ADAMTS‐13 activity in plasma is rapidly measured by a new ELISA method that uses recombinant VWF‐A2 domain as substrate

Whitelock, Jody L.; Nolasco, Leticia; Bernardo, Aubrey; Moake, Joel L.; Dong, Jing‐fei; Crúz, Miguel A.

doi:10.1111/j.1538-7836.2004.00601.x

Cited by 58 publications

(49 citation statements)

References 31 publications

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“…on April 10, 2019. by guest www.bloodjournal.org From domain. For example, we reported that the A2 domain can be effectively cleaved by ADAMTS-13 in plasma, [45][46][47] implying that the plasma vimentin, which binds to the A2 domain (supplemental Figure 1C), does not impair the cleavage activity. Moreover, the A2 domain bound to vimentin was detected with the monoclonal antibody VP-1, which recognizes a sequence in the N-terminal side next to the ADAMTS-13 cleavage site in the A2 domain, and it is a potent blocker of ADAMTS-13 activity.…”

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Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress

Behymer

Correa

et al. 2014

Blood

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• Vimentin expressed on the platelet surface serves as adhesive receptor for VWF.The interaction between platelet receptor glycoprotein Iba and the A1 domain of von Willebrand factor (VWF) mediates tethering/translocation of platelets to sites of vascular injury. Unexpectedly, we observed platelets translocating over A1A2A3 domains protein slower than on A1 domain at high shear stress. This observation suggests an additional interaction between A domains and an adhesive receptor. We investigated vimentin because we have data showing the interaction of vimentin with the A2 domain of VWF. Moreover, vimentin is expressed on the platelet surface. This novel interaction was analyzed by using purified VWF, recombinant proteins, anti-vimentin antibodies, parallel flow chamber adhesion assays, flow cytometry, and vimentin-deficient murine platelets. The active form of VWF bound to vimentin, and the purified A2 domain blocked that binding. The interaction of a gain-of-function A1A2A3 mutant with platelet was reduced using anti-vimentin antibody. Platelet adhesion to wild-type (WT) A1A2A3 protein, collagen, and fibrin(ogen) was inhibited (32-75%) by anti-vimentin antibody under high shear stress. Compared with WT mice, platelets from vimentin-deficient mice had a reduced flow-dependent adhesion to both collagen and purified murine VWF. Last, the vimentin knockout mice had a prolonged tail bleeding time. The results describe that platelet vimentin engages VWF during platelet adhesion under high shear stress. (Blood. 2014;123(17):2715-2721 Introduction Atherothrombotic events, including acute coronary syndrome and stroke, are the result of platelet adhesion and activation on the ruptured atherosclerotic plaques. This platelet-mediated arterial thrombosis starts with the contact of the rapidly flowing platelets to components of the damaged blood vessel. von Willebrand factor (VWF), a multimeric plasma and subendothelial glycoprotein, is relevant in mediating platelet adhesion and activation at sites of lesions in the coronary arteries, where high shear conditions prevail.1,2 VWF captures the circulating platelets through its interaction with the platelet receptor glycoprotein (GP)Ib/IX/V complex. This interaction is responsible for the tethering, rolling, and activation of platelets that eventually become firmly adhered, leading to thrombus formation within a coronary artery. 3,4 Mature VWF consists of a 2050-residue subunit formed by domains arranged in the order of D9-D3-A1-A2-A3-D4-B-C. 5 The A1 domain contains the binding site for the platelet receptor GPIba 6 ; the cleavage site for the enzyme ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-13 is localized in the A2 domain, 7 and the A3 domain binds to collagen. 8 Unlike the A3 domain, both the A1 and A2 domains do not have access to their ligands until their domain structure is altered.9 This structural modification can be induced by mutations, 10 hydrodynamic forces, 11 immobilization on a surface, or artificially with the modulator ristocetin....

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Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress

Behymer

Correa

et al. 2014

Blood

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“…Binding sites for platelet GPIb␣, heparin, sulfatides, and collagen (5)(6)(7)(8)(9) are within the A1 domain, whereas its homologous A3 domain only binds to collagen, and the A2 domain contains the cleavage site for the metalloprotease ADAMTS-13 (10 -12). The functions of these A domains relevant to the biology of VWF have been characterized by individual recombinant expression of each of the A domains (9,10,13).…”

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Destabilization of the A1 Domain in von Willebrand Factor Dissociates the A1A2A3 Tri-domain and Provokes Spontaneous Binding to Glycoprotein Ibα and Platelet Activation under Shear Stress

Auton

Sowa

Smith

et al. 2010

Journal of Biological Chemistry

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This study used recombinant A1A2A3 tri-domain proteins to demonstrate that A domain association in von Willebrand factor (VWF) regulates the binding to platelet glycoprotein Ib␣ (GPIb␣). We performed comparative studies between wild type (WT) A1 domain and the R1450E variant that dissociates the tri-domain complex by destabilizing the A1 domain. Using urea denaturation and differential scanning calorimetry, we demonstrated the destabilization of the A1 domain structure concomitantly results in a reduced interaction among the three A domains. This dissociation results in spontaneous binding of R1450E to GPIb␣ without ristocetin with an apparent K D of 85 ؎ 34 nM, comparable with that of WT (36 ؎ 12 nM) with ristocetin. The mutant blocked 100% ristocetin-induced platelet agglutination, whereas WT failed to inhibit. The mutant enhanced shear-induced platelet aggregation at 500 and 5000 s ؊1 shear rates, reaching 42 and 66%, respectively. Shear-induced platelet aggregation did not exceed 18% in the presence of WT. A1A2A3 variants were added before perfusion over a fibrin(ogen)-coated surface. At 1500 s ؊1 , platelets from blood containing WT adhered <10% of the surface area, whereas the mutant induced platelets to rapidly bind, covering 100% of the fibrin(ogen) surface area. Comparable results were obtained with multimeric VWF when ristocetin (0.5 mg/ml) was added to blood before perfusion. EDTA or antibodies against GPIb␣ and ␣IIb␤3 blocked the effect of the mutant and ristocetin on platelet activation/adhesion. Therefore, the termination of A domain association within VWF in solution results in binding to GPIba and platelet activation under high shear stress.Platelet adhesion at sites of vascular injury contributes to the arrest of bleeding as well as to the pathologic occlusion of diseased vessels under elevated shear stress. Under this high shear stress, the platelet-von Willebrand factor (VWF) 3 interaction is essential for platelet adhesion. The interaction between VWF and the exposed subendothelium permits the VWF to interact with circulating platelets via the receptor glycoprotein (GP)Ib/ IX/V complex (1). Mature VWF consists of a 2050-residue subunit that contains domains that are arranged in the order DЈ-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK (cystine knot) (2-4). The VWF contains a triplicate repeat sequence or A domains in the central portion of the subunit. Binding sites for platelet GPIb␣, heparin, sulfatides, and collagen (5-9) are within the A1 domain, whereas its homologous A3 domain only binds to collagen, and the A2 domain contains the cleavage site for the metalloprotease ADAMTS-13 (10 -12). The functions of these A domains relevant to the biology of VWF have been characterized by individual recombinant expression of each of the A domains (9, 10, 13).The interaction between VWF and GPIb␣ occurs when the binding site for GPIb␣ in the A1 domain of VWF has been exposed by the influence of high fluid forces or when the multimeric protein has been immobilized (14). This activation can also be induced by nat...

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“…6,8 Several assays have been developed which rapidly detect ADAMTS13 activity and help to confirm a clinical suspicion of TTP. [10][11][12][13][14] An enzyme-linked immunosorbent assay (ELISA)-based test has also been used to measure ADAMTS13 antigen levels. 15,16 While ADAMTS13 activity measured at the onset of TTP is known to help to confirm the diagnosis, the clinical value of ADAMTS13 antigen measurements in the evaluation of TTP disease severity, responses to therapy, and clinical outcomes has not been well studied in a large cohort of TTP patients with longitudinal follow-up.…”

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confidence: 99%

ADAMTS13 activity and antigen during therapy and follow-up of patients with idiopathic thrombotic thrombocytopenic purpura: correlation with clinical outcome

Yang¹,

Jin²,

Lin³

et al. 2011

Haematologica

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BackgroundThe assay for ADAMTS13 activity helps clinicians to confirm the clinical diagnosis of idiopathic thrombotic thrombocytopenic purpura. The clinical value of testing for the antigen level of ADAMTS13 protein is, however, less clear. Design and MethodsIn this study, both ADAMTS13 antigen and activity levels were measured in 835 sequential samples from 40 consecutive patients who were followed for an average of 29 months throughout the course of acute episode plasma exchange treatment and clinical remission. ResultsDuring acute episodes, ADAMTS13 activity was severely deficient while ADAMTS13 antigen levels were more variable, ranging from severely deficient to as high as within the reference range. A severe depletion of ADAMTS13 antigen level during acute disease was, however, statistically associated with disease mortality (P=0.0322). For patients who achieved initial clinical responses, ADAMTS13 antigen levels appeared to be restored faster than ADAMTS13 activity to the normal range. Further analysis demonstrated that the ADAMTS13 antigen level at the time of initial clinical recovery was significantly higher in the patients who subsequently achieved a sustained clinical remission than in the group who soon after had an exacerbation (P=0.0187). ConclusionsOur data suggest that evaluation of ADAMTS13 antigen levels during the course of therapy and follow-up may offer additional useful information for the management of patients with thrombotic thrombocytopenic purpura.Key words: thrombotic thrombocytopenic purpura, ADAMTS13, prognosis, biomarker.Citation: Yang S, Jin M, Lin S, Cataland S, and Wu H. ADAMTS13 activity and antigen during therapy and follow-up of patients with idiopathic thrombotic thrombocytopenic purpura: correlation with clinical outcome Haematologica 2011;96(10)

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ADAMTS‐13 activity in plasma is rapidly measured by a new ELISA method that uses recombinant VWF‐A2 domain as substrate

Cited by 58 publications

References 31 publications

Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress

Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress

Destabilization of the A1 Domain in von Willebrand Factor Dissociates the A1A2A3 Tri-domain and Provokes Spontaneous Binding to Glycoprotein Ibα and Platelet Activation under Shear Stress

ADAMTS13 activity and antigen during therapy and follow-up of patients with idiopathic thrombotic thrombocytopenic purpura: correlation with clinical outcome

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