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.

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

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 Investigation of the role of von Willebrand factor in thrombotic thrombocytopenic purpura

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1219-1221 ◽  
Author(s):  
EC Lian ◽  
FA Siddiqui
Keyword(s):  
Platelet Aggregation ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Platelet Glycoprotein ◽  
Plasma Samples ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Induced Aggregation ◽  
Willebrand Factor

Abstract Von Willebrand factor (vWF) has been implicated to function as a cofactor in platelet aggregation induced by thrombotic thrombocytopenic purpura (TTP) plasma. To investigate further this role of vWF, we have used rabbit monospecific anti-FVIII/vWF antibodies and a monoclonal antibody to platelet glycoprotein Ib (GP Ib) that blocks the ristocetin- induced platelet aggregation. The monoclonal anti-platelet GP Ib antibody inhibited the platelet aggregation induced by ristocetin in the presence of normal plasma, but not that by any of the five TTP plasma samples. The TTP plasma samples from five patients were incubated with the monospecific antibodies to FVIII/vWF. In all of the samples, the FVIII/vWF:Ag was drastically reduced; however, there was almost no effect on the platelet-aggregating activity. Therefore, it is concluded that vWF is unlikely to play a major role in platelet aggregation induced by majority of TTP plasmas and that the site of platelet GP Ib, to which vWF binds in the presence of ristocetin, is not involved in TTP plasma-induced aggregation.

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.

scholarly journals Investigation of the role of von Willebrand factor in thrombotic thrombocytopenic purpura

Blood ◽  
1985 ◽  
Vol 66 (5) ◽  
pp. 1219-1221
Author(s):  
EC Lian ◽  
FA Siddiqui
Keyword(s):  
Platelet Aggregation ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Platelet Glycoprotein ◽  
Plasma Samples ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Induced Aggregation ◽  
Willebrand Factor

Von Willebrand factor (vWF) has been implicated to function as a cofactor in platelet aggregation induced by thrombotic thrombocytopenic purpura (TTP) plasma. To investigate further this role of vWF, we have used rabbit monospecific anti-FVIII/vWF antibodies and a monoclonal antibody to platelet glycoprotein Ib (GP Ib) that blocks the ristocetin- induced platelet aggregation. The monoclonal anti-platelet GP Ib antibody inhibited the platelet aggregation induced by ristocetin in the presence of normal plasma, but not that by any of the five TTP plasma samples. The TTP plasma samples from five patients were incubated with the monospecific antibodies to FVIII/vWF. In all of the samples, the FVIII/vWF:Ag was drastically reduced; however, there was almost no effect on the platelet-aggregating activity. Therefore, it is concluded that vWF is unlikely to play a major role in platelet aggregation induced by majority of TTP plasmas and that the site of platelet GP Ib, to which vWF binds in the presence of ristocetin, is not involved in TTP plasma-induced aggregation.

scholarly journals Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study

2021 ◽  
Vol 6 (1) ◽  
pp. e000703
Author(s):  
Taleen A MacArthur ◽  
Julie Goswami ◽  
Laurie Moon Tasson ◽  
Alexander Tischer ◽  
Kent R Bailey ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Thrombin Generation ◽  
Trauma Patients ◽  
Phase Reaction ◽  
Time Points ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

BackgroundVon Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.MethodsWe assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.ResultsREAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0–264.0) vs. 92.0 (71.0–114.0), p<0.002) and at 6 hours (167.5 (108.0–312.5.0) vs. 92.0 (71.0–114.0), p<0.001). ADAMTS-13 antigen levels were also decreased in trauma patients both at 0 to 2 hours (0.84 (0.51–0.94) vs. 1.00 (0.89–1.09), p=0.010) and at 6 hours (0.653 (0.531–0.821) vs. 1.00 (0.89–1.09), p<0.001). Trauma patients had accelerated thrombin generation kinetics, with greater peak height and shorter time to peak than healthy volunteers at both time points.DiscussionTrauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.Level of evidenceProspective case cohort study.

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