Histone-induced thrombotic thrombocytopenic purpura in <i>adamts13</i><sup>−/−</sup> zebrafish depends on von Willebrand factor

Zheng, Liang; Abdelgawwad, Mohammad S.; Zhang, Di; Xu, Leimeng; Wei, Shi; Cao, Wenjing; Zheng, X. Long

doi:10.3324/haematol.2019.237396

Cited by 22 publications

(37 citation statements)

References 48 publications

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“…Also, the specific NETs components such as free histone, cfDNA, and histone/DNA complexes may activate the intrinsic and extrinsic coagulation cascade pathways and platelets while reducing tissue factor pathway inhibitor and protein C activity, leading to enhanced potential for thrombus formation 34,46 . Recent studies demonstrate that purified histone can directly trigger endothelial exocytosis, resulting in massive release of VWF from Weibel‐Palade bodies and thus thrombocytopenia in mice 52 and triggering a “TTP‐like” syndrome in ADAMTS13‐deficient zebrafish 9 …”

Section: Discussionmentioning

confidence: 99%

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Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

Sui

Halkidis

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Immune thrombotic thrombocytopenic purpura (iTTP) is a life‐threatening blood disorder, primarily resulting from autoantibodies against ADAMTS13. Infection or inflammation often precedes acute iTTP. However, the association of inflammation and inflammatory mediators with disease severity and outcome of acute iTTP is not fully assessed. Objectives Here, we determined plasma levels of S100A8/A9, histone/DNA complexes, citrullinated histone H3 (CitH3), and cell‐free DNA (cfDNA) in a cohort of 108 acute episodes from 94 unique iTTP patients and healthy controls, and assessed the association of each of these biomarkers with the disease severity and mortality. Results All acute iTTP patients had significantly increased plasma levels of S100A8/A9 (median 84.8, interquartile range [IQR] 31.2‐157.4 µg/mL), histone/DNA complexes (median 55.7, IQR 35.8‐130.8 U/mL), CitH3 (median 3.8, IQR 2.2‐6.4 ng/mL), and cfDNA (median 937.7, IQR 781.3‐1420.0 ng/mL) on the admission blood samples when compared with healthy controls. An increased plasma level of S100A8/A9, histone/DNA complex and cfDNA was associated with organ damage, coagulopathy, and mortality in iTTP. After being adjusted for age and history of hypertension, Cox proportional hazard regression analysis demonstrated that a hazard ratio (95% confidence interval) for an elevated plasma level of S100A8/A9, histone/DNA complexes, and cfDNA was 11.5 (1.4‐90.9) (P = .021), 10.3 (2.7‐38.5) (P = .001), and 12.8 (3.9‐42.0) (P = .014), respectively. Conclusion These results indicate that inflammation or plasma inflammatory mediators such as S100A8/A9 or NETosis markers such as histone/DNA complexes and cfDNA may play a role in pathogenesis of iTTP, which may help stratify patients with a high risk of death during acute iTTP episodes.

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Section: Discussionmentioning

confidence: 99%

“…Regardless of its etiology, severe deficiency of plasma ADAMTS13 is necessary, but often not sufficient to result in an acute episode of TTP. This was demonstrated in patients with cTTP 5 or in a murine model of TTP, [6][7][8][9][10] suggesting that additional triggers may be needed for the development of a full-blown TTP episode.…”

Section: Introductionmentioning

confidence: 99%

Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

Sui

Halkidis

et al. 2021

Journal of Thrombosis and Haemostasis

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“…In patients with acute TTP, elevated levels of DNA-histone complexes and MPO are detected compared to those in healthy donors, and these increased levels are inversely correlated with platelet counts, implying that DNA-histone complexes and MPO may contribute to thrombopenia (142). Zheng et al successfully established novel ADAMTS13 -/zebrafish lines that exhibited spontaneous but mild feature of TTP (143). They found that lysine-rich histone induced a more severe and persistent TTP phenotype and higher mortality rate in ADAMTS13 -/than in wild-type zebrafish, indicating that histone might trigger and aggravate TTP in individuals with severe ADAMTS13 deficiency.…”

Section: Nets Mediating Vwf and Adamts13 Activities May Form A Vicioumentioning

confidence: 99%

“…Zheng et al. successfully established novel ADAMTS 13 –/– zebrafish lines that exhibited spontaneous but mild feature of TTP ( 143 ). They found that lysine-rich histone induced a more severe and persistent TTP phenotype and higher mortality rate in ADAMTS 13 –/– than in wild-type zebrafish, indicating that histone might trigger and aggravate TTP in individuals with severe ADAMTS13 deficiency.…”

Section: The Net-vwf Axis In Immunothrombosis Provides Novel Potentiamentioning

confidence: 99%

“…Increased plasma levels of VWF antigen were also observed in ADAMTS 13 –/– zebrafish after treatment with histone. Both spontaneous and histone-induced TTP phenotypes were effectively prevented in ADAMTS 13 –/– via VWF gene knock-out, suggesting that VWF might be a potential therapeutic target in inflammation-induced acute TTP phenotype ( 143 ).…”

Section: The Net-vwf Axis In Immunothrombosis Provides Novel Potentiamentioning

confidence: 99%

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Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

Yang

Long

et al. 2020

Front. Immunol.

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Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

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Fishing for answers to hemostatic and thrombotic disease: Genome editing in zebrafish

Raghunath

Ferguson

Shavit

2022

Research and Practice in Thrombosis and Haemostasis

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Over the past two decades, the teleost vertebrate Danio rerio (zebrafish) has emerged as a model for hemostasis and thrombosis. At genomic and functional levels, there is a high degree of conservation of the hemostatic system with that of mammals. Numerous features of the fish model offer unique advantages for investigating hemostasis and thrombosis. These include high fecundity, rapid and external development, optical transparency, and extensive functional homology with mammalian hemostasis and thrombosis. Zebrafish are particularly suited to genome‐wide mutagenesis experiments for the study of modifier genes. They are also amenable to whole‐organism small‐molecule screens, a feature that is exceptionally relevant to hemostasis and thrombosis. Zebrafish coagulation factor knockouts that are in utero or neonatal lethal in mammals survive into adulthood before succumbing to hemorrhage or thrombosis, enabling studies not possible in mammals. In this illustrated review, we outline how zebrafish have been employed for the study of hemostasis and thrombosis using modern genome editing techniques, coagulation assays in larvae, and in vivo evaluation of patient‐specific variants to infer causality and demonstrate pathogenicity. Zebrafish hemostasis and thrombosis models will continue to serve as a clinically directed basic research tool and powerful alternative to mammals for the development of new diagnostic markers and novel therapeutics for coagulation disorders through high‐throughput genetic and small‐molecule studies.

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Histone-induced thrombotic thrombocytopenic purpura in adamts13^−/− zebrafish depends on von Willebrand factor

Abstract: Histone-induced thrombotic thrombocytopenic purpura in adamts13-/zebrafish depends on von Willebrand factor

Cited by 22 publications

References 48 publications

Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

Fishing for answers to hemostatic and thrombotic disease: Genome editing in zebrafish

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Histone-induced thrombotic thrombocytopenic purpura in adamts13−/− zebrafish depends on von Willebrand factor

Abstract: Histone-induced thrombotic thrombocytopenic purpura in adamts13-/zebrafish depends on von Willebrand factor

Cited by 22 publications

References 48 publications

Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

Fishing for answers to hemostatic and thrombotic disease: Genome editing in zebrafish

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Resources

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Histone-induced thrombotic thrombocytopenic purpura in adamts13^−/− zebrafish depends on von Willebrand factor