br J Haematol 2024; 204:1740-1751. [PMID: 38351734 DOI: 10.1111/bjh.19337] [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: 09/27/2023] [Revised: 01/22/2024] [Accepted: 02/01/2024] [Indexed: 05/15/2024]
Abstract
Thromboembolic events and bleeding are known complications in essential thrombocythaemia (ET) and polycythaemia vera (PV). Using multiple Swedish health care registers, we assessed the rate of arterial and venous events, major bleeding, all-cause stroke and all-cause mortality in ET and PV compared to matched controls. For each patient with ET (n = 3141) and PV (n = 2604), five matched controls were randomly selected. In total, 327 and 405 arterial or venous events were seen in the group of ET and PV patients respectively. Compared to corresponding controls, the rate of venous thromboembolism, major bleeding and all-cause mortality per 100 treatment years was significantly increased among both ET (0.63, 0.79 and 3.70) and PV patients (0.94, 1.20 and 4.80). The PV patients also displayed a significantly higher rate of arterial events and all-cause stroke compared to controls. When dividing the cohort into age groups, we found a significantly higher rate of arterial and venous events in all age groups of PV patients, and the rate of all-cause mortality was significantly higher in both ET and PV patients in all ages above the age of 50. This study confirms that PV and ET are diseases truly marked by thromboembolic complications and bleeding.
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Affiliation(s)
| | - Henrik Renlund
- Uppsala Clinical Research Centre Uppsala University, Uppsala, Sweden
| | | | - Henrik Holmberg
- Department of Epidemiology and Global Health, Umeå University, Umeå, Sweden
| | - Maria Liljeholm
- Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
| | - Anders Själander
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
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Tirandi A, Schiavetta E, Maioli E, Montecucco F, Liberale L. Inflammation as a cause of acute myocardial infarction in patients with myeloproliferative neoplasm. World J Cardiol 2024; 16:58-63. [PMID: 38456066 PMCID: PMC10915890 DOI: 10.4330/wjc.v16.i2.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/01/2024] [Accepted: 01/18/2024] [Indexed: 02/21/2024] Open
Abstract
Myeloproliferative neoplasms (MPN) are a group of diseases characterized by the clonal proliferation of hematopoietic progenitor or stem cells. They are clinically classifiable into four main diseases: chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, and primary myelofibrosis. These pathologies are closely related to cardio- and cerebrovascular diseases due to the increased risk of arterial thrombosis, the most common underlying cause of acute myocardial infarction. Recent evidence shows that the classical Virchow triad (hypercoagulability, blood stasis, endothelial injury) might offer an explanation for such association. Indeed, patients with MPN might have a higher number and more reactive circulating platelets and leukocytes, a tendency toward blood stasis because of a high number of circulating red blood cells, endothelial injury or overactivation as a consequence of sustained inflammation caused by the neoplastic clonal cell. These abnormal cancer cells, especially when associated with the JAK2V617F mutation, tend to proliferate and secrete several inflammatory cytokines. This sustains a pro-inflammatory state throughout the body. The direct consequence is the induction of a pro-thrombotic state that acts as a determinant in favoring both venous and arterial thrombus formation. Clinically, MPN patients need to be carefully evaluated to be treated not only with cytoreductive treatments but also with cardiovascular protective strategies.
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Affiliation(s)
- Amedeo Tirandi
- Department of Internal Medicine, University of Genoa, Genoa 16132, Italy
| | - Elisa Schiavetta
- Department of Internal Medicine, University of Genoa, Genoa 16132, Italy
| | - Elia Maioli
- Department of Internal Medicine, University of Genoa, Genoa 16132, Italy
| | - Fabrizio Montecucco
- Department of Internal Medicine, University of Genoa, Genoa 16132, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa - Italian Cardiovascular Network, Genoa 16132, Italy.
| | - Luca Liberale
- Department of Internal Medicine, University of Genoa, Genoa 16132, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa - Italian Cardiovascular Network, Genoa 16132, Italy
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Larsen MK, Skov V, Kjær L, Eickhardt-Dalbøge CS, Knudsen TA, Kristiansen MH, Sørensen AL, Wienecke T, Andersen M, Ottesen JT, Gudmand-Høyer J, Snyder JA, Andersen MP, Torp-Pedersen C, Poulsen HE, Stiehl T, Hasselbalch HC, Ellervik C. Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study. Blood Cancer J 2024; 14:28. [PMID: 38331919 PMCID: PMC10853217 DOI: 10.1038/s41408-024-00994-z] [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: 09/28/2023] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 02/10/2024] Open
Abstract
The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1-1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03-2.09) for the whole population and 2.93(2.44-3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71-2.69), 2.19(1.89-2.54), and 2.31(1.91-2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10-16), with a HR for NLR ≥ 6 of 2.23(2.17-2.29), 4.10(4.01-4.20), and 7.69(7.50-7.89), for CCI-score 0, 1-2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF.
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Affiliation(s)
- Morten Kranker Larsen
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | | | - Trine Alma Knudsen
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Marie Hvelplund Kristiansen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Neurology, Zealand University Hospital, Roskilde, Denmark
| | | | - Troels Wienecke
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Neurology, Zealand University Hospital, Roskilde, Denmark
| | - Morten Andersen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Johnny T Ottesen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | | | | | - Mikkel Porsborg Andersen
- Department of Cardiology, Copenhagen University Hospital, Nordsjællands Hospital, Hillerød, Denmark
| | - Christian Torp-Pedersen
- Department of Cardiology, Copenhagen University Hospital, Nordsjællands Hospital, Hillerød, Denmark
| | - Henrik Enghusen Poulsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Cardiology, Copenhagen University Hospital, Nordsjællands Hospital, Hillerød, Denmark
- Department of Endocrinology, Copenhagen University Hospital, Bispebjerg Frederiksberg Hospital, Copenhagen, Denmark
| | - Thomas Stiehl
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
- Institute for Computational Biomedicine - Disease Modelling, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Hans Carl Hasselbalch
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christina Ellervik
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Zealand University Hospital, Koege, Denmark
- Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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Skov V, Thomassen M, Kjaer L, Larsen MK, Knudsen TA, Ellervik C, Kruse TA, Hasselbalch HC. Whole blood transcriptional profiling reveals highly deregulated atherosclerosis genes in Philadelphia-chromosome negative myeloproliferative neoplasms. Eur J Haematol 2023; 111:805-814. [PMID: 37640394 DOI: 10.1111/ejh.14081] [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: 06/26/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.
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Affiliation(s)
- Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Lasse Kjaer
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | | | - Trine A Knudsen
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Christina Ellervik
- Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA
| | - Torben A Kruse
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
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Kristiansen MH, Kjær L, Skov V, Larsen MK, Ellervik C, Hasselbalch HC, Wienecke T. JAK2V617F mutation is highly prevalent in patients with ischemic stroke: a case-control study. Blood Adv 2023; 7:5825-5834. [PMID: 37522722 PMCID: PMC10561044 DOI: 10.1182/bloodadvances.2023010588] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/20/2023] [Accepted: 07/20/2023] [Indexed: 08/01/2023] Open
Abstract
Ischemic stroke has a high recurrence rate despite treatment. This underlines the significance of investigating new possible cerebrovascular risk factors, such as the acquired gene mutation JAK2V617F found in 3.1% of the general population. We aimed to investigate the prevalence of the JAK2V617F mutation in a population with ischemic stroke compared with that in matched controls. We enrolled 538 consecutive Danish patients with ischemic stroke (mean age, 69.5 ± 10.9 years; 39.2% female) within 7 days of symptom onset. Using multiple-adjusted conditional logistic regression analysis, we compared the prevalence of JAK2V617F with that in age- and sex-matched controls free of ischemic cerebrovascular disease (ICVD) from the Danish General Suburban Population Study. DNA was analyzed for JAK2V617F mutation using sensitive droplet digital polymerase chain reaction in patients and controls. Of the 538 patients with ischemic stroke, 61 (11.3%) had JAK2V617F mutation. There were no differences in patient demographics or cerebrovascular comorbidities between the patients with and without mutations. Patients with ischemic stroke were more likely to have the JAK2V617F mutation than matched controls, in whom the JAK2V617F prevalence was 4.4% (odds ratio, 2.37; 95% confidence interval, 1.57-3.58; P < .001). A subanalysis stratified by smoking history revealed that the association was strongest in current smokers (odds ratio, 4.78; 95% confidence interval, 2.22-10.28; P < .001). Patients with ischemic stroke were 2.4 times more likely to have the JAK2V617F mutation than matched controls without ICVD when adjusting for other cerebrovascular risk factors. This finding supports JAK2V617F mutation as a novel cerebrovascular risk factor.
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Affiliation(s)
- Marie Hvelplund Kristiansen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Neurology, Zealand University Hospital, Roskilde, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Vibe Skov
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Morten Kranker Larsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Christina Ellervik
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Data and Data Support, Region Zealand, Sorø, Denmark
- Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Hans Carl Hasselbalch
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Hematology, Zealand University Hospital, Roskilde, Denmark
| | - Troels Wienecke
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Neurology, Zealand University Hospital, Roskilde, Denmark
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Svingel LS, Christensen SF, Kjærsgaard A, Stenling A, Paulsson B, Andersen CL, Christiansen CF, Stentoft J, Starklint J, Severinsen MT, Borg Clausen M, Hagemann Hilsøe M, Hasselbalch HC, Frederiksen H, Bak M, Mikkelsen EM. Labor market affiliation of patients with myeloproliferative neoplasms: a population-based matched cohort study. Acta Oncol 2023; 62:1286-1294. [PMID: 37656802 DOI: 10.1080/0284186x.2023.2251670] [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: 03/01/2023] [Accepted: 08/19/2023] [Indexed: 09/03/2023]
Abstract
BACKGROUND Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce. MATERIAL AND METHODS We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation cross-sectionally from week -104 pre-diagnosis to week 104 post-diagnosis. RESULTS The study included 3,342 patients with MPN and 32,737 comparators. From two years pre-diagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis. CONCLUSION Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals.
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Affiliation(s)
- Lise Skovgaard Svingel
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Denmark
| | | | - Anders Kjærsgaard
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Denmark
| | | | | | | | - Christian Fynbo Christiansen
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Denmark
| | - Jesper Stentoft
- Department of Hematology, Aarhus University Hospital, Denmark
| | | | | | - Mette Borg Clausen
- Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Denmark
| | | | | | | | - Marie Bak
- Department of Hematology, Zealand University Hospital, Denmark
| | - Ellen Margrethe Mikkelsen
- Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Denmark
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Hasselbalch HC, Junker P, Skov V, Kjær L, Knudsen TA, Larsen MK, Holmström MO, Andersen MH, Jensen C, Karsdal MA, Willumsen N. Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms. Cancers (Basel) 2023; 15:4323. [PMID: 37686599 PMCID: PMC10486581 DOI: 10.3390/cancers15174323] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 09/10/2023] Open
Abstract
Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10-30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation-"a wound that never heals"-we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.
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Affiliation(s)
- Hans Carl Hasselbalch
- Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark; (V.S.); (L.K.); (T.A.K.); (M.K.L.)
| | - Peter Junker
- Department of Rheumatology, Odense University Hospital, 5000 Odense, Denmark;
| | - Vibe Skov
- Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark; (V.S.); (L.K.); (T.A.K.); (M.K.L.)
| | - Lasse Kjær
- Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark; (V.S.); (L.K.); (T.A.K.); (M.K.L.)
| | - Trine A. Knudsen
- Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark; (V.S.); (L.K.); (T.A.K.); (M.K.L.)
| | - Morten Kranker Larsen
- Department of Hematology, Zealand University Hospital, 4000 Roskilde, Denmark; (V.S.); (L.K.); (T.A.K.); (M.K.L.)
| | - Morten Orebo Holmström
- National Center for Cancer Immune Therapy, Herlev Hospital, 2730 Herlev, Denmark; (M.O.H.); (M.H.A.)
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Herlev Hospital, 2730 Herlev, Denmark; (M.O.H.); (M.H.A.)
| | - Christina Jensen
- Nordic Bioscience A/S, 2730 Herlev, Denmark; (C.J.); (M.A.K.); (N.W.)
| | - Morten A. Karsdal
- Nordic Bioscience A/S, 2730 Herlev, Denmark; (C.J.); (M.A.K.); (N.W.)
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Găman MA, Kipkorir V, Srichawla BS, Dhali A, Găman AM, Diaconu CC. Primary Arterial Hypertension and Drug-Induced Hypertension in Philadelphia-Negative Classical Myeloproliferative Neoplasms: A Systematic Review. Biomedicines 2023; 11:388. [PMID: 36830925 PMCID: PMC9952891 DOI: 10.3390/biomedicines11020388] [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: 12/31/2022] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
The impact of primary arterial hypertension (HTN) in myeloproliferative neoplasms (MPNs) remains unclear, with scant literature available, mostly focusing on cardiovascular risk factors as a singular entity or on organ-specific HTN. Furthermore, available studies reporting findings on drug-induced HTN in MPNs report varying and contradictory findings. In consideration of the above, this study set out to systematically review the available literature and shed light on the occurrence of HTN in MPNs, its association with thrombosis, as well as the drugs used in MPN management that could increase blood pressure. The literature search yielded 598 potentially relevant records of which 315 remained after the duplicates (n = 283) were removed. After we screened the titles and the abstracts of these publications, we removed irrelevant papers (n = 228) and evaluated the full texts of 87 papers. Furthermore, 13 records did not meet the inclusion criteria and were excluded from the systematic review. Finally, a total of 74 manuscripts were entered into the qualitative synthesis and included in the present systematic review. Our systematic review highlights that HTN is the most common comorbidity encountered in MPNs, with an impact on both the occurrence of thrombosis and survival. Moreover, drug-induced HTN remains a challenge in the management of MPNs. Further research should investigate the characteristics of patients with MPNs and HTN, as well as clarify the contribution of HTN to the development of thrombotic complications, survival and management in MPNs. In addition, the relationship between clonal hematopoiesis of indeterminate potential, HTN, cardiovascular disease and MPNs requires examination in upcoming assessments.
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Affiliation(s)
- Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Vincent Kipkorir
- Department of Human Anatomy and Physiology, University of Nairobi, Nairobi 30197, Kenya
| | | | - Arkadeep Dhali
- Department of Internal Medicine, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK
| | - Amelia Maria Găman
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- Clinic of Hematology, Filantropia City Hospital, 200143 Craiova, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
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Aini W, Xie L, Hu W, Tang Y, Peng H, Zhang G, Deng T. Exploration and identification of anoikis-related genes in polycythemia vera. Front Genet 2023; 14:1139351. [PMID: 36873934 PMCID: PMC9981965 DOI: 10.3389/fgene.2023.1139351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/09/2023] [Indexed: 02/19/2023] Open
Abstract
Background: Polycythemia Vera (PV) is a type of typical Myeloproliferative Neoplasms (MPNs) characterized with excessive erythropoiesis and thrombosis. Anoikis is a special programmed cell death mode induced by the adhesion disorder between cells and extracellular matrix (ECM) or adjacent cells facilitating cancer metastasis. However, few studies have focused on the role of anoikis in PV, especially on the development of PV. Methods: The microarray and RNA-seq results were screened from the Gene Expression Omnibus (GEO) database and the anoikis-related genes (ARGs) were downloaded from Genecards. The functional enrichment analysis of intersecting differentially expressed genes (DEGs) and protein-protein interaction (PPI) network analysis were performed to discover hub genes. The hub genes expression was tested in the training (GSE136335) and validation cohort (GSE145802), and RT-qPCR was performed to verify the gene expression in PV mice. Results: In the training GSE136335, a total of 1,195 DEGs was obtained from Myeloproliferative Neoplasm (MPN) patients compared with controls, among which 58 were anoikis-related DEGs. The significant enrichment of the apoptosis and cell adhesion pathways (i.e., cadherin binding) were shown in functional enrichment analysis. The PPI network was conducted to identify top five hub genes (CASP3, CYCS, HIF1A, IL1B, MCL1). The expression of CASP3 and IL1B were significantly upregulated both in validation cohort and PV mice and downregulated after treatment, suggesting that CASP3 and IL1B could be important indicators for disease surveillance. Conclusion: Our research revealed a relationship between anoikis and PV for the first time by combined analysis of gene level, protein interaction and functional enrichment, allowing novel insights into mechanisms of PV. Moreover, CASP3 and IL1B may become promising indicators of PV development and treatment.
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Affiliation(s)
- Wufuer Aini
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Limin Xie
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Wanyu Hu
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yuan Tang
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Hongling Peng
- Department of Hematology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Institute of Molecular Hematopathy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, Changsha, Hunan, China
| | - Guangsen Zhang
- Institute of Molecular Hematopathy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.,Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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11
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Christensen SF, Svingel LS, Kjærsgaard A, Stenling A, Darvalics B, Paulsson B, Andersen CL, Christiansen CF, Stentoft J, Starklint J, Severinsen MT, Clausen MB, Hilsøe MH, Hasselbalch HC, Frederiksen H, Mikkelsen EM, Bak M. Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study. Eur J Haematol 2022; 109:526-541. [PMID: 35900040 PMCID: PMC9804288 DOI: 10.1111/ejh.13841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 01/05/2023]
Abstract
Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.
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Affiliation(s)
| | - Lise Skovgaard Svingel
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | - Anders Kjærsgaard
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | | | - Bianka Darvalics
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | | | - Christen Lykkegaard Andersen
- Department of HematologyCopenhagen University HospitalRigshospitaletDenmark,The Research Unit for General Practice and Section of General Practice, Department of Public HealthUniversity of CopenhagenCopenhagenDenmark
| | - Christian Fynbo Christiansen
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | - Jesper Stentoft
- Department of HematologyAarhus University HospitalAarhusDenmark
| | - Jørn Starklint
- Department of HematologyHolstebro HospitalHolstebroDenmark
| | | | - Mette Borg Clausen
- Department of HematologyCopenhagen University HospitalRigshospitaletDenmark
| | | | | | | | - Ellen Margrethe Mikkelsen
- Department of Clinical Epidemiology, Department of Clinical MedicineAarhus University Hospital and Aarhus UniversityAarhusDenmark
| | - Marie Bak
- Department of HematologyZealand University HospitalRoskildeDenmark,Department of HematologyCopenhagen University HospitalRigshospitaletDenmark
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12
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Larsen MK, Skov V, Kjær L, Møller‐Palacino NA, Pedersen RK, Andersen M, Ottesen JT, Cordua S, Poulsen HE, Dahl M, Knudsen TA, Eickhardt‐Dalbøge CS, Koschmieder S, Pedersen KM, Çolak Y, Bojesen SE, Nordestgaard BG, Stiehl T, Hasselbalch HC, Ellervik C. Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up. Eur J Haematol 2022; 109:576-585. [PMID: 36054308 PMCID: PMC9804367 DOI: 10.1111/ejh.13845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/08/2022] [Indexed: 01/05/2023]
Abstract
The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation-positive individuals without haematological malignancy were defined as having CHIP (N = 629). We used multiple and inverse probability weighted (IPW)-adjusted linear regression analysis to estimate adjusted mean (95% confidence interval) differences in estimated glomerular filtration rate (eGFR; ml/min/1.73 m2 ) by mutation status, variant allele frequency (VAF%), blood cell counts, and neutrophil-to-lymphocyte ratio (NLR). We performed 11-year longitudinal follow-up of eGFR in all individuals. Compared to CHIP-negative individuals, the mean differences in eGFR were -5.6 (-10.3, -0.8, p = .02) for CALR, -11.9 (-21.4, -2.4, p = 0.01) for CALR type 2, and -10.1 (-18.1, -2.2, p = .01) for CALR with VAF ≥ 1%. The IPW-adjusted linear regression analyses showed similar results. NLR was negatively associated with eGFR. Individuals with CALR type 2 had a worse 11-year longitudinal follow-up on eGFR compared to CHIP-negative individuals (p = .004). In conclusion, individuals with CALR mutations, especially CALR type 2, had impaired kidney function compared to CHIP-negative individuals as measured by a lower eGFR at baseline and during 11-year follow-up.
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Affiliation(s)
- Morten K. Larsen
- Department of HaematologyZealand University HospitalRoskildeDenmark,Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Vibe Skov
- Department of HaematologyZealand University HospitalRoskildeDenmark
| | - Lasse Kjær
- Department of HaematologyZealand University HospitalRoskildeDenmark
| | | | | | - Morten Andersen
- Department of Science and EnvironmentRoskilde UniversityRoskildeDenmark
| | - Johnny T. Ottesen
- Department of Science and EnvironmentRoskilde UniversityRoskildeDenmark
| | - Sabrina Cordua
- Department of HaematologyCopenhagen University Hospital RigshospitaletCopenhagenDenmark
| | - Henrik E. Poulsen
- Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of EndocrinologyCopenhagen University Hospital, Bispebjerg Frederiksberg HospitalCopenhagenDenmark,Department of CardiologyCopenhagen University Hospital, Nordsjællands HospitalHillerødDenmark
| | - Morten Dahl
- Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of Clinical BiochemistryZealand University HospitalKøgeDenmark
| | - Trine A. Knudsen
- Department of HaematologyZealand University HospitalRoskildeDenmark,Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Christina Schjellerup Eickhardt‐Dalbøge
- Department of HaematologyZealand University HospitalRoskildeDenmark,Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Steffen Koschmieder
- Department of Haematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of MedicineRWTH Aachen UniversityAachenGermany
| | - Kasper M. Pedersen
- Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of Clinical Biochemistry and the Copenhagen General Population StudyCopenhagen University Hospital, Herlev and Gentofte HospitalHerlevDenmark
| | - Yunus Çolak
- Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of Clinical Biochemistry and the Copenhagen General Population StudyCopenhagen University Hospital, Herlev and Gentofte HospitalHerlevDenmark,Department of Respiratory MedicineCopenhagen University Hospital, Herlev and Gentofte HospitalDenmark
| | - Stig E. Bojesen
- Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of Clinical Biochemistry and the Copenhagen General Population StudyCopenhagen University Hospital, Herlev and Gentofte HospitalHerlevDenmark
| | - Børge G. Nordestgaard
- Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of Clinical Biochemistry and the Copenhagen General Population StudyCopenhagen University Hospital, Herlev and Gentofte HospitalHerlevDenmark
| | - Thomas Stiehl
- Department of Science and EnvironmentRoskilde UniversityRoskildeDenmark,Institute for Computational Biomedicine ‐ Disease ModellingFaculty of Medicine, RWTH Aachen UniversityAachenGermany
| | - Hans C. Hasselbalch
- Department of HaematologyZealand University HospitalRoskildeDenmark,Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Christina Ellervik
- Department Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of Data SupportRegion ZealandDenmark,Department of PathologyHarvard Medical SchoolBostonUSA
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13
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Lun R, Roy DC, Hao Y, Deka R, Huang WK, Navi BB, Siegal DM, Ramsay T, Fergusson D, Shorr R, Dowlatshahi D. Incidence of stroke in the first year after diagnosis of cancer-A systematic review and meta-analysis. Front Neurol 2022; 13:966190. [PMID: 36203979 PMCID: PMC9530058 DOI: 10.3389/fneur.2022.966190] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/26/2022] [Indexed: 11/28/2022] Open
Abstract
Background Patients newly diagnosed with cancer represent a population at highest risk for stroke. The objective of this systematic review and meta-analysis was to estimate the incidence of stroke in the first year following a new diagnosis of cancer. Methods We searched MEDLINE and EMBASE from January 1980 to June 2021 for observational studies that enrolled adults with a new diagnosis of all cancers excluding non-melanoma skin cancer, and that reported the incidence of stroke at 1 year. PRISMA guidelines for meta-analyses were followed. Two reviewers independently extracted data and appraised risk of bias. We used the Dersimonian and Laird random effects method to pool cumulative incidences after logit transformation, and reported pooled proportions as percentages. Statistical heterogeneity was assessed using the I 2 statistic. Results A total of 12,083 studies were screened; 41 studies were included for analysis. Data from 2,552,121 subjects with cancer were analyzed. The cumulative incidence of total stroke at 1 year was 1.4% (95% CI 0.9-2.2%), while the pooled incidence of ischemic stroke was 1.3% (95% CI 1.0-1.8%) and 0.3% (95% CI 0.1-0.9%) for spontaneous intracerebral hemorrhage (ICH), with consistently high statistical heterogeneity (>99% I 2). Conclusion The estimated incidence of stroke during the first year after a new diagnosis of cancer is 1.4%, with a higher risk for ischemic stroke than ICH. Cancer patients should be educated on the risk of stroke at the time of diagnosis. Future studies should evaluate optimal primary prevention strategies in this high-risk group of patients. Systematic review registration https://osf.io/ucwy9/.
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Affiliation(s)
- Ronda Lun
- Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- School of Epidemiology, University of Ottawa, Ottawa, ON, Canada
- Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | | | - Yu Hao
- Biomedical Sciences Department, University of Calgary, Calgary, AB, Canada
| | - Rishi Deka
- Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, San Diego, CA, United States
- Department of Radiation Medicine and Applied Sciences, University of California, San Diego School of Medicine, San Diego, San Diego, CA, United States
- Veterans Affairs Health Care System, San Diego, CA, United States
| | - Wen-Kuan Huang
- Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Babak B. Navi
- Clinical and Translational Neuroscience Unit, Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medicine, New York, NY, United States
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Deborah M. Siegal
- Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Division of Hematology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Tim Ramsay
- School of Epidemiology, University of Ottawa, Ottawa, ON, Canada
- Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Dean Fergusson
- School of Epidemiology, University of Ottawa, Ottawa, ON, Canada
- Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Risa Shorr
- Department of Education, The Ottawa Hospital, Ottawa, ON, Canada
| | - Dar Dowlatshahi
- Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, Ottawa, ON, Canada
- School of Epidemiology, University of Ottawa, Ottawa, ON, Canada
- Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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14
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Gerds AT, Lyons RM, Colucci P, Kalafut P, Paranagama D, Verstovsek S. Disease and Clinical Characteristics of Patients With a Clinical Diagnosis of Myelofibrosis Enrolled in the MOST Study. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:e532-e540. [PMID: 35256316 DOI: 10.1016/j.clml.2022.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/28/2022] [Accepted: 02/03/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Clinical characteristics and treatment patterns of patients with lower-risk myelofibrosis (MF) are not well described. This analysis from the MOST (NCT02953704) assessed the demographic and clinical characteristics and treatment patterns of patients with the clinical diagnosis of lower-risk MF at enrollment. PATIENTS AND METHODS MOST is an ongoing, prospective, observational study in patients with clinical diagnoses of MF or essential thrombocythemia enrolled at clinical practices throughout the United States. Patients included in the MF cohort (≥18 years of age) had low-risk MF by the Dynamic International Prognostic Scoring System or intermediate-1 (INT-1) risk MF (by age >65 years only) at enrollment. Patient data were entered into an electronic case report form during usual-care visits over a planned 36 month observation period. RESULTS Two hundred five patients were eligible for this analysis (low risk, n = 85; INT-1 risk, n = 120; median age, 68 years [range, 35-88]); 166 patients (81.0%) had mutation testing results available. The median time from MF diagnosis to enrollment was 1.8 years. Hemoglobin and hematocrit levels were below the normal range in 50.5% and 48.7% of patients, respectively. Nearly all (98.0%) patients had comorbid conditions, most commonly hypertension (49.8%). Fatigue was the most common physician-reported MF symptom (30.7%). At enrollment, 55.6% of patients were receiving MF-directed monotherapy, most frequently hydroxyurea (46.5%) or ruxolitinib (40.4%). CONCLUSION Future longitudinal analyses of data from MOST will help identify unmet needs and characterize how patients with lower-risk MF are managed throughout the disease course.
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Affiliation(s)
- Aaron T Gerds
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.
| | - Roger M Lyons
- Texas Oncology and US Oncology Research, San Antonio, TX
| | | | | | | | - Srdan Verstovsek
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
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15
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Solli CN, Chamat-Hedemand S, Elming H, Ngo A, Kjær L, Skov V, Sørensen AL, Ellervik C, Fuchs A, Sigvardsen PE, Kühl JT, Kofoed KF, Nordestgaard BG, Hasselbalch H, Bruun NE. Coronary artery- and aortic valve calcifications in patients with Philadelphia-negative myeloproliferative neoplasms. Int J Cardiol 2022; 364:112-118. [PMID: 35716942 DOI: 10.1016/j.ijcard.2022.06.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/24/2022] [Accepted: 06/10/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND Patients with the hematological cancers Philadelphia-negative Myeloproliferative Neoplasms (MPNs) have an increased risk of cardiovascular disease. However, whether MPNs have an increased burden of cardiac calcification has not been thoroughly investigated. Our aim is to investigate whether patients with MPNs have an increased burden of cardiac calcification that could help explain their increased risk of cardiovascular disease. METHODS AND RESULTS We recruited 161 patients (mean age 65 years, 52% men) with an MPN diagnosis between 2016 and 2018. Coronary artery calcium score (CACS) and aortic valve calcification (AVC) were measured by cardiac computer tomography, and detailed information on cardiovascular risk factors was recorded. MPNs were matched on age and sex, with 805 controls from the Copenhagen General Population Study. A CACS>400 was present in 26% of MPNs and 19% of controls (p = 0.031). AVC was present in 58% of MPNs and 34% of controls (p < 0.0001). After adjustment for cardiovascular risk factors, the odds ratio (OR) of a CACS>400 was 1.9 (95% CI 1.2-3.1, p = 0.008) in MPNs compared to controls, and the OR of AVC was 4.4 (95% CI 2.9-6.9, p < 0.0001) in MPNs compared to controls. CONCLUSION Patients with MPNs have a significantly higher prevalence of a CACS >400 and AVC, compared to controls from the general population. The association between MPN and a CACS>400 or AVC remains significant after adjustment for cardiovascular risk factors. These novel data support the hypothesis that MPNs have an increased burden of cardiac calcifications, independent of other cardiovascular risk factors.
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Affiliation(s)
- Camilla Nordheim Solli
- Dept. of Cardiology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Sandra Chamat-Hedemand
- Dept. of Cardiology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hanne Elming
- Dept. of Cardiology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark
| | - Anh Ngo
- Dept. of Cardiology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark
| | - Lasse Kjær
- Dept. of Hematology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark
| | - Vibe Skov
- Dept. of Hematology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark
| | | | - Christina Ellervik
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Data Support, Region Zealand, Sorø, Denmark
| | - Andreas Fuchs
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Per Ejlstrup Sigvardsen
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Jørgen Tobias Kühl
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Klaus Fuglsang Kofoed
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark; Dept. of Radiology, Rigshospitalet, Copenhagen, Denmark
| | - Børge G Nordestgaard
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Clinical Biochemistry, the Copenhagen General Population Study, Herlev- Gentofte Hospital, Herlev, Denmark
| | - Hans Hasselbalch
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Dept. of Hematology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark
| | - Niels Eske Bruun
- Dept. of Cardiology, Zealand University Hospital, 4000 Roskilde, Region Zealand, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health and Medical Sciences, Aalborg University, Aalborg, Denmark
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16
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García-Fortes M, Hernández-Boluda JC, Álvarez-Larrán A, Raya JM, Angona A, Estrada N, Fox L, Cuevas B, García-Hernández MC, Gómez-Casares MT, Ferrer-Marín F, Saavedra S, Cervantes F, García-Delgado R. Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis. Cancers (Basel) 2022; 14:cancers14092331. [PMID: 35565461 PMCID: PMC9104306 DOI: 10.3390/cancers14092331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/21/2022] [Accepted: 05/03/2022] [Indexed: 11/30/2022] Open
Abstract
The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.
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Affiliation(s)
- María García-Fortes
- Hematology Department, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain;
- Facultad de Medicina, Universidad de Málaga, 29010 Málaga, Spain
- Correspondence:
| | | | | | - José M. Raya
- Hematology Department, Hospital Universitario de Canarias, 38320 Santa Cruz de Tenerife, Spain;
| | - Anna Angona
- Hematology Department, Hospital del Mar, 08003 Barcelona, Spain;
| | - Natalia Estrada
- Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, 08916 Badalona, Spain;
| | - Laura Fox
- Hematology Department, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain;
| | - Beatriz Cuevas
- Hematology Department, Hospital Universitario de Burgos, 09006 Burgos, Spain;
| | | | | | - Francisca Ferrer-Marín
- Hematology Department, Hospital General Universitario Morales Meseguer, CIBERER, IMIB, UCAM, 30008 Murcia, Spain;
| | - Silvana Saavedra
- Hematology Department, Hospital Santa Creu i Sant Pau, 08025 Barcelona, Spain;
| | - Francisco Cervantes
- Hematology Department, Hospital Clínic, 08036 Barcelona, Spain; (A.Á.-L.); (F.C.)
| | - Regina García-Delgado
- Hematology Department, Hospital Universitario Virgen de la Victoria, 29010 Málaga, Spain;
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17
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Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. Lancet Haematol 2022; 9:e301-e311. [DOI: 10.1016/s2352-3026(22)00046-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 02/06/2023]
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18
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Tanashyan M, Shabalina A, Roitman E. Microrheological disorders in patients with polycythemia vera suffered acute ischemic stroke. Mol Cell Biochem 2022; 477:989-994. [PMID: 34984595 DOI: 10.1007/s11010-021-04352-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/23/2021] [Indexed: 11/27/2022]
Abstract
The relevance of the study is determined by the fact that the combination of cerebrovascular disorders and myeloproliferative diseases requires the search for a predictive biomarker to improve outcomes. The aim of this article was to explore the meanings of microrheological disorders in patients with polycythemia vera (PV) who suffered an acute ischemic stroke (AIS). The study was carried out at the Research center of Neurology. We studied microrheological properties in 181 patients (aged 42-75 years). From the AIS developed in 68 (38%) patients with PV; 59 (32%) patients with AIS were without PV; 54 (30%) patients with PV did not suffer AIS. Microrheological disorders, first of all, the red blood cells (RBC) deformability correlated to AIS severity and its features in comorbid patients. The RBC deformability was dependent on the allelic load of the V617F mutation in the JAK2 gene. Additionally, it was found that RBC deformability perform diagnostic value in the acute phase of ischemic stroke as well as get predictive value for thrombotic complications development within 2 years after AIS in such patients. We suppose that in patients with PV an ischemic stroke and thrombosis would directly depend on the success of PV treatment. In turn, RBC deformability is applicable for some predictive models to late thrombosis development.
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Affiliation(s)
- Marine Tanashyan
- Department of Neurological No. 1, Research Center of Neurology, 80 Volokolamskoye Shosse, 125367, Moscow, Russian Federation
| | - Alla Shabalina
- Laboratory of Hemorheology, Hemostasis and Pharmacokinetics with Clinical Laboratory Diagnostics, Research Center of Neurology, 80 Volokolamskoye Shosse, 125367, Moscow, Russian Federation
| | - Eugene Roitman
- Laboratory of Hemorheology, Hemostasis and Pharmacokinetics with Clinical Laboratory Diagnostics, Research Center of Neurology, 80 Volokolamskoye Shosse, 125367, Moscow, Russian Federation.
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19
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Chornenki NLJ, Siegal DM, Qamar K, Woolgar S, Rangarajan S, Karampatos S, Leong DP, Hillis CM. Characterizing Frailty In Myeloproliferative Neoplasms: results from the ORCHID study. Leuk Res 2022; 113:106788. [PMID: 35042128 DOI: 10.1016/j.leukres.2022.106788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 01/08/2022] [Accepted: 01/08/2022] [Indexed: 11/17/2022]
MESH Headings
- Aged
- Canada/epidemiology
- Female
- Frailty/diagnosis
- Frailty/drug therapy
- Frailty/epidemiology
- Geriatric Assessment/methods
- Geriatric Assessment/statistics & numerical data
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology
- Male
- Middle Aged
- Myeloproliferative Disorders/diagnosis
- Myeloproliferative Disorders/drug therapy
- Myeloproliferative Disorders/epidemiology
- Polycythemia Vera/diagnosis
- Polycythemia Vera/drug therapy
- Polycythemia Vera/epidemiology
- Prevalence
- Prospective Studies
- Protein Kinase Inhibitors/therapeutic use
- Surveys and Questionnaires
- Thrombocythemia, Essential/diagnosis
- Thrombocythemia, Essential/drug therapy
- Thrombocythemia, Essential/epidemiology
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Affiliation(s)
| | | | - Kiran Qamar
- Population Health Research Institute, Canada
| | | | | | | | - Darryl P Leong
- Population Health Research Institute, Canada; Department of Medicine, McMaster University, Canada
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20
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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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21
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Sunu C, Gunes AK, Akat GK, Kalpakci Y, Ceran F, Dagdas S, Ozet G. The evaluation of patients with essential thrombocythemia in terms of risk of thrombosis. ACTA ACUST UNITED AC 2021; 67:385-389. [PMID: 34468602 DOI: 10.1590/1806-9282.20200778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The aim of this study was to compare the incidence of factors associated with an increased risk of thrombosis in patients with essential thrombocythemia. METHODS A total of 200 patients followed-up in our unit with a diagnosis of essential thrombocythemia in 13 years were analyzed retrospectively. RESULTS Of the study participants, 60.5% were females and 39.5% were males, with an overall mean (±SD) age of 54.93 (±14.21) years. In 119 patients, Janus Kinase 2 was positive with 56.3% of cases. When two patient categories were defined as those with or without history of thrombosis, no significant differences were found in terms of Janus Kinase 2 positivity, mean age, as well as white blood cells and platelet counts (p>0.05). Also, no significant differences in thrombotic event incidence were found between patient categories defined on the basis of cut-off values for white blood cells (cut-off values of 15×103/mm3 and 8.7×103/mm3) and platelets (cut-off values of 1500×103/mm3) (p>0.05). CONCLUSION Although our results are generally in line with the published data, some divergence from previous results has been observed with respect to risk factors for thrombotic events. Absence of a correlation between leukocytosis and thrombosis may be related with the significant decline in white blood cells after treatment. Also, a significant reduction in platelet counts occurring in association with treatment is linked with a lowered incidence of thrombosis. Janus Kinase 2-positive patients had a similar thrombosis frequency with that reported in the literature.
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Affiliation(s)
- Cenk Sunu
- Sakarya University Training and Research Hospital, Department of Hematology - Sakarya, Turkey
| | | | | | - Yasin Kalpakci
- Sakarya University Training and Research Hospital, Department of Hematology - Sakarya, Turkey
| | - Funda Ceran
- Ankara City Hospital, Department of Hematology - Ankara, Turkey
| | - Simten Dagdas
- Ankara City Hospital, Department of Hematology - Ankara, Turkey
| | - Gulsum Ozet
- Ankara City Hospital, Department of Hematology - Ankara, Turkey
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22
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Clinical insights into the origins of thrombosis in myeloproliferative neoplasms. Blood 2021; 137:1145-1153. [PMID: 33237986 DOI: 10.1182/blood.2020008043] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are hematopoietic stem cell disorders that are defined by activating mutations in signal transduction pathways and are characterized clinically by the overproduction of platelets, red blood cells, and neutrophils, significant burden of disease-specific symptoms, and high rates of vascular events. The focus of this review is to critically reevaluate the clinical burden of thrombosis in MPNs, to review the clinical associations among clonal hematopoiesis, JAK2V617F burden, inflammation, and thrombosis, and to provide insights into novel primary and secondary thrombosis-prevention strategies.
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23
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Plaçais L, Rabel C, Chassin O, Sarov M, Legris N, Noël N, Denier C. Characteristics of arterial stroke in myeloproliferative neoplasms: A French monocentric study. Am J Hematol 2021; 96:E240-E243. [PMID: 33811774 DOI: 10.1002/ajh.26180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/25/2021] [Accepted: 03/28/2021] [Indexed: 12/19/2022]
Affiliation(s)
- Léo Plaçais
- AP‐HP, GHU Paris‐Saclay Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique Le Kremlin Bicêtre France
- INSERM Institut National de la Santé et de la Recherche Médicale ‐ Université Paris Saclay (COMUE) Le Kremlin‐Bicêtre France
- CEA, DSV/iMETI, IDMIT Fontenay‐aux‐Roses France
| | - Constance Rabel
- Neurology Department Assistance Publique‐Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre Le Kremlin Bicêtre France
- INSERM U1195 & Paris Saclay University Le Kremlin Bicêtre France
| | - Olivier Chassin
- Neurology Department Assistance Publique‐Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre Le Kremlin Bicêtre France
| | - Mariana Sarov
- Neurology Department Assistance Publique‐Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre Le Kremlin Bicêtre France
| | - Nicolas Legris
- Neurology Department Assistance Publique‐Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre Le Kremlin Bicêtre France
| | - Nicolas Noël
- AP‐HP, GHU Paris‐Saclay Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique Le Kremlin Bicêtre France
- INSERM Institut National de la Santé et de la Recherche Médicale ‐ Université Paris Saclay (COMUE) Le Kremlin‐Bicêtre France
- CEA, DSV/iMETI, IDMIT Fontenay‐aux‐Roses France
- Faculté de Médecine, Université Paris Saclay Le Kremlin Bicêtre France
| | - Christian Denier
- Neurology Department Assistance Publique‐Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Hôpital Bicêtre Le Kremlin Bicêtre France
- INSERM U1195 & Paris Saclay University Le Kremlin Bicêtre France
- Faculté de Médecine, Université Paris Saclay Le Kremlin Bicêtre France
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24
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Kwiatkowski J, Kuliszkiewicz-Janus M, Rymer W, Jaźwiec B, Małecki R. Treatment of Essential Thrombocythemia with Anagrelide Is Associated with an Increased Risk of Worsened Kidney Function. Pharmacology 2021; 106:316-322. [PMID: 33691325 DOI: 10.1159/000513377] [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: 06/03/2020] [Accepted: 11/23/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND AND PURPOSE When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation. EXPERIMENTAL APPROACH The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment. KEY RESULTS A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m2 [interquartile range (IQR) (-4)-(+7)] in the HU group vss. median -13 mL/min/1.73 m2 [IQR (-18)-(-6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17-15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m2 occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21-3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998). CONCLUSIONS AND IMPLICATIONS The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function.
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Affiliation(s)
- Jacek Kwiatkowski
- Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland,
| | | | - Weronika Rymer
- Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiences, Wrocław Medical University, Wrocław, Poland
| | - Bożena Jaźwiec
- Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland
| | - Rafał Małecki
- Department and Clinic of Angiology, Hypertension, and Diabetology, Wrocław Medical University, Wrocław, Poland
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25
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Benevolo G, Elli EM, Bartoletti D, Latagliata R, Tiribelli M, Heidel FH, Cavazzini F, Bonifacio M, Crugnola M, Binotto G, D'Addio A, Tieghi A, Bergamaschi M, Caocci G, Polverelli N, Bossi E, Auteri G, Carmosino I, Catani L, Cuneo A, Krampera M, Lanza F, Lemoli RM, Vianelli N, Breccia M, Palumbo GA, Cavo M, Palandri F. Impact of comorbidities and body mass index on the outcome of polycythemia vera patients. Hematol Oncol 2021; 39:409-418. [PMID: 33590502 DOI: 10.1002/hon.2843] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 01/12/2021] [Accepted: 02/08/2021] [Indexed: 11/10/2022]
Abstract
In 816 patients with 2016 World Health Organization-defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post-PV myelofibrosis (PPV-MF) and survival. Patients were subgrouped according to CCI = 0 (58.1%, no comorbidities) or CCI ≥ 1 (41.9%) and according to normal/underweight (BMI < 25, 54.5%) or overweight/obesity (BMI ≥ 25, 45.5%) at PV diagnosis. BMI was available for 529 patients. Patients with CCI ≥ 1 were older and more frequently presented cardiovascular risk factors compared to patients with CCI = 0 (p < 0.001), while overweight/obese patients were more frequently males (p < 0.001). Cumulative incidence of thromboses with death as competing risk was 13.3% at 10 years. Multivariable analysis with death as competing risk showed that previous thromboses (subdistribution hazard ratio [SHR]: 2.1, p = 0.01) and hypertension (SHR: 1.77, p = 0.04) were significantly associated with a higher thrombotic risk, while BMI ≥ 25 lost statistical significance (SHR: 1.69, p = 0.05) and CCI ≥ 1 was excluded after evaluation of goodness of fit. After a median follow-up of 6.1 years, progression to PPV-MF occurred in 44 patients, and 75 patients died. BMI ≥ 25 was associated with a lower probability of progression to PPV-MF (SHR: 0.38, CI95%: 0.15-0.94, p = 0.04) and better survival (hazard ratio [HR]: 0.42, CI95%: 0.18-0.97, p = 0.04). CCI ≥ 1 did not affect progression to PPV-MF (p = 0.44) or survival (p = 0.71). The evaluation of CCI and BMI may improve the prognostic definition of PV. In patients with hypertension an accurate evaluation of thrombotic risk is warranted.
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Affiliation(s)
- Giulia Benevolo
- Division of Hematology, Città della Salute e della Scienza Hospital, Torino, Italy
| | - Elena M Elli
- Hematology Division, San Gerardo Hospital, ASST Monza, Monza, Italy
| | - Daniela Bartoletti
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna Bologna, Italy
| | - Roberto Latagliata
- Division of Cellular Biotechnologies and Hematology, University Sapienza, Rome, Italy
| | - Mario Tiribelli
- Division of Hematology and BMT, Azienda Sanitaria Universitaria Integrata di Udine, Italy
| | - Florian H Heidel
- Department of Hematology and Oncology, Friedrich-Schiller-University Medical Center, Jena, Germany
| | | | | | - Monica Crugnola
- Division of Hematology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Gianni Binotto
- Unit of Hematology and Clinical Immunology, University of Padova, Padova, Italy
| | - Alessandra D'Addio
- Division of Hematology, Onco-Hematologic Department, AUSL della Romagna, Ravenna, Italy
| | - Alessia Tieghi
- Department of Hematology, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Micaela Bergamaschi
- Department of Internal Medicine (DiMI), Clinic of Hematology, University of Genoa, Genova, Italy
| | - Giovanni Caocci
- Hematology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | - Nicola Polverelli
- Unit of Blood Diseases and Stem Cell Transplantation, ASST Spedali Civili di Brescia, Brescia, Italy
| | - Elisa Bossi
- Hematology Division, San Gerardo Hospital, ASST Monza, Monza, Italy
| | - Giuseppe Auteri
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.,Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna Bologna, Italy
| | - Ida Carmosino
- Division of Cellular Biotechnologies and Hematology, University Sapienza, Rome, Italy
| | - Lucia Catani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Antonio Cuneo
- Division of Hematology, University of Ferrara, Ferrara, Italy
| | - Mauro Krampera
- Department of Hematology, University of Verona, Verona, Italy
| | - Francesco Lanza
- Division of Hematology, Onco-Hematologic Department, AUSL della Romagna, Ravenna, Italy
| | - Roberto M Lemoli
- Department of Internal Medicine (DiMI), Clinic of Hematology, University of Genoa, Genova, Italy.,IRCCS Policlinico San Martino, Genova, Italy
| | - Nicola Vianelli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Massimo Breccia
- Division of Cellular Biotechnologies and Hematology, University Sapienza, Rome, Italy
| | - Giuseppe A Palumbo
- Department of Scienze Mediche, Chirurgiche e Tecnologie Avanzate "G.F. Ingrassia", University of Catania, Catania, Italy
| | - Michele Cavo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
| | - Francesca Palandri
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy
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26
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Schafer AI. Thrombotic, Vascular, and Bleeding Complications of the Myeloproliferative Neoplasms. Hematol Oncol Clin North Am 2021; 35:305-324. [PMID: 33641871 DOI: 10.1016/j.hoc.2020.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Thrombotic, vascular, and bleeding complications are the most frequent causes of morbidity and mortality in myeloproliferative neoplasms (MPNs). The interplay and reciprocal amplification between two factors are considered to lead to thrombosis in MPNs: (1) circulating blood cell-intrinsic abnormalities caused by an MPN driver mutation in their hematopoietic progenitor/stem cells, interacting with vascular endothelial cells, show prothrombotic and proadhesive phenotypes; and (2) a state of usually subclinical systemic inflammation that fuels the thrombotic tendency. Prevention and treatment require maintenance of hematocrit less than 45% and cytoreductive therapy in patients with a high risk for thrombotic and vascular complications.
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Affiliation(s)
- Andrew I Schafer
- Weill Cornell Medicine, 1305 York Avenue, 8th Floor, Room Y-811, New York, NY 10021, USA.
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27
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Ferro JM, Infante J. Cerebrovascular manifestations in hematological diseases: an update. J Neurol 2021; 268:3480-3492. [PMID: 33586004 PMCID: PMC8357668 DOI: 10.1007/s00415-021-10441-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/31/2021] [Accepted: 02/01/2021] [Indexed: 01/04/2023]
Abstract
Patients with hematological diseases often experience cerebrovascular complications including ischemic stroke, intracerebral and subarachnoid hemorrhage, microbleeds, posterior reversible encephalopathy syndrome, and dural sinus and cerebral vein thrombosis (CVT). In this update, we will review recent advances in the management of cerebrovascular diseases in the context of myeloproliferative neoplasms, leukemias, lymphomas, multiple myeloma, POEMS, paroxysmal nocturnal hemoglobinuria (PNH), thrombotic thrombocytopenic purpura (TTP), and sickle-cell disease. In acute ischemic stroke associated with hematological diseases, thrombectomy can in general be applied if there is a large vessel occlusion. Intravenous thrombolysis can be used in myeloproliferative neoplasms and sickle-cell anemia, but in other diseases, a case-by-case evaluation of the bleeding risks is mandatory. Patients with sickle-cell disease and acute stroke need very often to be transfused. In PNH, acute ischemic stroke patients must be anticoagulated. Most patients with CVT can be treated with low-molecular weight heparin (LMWH) acutely, even those with leukemias. Prevention of recurrence of cerebral thrombotic events depends on the control of the underlying disease, combined in some conditions with antithrombotic drugs. The recent introduction of specific monoclonal antibodies in the treatment of PHN and TTP has dramatically reduced the risk of arterial and venous thrombosis.
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Affiliation(s)
- José M Ferro
- Serviço de Neurologia, Departamento de Neurociências e Saúde Mental, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal. .,Faculdade de Medicina, Universidade de Lisboa, Hospital de Santa Maria, Neurology, 6th Floor, Avenida Professor Egas Moniz s/n, 1649-035, Lisbon, Portugal.
| | - Joana Infante
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
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28
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Low-Risk Essential Thrombocythemia: A Comprehensive Review. Hemasphere 2021; 5:e521. [PMID: 33880431 PMCID: PMC8051994 DOI: 10.1097/hs9.0000000000000521] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/13/2020] [Indexed: 12/25/2022] Open
Abstract
Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by a persistently elevated platelet count in the absence of a secondary cause. The clinical consequences of uncontrolled thrombocytosis can include both thrombosis and hemorrhage. Patients with features conferring a “high risk” of vascular events benefit from reduction of the platelet count through cytoreductive therapy. The management of patients who lack such high-risk features has until recently been less well defined, but it is now apparent that many require minimal or even no intervention. In this review, we discuss the diagnostic pathway for younger patients with unexplained thrombocytosis, including screening molecular investigations, the role of bone marrow biopsy, and investigations in those patients negative for the classic myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL). We discuss conventional and novel risk stratification methods in essential thrombocythemia and how these can be best applied in clinical practice, particularly in the era of more comprehensive genomic testing. The treatment approach for “low risk” patients is discussed including antiplatelets and the options for cytoreductive therapy, if indicated, together with areas of clinical need for future study.
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29
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Moliterno AR, Kaizer H. Applied genomics in MPN presentation. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2020; 2020:434-439. [PMID: 33275725 PMCID: PMC7727573 DOI: 10.1182/hematology.2020000128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Polycythemia vera, essential thrombocytosis (ET), and primary myelofibrosis (PMF) are grouped together as myeloproliferative neoplasms (MPNs) because of shared clinical, pathologic, and molecular features. The 2005 discovery of the driver mutation JAK2V617F, found in more than 70% of individuals with MPNs and 98% of those with PV, has transformed the diagnosis and management of MPNs. Although PV is the most common phenotype associated with JAK2V617F, roughly 60% of individuals with ET or PMF also have the mutation, and JAK2V617F is now recognized as a common lesion in clonal hematopoiesis (CH). JAK2V617F+ CH and MPN are indolent disorders that evolve over time, with transitions to different disease phases, transformation to bone marrow failure or leukemia, and high thrombosis rates. Genomic assessment has taken center stage as an important tool to define disease phenotype, disease burden, prognosis, and even thrombosis risk of MPNs. Genomics has also unveiled the causes and factors that modify the risk of acquiring and expanding CH and MPNs and points to new pathways for targeted therapies to treat and ultimately prevent them. Genomic assessment of patients with MPNs, like other cancers, enables the clinician to capitalize on large population data sets to inform the individual patient of risk, identify treatment, and improve outcomes.
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Affiliation(s)
| | - Hannah Kaizer
- Johns Hopkins University School of Medicine, Baltimore, MD
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Brabrand M, Frederiksen H. Risks of Solid and Lymphoid Malignancies in Patients with Myeloproliferative Neoplasms: Clinical Implications. Cancers (Basel) 2020; 12:cancers12103061. [PMID: 33092233 PMCID: PMC7589412 DOI: 10.3390/cancers12103061] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/05/2020] [Accepted: 10/19/2020] [Indexed: 01/21/2023] Open
Abstract
Simple Summary Patients with chronic myeloproliferative neoplasms (MPNs) such as polycythemia vera and essential thrombocythemia have an elevated risk of acute leukemia. Recently, it has been recognized that the risk of solid cancers is also increased. In the past decade, several studies have compared cancer frequency in patients with MPNs with the general population. In our study, we present results sampled from 12 previous studies, totaling more than 65,000 patients with MPNs identified through large registries. Patients with MPNs were compared to the age/sex-matched general population. Our results show that risk of new cancers is 1.5–3.0-fold elevated in patients with MPNs. In particular, lymphomas and cancers of the skin, lung, kidney, and thyroid gland occur more frequently. The difference in cancer occurrence is highest in the age group 60–79 years. Our results indicate that clinical follow up of patients with MPNs should include awareness of the increased cancer risk. Abstract In the past decade, several studies have reported that patients with chronic myeloproliferative neoplasms (MPNs) have an increased risk of second solid cancer or lymphoid hematological cancer. In this qualitative review study, we present results from studies that report on these cancer risks in comparison to cancer incidences in the general population or a control group. Our literature search identified 12 such studies published in the period 2009–2018 including analysis of more than 65,000 patients. The results showed that risk of solid cancer is 1.5- to 3.0-fold elevated and the risk of lymphoid hematological cancer is 2.5- to 3.5-fold elevated in patients with MPNs compared to the general population. These elevated risks apply to all MPN subtypes. For solid cancers, particularly risks of skin cancer, lung cancer, thyroid cancer, and kidney cancer are elevated. The largest difference in cancer risk between patients with MPN and the general population is seen in patients below 80 years. Cancer prognosis is negatively affected due to cardiovascular events, thrombosis, and infections by a concurrent MPN diagnosis mainly among patients with localized cancer. Our review emphasizes that clinicians caring for patients with MPNs should be aware of the very well-documented increased risk of second non-myeloid cancers.
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Affiliation(s)
- Mette Brabrand
- Department of Haematology, Odense University Hospital, 5000 Odense, Denmark;
- Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, 5000 Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
| | - Henrik Frederiksen
- Department of Haematology, Odense University Hospital, 5000 Odense, Denmark;
- Department of Clinical Epidemiology, Aarhus University Hospital, 8200 Aarhus, Denmark
- Correspondence:
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Tanashyan MM, Shabalina AA, Roitman EV, Vavilova TV, Kuznetsova PI. Thrombogenicity in patients with ischemic stroke and pre-existing polycythemia vera. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2020. [DOI: 10.24075/brsmu.2020.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Thrombogenicity and its causes in patients with ischemic stroke (IS) and pre-existing polycythemia vera (PV) is a significant clinical concern. The aim of this study was to identify the range of factors associated with increased thrombogenicity in patients with IS and pre-existing PV. We performed a physical examination and laboratory tests on 127 patients in the hyperacute stroke stage and 16-18 months after. Of them, 68 patients had PV (the main group) and 59 did not have this condition (the comparison group). Laboratory tests were conducted to evaluate blood rheology, hemostasis, endothelial function, angiogenesis, proinflammatory cytokine levels; we also tested patients for the presence of the V617F mutation in the JAK2 gene and analyzed the contribution of all studied parameters to the development of thrombotic and hemorrhagic complications. We found that the neurological picture did not differ between the groups: mean NIHSS scores were 12 and 13 points, respectively. Morphological and functional characteristics of red blood cells and platelets, hemostasis and cytokine profiles were compared between patients with IS and pre-existing PV and the comparison group. One of the key elements in potentiating thrombotic complications in patients with IS and PV was JAK2 V617F allele burden. The obtained data suggest the cumulative effect of the identified factors promoting thrombus formation in post-stroke patients with PV and overpowering the effect of antiplatelet therapy.
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Affiliation(s)
| | | | - EV Roitman
- Research Center of Neurology, Moscow, Russia
| | - TV Vavilova
- Almazov National Medical Research Centre, Saint Petersburg, Russia
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