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Ethiopian Journal of Health Sciences Nov 2023Surgical treatment has transformed the course and outcome of congenital heart defects in high-income countries, but children with congenital heart diseases in...
BACKGROUND
Surgical treatment has transformed the course and outcome of congenital heart defects in high-income countries, but children with congenital heart diseases in sub-Saharan Africa, where access to cardiac surgery is limited, often experience the natural course of untreated lesions and their complications. The objective of this study was to determine the prevalence of hematologic derangements among Ethiopian children with unoperated cyanoticcongenital heart diseases, to identify factors associated with coagulopathy in this population, and to describe how these complications are managed in this setting.
METHODS
In this single-center cross-sectional study, we prospectively collected clinical and demographic data from children (<18 years) with cyanotic congenital heart diseases. Blood samples were collected to measure hematologic parameters. Polycythemia was defined as hematocrit >50% and thrombocytopenia as <150,000 per microliter.
RESULTS
Among 70 children recruited, the overall prevalence of polycythemia and thrombocytopenia was 63% (n=44) and 26% (n=18), respectively. On multivariate logistic regression analysis, hematocrit ≥65% (p-value=.024), and oxygen saturation <85% (p-value=.018) were independently associated with moderate or severe thrombocytopenia. Thirty-one (44%) patients had undergone therapeutic phlebotomy, and 84% (26/31) of these patients received iron supplementation.
CONCLUSION
We report a high prevalence of polycythemia and thrombocytopenia in Ethiopian children with untreated cyanotic congenital heart diseases. There was variable implementation of iron supplementation and therapeutic phlebotomy, highlighting the need to optimize supportive management strategies in this population to mitigate the risk of life-threatening complications.
Topics: Humans; Ethiopia; Female; Heart Defects, Congenital; Male; Cross-Sectional Studies; Polycythemia; Child, Preschool; Infant; Child; Thrombocytopenia; Prevalence; Hematocrit; Cyanosis; Adolescent; Prospective Studies; Phlebotomy
PubMed: 38784485
DOI: 10.4314/ejhs.v33i6.5 -
Clinical Cancer Research : An Official... May 2024Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of...
PURPOSE
Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of Bcr-Abl-ve MPN, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF), and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear.
EXPERIMENTAL DESIGN
To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1,711 genes for mutations along with whole transcriptome RNA sequencing of 137 patients with MPN.
RESULTS
In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N = 106) and ET/PV/PrePMF (N = 31), respectively. Overt MF had more mutations compared with ET/PV/prePMF (5 vs. 4 per subject, P = 0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1) and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2, and NF1 were exclusive to MF. Advancing age, higher DIPSS, and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2, and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells.
CONCLUSIONS
Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression and potential targets for therapeutic intervention.
Topics: Humans; Primary Myelofibrosis; Mutation; Middle Aged; Aged; Male; Female; High-Throughput Nucleotide Sequencing; Adult; Aged, 80 and over; Genomics; Age Factors; Gene Expression Profiling; Transcriptome; Polycythemia Vera
PubMed: 38386293
DOI: 10.1158/1078-0432.CCR-23-0372 -
Annals of Hematology Mar 2024To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or...
Genomic classification and outcomes of young patients with polycythemia vera and essential thrombocythemia according to the presence of splanchnic vein thrombosis and its chronology.
To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9-4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4-24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.
Topics: Humans; Adult; Middle Aged; Polycythemia Vera; Thrombocythemia, Essential; Venous Thrombosis; Thrombosis; Genomics; Disease Progression; Janus Kinase 2
PubMed: 38263537
DOI: 10.1007/s00277-023-05610-x -
Photodiagnosis and Photodynamic Therapy Feb 2024To evaluate the choroidal thickness and retrobulbar hemodynamic parameters in polycythemia vera (PV) patients in comparison with healthy individuals, and to investigate... (Review)
Review
BACKGROUND
To evaluate the choroidal thickness and retrobulbar hemodynamic parameters in polycythemia vera (PV) patients in comparison with healthy individuals, and to investigate the relationship of these values with blood hematocrit levels.
METHODS
This prospective study included the 35 eyes of 35 PV patients and the 30 eyes of 30 healthy individuals. Choroidal thickness was measured at the subfoveal area and at 500 µm intervals nasal and temporal to the fovea up to a distance of 1500 µm. Color Doppler ultrasonography (CDU) was used to evaluate the retrobulbar vessels. Complete blood count values were recorded.
RESULTS
Choroidal thickness was found to be significantly lower in the PV group than in the control group at the subfoveal, nasal 500, and temporal 500 and 1000 µm measurement points (p = 0.01, p = 0.011, p = 0.04, p = 0.045, respectively). The central retinal artery (CRA) peak systolic velocity (PSV) and end diastolic velocity (EDV) values and the ophthalmic artery (OA) PSV value were significantly lower in the PV group than in the control group (p < 0.001, p < 0.001, p = 0.019, respectively). No significant difference was present between the groups in terms of CRA and OA resistive index (RI) and pulsatile index (PI) values (p = 0.388, p = 0.564, p = 0.897, p = 0.693, respectively). A negative correlation was found between the blood hematocrit levels and the subfoveal, nasal 500 µm, and temporal 500 µm choroidal thickness measurements and the CRA PSV and EDV and the OA PSV values.
CONCLUSIONS
PV may cause microvascular changes and lead to ocular vascular complications by affecting the choroidal and retrobulbar blood flow.
Topics: Humans; Prospective Studies; Polycythemia Vera; Blood Flow Velocity; Photochemotherapy; Photosensitizing Agents; Hemodynamics; Choroid
PubMed: 38246214
DOI: 10.1016/j.pdpdt.2024.103985 -
World Journal of Hepatology Nov 2023Classical Philadelphia-negative myeloproliferative neoplasms (MPNs), , polycythemia vera, essential thrombocythemia, and primary/secondary myelofibrosis, are clonal... (Review)
Review
Classical Philadelphia-negative myeloproliferative neoplasms (MPNs), , polycythemia vera, essential thrombocythemia, and primary/secondary myelofibrosis, are clonal disorders of the hematopoietic stem cell in which an uncontrolled proliferation of terminally differentiated myeloid cells occurs. MPNs are characterized by mutations in driver genes, the JAK2V617F point mutation being the most commonly detected genetic alteration in these hematological malignancies. Thus, JAK inhibition has emerged as a potential therapeutic strategy in MPNs, with ruxolitinib being the first JAK inhibitor developed, approved, and prescribed in the management of these blood cancers. However, the use of ruxolitinib has been associated with a potential risk of infection, including opportunistic infections and reactivation of hepatitis B. Here, we briefly describe the association between ruxolitinib treatment in MPNs and hepatitis B reactivation.
PubMed: 38075009
DOI: 10.4254/wjh.v15.i11.1188 -
Nature Communications May 2024Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we...
Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2 mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.
Topics: Polycythemia; Erythroblasts; Erythropoiesis; Heme; Humans; Animals; Lipoproteins; Macrophages; Mice; GATA1 Transcription Factor; Janus Kinase 2; Thrombomodulin; Mice, Knockout; Ferrochelatase; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Female
PubMed: 38729948
DOI: 10.1038/s41467-024-48328-8 -
International Journal of Molecular... Jan 2024Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively.... (Review)
Review
Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.
Topics: Humans; Polycythemia Vera; Thrombocythemia, Essential; Thrombosis; Thrombocytosis; Erythrocytes
PubMed: 38338695
DOI: 10.3390/ijms25031417 -
World Journal of Hepatology Sep 2023The liver has a central role in metabolism, therefore, it is susceptible to harmful effects of ingested medications (drugs, herbs, and nutritional supplements).... (Review)
Review
The liver has a central role in metabolism, therefore, it is susceptible to harmful effects of ingested medications (drugs, herbs, and nutritional supplements). Drug-induced liver injury (DILI) comprises a range of unexpected reactions that occur after exposure to various classes of medication. Even though most cases consist of mild, temporary elevations in liver enzyme markers, DILI can also manifest as acute liver failure in some patients and can be associated with mortality. Herein, we briefly review available data on DILI induced by targeted anticancer agents in managing classical myeloproliferative neoplasms: Chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and myelofibrosis.
PubMed: 37900211
DOI: 10.4254/wjh.v15.i9.1021 -
Cancers Jul 2023In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for...
In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients' triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly ( = 0.03), pruritus ( = 0.002), and a median HU dose of ≥1 g/day ( < 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised.
PubMed: 37509367
DOI: 10.3390/cancers15143706 -
Annals of Hematology Dec 2023To date, no therapeutic strategy has been shown to be effective in reducing the risk of polycythemia vera (PV) transforming into myelofibrosis or leukemia, and the main...
To date, no therapeutic strategy has been shown to be effective in reducing the risk of polycythemia vera (PV) transforming into myelofibrosis or leukemia, and the main goal of current treatment is to prevent thrombotic events. Recent studies have shown that higher levels of inflammation are associated with an increased risk of thrombosis in PV patients, while the correlation between inflammation and abnormal lipid metabolism with the risk of thrombosis in PV has not been reported. In this retrospective study, 148 patients with newly diagnosed PV who visited the Affiliated Hospitals of Nanchang University from January 2013 to June 2023 were categorized into low-risk group and high-risk group according to the risk of thrombosis, and were subsequently divided into thrombosis non-progression group and progression group. The differences of novel inflammatory markers PHR, NHR, MHR, LHR, and SIRI in each group were analyzed and compared with healthy adults who underwent physical examination in the hospitals during the same period. The results showed that PHR, NHR, MHR, and SIRI levels were significantly higher in the PV group than in the control group (P < 0.001), while HDL-C levels were considerably lower (1.09 vs. 1.31, P < 0.001). Comparisons within the groups of PV patients revealed that PHR, MHR, NHR, NLR, and SIRI levels were significantly higher in the high-risk group for thrombosis than in the low-risk group (P < 0.01); the thrombosis PHR, NHR, NLR, and SIRI levels were higher in the group with progression of thrombosis than in the group without progression of thrombosis (P < 0.05), while HDL-C levels were significantly lower (1.02 vs. 1.12, P < 0.001). The results of the ROC curve analysis showed that NHR (AUC = 0.791), HDL-C (AUC = 0.691), PHR (AUC = 0.668), NLR(AUC = 0.658), and SIRI (AUC = 0.638) had high diagnostic efficacy for identifying PV patients with thrombosis progression. Multivariate analysis showed that NHR, NLR, MHR, and LHR were independent risk factors for PV patients with thrombosis progression (P < 0.05). Kaplan-Meier survival curves showed that NHR ≥ 5.82 × 10/mmol, NLR ≥ 6.295, PHR ≥ 280.4 × 10/mmol, MHR ≥ 0.295 × 10/mmol, LHR ≥ 1.41 × 10/mmol, and SIRI ≥ 1.53 × 10/L were risk factors for PFS in PV patients. The study demonstrates for the first time that novel inflammatory markers PHR, NHR, MHR, LHR, and SIRI may be used as new predictors for PV patients with thrombosis progression. NHR has the highest value in predicting thrombosis in PV patients and is superior to NLR which was reported previously.
Topics: Adult; Humans; Polycythemia Vera; Retrospective Studies; Lipid Metabolism; Thrombosis; Inflammation
PubMed: 37907800
DOI: 10.1007/s00277-023-05518-6