scholarly journals Platelet factor 4 inhibits ADAMTS13 activity and regulates the multimeric distribution of von Willebrand factor

2020 ◽  
Vol 190 (4) ◽  
pp. 594-598
Author(s):  
Ishac Nazy ◽  
Taylor D. Elliott ◽  
Donald M. Arnold
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Factor 4 ◽  
Adamts13 Activity ◽  
Platelet Factor ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Human platelet surface binding of endogenous secreted factor VIII-von Willebrand factor and platelet factor 4

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 194-197 ◽  
Author(s):  
JN George ◽  
AR Onofre
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Membrane Surface ◽  
Platelet Factor 4 ◽  
Secreted Proteins ◽  
Surface Binding ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Washed human platelets in buffers containing either 2 mM Ca++ or 4 mM EDTA were stimulated by human alpha-thrombin to induce secretion. The binding of two endogenous secreted proteins, factor-VIII-related protein (VIII-R) (von Willebrand factor) and platelet factor 4, was measured by reacting thrombin-treated and control platelets with specific antibodies to these proteins, then quantifying antibody binding with 125I-staphylococcal protein A. Both of these granule proteins were associated with the platelet membrane surface by a calcium-dependent mechanism after thrombin-induced secretion. This ability to bind endogenous secreted proteins to the plasma membrane surface may provide a mechanism by which the platelet can concentrate and organize its secreted proteins for subsequent physiologic reactions.

scholarly journals Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders

Blood ◽  
2012 ◽  
Vol 120 (20) ◽  
pp. 4134-4142 ◽  
Author(s):  
Douglas B. Cines ◽  
Keith R. McCrae ◽  
X. Long Zheng ◽  
Bruce S. Sachais ◽  
Eline T. Luning Prak ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Antiphospholipid Syndrome ◽  
Von Willebrand Factor ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Thrombocytopenic Purpura ◽  
Heparin Induced Thrombocytopenia ◽  
Systemic Anticoagulation ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractPrevailing approaches to manage autoimmune thrombotic disorders, such as heparin-induced thrombocytopenia, antiphospholipid syndrome and thrombotic thrombocytopenic purpura, include immunosuppression and systemic anticoagulation, though neither provides optimal outcome for many patients. A different approach is suggested by the concurrence of autoantibodies and their antigenic targets in the absence of clinical disease, such as platelet factor 4 in heparin-induced thrombocytopenia and β2-glycoprotein-I (β2GPI) in antiphospholipid syndrome. The presence of autoantibodies in the absence of disease suggests that conformational changes or other alterations in endogenous protein autoantigens are required for recognition by pathogenic autoantibodies. In thrombotic thrombocytopenic purpura, the clinical impact of ADAMTS13 deficiency caused by autoantibodies likely depends on the balance between residual antigen, that is, enzyme activity, and demand imposed by local genesis of ultralarge multimers of von Willebrand factor. A corollary of these concepts is that disrupting platelet factor 4 and β2GPI conformation (or ultralarge multimer of von Willebrand factor oligomerization or function) might provide a disease-targeted approach to prevent thrombosis without systemic anticoagulation or immunosuppression. Validation of this approach requires a deeper understanding of how seemingly normal host proteins become antigenic or undergo changes that increase antibody avidity, and how they can be altered to retain adaptive functions while shedding epitopes prone to elicit harmful autoimmunity.

scholarly journals Human platelet surface binding of endogenous secreted factor VIII-von Willebrand factor and platelet factor 4

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 194-197 ◽  
Author(s):  
JN George ◽  
AR Onofre
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Membrane Surface ◽  
Platelet Factor 4 ◽  
Secreted Proteins ◽  
Surface Binding ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Von Willebrand ◽  
Willebrand Factor

Washed human platelets in buffers containing either 2 mM Ca++ or 4 mM EDTA were stimulated by human alpha-thrombin to induce secretion. The binding of two endogenous secreted proteins, factor-VIII-related protein (VIII-R) (von Willebrand factor) and platelet factor 4, was measured by reacting thrombin-treated and control platelets with specific antibodies to these proteins, then quantifying antibody binding with 125I-staphylococcal protein A. Both of these granule proteins were associated with the platelet membrane surface by a calcium-dependent mechanism after thrombin-induced secretion. This ability to bind endogenous secreted proteins to the plasma membrane surface may provide a mechanism by which the platelet can concentrate and organize its secreted proteins for subsequent physiologic reactions.

Von Willebrand Factor Cleaving Protease (ADAMTS-13) Antigen Levels Are Decreased in Patients with Heparin-Induced Thrombocytopenia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3970-3970
Author(s):  
Debra Hoppensteadt ◽  
Josephine Cunanan ◽  
Jeanine M. Walenga ◽  
Michael P. Ero ◽  
Walter P. Jeske ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Von Willebrand Factor ◽  
Platelet Factor 4 ◽  
Plasma Samples ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Related Proteins ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Heparin-induced thrombocytopenia (HIT) represents a complex pathologic syndrome including all components of the hemostatic system and inflammatory response. ADAMTS-13 is a metalloprotease which mediates the cleavage of von Willebrand factor (vWF) multimers. A deficiency or decreased activity of this protease may result in a TTP-related syndrome manifested by the development of intravascular platelet aggregates, thrombocytopenia, endothelial dysfunction and the deposition of vWF at thrombotic sites. Several recent reports have described decreased functionality of ADAMTS-13 in patients with HIV. This may be due to antibodies than inhibit ADAMTS-13. HIT is characterized by the generation of heparin-induced anti-heparin platelet factor 4 antibodies which are molecularly and functionally heterogeneous. No data is available on the effect of these antibodies on ADAMTS-13. However, increased vWF levels and the generation of ultrahigh molecular weight vWF multimers have been reported in HIT patients. This study was designed to determine the ADAMTS-13 antigen levels in HIT patient plasma samples (n=30) prior to and after treatment with the direct anti-thrombin agent argatroban (ARG 911 study). Plasma samples from normal healthy volunteers (n=30) were used as controls for comparison purposes. ADAMTS-13 antigen levels were quantitated using a newly developed ELISA method from American Diagnostica (Stamford, CT). vWF antigen levels were also measured using an ELISA-based method. The levels of ADAMTS-13 and vWF antigen were reported as percent normal based on the results obtained with the samples from healthy volunteers. The baseline ADAMTS-13 antigen levels varied widely among the HIT patients enrolled in the ARG 911 trial (30–180% NHP) with a mean of 62 ± 24% NHP. On treatment day 1, no significant changes were noted in the ADAMTS-13 levels in HIT patients. However, on the third and 5th-7th day following initiation of argatroban treatment, ADAMTS-13 levels were increased to 81 ± 6% NHP and 86 ± 24% NHP, respectively. The HIT patient group also exhibited higher levels of vWF antigen at baseline (170 ± 27% NHP) which were marginally decreased following treatment with argatroban. During argatroban treatment, a decrease in anti-heparin platelet factor 4 antibody titer and an improvement in platelet count were noted. These results are highly suggestive of a pathogenic role of vWF multimers in HIT syndrome. Furthermore, a decreased ADAMTS-13 antigen level indicates that its regulation in HIT patients may be altered. Additional results on ADAMTS-13 functionality, ADAMTS-13-factor XI complexes and autoantibodies to the metalloprotease may provide additional insights into the pathogenesis of HIT and the pathologic role of vWF related proteins.

Studies of α-granule proteins in cultured human megakaryocytes

2003 ◽  
Vol 90 (11) ◽  
pp. 844-852 ◽  
Author(s):  
Dragoslava Veljkovic ◽  
Elisabeth Cramer ◽  
Gulie Alimardani ◽  
Serge Fichelson ◽  
Jean-Marc Massé ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Protein Processing ◽  
Platelet Factor ◽  
Protein Storage ◽  
Granule Protein ◽  
Granule Proteins ◽  
Processing And Storage ◽  
Von Willebrand ◽  
And Storage ◽  
Willebrand Factor

Summaryα-Granule protein storage is important for producing platelets with normal haemostatic function. The low to undetectable levels of several megakaryocyte-synthesized α-granule proteins in normal plasma suggest megakaryocytes are important to sequester these proteins in vivo. α-Granule protein storage in vitrohas been studied using other cell types, with differences observed in how some proteins are processed compared to platelets. Human megakaryocytes, cultured from cord blood CD34+cells and grown in serum-free media containing thrombopoietin, were investigated to determine if they could be used as a model for studying normal α-granule protein processing and storage. ELISA indicated that cultured megakaryocytes contained the α-granule proteins multimerin, von Willebrand factor, thrombospondin-1, β-thromboglobulin and platelet factor 4, but no detectable fibrinogen and factor V. A significant proportion of the α-granule protein in megakaryocyte cultures was contained within the cells (averages: 41 – 71 %), consistent with storage. Detailed analyses of multimerin and von Willebrand factor confirmed that α-granule proteins were processed to mature forms and were predominantly located in the α-granules of cultured megakaryocytes. Thrombopoietin-stimulated cultured megakaryocytes provide a useful model for studying α-granule protein processing and storage.

von Willebrand Factor, ADAMTS13 Activity, and Decline in Kidney Function: A Population-Based Cohort Study

2016 ◽  
Vol 68 (5) ◽  
pp. 726-732 ◽  
Author(s):  
Sanaz Sedaghat ◽  
Paul S. de Vries ◽  
Johan Boender ◽  
Michelle A.H. Sonneveld ◽  
Ewout J. Hoorn ◽  
...  
Keyword(s):  
Cohort Study ◽  
Kidney Function ◽  
Von Willebrand Factor ◽  
Population Based ◽  
Adamts13 Activity ◽  
Von Willebrand ◽  
Willebrand Factor
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