Variants in chondroitin sulfate metabolism genes in thrombotic storm

Nuytemans, Karen; Ortel, Thomas L.; Gomez, Lissette; Hofmann, Natalia K.; Alves, Natalie; Beecham, Ashley; Whitehead, Patrice L.; Estabrooks, Susan Hahn; Kitchens, Craig S.; Erkan, Doruk; Brandão, Leonardo R.; James, Andra H.; Kulkarni, Roshni; Manco‐Johnson, Marilyn J.; Pericak‐Vance, Margaret A.; Vance, Jeffery M.

doi:10.1016/j.thromres.2017.11.016

Cited by 5 publications

(10 citation statements)

References 55 publications

(62 reference statements)

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“…DiI-coated 4-μm microspheres, which label stalled segments in capillaries ( Nuytemans et al, 2018 ), were intravenously injected under isoflurane anesthesia, 3 h before the sacrifice. Specifically, we coated 4-μm microspheres (Thermo Fisher Scientific, F8858) with DiI solution (Thermo Fisher Scientific, D282) as previously described ( Reeson et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Pericyte Loss Leads to Capillary Stalling Through Increased Leukocyte-Endothelial Cell Interaction in the Brain

Choe

Yoon

Joo

et al. 2022

Front. Cell. Neurosci.

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The neurovascular unit is a functional unit composed of neurons, glial cells, pericytes, and endothelial cells which sustain brain activity. While pericyte is a key component of the neurovascular unit, its role in cerebral blood flow regulation remains elusive. Recently, capillary stalling, which means the transient interruption of microcirculation in capillaries, has been shown to have an outsized impact on microcirculatory changes in several neurological diseases. In this study, we investigated capillary stalling and its possible causes, such as the cerebral endothelial glycocalyx and leukocyte adhesion molecules after depleting pericytes postnatally in mice. Moreover, we investigated hypoxia and gliosis as consequences of capillary stalling. Although there were no differences in the capillary structure and RBC flow, longitudinal optical coherence tomography angiography showed an increased number of stalled segments in capillaries after pericyte loss. Furthermore, the extent of the cerebral endothelial glycocalyx was decreased with increased expression of leukocyte adhesion molecules, suggesting enhanced interaction between leukocytes and endothelial cells. Finally, pericyte loss induced cerebral hypoxia and gliosis. Cumulatively, the results suggest that pericyte loss induces capillary stalling through increased interaction between leukocytes and endothelial cells in the brain.

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Section: Methodsmentioning

confidence: 99%

Pericyte Loss Leads to Capillary Stalling Through Increased Leukocyte-Endothelial Cell Interaction in the Brain

Choe

Yoon

Joo

et al. 2022

Front. Cell. Neurosci.

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“…Reports on the presence of this variant in thrombosis patients5,6 outweigh those in FV deficiency 7. Both variants in CS gene STAB2 are predicted to be damaging (frameshift and p.P510H), similar to all STAB2 variants identified in the previous TS report 4. Further studies will be needed to assess their impact on protein function.…”

Section: Discussionmentioning

confidence: 78%

“…More common variants linked to thrombosis or predicted to have a strong functional effect were observed in F5 and STAB2 , indicating potential double hits for these genes as seen in the TS genetic report (Table 3). 4…”

Section: Case Discussionmentioning

confidence: 99%

“…Recently, the Thrombotic Storm Study Group reported genetic analyses on 26 TS patients, describing the limited contribution of the known thrombosis genes (with FV being the largest contributor), and suggested an accumulation of variants in the CS metabolism genes 4. Our patient carried 3 variants in FV and 3 variants in 2 CS genes, supporting the observation from the original report of the potential involvement of CS in (extreme forms of) thrombosis 4. Though none of the variants in FV are the FV Leiden, 2 of the 3 are predicted to be damaging.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, p.M2148T was observed in multiple affected of a multiplex TS family4 but is considered benign by ACMG guidelines. In addition, p.R513K was detected in 2 of the 26 TS probands 4. Reports on the presence of this variant in thrombosis patients5,6 outweigh those in FV deficiency 7.…”

Section: Discussionmentioning

confidence: 99%

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Successful Management of Catastrophic Thrombotic Storm in a Young Boy: A Case Report From Northern India

Jindal

Ahluwalia

Suku

et al. 2021

Journal of Pediatric Hematology/Oncology

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Thrombotic storm is a rare clinical entity characterized by acute to subacute thrombosis developing at multiple sites over a few days to a few weeks. An 11-year-old boy presented with headache and facial nerve palsy. He was found to have cortical sinus venous thrombosis and was initiated on low molecular weight heparin, but rapidly progressed with thromboses involving the pulmonary arteries and deep veins of the legs. Thereafter managed on high-dose unfractionated heparin, he eventually stabilized after a hospital stay of 34 days. Genetic analysis showed potentially pathogenic variants in the factor V and stabilin-2 genes.

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Carbohydrate sulfotransferases

Begolli

Marković

Knežević³

et al. 2023

Biochem. med. (Online)

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Carbohydrate sulfotransferases (CHST) catalyse the biosynthesis of proteoglycans that enable physical interactions and signalling between different neighbouring cells in physiological and pathological states. The study aim was to provide an overview of emerging diagnostic and prognostic applications of CHST. PubMed database search was conducted using the keywords “carbohydrate sulfotransferase” together with appropriate inclusion and exclusion criteria, whereby 41 publications were selected. Additionally, 40 records on CHST genetic and biochemical properties were hand-picked from UniProt, GeneCards, InterPro, and neXtProt databases. Carbohydrate sulfotransferases have been applied mainly in diagnostics of connective tissue disorders, cancer and inflammations. The lack of CHST activity was found in congenital connective tissue disorders while CHST overexpression was detected in different malignancies. Mutations of CHST3 gene cause skeletal dysplasia, chondrodysplasia, and autosomal recessive multiple joint dislocations while increased tissue expression of CHST11, CHST12 and CHST15 is an unfavourable prognostic factor in ovarian cancer, glioblastoma and pancreatic cancer, respectively. Recently, CHST11 and CHST15 overexpression in the vascular smooth muscle cells was linked to the severe lung pathology in COVID-19 patients. Promising CHST diagnostic and prognostic applications have been described but larger clinical studies and robust analytical procedures are required for the more reliable diagnostic performance estimations.

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Variants in chondroitin sulfate metabolism genes in thrombotic storm

Cited by 5 publications

References 55 publications

Pericyte Loss Leads to Capillary Stalling Through Increased Leukocyte-Endothelial Cell Interaction in the Brain

Pericyte Loss Leads to Capillary Stalling Through Increased Leukocyte-Endothelial Cell Interaction in the Brain

Successful Management of Catastrophic Thrombotic Storm in a Young Boy: A Case Report From Northern India

Carbohydrate sulfotransferases

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