Hematological manifestations and complications of Gaucher disease

Revel‐Vilk, Shoshana; Szer, Jeff; Zimran, Ari

doi:10.1080/17474086.2021.1908120

Cited by 20 publications

(33 citation statements)

References 71 publications

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“…Using a standardized bleeding questionnaire in our study enabled us to capture all bleeding manifestations occurring since the last visit. The clinical bleeding phenotype in our cohort is consistent with the bleeding manifestations reported in patients with GD [5]. Although GDspecific treatment and splenectomy were shown to improve the bleeding diathesis [37], it is important to note that bleeding problems were still reported in treated and splenectomized patients and were unrelated to the platelet count.…”

Section: Accepted Manuscriptsupporting

confidence: 84%

Platelet Activation and Reactivity in a Large Cohort of Patients with Gaucher Disease

et al. 2021

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Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data. Methods: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients. Results: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r 0.17, p-value 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (-2 SD of reference range) was found in 79 (53%, 95% CI 44%-61%) patients, of whom 10 (6.7%, 95% CI 3.3%-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (OR (95% CI), 1.05 (1.01-1.1)) and low P-selectin reactivity (OR (95% CI), 2.03 (1.25-3.35)) were associated with more than one bleeding manifestation. Conclusion: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.

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Section: Accepted Manuscriptsupporting

confidence: 84%

Platelet Activation and Reactivity in a Large Cohort of Patients with Gaucher Disease

et al. 2021

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“…Numerous mechanisms have been proposed to explain the GBA-associated neurodegenerative phenotype, although most related studies have focused on both gain- and loss-of-function mechanisms of the GCase enzyme in neurons, thus neglecting the involvement of other cells composing the central nervous system [ 62 ]. While the systemic immune dysregulation associated with Gaucher’s disease has been widely investigated [ 63 ], only a few papers have postulated the involvement of the observed sustained inflammation in the pathogenesis of Gaucher-associated Parkinson’s disease [ 12 , 64 , 65 ]. Recently, PET scans of GBA mutation carriers revealed microglial activation in Lewy-susceptible brain regions in subjects without either a prodromal or clinical diagnosis of Parkinson’s disease [ 18 ], strongly indicating that GCase deficiency can cause microglial dysfunction at the early stages of the disease.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons

Brunialti

Villa

Mekhaeil

et al. 2021

J Neuroinflammation

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Background Homozygotic mutations in the GBA gene cause Gaucher’s disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher’s disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Methods We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. Results Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. Conclusion This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication.

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“…1,[3][4][5][6][7] In patients with GD the relative risk of MM is reported to be up to 50-fold. 1,4,5,8 The prevalence of polyclonal gammopathy in Gaucher patients varied between 25% and 91%, while MGUS was reported in 1-35% of cases and its prevalence increased with age. 1,5,[8][9][10][11][12] The pathophysiology underlying the development of malignancies in GD is still unclear.…”

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confidence: 99%

Enzyme replacement therapy leading to improvement in myeloma indices in a patient with concomitant Gaucher disease

Harel

Gavish

Aviv

et al. 2022

Internal Medicine Journal

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Patients with Gaucher disease (GD) have been shown previously to carry an increased risk for cancer, most commonly multiple myeloma (MM). It is currently unknown whether treatment for GD has an effect on the prevention or amelioration of MM. We present the case of a 41‐year‐old patient simultaneously diagnosed with GD and smouldering MM. Enzyme replacement therapy with Velaglucerase‐alfa significantly improved myeloma indices.

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Hematological manifestations and complications of Gaucher disease

Cited by 20 publications

References 71 publications

Platelet Activation and Reactivity in a Large Cohort of Patients with Gaucher Disease

Platelet Activation and Reactivity in a Large Cohort of Patients with Gaucher Disease

Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons

Enzyme replacement therapy leading to improvement in myeloma indices in a patient with concomitant Gaucher disease

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