ArticleThe Journal of biological chemistry2012
Light chain of factor VIII is sufficient for accelerating cleavage of von Willebrand factor by ADAMTS13 metalloprotease.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- A Vortex-Shear-Based Assay for Cleavage of Multimeric VWF by ADAMTS13.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Novel mechanisms of action of emerging therapies of hereditary thrombotic thrombocytopenic purpura.Expert review of hematology · 2024Review
- Coagulation factor VIII regulates von Willebrand factor homeostasis invivo.Journal of thrombosis and haemostasis : JTH · 2023Article
- Defective VWF secretion due to expression of MYH9-RD E1841K mutant in endothelial cells disrupts hemostasis.Blood advances · 2022Article
- Factor VIII binding affects the mechanical unraveling of the A2 domain of von Willebrand factor.Journal of thrombosis and haemostasis : JTH · 2020Article
- Expression and assembly of largest foreign protein in chloroplasts: oral delivery of human FVIII made in lettuce chloroplasts robustly suppresses inhibitor formation in haemophilia A mice.Plant biotechnology journal · 2018Article
- Mice deficient in the anti-haemophilic coagulation factor VIII show increased von Willebrand factor plasma levels.PloS one · 2017Article
- Probing ADAMTS13 substrate specificity using phage display.PloS one · 2015Article
- Normal cleavage of von Willebrand factor by ADAMTS-13 in the absence of factor VIII in patients with severe hemophilia A.Journal of thrombosis and haemostasis : JTH · 2013Article
- Compromised shear-dependent cleavage of type 2N von Willebrand factor variants by ADAMTS13 in the presence of factor VIII.Thrombosis and haemostasis · 2013Article
- Structure-function and regulation of ADAMTS-13 protease.Journal of thrombosis and haemostasis : JTH · 2013Review
- In vitro and in vivo evaluation of the effect of elevated factor VIII on the thrombogenic process.Thrombosis and haemostasis · 2013Article
- von Willebrand Factor as a Predictor for Transplant-Associated Thrombotic Microangiopathy.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/HemostasisArticle
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
We previously demonstrated that coagulation factor VIII (FVIII) accelerates proteolytic cleavage of von Willebrand factor (VWF) by A disintegrin and metalloprotease with thrombospondin type 1 repeats (ADAMTS13) under fluid shear stress. In this study, the structural elements of FVIII required for the rate-enhancing effect and the biological relevance of this cofactor activity are determined using a murine model. An isolated light chain of human FVIII (hFVIII-LC) increases proteolytic cleavage of VWF by ADAMTS13 under shear in a concentration-dependent manner. The maximal rate-enhancing effect of hFVIII-LC is ∼8-fold, which is comparable with human full-length FVIII and B-domain deleted FVIII (hFVIII-BDD). The heavy chain (hFVIII-HC) and the light chain lacking the acidic (a3) region (hFVIII-LCΔa3) have no effect in accelerating VWF proteolysis by ADAMTS13 under the same conditions. Although recombinant hFVIII-HC and hFVIII-LCΔa3 do not detectably bind immobilized VWF, recombinant hFVIII-LC binds VWF with high affinity (K(D), ∼15 nM). Moreover, ultra-large VWF multimers accumulate in the plasma of fVIII(-/-) mice after hydrodynamic challenge but not in those reconstituted with either hFVIII-BDD or hFVIII-LC. These results suggest that the light chain of FVIII, which is not biologically active for clot formation, is sufficient for accelerating proteolytic cleavage of VWF by ADAMTS13 under fluid shear stress and (patho) physiological conditions. Our findings provide novel insight into the molecular mechanism of how FVIII regulates VWF homeostasis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.