VWF - Mechanisms of Regulation

VWF - 监管机制

• 批准号: 10191003
• 负责人: SANDRA HABERICHTER
• 金额: $ 41.66万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10191003
• 关键词: Adhesions; Affect; Alpha Granule; Biological Assay; Blood; Blood Circulation; Blood Coagulation Disorders; Blood Platelets; Carrier Proteins; Cells; Clinical; Cytoplasmic Granules; DDAVP; Defect; Desmopressin; Diagnosis; Disease susceptibility; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Factor VIII; Factor VIII-Related Antigen; Family member; Galactose; Glycoproteins; Half-Life; Hemorrhage; Hemostatic function; Impairment; Individual; Inherited; Knowledge; Lectin; Link; Longevity; Mammalian Cell; Mannose; Measures; Mediating; Megakaryocytes; Metabolic Clearance Rate; Modeling; Modification; Mus; Patients; Plasma; Polysaccharides; Population Control; Proteins; Regulation; Reporting; Sampling; Sialic Acids; Site; Time; Variant; Weibel-Palade Bodies; base; cohort; common treatment; disorder subtype; effective therapy; ethnic diversity; glycoproteomics; glycosylation; improved; indexing; mouse model; mutant; novel; release factor; response; vascular injury; von Willebrand Disease; von Willebrand Factor; von Willebrand factor receptor

Project Summary The regulation of plasma von Willebrand factor (VWF) level is critical for hemostasis, as VWF both mediates platelet adhesion at sites of vascular injury and serves as carrier protein for coagulation factor VIII. Type 1 von Willebrand disease (VWD) is the most common VWD subtype with quantitative deficiency of VWF. The reduced survival of plasma VWF is a novel VWD mechanism, termed type 1C. Type 1C VWD patients have a significantly decreased VWF half-life (1-3 hrs vs 12-16 hrs), which severely impacts the efficacy of DDAVP treatment. DDAVP releases VWF from endothelial cell storage granules into plasma and is the most common treatment in type 1 VWD. Rapid VWF clearance substantially impairs therapy of type 1C patients. Type 1C patients are identified by increased VWF propeptide (VWFpp) to VWF antigen (VWF:Ag) ratio. Our hypothesis is that the assay of plasma VWFpp and VWFpp/VWF:Ag can be used to predict the release of VWF and its clearance rate after DDAVP administration in types 1 and 1C VWD. This could potentially reduce the need for DDAVP trials in patients or affected family members. The underlying mechanisms causing reduced VWF survival in patients remain largely undefined. A number of studies have suggested a link between VWF glycosylation and VWF clearance. The glycan composition of VWF was recently determined using pooled plasma from healthy donors. However, VWF glycan variation in individual healthy controls and VWD patients has not been studied. Our hypothesis is that type 1C VWD subjects will have an altered VWF glycosylation profile compared to healthy controls resulting in increased VWF clearance from plasma. We propose to systematically define this variation in a large cohort of healthy controls and well-characterized VWF patients and link alteration of VWF glycosylation with increased clearance from plasma. This project is directed at improving treatment in type 1 VWD patients as well as enhancing our scientific knowledge of VWF glycan variability and the link to VWF clearance.

项目总结

项目成果

Evidence-Based Minireview: Perioperative management of the VWD patient at elevated thrombotic risk.

循证小型回顾：血栓风险升高的 VWD 患者的围手术期管理。

• DOI: 10.1182/hematology.2019000078
• 发表时间: 2019
• 期刊: Hematology. American Society of Hematology. Education Program
• 作者: Husseinzadeh,HollehD;Haberichter,Sandra
• 通讯作者: Haberichter,Sandra

Sialylation on O-linked glycans protects von Willebrand factor from macrophage galactose lectin-mediated clearance.

• DOI: 10.3324/haematol.2020.274720
• 发表时间: 2022-03-01
• 期刊: Haematologica
• 影响因子: 10.1
• 作者: Ward SE;O'Sullivan JM;Moran AB;Spencer DIR;Gardner RA;Sharma J;Fazavana J;Monopoli M;McKinnon TAJ;Chion A;Haberichter S;O'Donnell JS
• 通讯作者: O'Donnell JS

Enhanced VWF clearance in low VWF pathogenesis: limitations of the VWFpp/VWF:Ag ratio and clinical significance.

VWF低发病机理中增强的VWF清除率：VWFPP/VWF的局限性：Ag比率和临床意义。

• DOI: 10.1182/bloodadvances.2022007340
• 发表时间: 2023-02-14
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Doherty, Dearbhla;Lavin, Michelle;Byrne, Mary;Nolan, Margaret;O'Sullivan, Jamie M.;Ryan, Kevin;O'Connell, Niamh M.;Haberichter, Sandra L.;Christopherson, Pamela A.;Di Paola, Jorge;James, Paula D.;O'Donnell, James S.
• 通讯作者: O'Donnell, James S.

Ristocetin dependent cofactor activity in von Willebrand disease diagnosis: Limitations of relying on a single measure.

• DOI: 10.1002/rth2.12807
• 发表时间: 2022-10
• 期刊: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
• 影响因子: 4.6
• 作者: Christopherson, Pamela A.;Haberichter, Sandra L.;Flood, Veronica H.;Sicking, Ursula O.;Abshire, Thomas C.;Montgomery, Robert R.
• 通讯作者: Montgomery, Robert R.