Altered VWF:ADAMTS13 homeostasis is a target for therapeutic intervention in sickle cell disease

Chaturvedi, Shruti; DeBaun, Michael R.

doi:10.1073/pnas.2213079119

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…In Significantly, they presented imbalance between VWF (increased levels and activity) and ADAMTS13 (reduced activity), which leads to a shift toward a hypercoagulable and proinflammatory state that has been implicated in the pathogenesis of microthrombotic disorders and, recently, in SCD. 18 Moreover, they have lower PAI-1 and t-PA compared to controls. A role of t-PA in thrombi formation in SCT was recently suggested through resistance to tPA-mediated fibrinolysis of the clot formed from whole blood of SCT subjects, 11 with an intermediate phenotype in SCT between SS and AA.…”

Section: Discussionmentioning

confidence: 99%

“…SCT children present increased endothelial activation, with increased FVIII, VWF and ADAMTS13, and a mild coagulation activation, as shown by an increase in markers of thrombin generation (TAT and F1+2) and secondary fibrinolysis (D‐dimer) and mild reduction of fibrinolytic factors. Significantly, they presented imbalance between VWF (increased levels and activity) and ADAMTS13 (reduced activity), which leads to a shift toward a hypercoagulable and proinflammatory state that has been implicated in the pathogenesis of microthrombotic disorders and, recently, in SCD 18 . Moreover, they have lower PAI‐1 and t‐PA compared to controls.…”

Section: Discussionmentioning

confidence: 99%

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Early‐onset indicators of a hypercoagulable state and clinical complications in a cohort of children with sickle cell trait

Reggiani,

Boaro,

Menzato

et al. 2024

Pediatric Blood & Cancer

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Adults with sickle cell trait (SCT) have a procoagulant state with increased risk of thromboembolism, but limited data are available for children. We compared the coagulation profile of children with SCT, different sickle cell disease (SCD) genotypes, and healthy controls. Compared to controls and similarly to HbSC patients, 41 SCT children (mean age 6.85 years; 20 males; 88% Africans) had a characteristic procoagulant profile: higher levels of factor VIII, von Willebrand factor (VWF) Ag and CBA, D‐dimer; lower levels of ADAMTS 13 activity, ADAMTS13 activity: VWFAg, plasminogen activator inhibitor, tissue plasminogen activator. Moreover, 13/41 had clinical complications of SCD, five requiring hospitalization.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early‐onset indicators of a hypercoagulable state and clinical complications in a cohort of children with sickle cell trait

Reggiani,

Boaro,

Menzato

et al. 2024

Pediatric Blood & Cancer

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Numerical study of ultra-large von Willebrand factor multimers in coagulopathy

Rahmati,

Keshavarz Motamed,

Maftoon

2024

Biomech Model Mechanobiol

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Clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in sickle cell anemia mice

Shi,

Gao,

Kirby

et al. 2024

Blood

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Although it is caused by a single nucleotide mutation in the -globin gene, sickle cell anemia (SCA) is a systemic disease with complex, incompletely elucidated pathologies. The mononuclear phagocyte system plays critical roles in SCA pathophysiology. However, how heterogeneous populations of hepatic macrophages contribute to SCA remains unclear. Using a combination of single-cell RNA sequencing and spatial transcriptomics via multiplexed error-robust fluorescence in situ hybridization (MERFISH), we identified distinct macrophage populations with diversified origins and biological functions in SCA mouse liver. We previously found that administering the von Willebrand factor (VWF)-cleaving protease ADAMTS13 alleviated vaso-occlusive episode in SCA mice. Here, we discovered that the ADAMTS13-cleaved VWF was cleared from the circulation by a Clec4f+Marcohigh macrophage subset in a desialylation-dependent manner in the liver. In addition, sickle erythrocytes were phagocytized predominantly by Clec4f+Marcohigh macrophages. Depletion of macrophages not only abolished the protective effect of ADAMTS13 but exacerbated vaso-occlusive episode in SCA mice. Furthermore, promoting macrophage-mediated VWF clearance reduced vaso-occlusion in SCA mice. Our study demonstrates that hepatic macrophages are important in the pathogenesis of SCA, and efficient clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in SCA mice.

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Altered VWF:ADAMTS13 homeostasis is a target for therapeutic intervention in sickle cell disease

Cited by 3 publications

References 17 publications

Early‐onset indicators of a hypercoagulable state and clinical complications in a cohort of children with sickle cell trait

Early‐onset indicators of a hypercoagulable state and clinical complications in a cohort of children with sickle cell trait

Numerical study of ultra-large von Willebrand factor multimers in coagulopathy

Clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in sickle cell anemia mice

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