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American Journal of Hematology Sep 2023Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis; other features include leukocytosis, thrombocytosis,... (Review)
Review
DISEASE OVERVIEW
Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis; other features include leukocytosis, thrombocytosis, splenomegaly, pruritus, constitutional symptoms, microcirculatory disturbances, and increased risk of thrombosis and progression into myelofibrosis (post-PV MF) or acute myeloid leukemia (AML).
DIAGNOSIS
A working diagnosis is considered in the presence of a JAK2 mutation associated with hemoglobin/hematocrit levels of >16.5 g/dL/49% in men or 16 g/dL/48% in women; morphologic confirmation by bone marrow examination is advised but not mandated.
CYTOGENETICS
Abnormal karyotype is seen in 15%-20% of patients with the most frequent sole abnormalities being +9 (5%), loss of chromosome Y (4%), +8 (3%), and 20q- (3%).
MUTATIONS
Over 50% of patients harbor DNA sequence variants/mutations other than JAK2, with the most frequent being TET2 (18%) and ASXL1 (15%). Prognostically adverse mutations include SRSF2, IDH2, RUNX1, and U2AF1, with a combined incidence of 5%-10%.
SURVIVAL AND PROGNOSIS
Median survival is ⁓15 years but exceeds 35 years for patients aged ≤40 years. Risk factors for survival include older age, leukocytosis, abnormal karyotype, and the presence of adverse mutations. Twenty-year risk for thrombosis, post-PV MF, or AML are ⁓26%, 16% and 4%, respectively.
RISK FACTORS FOR THROMBOSIS
Two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). Additional predictors for arterial thrombosis include cardiovascular risk factors and for venous thrombosis higher absolute neutrophil count and JAK2V617F allele burden.
TREATMENT
Current goal of therapy is to prevent thrombosis. Periodic phlebotomy, with a hematocrit target of <45%, combined with once- or twice-daily aspirin (81 mg) therapy, absent contraindications, is the backbone of treatment in all patients, regardless of risk category. Cytoreductive therapy is reserved for high-risk disease with first-line drugs of choice being hydroxyurea and pegylated interferon-α and second-line busulfan and ruxolitinib. In addition, systemic anticoagulation is advised in patients with venous thrombosis history.
ADDITIONAL TREATMENT CONSIDERATIONS
At the present time, we do not consider a drug-induced reduction in JAK2V617F allele burden, which is often incomplete and seen not only with peg-IFN but also with ruxolitinib and busulfan, as an indicator of disease-modifying activity, unless accompanied by cytogenetic and independently-verified morphologic remission. Accordingly, we do not use the specific parameter to influence treatment choices. The current review also includes specific treatment strategies in the context of pregnancy, splanchnic vein thrombosis, pruritus, perioperative care, and post-PV MF.
Topics: Male; Humans; Female; Polycythemia Vera; Busulfan; Thrombocythemia, Essential; Leukocytosis; Microcirculation; Thrombosis; Leukemia, Myeloid, Acute; Janus Kinase 2
PubMed: 37357958
DOI: 10.1002/ajh.27002 -
American Journal of Hematology Apr 2024Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often... (Review)
Review
OVERVIEW
Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia.
DIAGNOSIS
In addition to thrombocytosis (platelets ≥450 × 10 /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters.
GENETICS
Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-.
SURVIVAL AND PROGNOSIS
Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years.
RISK FACTORS FOR THROMBOSIS
Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation).
MUTATIONS AND PROGNOSIS
MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype.
TREATMENT
The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan.
ADDITIONAL CONTENT
The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.
Topics: Humans; Middle Aged; Thrombocythemia, Essential; Microcirculation; Polycythemia Vera; Thrombocytosis; Thrombosis; Myeloproliferative Disorders; Primary Myelofibrosis; Mutation; Risk Assessment; Abnormal Karyotype; Janus Kinase 2; Calreticulin
PubMed: 38269572
DOI: 10.1002/ajh.27216 -
Frontiers in Medicine 2023Microcirculatory dysfunction plays a key role in the pathogenesis of tissue dysoxia and organ failure in sepsis. Sublingual videomicroscopy techniques enable the... (Review)
Review
Microcirculatory dysfunction plays a key role in the pathogenesis of tissue dysoxia and organ failure in sepsis. Sublingual videomicroscopy techniques enable the real-time non-invasive assessment of microvascular blood flow. Alterations in sublingual microvascular perfusion were detected during sepsis and are associated with poor outcome. More importantly, sublingual videomicroscopy allowed to explore the effects of commonly applied resuscitative treatments in septic shock, such as fluids, vasopressors and inotropes, and showed that the optimization of macro-hemodynamic parameters may not be accompanied by an improvement in microvascular perfusion. This loss of "hemodynamic coherence," i.e., the concordance between the response of the macrocirculation and the microcirculation, advocates for the integration of microvascular monitoring in the management of septic patients. Nonetheless, important barriers remain for a widespread use of sublingual videomicroscopy in the clinical practice. In this review, we discuss the actual limitations of this technique and future developments that may allow an easier and faster evaluation of the microcirculation at the bedside, and propose a role for sublingual microvascular monitoring in guiding and titrating resuscitative therapies in sepsis.
PubMed: 37476612
DOI: 10.3389/fmed.2023.1212321 -
Science (New York, N.Y.) Aug 2023Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align...
Aging is a major risk factor for impaired cardiovascular health. Because the aging myocardium is characterized by microcirculatory dysfunction, and because nerves align with vessels, we assessed the impact of aging on the cardiac neurovascular interface. We report that aging reduces nerve density in the ventricle and dysregulates vascular-derived neuroregulatory genes. Aging down-regulates microRNA 145 (miR-145) and derepresses the neurorepulsive factor semaphorin-3A. miR-145 deletion, which increased expression or endothelial overexpression, reduced axon density, mimicking the aged-heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reversed expression, preserved heart rate patterns, and reduced electrical instability. These data suggest that senescence-mediated regulation of nerve density contributes to age-associated cardiac dysfunction.
Topics: Heart; Microcirculation; MicroRNAs; Semaphorin-3A; Animals; Mice; Aging; Male; Mice, Inbred C57BL; Cellular Senescence; Myocardium; Axons; Microvascular Density
PubMed: 37616346
DOI: 10.1126/science.ade4961 -
Redox Biology Nov 2023Microvascular endothelial damage caused by intestinal ischemia‒reperfusion (II/R) is a primary catalyst for microcirculation dysfunction and enterogenous infection....
Microvascular endothelial damage caused by intestinal ischemia‒reperfusion (II/R) is a primary catalyst for microcirculation dysfunction and enterogenous infection. Previous studies have mainly focused on how neutrophil extracellular traps (NETs) and ferroptosis cause intestinal epithelial injury, and little attention has been given to how NETs, mainly from circulatory neutrophils, affect intestinal endothelial cells during II/R. This study aimed to unravel the mechanisms through which NETs cause intestinal microvascular dysfunction. We first detected heightened local NET infiltration around the intestinal microvasculature, accompanied by increased endothelial cell ferroptosis, resulting in microcirculation dysfunction in both human and animal II/R models. However, the administration of the ferroptosis inhibitor ferrostatin-1 or the inhibition of NETs via neutrophil-specific peptidylarginine deiminase 4 (Pad4) deficiency led to positive outcomes, with reduced intestinal endothelial ferroptosis and microvascular function recovery. Moreover, RNA-seq analysis revealed a significant enrichment of mitophagy- and ferroptosis-related signaling pathways in HUVECs incubated with NETs. Mechanistically, elevated NET formation induced Fundc1 phosphorylation at Tyr18 in intestinal endothelial cells, which led to mitophagy inhibition, mitochondrial quality control imbalance, and excessive mitochondrial ROS generation and lipid peroxidation, resulting in endothelial ferroptosis and microvascular dysfunction. Nevertheless, using the mitophagy activator urolithin A or AAV-Fundc1 transfection could reverse this process and ameliorate microvascular damage. We first demonstrate that increased NETosis could result in intestinal microcirculatory dysfunction and conclude that suppressed NET formation can mitigate intestinal endothelial ferroptosis by improving Fundc1-dependent mitophagy. Targeting NETs could be a promising approach for treating II/R-induced intestinal microcirculatory dysfunction.
Topics: Animals; Humans; Extracellular Traps; Endothelial Cells; Ferroptosis; Mitophagy; Microcirculation; Neutrophils
PubMed: 37812880
DOI: 10.1016/j.redox.2023.102906 -
Journal of the American College of... Sep 2023Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for... (Review)
Review
Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for suspected ischemic heart disease. This working diagnosis encompasses coronary microvascular dysfunction, microvascular and epicardial spasm, myocardial bridging, and other occult coronary abnormalities. Patients with ANOCA often face a high burden of symptoms and may experience repeated presentations to multiple medical providers before receiving a diagnosis. Given the challenges of establishing a diagnosis, patients with ANOCA frequently experience invalidation and recidivism, possibly leading to anxiety and depression. Advances in scientific knowledge and diagnostic testing now allow for routine evaluation of ANOCA noninvasively and in the cardiac catheterization laboratory with coronary function testing (CFT). CFT includes diagnostic coronary angiography, assessment of coronary flow reserve and microcirculatory resistance, provocative testing for endothelial dysfunction and coronary vasospasm, and intravascular imaging for identification of myocardial bridging, with hemodynamic assessment as needed.
Topics: Humans; Microcirculation; Myocardial Bridging; Myocardial Ischemia; Angina Pectoris; Coronary Angiography
PubMed: 37704315
DOI: 10.1016/j.jacc.2023.06.043 -
Nature Reviews. Cardiology Sep 2023Platelets have a crucial role in haemostasis and atherothrombosis. Pharmacological control of platelet hyper-reactivity has become a cornerstone in the prevention of... (Review)
Review
Platelets have a crucial role in haemostasis and atherothrombosis. Pharmacological control of platelet hyper-reactivity has become a cornerstone in the prevention of thrombo-ischaemic complications in atherosclerotic diseases. Current antiplatelet therapies substantially improve clinical outcomes in patients with coronary artery disease, but at the cost of increased risk of bleeding. Beyond their role in thrombosis, platelets are known to regulate inflammatory (thrombo-inflammatory) and microcirculatory pathways. Therefore, controlling platelet hyper-reactivity might have implications for both tissue inflammation (myocardial ischaemia) and vascular inflammation (vulnerable plaque formation) to prevent atherosclerosis. In this Review, we summarize the pathophysiological role of platelets in acute myocardial ischaemia, vascular inflammation and atherosclerotic progression. Furthermore, we highlight current clinical concepts of antiplatelet therapy that have contributed to improving patient care and have facilitated more individualized therapy. Finally, we discuss novel therapeutic targets and compounds for antiplatelet therapy that are currently in preclinical development, some of which have a more favourable safety profile than currently approved drugs with regard to bleeding risk. These novel antiplatelet targets might offer new strategies to treat cardiovascular disease.
Topics: Humans; Platelet Aggregation Inhibitors; Microcirculation; Blood Platelets; Atherosclerosis; Coronary Artery Disease; Inflammation
PubMed: 37016032
DOI: 10.1038/s41569-023-00854-6 -
Microcirculation (New York, N.Y. : 1994) Nov 2023The objective of this study was to evaluate the association between serum albumin levels and microcirculation changes, glycocalyx degradation, and the clinical outcomes... (Observational Study)
Observational Study
OBJECTIVE
The objective of this study was to evaluate the association between serum albumin levels and microcirculation changes, glycocalyx degradation, and the clinical outcomes of interest.
METHODS
Observational, prospective study in children with sepsis. The primary outcome was the association between hypoalbuminemia and microcirculation disorders, endothelial activation and glycocalyx degradation using a perfused boundary region (PBR) (abnormal >2.0 μm on sublingual video microscopy) or plasma biomarkers (syndecan-1, angiopoietin-2).
RESULTS
A total of 125 patients with sepsis were included. The median age was 2.0 years (IQR 0.5-12.5). Children with hypoalbuminemia had more abnormal microcirculation with a higher PBR (2.16 μm [IQR 2.03-2.47] vs. 1.92 [1.76-2.28]; p = .01) and more 4-6 μm capillaries recruited (60% vs. 40%; p = .04). The low albumin group that had the worst PBR had the most 4-6 μm capillaries recruited (rho 0.29; p < .01), 48% higher Ang-2 (p = .04), worse annexin A5 (p = 0.03) and no syndecan-1 abnormalities (p = .21). Children with hypoalbuminemia and a greater percentage of blood volume in their capillaries needed mechanical ventilation more often (56.3% vs. 43.7%; aOR 2.01 95% CI 1.38-3.10: p < .01).
CONCLUSIONS
In children with sepsis, an association was found between hypoalbuminemia and microcirculation changes, vascular permeability, and greater endothelial glycocalyx degradation.
Topics: Humans; Child; Child, Preschool; Glycocalyx; Microcirculation; Prospective Studies; Hypoalbuminemia; Endothelium; Sepsis
PubMed: 37639384
DOI: 10.1111/micc.12829 -
Vascular Pharmacology Dec 2023The term "coronary microvascular dysfunction" (CMD) encompasses several pathogenetic mechanisms resulting in functional and/or structural changes in the coronary...
The term "coronary microvascular dysfunction" (CMD) encompasses several pathogenetic mechanisms resulting in functional and/or structural changes in the coronary microcirculation. CMD often determines angina and myocardial ischemia in a broad spectrum of cardiovascular diseases, including patients with ischemia with non-obstructive coronary arteries or ischemia with obstructive coronary artery disease, infarction with non-obstructive coronary arteries, cardiomyopathies, the Takotsubo syndrome and heart failure, especially heart failure with preserved ejection fraction. In this article, we provide updated evidence regarding the pathophysiological mechanisms underlying CMD across the different cardiovascular diseases, aiming to pave the way for further research and the development of novel strategies for a precision medicine approach.
Topics: Humans; Cardiovascular Diseases; Coronary Circulation; Myocardial Ischemia; Coronary Artery Disease; Coronary Vessels; Heart Failure; Ischemia; Microcirculation
PubMed: 37898380
DOI: 10.1016/j.vph.2023.107239 -
Animal Models and Experimental Medicine Aug 2023Pericytes are the main cellular components of tiny arteries and capillaries. Studies have found that pericytes can undergo morphological contraction or relaxation under... (Review)
Review
Pericytes are the main cellular components of tiny arteries and capillaries. Studies have found that pericytes can undergo morphological contraction or relaxation under stimulation by cytokines, thus affecting the contraction and relaxation of microvessels and playing an essential role in regulating vascular microcirculation. Moreover, due to the characteristics of stem cells, pericytes can differentiate into a variety of inflammatory cell phenotypes, which then affect the immune function. Additionally, pericytes can also participate in angiogenesis and wound healing by interacting with endothelial cells in vascular microcirculation disorders. Here we review the origin, biological phenotype and function of pericytes, and discuss the potential mechanisms of pericytes in vascular microcirculation disorders, especially in pulmonary hypertension, so as to provide a sound basis and direction for the prevention and treatment of vascular microcirculation diseases.
Topics: Pericytes; Microcirculation; Endothelial Cells; Capillaries; Biology
PubMed: 37317664
DOI: 10.1002/ame2.12334