Markers of endothelial cell activation and neutrophil extracellular traps are elevated in immune thrombocytopenia but are not enhanced by thrombopoietin receptor agonists

Garabet, Lamya; Henriksson, Carola E.; Lozano, Marı́a Luisa; Bussel, James B.; Brodin, Ellen; Fernández-Pérez, María Piedad; Martı́nez, Constantino; Gónzález-Conejero, Rocío; Mowinckel, Marie‐Christine; Sandset, Per Morten

doi:10.1016/j.thromres.2019.11.031

Cited by 23 publications

(28 citation statements)

References 48 publications

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“…Increased levels of ICAM-1, VEGF, and Angiopoietin-2 were found in corticosteroid resistant ITP patients compared with healthy controls, indicating the occurrence of endothelial dysfunction in ITP. This is consistent with previous report that endothelium activation is found before and after thrombopoietin receptor agonist treatment (27) transmigration (35). Chao et al reported that TNF-a stimulation could markedly upregulate ICAM-1 through restraining NF-kB activation and ROS signal in endothelial cells (36).…”

Section: Discussionsupporting

confidence: 93%

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Predictive Value of High ICAM-1 Level for Poor Treatment Response to Low-Dose Decitabine in Adult Corticosteroid Resistant ITP Patients

Sun

et al. 2021

Front. Immunol.

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Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disease. Endothelial cell activation/injury has been found in some autoimmune diseases including SLE, systemic sclerosis, and rheumatoid arthritis, but its role in ITP pathogenesis remains unclear. This study attempted to elucidate the correlation between endothelial dysfunction and disease severity of ITP and find related markers to predict response to low-dose decitabine treatment. Compared with healthy volunteers, higher plasma levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), and Angiopoietin-2 were found in adult corticosteroid resistant ITP patients. Notably, ICAM-1 levels were negatively correlated with the platelet count, and positively associated with the bleeding score. Recently, we have reported the efficacy and safety of low-dose decitabine in adult patients with ITP who failed for the first line therapies. Here, we evaluated the correlation of plasma ICAM-1 level with the efficacy of low-dose decitabine therapy for corticosteroid resistant ITP. A total of 29 adult corticosteroid resistant ITP patients who received consecutive treatments of low-dose decitabine were enrolled in this study. Fourteen patients showed response (nine showed complete response and five showed partial response). The levels of ICAM-1 before and after treatment were significantly higher in the non-responsive ITP patients than in the responsive patients. As shown in the multivariable logistic regression model, the odds of developing no-response to low-dose decitabine increased by 36.8% for per 5 ng/ml increase in plasma ICAM-1 level [odds ratio (OR) 1.368, 95% confidence interval (CI): 1.060 to 1.764]. In summary, this was the first study to elucidate the relationship between endothelial dysfunction and corticosteroid resistant ITP and identify the potential predictive value of ICAM-1 level for response to low-dose decitabine.

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Section: Discussionsupporting

confidence: 93%

“…Dana et al found endothelial alterations in a canine model of immune thrombocytopenia (26). Endothelial cell activation/injury has been reported in ITP patients, with elevated levels of ICAM-1, thrombomodulin, and H3Cit-DNA (27). However, the pathogenetic role of endothelial dysfunction in corticosteroid resistant ITP remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Predictive Value of High ICAM-1 Level for Poor Treatment Response to Low-Dose Decitabine in Adult Corticosteroid Resistant ITP Patients

Sun

et al. 2021

Front. Immunol.

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“…50 Some studies have shown that TPO-RA may increase platelet apoptosis, formation of microparticles, and levels of both PAI-1 and P-selectin, all of which favor TEE development, 43,44 especially with increased platelet production by TPO-RAs. 7 Other treatments for ITP, including corticosteroids and anti-CD20 antibody, have not been evaluated in registrational trials in ITP patients; however, long-term studies of splenectomy based on registries have demonstrated a significantly increased risk of stroke. 1,51 Most patients in the fostamatinib studies had additional risk factors for TEEs (as described in Table 2).…”

Section: Discussionmentioning

confidence: 99%

Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Cooper

Altomare

Thomas

et al. 2021

Therapeutic Advances in Hematology

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Background: Patients with immune thrombocytopenia (ITP) are at risk of bleeding and, paradoxically, thromboembolic events (TEEs), irrespective of thrombocytopenia. The risk of thrombosis is increased by advanced age, obesity, and prothrombotic comorbidities: cancer, hyperlipidemia, diabetes, hypertension, coronary artery disease, and chronic kidney disease, among others. Certain ITP treatments further increase the risk of TEE, especially splenectomy and thrombopoietin receptor agonists. Spleen tyrosine kinase (SYK) is a key signaling molecule common to thromboembolic and hemostatic (in addition to inflammatory) pathways. Fostamatinib is an orally administered SYK inhibitor approved in the USA and Europe for treatment of chronic ITP in adults. Methods: The phase III and extension studies included heavily pretreated patients with long-standing ITP, many of whom had risk factors for thrombosis prior to initiating fostamatinib. This report describes long-term safety and efficacy of fostamatinib in 146 patients with up to 5 years of treatment, a total of 229 patient-years, and assesses the incidence of thromboembolic events (by standardized MedDRA query). Results: Platelet counts ⩾50,000/µL were achieved in 54% of patients and the safety profile was as described in the phase III clinical studies with no new toxicities observed over the 5 years of follow-up. The only TEE occurred in one patient (0.7%, or 0.44/100 patient-years), who experienced a mild transient ischemic attack. This is a much lower rate than might be expected in ITP patients. Conclusion: This report demonstrates durable efficacy and a very low incidence of TEE in patients receiving long-term treatment of ITP with the SYK inhibitor fostamatinib. identifiers: NCT02076399, NCT02076412, and NCT02077192.

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“…This potential pathologic response could trigger the formation of neutrophil extracellular traps, or neutrophil extracellular traps could underly the possible presence of CD31+ in the pancreata of NOD mice, but not C57BL/6 mice. Citrullinated histone H3 has been shown to colocalize with neutrophil extracellular traps and is considered to be a reliable marker of NET formation (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). We therefore used this marker as a surrogate of possible NET formation in the pancreata of NOD mice.…”

Section: Citrullinated Histone H3 Expression Is Evident At 4 Weeks Ofmentioning

confidence: 99%

Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice

et al. 2021

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A growing body of evidence indicates that neutrophils are the first major leukocyte population accumulating inside the pancreas even before the onset of a lymphocytic-driven impairment of functional beta cells in type 1 diabetes mellitus (T1D). In humans, pancreata from T1D deceased donors exhibit significant neutrophil accumulation. We present a time course of previously unknown inflammatory changes that accompany neutrophil and neutrophil elastase accumulation in the pancreas of the non-obese diabetic (NOD) mouse strain as early as 2 weeks of age. We confirm earlier findings in NOD mice that neutrophils accumulate as early as 2 weeks of age. We also observe a concurrent increase in the expression of neutrophil elastase in this time period. We also detect components of neutrophil extracellular traps (NET) mainly in the exocrine tissue of the pancreas during this time as well as markers of vascular pathology as early as 2 weeks of age. Age- and sex-matched C57BL/6 mice do not exhibit these features inside the pancreas. When we treated NOD mice with inhibitors of myeloperoxidase and neutrophil elastase, two key effectors of activated neutrophil activity, alone or in combination, we were unable to prevent the progression to hyperglycemia in any manner different from untreated control mice. Our data confirm and add to the body of evidence demonstrating neutrophil accumulation inside the pancreas of mice genetically susceptible to T1D and also offer novel insights into additional pathologic mechanisms involving the pancreatic vasculature that have, until now, not been discovered inside the pancreata of these mice. However, inhibition of key neutrophil enzymes expressed in activated neutrophils could not prevent diabetes. These findings add to the body of data supporting a role for neutrophils in the establishment of early pathology inside the pancreas, independently of, and earlier from the time at onset of lymphocytic infiltration. However, they also suggest that inhibition of neutrophils alone, acting via myeloperoxidase and neutrophil elastase only, in the absence of other other effector cells, is insufficient to alter the natural course of autoimmune diabetes, at least in the NOD model of the disease.

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Markers of endothelial cell activation and neutrophil extracellular traps are elevated in immune thrombocytopenia but are not enhanced by thrombopoietin receptor agonists

Cited by 23 publications

References 48 publications

Predictive Value of High ICAM-1 Level for Poor Treatment Response to Low-Dose Decitabine in Adult Corticosteroid Resistant ITP Patients

Predictive Value of High ICAM-1 Level for Poor Treatment Response to Low-Dose Decitabine in Adult Corticosteroid Resistant ITP Patients

Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice

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