ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions

Dong, Jing; Moake, Joel L.; Nolasco, Leticia; Bernardo, Aubrey; Arceneaux, Wendy; Shrimpton, Corie N.; Schade, Alicia J.; McIntire, Larry V.; Fujikawa, Kazuo; López, José A.

doi:10.1182/blood-2002-05-1401

Cited by 780 publications

(936 citation statements)

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“…62 These observations corroborated previous studies which found that shear-induced stretching of large vWF multimers results in the exposure of the scissile Tyr 1605 -Met 1606 bond within the A2 domain, facilitating cleavage by ADAMST-13 in normal plasma. 56,57 Smaller vWF multimers in microcirculation equally undergo stretching in regions of high shear, such as a bleeding arteriole, which expose bonding sites in the A1 domain of vWF for complexation with platelets during haemostasis. 57,60,63 While studies of vWF provided clear evidence that shear flow can alter protein structure, it may be argued that different proteins experience different shear since the strain rates required to trigger structural alterations decreases with increasing molecular weight and solvent viscosity.…”

Section: Effects Of Shear Flow On Protein Structure and Functionmentioning

confidence: 99%

“…vWF molecules, which are initially secreted by the endothelial cells as large, hyperactive multimers, with relative molecular mass up to $50 3 10 6 , circulate as a series of smaller, less active proteolytic fragments in the plasma as a result of the action of the metalloprotease ADAMTS-13. 56,57 Interestingly, the proteolysis of large vWF multimers is not observed when normal plasma is incubated in vitro. 58 This lead to the conclusion that the generation of proteolytic fragments of vWF in circulation depends on haemodynamic shear stress.…”

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confidence: 99%

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The effects of shear flow on protein structure and function

Bekard

Asimakis

Bertolini³

et al. 2011

Biopolymers

180

140

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Toxoplasma gondii usually causes an asymptomatic and then latent infection in human adults; however, a potentially fatal disseminated form can occur in immunocompromised patients. Given that the diagnosis of acute Toxoplasma infection, as opposed to latent disease, relies on finding direct evidence of T. gondii infection in tissue, pathologic examination is critical. There have only been a few reports describing the cytomorphology of Toxoplasma in exfoliative cytology, and no reports of the findings in Thin Prep. In this report, we describe a fatal case of toxoplasmosis in a cardiac transplant patient that was diagnosed by respiratory cytopathology. Although the extracellular organisms were well visualized on the Wright‐Giemsa stained cytospin, they were only faintly seen on the Pap‐stained cytospin trapped within mucin and were not easily appreciated on the ThinPrep slides nor the H&E stained cell block sections. An immunohistochemical stain for Toxoplasma performed on the cell block was strongly positive, and an autopsy performed on the patient confirmed disseminated infection. Our case illustrates that the diagnosis of Toxoplasma in exfoliative cytology specimens can be challenging since organisms are not well visualized on ThinPrep or Pap‐stained material; therefore, Wright‐Giemsa stained material can be particularly helpful. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.

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Section: Effects Of Shear Flow On Protein Structure and Functionmentioning

confidence: 99%

mentioning

confidence: 99%

The effects of shear flow on protein structure and function

Bekard

Asimakis

Bertolini³

et al. 2011

Biopolymers

180

140

View full text Add to dashboard Cite

show abstract

“…In vitro and in vivo studies have observed that some VWF molecules may be anchored to endothelial surface upon secretion from endothelial cells [31][32][33]. This anchoring appears fragile but may be sufficient to allow conformational unfolding of VWF by shear stress.…”

Section: Adamts13 Prevents Microvascular Platelet Thrombosismentioning

confidence: 99%

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

Tsai

2007

Hematology/Oncology Clinics of North America

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“…23 They also studied the formation of ultra large von Willebrand factor-platelet strings on endothelial cells using a flow chamber with defined flow and shear stress. 23,35 Although information can be obtained regarding cell association of Ad5 using purified platelets and Complement activation caused by adenovirus differs between in vitro and in vivo systems. In a recent study, it was shown that antibodies are needed for activation of the classical pathway in vitro in contrast to mice where the major mechanism for complement activation was antibody-independent.…”

Section: Discussionmentioning

confidence: 99%

An ex vivo loop system models the toxicity and efficacy of PEGylated and unmodified adenovirus serotype 5 in whole human blood

et al. 2010

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Polyethylene glycol coating (PEGylation) of adenovirus serotype 5 (Ad5) has been shown to effectively reduce immunogenicity and increase circulation time of intravenously administered virus in mouse models. Herein, we monitored clot formation, complement activation, cytokine release and blood cell association upon addition of uncoated or PEGylated Ad5 to human whole blood. We used a novel blood loop model where human blood from healthy donors was mixed with virus and incubated in heparin-coated PVC tubing while rotating at 37 1C for up to 8 h. Production of the complement components C3a and C5a and the cytokines IL-8, RANTES and MCP-1 was significantly lower with 20K-PEGylated Ad5 than with uncoated Ad5. PEGylation prevented clotting and reduced Ad5 binding to blood cells in blood with low ability to neutralize Ad5. The effect was particularly pronounced in monocytes, granulocytes, B-cells and T-cells, but could also be observed in erythrocytes and platelets. In conclusion, PEGylation of Ad5 can reduce the immune response mounted in human blood, although the protective effects are rather modest in contrast to published mouse data. Our findings underline the importance of developing reliable models and we propose the use of human whole blood models in pre-clinical screening of gene therapy vectors.

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ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions

Cited by 780 publications

References 29 publications

The effects of shear flow on protein structure and function

The effects of shear flow on protein structure and function

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

An ex vivo loop system models the toxicity and efficacy of PEGylated and unmodified adenovirus serotype 5 in whole human blood

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