Granulocyte proteases do not process endothelial cell‐derived unusually large von willebrand factor multimers to plasma vWF in vivo

Phillips, Martin D.; Vu, Chau; Nolasco, Leticia; Moake, Joel L.

doi:10.1002/ajh.2830370204

Cited by 10 publications

(4 citation statements)

References 11 publications

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“…After depletion of neutrophils in ADAMTS-13 )/) mice, we did not observe a change in VWF multimer composition or satellite band appearance (not shown), suggesting that circulating neutrophils do not play a major role in regulating VWF size distribution, at least under normal, nonactivating conditions. These results are in accordance with the normal VWF size distribution observed in neutropenic patients [10]. Whether proteases from activated neutrophils could play a physiological role in VWF cleavage remains to be determined.…”

Section: In Vivo Vonsupporting

confidence: 89%

In vivo von Willebrand factor size heterogeneity in spite of the clinical deficiency of ADAMTS‐13

Meyer

Budde²,

Deckmyn

et al. 2011

Journal of Thrombosis and Haemostasis

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Section: In Vivo Vonsupporting

confidence: 89%

In vivo von Willebrand factor size heterogeneity in spite of the clinical deficiency of ADAMTS‐13

Meyer

Budde²,

Deckmyn

et al. 2011

Journal of Thrombosis and Haemostasis

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“…39,40 In a study of plasma VWF multimer patterns in patients with high or low neutrophil counts, 7 of 10 patients who exhibited decreased VWF multimer sizes had very high neutrophil counts, suggesting that high neutrophil counts were associated with increased VWF proteolysis. 41 Disseminated intravascular coagulation is associated with severe secondary deficiency of ADAMTS13 activity and might be expected to be accompanied by unusually large VWF multimers. 42 However, no significant correlation between ADAMTS13 deficiency and the presence of unusually large VWF multimers has been observed.…”

Section: Discussionmentioning

confidence: 99%

Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site

Raife

Cao

Atkinson

et al. 2009

Blood

101

110

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The function of von Willebrand factor (VWF) is regulated by proteolysis, which limits its multimeric size and ability to tether platelets. The importance of ADAMTS13 metalloprotease in VWF regulation is demonstrated by the association between severe deficiency of ADAMTS13 and thrombotic thrombocytopenic purpura (TTP). However, ADAMTS13 activity levels do not always correlate with the clinical course of TTP, suggesting that other proteases could be important in regulating VWF. We identified 4 leukocyte IntroductionThe hemostatic activity of von Willebrand factor (VWF) is regulated in blood by the metalloprotease ADAMTS13, which cleaves VWF in the A2 domain. 1 The importance of VWF regulation by ADAMTS13 is demonstrated by the close association between severe deficiency of ADAMTS13 activity and thrombotic thrombocytopenic purpura (TTP). 2,3 However, the association between ADAMTS13 activity and TTP is imperfect. Patients with inhibitor-mediated ADAMTS13 deficiency can achieve clinical remission despite persistent severe deficiency of ADAMTS13 activity, 2,4 and not all patients with congenital deficiency of ADAMTS13 develop TTP. 5 Moreover, VWF proteolysis can be paradoxically increased in TTP patients during acute episodes. 6 These observations suggest the existence of other important disease-modifying factors in TTP, in addition to ADAMTS13.Disease-modifying factors in TTP may include other VWFcleaving proteases. Before the discovery of ADAMTS13, the proteases calpain, neutrophil elastase, and cathepsin G were known to cleave VWF. [7][8][9][10][11][12] However, the exact cleavage sites were not determined, and the physiologic relevance of these proteases was unknown. It was known that normal plasma contained proteolytic fragments of VWF having masses of approximately 176 kDa and 140 kDa. The primary cleavage site that gave rise to these fragments was identified as the Y1605-M1606 peptide bond. 13 In studies seeking to identify the responsible protease, Tsai et al 8,9,14 observed that neutrophil proteases cleaved high-molecular-weight VWF into a series of multimers indistinguishable from those found in normal plasma. By contrast, Berkowitz et al 10 concluded that VWF cleavage fragments generated by neutrophil elastase were different from the 176-kDa and 140-kDa fragments found in plasma. The role of leukocyte proteases in VWF regulation remained unresolved, and was later overshadowed by the discovery of ADAMTS13.In this study, we demonstrate that under denaturing and fluid shear stress conditions multiple leukocyte proteases cleave VWF predominantly in the central A2 domain. We also show that activated neutrophils, but not normal neutrophils, retain VWF cleaving activity in the presence of plasma inhibitors, suggesting that leukocyte proteases may regulate VWF function under physiologic conditions. Methods Patients and plasmaBlood samples were obtained from volunteer subjects after informed consent, in accordance with the Declaration of Helsinki, sanctioned by the institutional human research subject committees o...

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“…Crystal structure analysis has revealed that the cleavage sites are located in a β sheet that is loosely packed in the core of the A2 domain [83]. Since profound leucopenia is not accompanied by evidence of VWF size change, it is questionable that leukocyte proteases are involved in the regulation of VWF activity [84]. …”

Section: Adamts13 Is a Vwf Cleaving Metalloproteasementioning

confidence: 99%

Pathophysiology of thrombotic thrombocytopenic purpura

2010

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Thrombotic thrombocytopenic purpura (TTP) is a disorder with characteristic von Willebrand factor (VWF)-rich microthrombi affecting the arterioles and capillaries of multiple organs. The disorder frequently leads to early death unless the patients are treated with plasma exchange or infusion. Studies in the last decade have provided ample evidence to support that TTP is caused by deficiency of a plasma metalloprotease, ADAMTS13. When exposed to high shear stress in the microcirculation, VWF and platelets are prone to form aggregates. This propensity of VWF and platelet to form microvascular thrombosis is mitigated by ADAMTS13, which cleaves VWF before it is activated by shear stress to cause platelet aggregation in the circulation. Deficiency of ADAMTS13, due to autoimmune inhibitors in patients with acquired TTP and mutations of the ADAMTS13 gene in hereditary cases, leads to VWF-platelet aggregation and microvascular thrombosis of TTP. In this review, we discuss the current knowledge on the pathogenesis, diagnosis and management of TTP, address the ongoing controversies, and indicate the directions of future investigations.

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Granulocyte proteases do not process endothelial cell‐derived unusually large von willebrand factor multimers to plasma vWF in vivo

Cited by 10 publications

References 11 publications

In vivo von Willebrand factor size heterogeneity in spite of the clinical deficiency of ADAMTS‐13

In vivo von Willebrand factor size heterogeneity in spite of the clinical deficiency of ADAMTS‐13

Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site

Pathophysiology of thrombotic thrombocytopenic purpura

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