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Cureus Dec 2020Leukostasis in acute and chronic leukemias leads to increased cell burden and increased blood viscosity. Therapeutic leukocytapheresis is an automated procedure aimed at...
Leukostasis in acute and chronic leukemias leads to increased cell burden and increased blood viscosity. Therapeutic leukocytapheresis is an automated procedure aimed at white blood cell depletion, and it thereby reduces the complications associated with increased blood viscosity, such as thrombotic events and mortality. In this report, we present the case of a 25-year-old patient with leukostasis and splenic laceration who was treated with therapeutic leukocytapheresis with symptomatic relief in leukostasis.
PubMed: 33527056
DOI: 10.7759/cureus.12375 -
Cureus Nov 2022Leukostasis is a life-threatening complication that causes vascular occlusion leading to organ damage in leukemia patients. Organs with impairment due to leukostasis are...
Leukostasis is a life-threatening complication that causes vascular occlusion leading to organ damage in leukemia patients. Organs with impairment due to leukostasis are usually the lungs and kidneys, but other organs may also be damaged. We experienced an autopsy case of severe infarction in multiple organs including the spleen probably due to leukostasis in a patient with acute myeloid leukemia.
PubMed: 36532923
DOI: 10.7759/cureus.31518 -
Scientific Reports Jul 2020Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against...
Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM). ChIP-qPCR and luciferase reporter analyses showed that PPARα directly regulated THBD expression via binding to the promoter. In the rat diabetic retina, treatment with pemafibrate inhibited the expression of inflammatory molecules such as VCAM-1 and MCP1, and these effects were attenuated by intravitreal injection of small interfering RNA targeted to THBD. Furthermore, pemafibrate treatment inhibited diabetes-induced vascular leukostasis and leakage through the upregulation of THBD. Our results indicate that PPARα activation inhibits inflammatory and vasopermeable responses in the diabetic retina through the upregulation of TM.
Topics: Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Models, Animal; Endothelium, Vascular; Genome-Wide Association Study; Male; PPAR alpha; Rats; Rats, Wistar; Thrombomodulin
PubMed: 32616724
DOI: 10.1038/s41598-020-67579-1 -
Leukemia Research Reports 2021Leukemoid reactions following surgery are commonly caused by infections or tissue injury. Management is directed towards underlying condition and cytoreduction is not...
Leukemoid reactions following surgery are commonly caused by infections or tissue injury. Management is directed towards underlying condition and cytoreduction is not indicated. Chronic myelo-monocytic leukemia (CMML) is a clonal hematological malignancy characterized by persistent monocytosis and overlapping features of myelodysplastic and myeloproliferative neoplasms.In this case report we describe a 51-year-old Hispanic female without any significant prior medical history, who underwent a cholecystectomy for calculous cholecystitis. Post-operative course was complicated by hyperleukocytosis leading to splenic infarction and intracranial hemorrhage. Further investigations led to a diagnosis of CMML-2. A literature review of patients with CMML who developed post-operative leukocytosis and leukostasis (POLL) is presented.Case high lights two critical points: Post-operative hyperleukocytosis with leukostasis can be the first presentation of CMML Rapid diagnosis and institution of cytoreductive therapy with hydroxyurea is critical to avoid high morbidity and mortality.
PubMed: 34934616
DOI: 10.1016/j.lrr.2021.100283 -
Investigative Ophthalmology & Visual... Oct 2021Previous studies indicate that leukocytes, notably neutrophils, play a causal role in the capillary degeneration observed in diabetic retinopathy (DR), however, the...
PURPOSE
Previous studies indicate that leukocytes, notably neutrophils, play a causal role in the capillary degeneration observed in diabetic retinopathy (DR), however, the mechanism by which they cause such degeneration is unknown. Neutrophil elastase (NE) is a protease released by neutrophils which participates in a variety of inflammatory diseases. In the present work, we investigated the potential involvement of NE in the development of early DR.
METHODS
Experimental diabetes was induced in NE-deficient mice (Elane-/-), in mice treated daily with the NE inhibitor, sivelestat, and in mice overexpressing human alpha-1 antitrypsin (hAAT+). Mice were assessed for diabetes-induced retinal superoxide generation, inflammation, leukostasis, and capillary degeneration.
RESULTS
In mice diabetic for 2 months, deletion of NE or selective inhibition of NE inhibited diabetes-induced retinal superoxide levels and inflammation, and inhibited leukocyte-mediated cytotoxicity of retinal endothelial cells. In mice diabetic for 8 months, genetic deletion of NE significantly inhibited diabetes-induced retinal capillary degeneration.
CONCLUSIONS
These results suggest that a protease released from neutrophils contributes to the development of DR, and that blocking NE activity could be a novel therapy to inhibit DR.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peptide Hydrolases; Retina
PubMed: 34643662
DOI: 10.1167/iovs.62.13.7 -
Critical Care Explorations Feb 2020Leukostasis is a life-threatening complication of acute hyperleukocytic leukemia, and is associated with substantial mortality. Management of leukostasis requires...
UNLABELLED
Leukostasis is a life-threatening complication of acute hyperleukocytic leukemia, and is associated with substantial mortality. Management of leukostasis requires time-sensitive diagnostics and therapeutics, and leukapheresis remains a mainstay of treatment in select patients. Leukapheresis requires coordination of multi-disciplinary resources, which can prove challenging in the emergency department setting, and delays in treatment due to the complexity and coordination required are common. The objective of this study was to assess the effect of utilization of an emergency department-ICU and a multidisciplinary care pathway on outcomes of critically ill leukostasis patients presenting to the emergency department.
DESIGN
Retrospective cohort study.
SETTING
Single large academic medical center in the United States.
PATIENTS
Adult emergency department patients with signs and symptoms of leukostasis requiring emergent leukapheresis from 2012-2019.
INTERVENTIONS
Implementation of a hybrid emergency department-ICU setting (emergency critical care center) and a multidisciplinary care pathway with members from Emergency Medicine, Hematology, Blood Bank, and Clinical Pathology.
MEASUREMENTS AND MAIN RESULTS
A total of 70 patients were identified and included for analysis: 14 preemergency critical care center; 32 postemergency critical care center, premultidisciplinary care pathway; and 24 postemergency critical care center, postmultidisciplinary care pathway. A statistically significant reduction in the time from emergency department presentation to initiation of leukapheresis was observed from preemergency critical care center to postemergency critical care center, premultidisciplinary care pathway and postemergency critical care center, postmultidisciplinary care pathway (11.5 vs 7.9 vs 7.7 hr; = 0.004). Statistically significant reductions in in-hospital mortality were observed from preemergency critical care center to postemergency critical care center, premultidisciplinary care pathway and postemergency critical care center, postmultidisciplinary care pathway (64.3% vs 21.9% vs 25.0%; = 0.01). A trend toward decreased inpatient ICU utilization was observed, although was not statistically significant (35.7% vs 12.5% vs 25.0%; = 0.14.).
CONCLUSIONS AND RELEVANCE
Implementation of a multidisciplinary care pathway via use of an emergency department-ICU for critically ill patients with leukostasis was associated with statistically significant reductions in time to leukapheresis and in-hospital mortality. These findings suggest an emergency department-ICU model may allow for maximal resource and care coordination at the point of contact with critically ill patients and improved clinical outcomes.
PubMed: 32211616
DOI: 10.1097/CCE.0000000000000084 -
Children (Basel, Switzerland) Apr 2022Hyperleukocytosis in pediatric acute leukemia is associated with increased morbidity and mortality and at present there is no consensus on the use of leukapheresis (LPH)...
Hyperleukocytosis in pediatric acute leukemia is associated with increased morbidity and mortality and at present there is no consensus on the use of leukapheresis (LPH) for its management. Our aim was to review characteristics and outcomes of newly diagnosed leukemia patients with hyperleukocytosis (HL) comparing those who received LPH and those who did not. An IRB approved retrospective case control study reviewed data from a single institution over a 10 year period. At our institution, LPH was used in 8 of 62 (13%) patients with hyperleukocytosis with minimal complications. Mean leukocyte count in patients who received LPH versus those who did not was 498 k cells/mm and 237 k cells/mm, respectively. Patients who had symptoms of neurologic (63 vs. 17%) or pulmonary leukostasis (75 vs. 17%) were more likely to have undergone leukapheresis. The time from presentation to the initiation of chemotherapy was not different between those who received LPH and those who did not (mean of 35 h vs. 34 h). There was one death in the LPH group, that was the result of neurologic sequelae of hyperleukocytosis and not LPH itself. The use of LPH in patients with hyperleukocytosis is safe, well tolerated and does not alter time to chemotherapy at our institution.
PubMed: 35455547
DOI: 10.3390/children9040503 -
Journal of Neuroinflammation Dec 2016Hyperglycemia is a significant risk factor for diabetic retinopathy and induces increased inflammatory responses and retinal leukostasis, as well as vascular damage....
BACKGROUND
Hyperglycemia is a significant risk factor for diabetic retinopathy and induces increased inflammatory responses and retinal leukostasis, as well as vascular damage. Although there is an increasing amount of evidence that miRNA may be involved in the regulation in the pathology of diabetic retinopathy, the mechanisms by which miRNA mediate cellular responses to control onset and progression of diabetic retinopathy are still unclear. The purpose of our study was to investigate the hypothesis that miR-15a/16 inhibit pro-inflammatory signaling to reduce retinal leukostasis.
METHODS
We generated conditional knockout mice in which miR-15a/16 are eliminated in vascular endothelial cells. For the in vitro work, human retinal endothelial cells (REC) were cultured in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. Transfection was performed on REC in high glucose with miRNA mimic (hsa-miR-15a-5p, hsa-miR-16-5p). Statistical analyses were done using unpaired Student t test with two-tailed p value. p < 0.05 was considered significant. Data are presented as mean ± SEM.
RESULTS
We demonstrated that high glucose conditions decreased expression of miR-15a/16 in cultured REC. Overexpression of miR-15a/16 with the mimic significantly decreased pro-inflammatory signaling of IL-1β, TNFα, and NF-κB in REC. In vivo data demonstrated that the loss of miR-15a/16 in vascular cells led to increased retinal leukostasis and CD45 levels, together with upregulated levels of IL-1β, TNFα, and NF-κB.
CONCLUSIONS
The data indicate that miR-15a/16 play significant roles in reducing retinal leukostasis, potentially through inhibition of inflammatory cellular signaling. Therefore, we suggest that miR-15a/16 offer a novel potential target for the inhibition of inflammatory mediators in diabetic retinopathy.
Topics: Animals; Cytokines; Endothelial Cells; Flow Cytometry; Glucose; Humans; Leukostasis; Mice; Mice, Transgenic; MicroRNAs; RNA, Messenger; Retina; Signal Transduction; Transfection; Tumor Necrosis Factor-alpha
PubMed: 27931222
DOI: 10.1186/s12974-016-0771-8 -
Journal of Neuroinflammation Jul 2019Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in...
BACKGROUND
Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in retinal vessels in diabetes. In this study, we investigated the role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and its contribution to retinal microvascular degeneration.
METHODS
Forty-one patients with type 1 diabetes (T1D) [mild non-proliferative diabetic retinopathy (mNPDR) (n = 13), active proliferative DR (aPDR) (n = 14), inactive PDR (iPDR) (n = 14)] and 13 age- and gender-matched healthy controls were recruited to the study. C57BL/6 J WT mice, SOCS3 and LysMSOCS3 mice were rendered diabetic by Streptozotocin injection. The expression of the phosphorylated human and mouse STAT3 (pSTAT3), mouse LFA-1, CD62L, CD11b and MHC-II in circulating immune cells was evaluated by flow cytometry. The expression of suppressor of cytokine signalling 3 (SOCS3) was examined by real-time RT-PCR. Mouse plasma levels of cytokines were measured by Cytometric Beads Array assay. Retinal leukostasis was examined following FITC-Concanavalin A perfusion and acellular capillary was examined following Isolectin B4 and Collagen IV staining.
RESULTS
Compared to healthy controls, the expression of pSTAT3 in circulating leukocytes was statistically significantly higher in mNPDR but not aPDR and was negatively correlated with diabetes duration. The expression of pSTAT3 and its inhibitor SOCS3 was also significantly increased in leukocytes from diabetic mice. Diabetic mice had higher plasma levels of IL6 and CCL2 compared with control mice. LysMSOCS3 mice and SOCS3 mice developed comparative levels of diabetes, but leukocyte activation, retinal leukostasis and number of acellular capillaries were statistically significantly increased in LysMSOCS3 diabetic mice.
CONCLUSION
STAT3 activation in circulating immune cells appears to contribute to retinal microvascular degeneration and may be involved in DR initiation in T1D.
Topics: Animals; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Humans; Leukocytes, Mononuclear; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microvessels; Retinal Vessels; STAT3 Transcription Factor
PubMed: 31286987
DOI: 10.1186/s12974-019-1533-1 -
Glia Sep 2022Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia...
Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia-specific Transforming Growth Factor-β (Tgfβ) receptor knock out mouse model and human iPSC-derived microglia to examine the role of Tgfβ signaling in activated microglia during retinal NV. Using a tamoxifen-inducible, microglia-specific Tgfβ receptor type 2 (Tgfβr2) knockout mouse [Tgfβr2 KO (ΔMG)] we show that Tgfβ signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgfβ signaling represses expression of the pro-angiogenic factor, Insulin-like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen-induced retinopathy (OIR) we show that Tgfβ signaling in activated microglia plays a role in hypoxia-induced NV where a loss in Tgfβ signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC-derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor-β1 (Tgfβ1) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgfβ signaling in microglia is essential for microglial homeostasis and that the disruption of Tgfβ signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression.
Topics: Animals; Disease Models, Animal; Hypoxia; Insulin-Like Growth Factor I; Leukostasis; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neovascularization, Pathologic; Oxygen; Retinal Diseases; Retinal Neovascularization; Transforming Growth Factor beta
PubMed: 35611927
DOI: 10.1002/glia.24218