scholarly journals von Willebrand factor–cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke

Blood ◽  
2009 ◽  
Vol 114 (15) ◽  
pp. 3329-3334 ◽  
Author(s):  
Bing-Qiao Zhao ◽  
Anil K. Chauhan ◽  
Matthias Canault ◽  
Ian S. Patten ◽  
Janie J. Yang ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Wild Type Mouse ◽  
Recombinant Tissue Plasminogen Activator ◽  
Experimental Stroke ◽  
High Dose ◽  
Type I ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke.

Quantitative Analysis of von Willebrand Factor and Its Propeptide in Plasma in Acquired von Willebrand Syndrome

1998 ◽  
Vol 80 (09) ◽  
pp. 495-498 ◽  
Author(s):  
Ria Boertjes ◽  
Jan van Mourik ◽  
Perry van Genderen
Keyword(s):  
Quantitative Analysis ◽  
Von Willebrand Factor ◽  
Intravenous Immunoglobulins ◽  
Von Willebrand Disease ◽  
High Dose ◽  
Type I ◽  
Acquired Von Willebrand Syndrome ◽  
Normal Individuals ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryMeasurement of the von Willebrand factor (vWF) propeptide, also known as von Willebrand antigen II, has been suggested to be helpful in the discrimination of congenital von Willebrand disease type I from type 2 and in assessing the extent of activation of the endothelium. We performed a quantitative analysis of mature vWF and its propeptide in plasma in 8 patients with acquired von Willebrand syndrome (AvWS) and in 20 normal individuals. Mature vWF levels were significantly lower in AvWS as compared with normal individuals (13.4 ± 3.5 vs 35.6 ± 3.3 nM, p <0.001). In contrast, propeptide levels were significantly higher in AvWS (11.4 ± 1.1 vs 4.7 ± 0.2 nM, p < 0.001), probably reflecting a compensatory increase in vWF synthesis or increased perturbation of the endothelium in AvWS. After treatment with DDAVP, propeptide and mature vWF levels rose 5-fold in AvWS, whereas propeptide levels were not altered by the infusion of a vWF concentrate or treatment with high dose intravenous immunoglobulins, indicating that plasma propeptide levels are a reliable reflection of vWF synthesis. Measurement of propeptide levels may provide additional information in AvWS as to whether decreased levels of mature vWF in the circulation are due to a decrease in synthesis or due to an accelerated removal of vWF from the circulation.

Interventional Thermal Injury of the Arterial Wall: Unfolding of von Willebrand Factor and Its Increased Binding to Collagen after 55° C Heating

1996 ◽  
Vol 75 (03) ◽  
pp. 515-519 ◽  
Author(s):  
Mark J Post ◽  
Anke N de Graaf-Bos ◽  
George Posthuma ◽  
Philip G de Groot ◽  
Jan J Sixma ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Conformational Changes ◽  
Arterial Wall ◽  
Platelet Adhesion ◽  
Type I ◽  
Temperature Dependent ◽  
Collagen Types ◽  
Electron Microscopic ◽  
Von Willebrand ◽  
Willebrand Factor

Summary Purpose. Thermal angioplasty alters the thrombogenicity of the arterial wall. In previous studies, platelet adhesion was found to increase after heating human subendothelium to 55° C and decrease after heating to 90° C. In the present electron microscopic study, the mechanism of this temperature-dependent platelet adhesion to the heated arterial wall is elucidated by investigating temperature-dependent conformational changes of von Willebrand factor (vWF) and collagen types I and III and the binding of vWF to heated collagen. Methods. Purified vWF and/or collagen was applied to electron microscopic grids and heated by floating on a salt-solution of 37° C, 55° C or 90° C for 15 s. After incubation with a polyclonal antibody against vWF and incubation with protein A/gold, the grids were examined by electron microscopy. Results. At 37° C, vWF was coiled. At 55° C, vWF unfolded, whereas heating at 90° C caused a reduction in antigenicity. Collagen fibers heated to 37° C were 60.3 ± 3.1 nm wide. Heating to 55° C resulted in the unwinding of the fibers, increasing the width to 87.5 ± 8.2 nm (p < 0.01). Heating to 90° C resulted in denatured fibers with an enlarged width of 85.1 ± 6.1 nm (p < 0.05). Heating of collagen to 55° C resulted in an increased vWF binding as compared to collagen heated to 37° C or to 90° C. Incubation of collagen with vWF, prior to heating, resulted in a vWF binding after heating to 55° C that was similar to the 37° C binding and a decreased binding after 90° C. Conclusions. After 55° C heating, the von Willebrand factor molecule unfolds and collagen types I and III exhibit an increased adhesiveness for von Willebrand factor. Heating to 90° C denatures von Willebrand factor and collagen. The conformation changes of von Willebrand factor and its altered binding to collagen type I and III may explain the increased and decreased platelet adhesion to subendothelium after 55° C and 90° C heating, respectively.

The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

1993 ◽  
Vol 69 (02) ◽  
pp. 173-176 ◽  
Author(s):  
Anna M Randi ◽  
Elisabetta Sacchi ◽  
Gian Carlo Castaman ◽  
Francesco Rodeghiero ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Autosomal Dominant ◽  
Genetic Defect ◽  
Von Willebrand Disease ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Gene ◽  
Low Levels ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

Abciximab Preferentially Binds von Willebrand Factor Compared to High Dose Tirofiban

2007 ◽  
Vol 16 ◽  
pp. S130-S131
Author(s):  
M.J. Ray ◽  
M. Juneja ◽  
A. Limpus ◽  
R. Chua ◽  
S. Seniveratne ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
High Dose ◽  
Von Willebrand ◽  
Willebrand Factor

PRIMARY BINDING SITE OF VON WILLEBRAND FACTOR IN THE SUBENDOTHELIUM WHICH MEDIATES PLATELET ADHESION IS NOT COLLAGEN

1987 ◽  
Author(s):  
Philip G de Groot ◽  
Jan A van Mourik ◽  
Jan J Sixma
Keyword(s):  
Monoclonal Antibody ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Collagen Type ◽  
Collagen Type I ◽  
Extracellular Matrices ◽  
Type I ◽  
Type Iii ◽  
Von Willebrand ◽  
Willebrand Factor

We have studies the binding of von Willebrand factor (vWF) to extracellular matrices of endothelial cells and smooth muscle cells and to the vessel wall of human umbilical arteries in relation to its function in supporting platelet adhesion at high shear rates. CLB-RAg 38, a monoclonal antibody directed against vWF inhibits the binding of 125I-vWF extracellular matrices completely. The binding of 125I-vWF to subendothelium is not inhibited, because there are many different binding sites. CLB-RAg 38 inhibits platelet adhesion to extracellular matrices and subendothelium, in sofar as it is dependent on plasma vWF. CLB-RAg 38 has no effect on adhesion depending on vWF already bound to the matrix or subendothelium. CLB-RAg 38 does not inhibit binding of vWF to collagen type I and type III. Another monoclonal antibody against vWF, CLB-RAg 201, completely inhibits binding of vWF to collagen type I and type III. CLB-RAg 201 does not inhibit binding of 125I-vWF ot the extracellular matrices. CLB-RAg 201 partly inhibits platelet adhesion but this inhibition is also present when the adhesion depends on vWF already present in matrix or subendothelium, indicating that CLB-RAg 201 also inhibits the adhesion of platelets directly, this in contrast to CLB-RAg 38. The epitopes for CLB-RAg 201 and 38 were found on different tryptic fragments of vWF. These data indicate that vWF binds to subendothelium and to matrices of cultured cells by mechanism that is different from binding to collagen.

scholarly journals Clinical Significance of Inhibitors in Acquired von Willebrand Syndrome

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3623-3629 ◽  
Author(s):  
Hiroshi Mohri ◽  
Shigeki Motomura ◽  
Heiwa Kanamori ◽  
Michio Matsuzaki ◽  
Shin-ichiro Watanabe ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Immunoglobulin Therapy ◽  
High Dose ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
Intravenous Immunoglobulin Therapy ◽  
Acquired Von Willebrand Syndrome ◽  
Underlying Diseases ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Of 260 patients enrolled, 25 patients (9.6%) were associated with acquired von Willebrand syndrome (AvWS). We studied 25 patients with AvWS, retrospectively. AvWS was diagnosed by reduced levels of von Willebrand factor (vWF) (decrease of von Willebrand factor antigen [vWF:Ag] and von Willebrand ristocetin cofactor [vWF:RCoF]), a decrease of ristocetin-induced platelet agglutination (RIPA), sometimes decreased high-molecular-weight multimers, and prolonged bleeding time with neither prior nor family histories of bleeding problems and the evidence of normal vWF:RCoF in their families. The inhibitor of vWF was determined by mixing patient plasma with pooled normal plasma. Eight patients in this study had the inhibitors to vWF that were of the IgG class; the subclasses were IgG1 (7 cases) and IgG2 (1 case). Multimeric analysis of vWF showed selective loss of large multimers in most patients with AvWS similar to that of congenital type-2 von Willebrand disease (vWD). All inhibitors blocked ristocetin-mediated vWF binding to platelets. Five out of 6 IgGs evaluated here recognized the 39/34-kD fragment (residues 480/481-718) and Fragment III (residues 1-1365) that implied binding domain of glycoprotein Ib (GPIb), whereas 1 recognized Fragment I (residues 911-1365). A close relationship was found between the presence of the inhibitor and bleeding tendency. Of the 7 patients with inhibitors, 6 patients (86%) had a bleeding tendency, as well as 1 of the 15 patients without inhibitors (6%). The efficacy of treatment of underlying diseases and/or therapy with deamino D-arginine vasopressin (DDAVP) for the treatment of AvWS also depends on the presence of an inhibitor. Four of 8 patients with inhibitors (50%) had poor response to treatment of the underlying disease and/or therapy with DDAVP, as well as 1 of the 16 patients without inhibitors (6%). These results indicate that patients with AvWS developing inhibitors to vWF are likely to have bleeding problems and might be resistant to treatment of underlying diseases and/or therapy with DDAVP for bleeding to AvWS. We also showed evidence that intravenous immunoglobulin therapy (0.3 g/kg, 3 days) was effective to correct a hemostatic defect and manage severe bleeding in a patient with AvWS developing inhibitors. We might consider an additional treatment including expensive high-dose immunoglobulin therapy when uncontrollable bleeding is continued after the treatment of the underlying diseases and/or therapy with DDAVP.

The role of platelet von Willebrand factor in platelet adhesion and thrombus formation: a study of 34 patients with various subtypes of type I von Willebrand disease

1994 ◽  
Vol 86 (2) ◽  
pp. 327-332 ◽  
Author(s):  
Edith Fressinaud ◽  
Augusto B. Federici ◽  
Giancarlo Castaman ◽  
Chantal Rothschild ◽  
Francesco Rodeghiero ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Von Willebrand Disease ◽  
Type I ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand's disease subtypes

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1272-1278 ◽  
Author(s):  
ZM Ruggeri ◽  
PM Mannucci ◽  
R Lombardi ◽  
AB Federici ◽  
TS Zimmerman
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Resting State ◽  
Bleeding Time ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Plasma Factor ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We have studied the modifications in the multimeric composition of plasma factor VIII/von Willebrand factor and the bleeding time response following administration of 1-Deamino-[8-D-arginine]-Vasopressin (DDAVP) to patients with different subtypes of von Willebrand's disease. In type I, all multimers were present in plasma in the resting state, though they were decreased in concentration. Administration of DDAVP resulted in an increased concentration of these forms as well as the appearance of larger forms than were previously present. There was concomitant correction of the bleeding time. In type IIA, large multimers were absent in the resting state, and although DDAVP induced an average threefold increase in the plasma concentration of factor VIII/von Willebrand factor, the larger multimers did not appear and the bleeding time, although shortened, was not corrected. In contrast, the larger multimers that were also absent from type IIB plasma in the resting state rapidly appeared following DDAVP administration. However, their appearance was transitory and the bleeding time, as in IIA patients, was shortened but not corrected. The characteristic multimeric composition of platelet factor VIII/von Willebrand factor in given subtypes predicted the alteration in plasma factor VIII/von Willebrand factor induced by DDAVP. These studies provide evidence that the different subtypes of von Willebrand's disease represent distinct abnormalities of factor VIII/von Willebrand factor. They also suggest that complete hemostatic correction following DDAVP can be routinely expected only in type I von Willebrand's disease, and only if factor VIII/von Willebrand factor can be raised to normal levels.

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