Multimeric composition of plasma von Willebrand factor in chronic myeloproliferative disorders

Tatewaki, Wataru; Takahashi, Hiroyuki; Shibata, Akira

doi:10.1111/j.1365-2257.1988.tb01190.x

Cited by 21 publications

(16 citation statements)

References 27 publications

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“…Interestingly, decreased clot stability was observed in Tie2Cre/JAK2 V617F as in VavCre and SCLCreER t /JAK2 V617F mice (this study), all models displaying a PMF-like phenotype. 34 These results (1) emphasize the role of MPN disease phenotype and not JAK2 V617F in the hemostasis disorders observed in different mouse models of MPN, (2) are consistent with the variability of the disorders observed in MPN patients, and (3) offer the opportunity to develop biomarkers for the preclinical study of thrombosis and to determine the etiology of disturbed hemostasis in MPN. …”

Section: Jak2supporting

confidence: 64%

“…This is reminiscent of the acquired von Willebrand syndrome (AVWS) described in MPN patients with extremely high platelet counts causing an increased clearance of platelet-bound large VWF multimers. 34,35 To determine whether VWF proteolysis is caused by the disintegrin and metalloprotease with thrombospondin type I repeats-13 (ADAMTS-13), or by other proteases, in increased shear conditions requires additional studies.…”

Section: Jak2mentioning

confidence: 99%

“…51 Differences may be attributable to the ET phenotype of this model instead of the PV/PMF phenotype of our model. On the other hand, Etheridge et al, 34 using Tie2Cre/JAK2 V617F TG mice (expressing human JAK2 V617F in endothelial and hematopoietic cells) displaying an ET/PMF phenotype, showed attenuated arterial For personal use only. on May 10, 2018. by guest www.bloodjournal.org From thrombosis after injury and an AVWS.…”

Section: Jak2mentioning

confidence: 99%

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Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

Lamrani

Lacout

Ollivier

et al. 2014

Blood

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Section: Jak2supporting

confidence: 64%

Section: Jak2mentioning

confidence: 99%

Section: Jak2mentioning

confidence: 99%

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Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

Lamrani

Lacout

Ollivier

et al. 2014

Blood

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“…37,38 VWF degradation was also observed to be enhanced in direct proportion to the leukocyte count in myeloproliferative disorders. 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.…”

Section: Discussionmentioning

confidence: 99%

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

Raife

Cao

Atkinson

et al. 2009

Blood

100

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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“…Type 2A is the major subtype observed in patients with MPD, indicating that the high molecular weight multimers (HMWM) are the key players in the pathogenesis of AVWD in these disorders. The objective measurement of HMWM by SDS PAGE followed by densitometry scanning has shown reduced levels of HMWM in PV and ET but not in patients with myelofibrosis (MF) (40), and they were negatively correlated with platelet count. Another mechanism proposed in MPDs is increased viscosity of blood in MPDs resulting in high shear stress leading to an acceleration of proteolysis of VWF that is bound to platelets.…”

Section: Myeloproliferative Disorders (Mpd)mentioning

confidence: 99%

Pathophysiology of acquired von Willebrand disease: a concise review

Shetty

Kasatkar

Ghosh

2011

European Journal of Haematology

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Acquired von Willebrand disease (AVWD) is a rare, underdiagnosed hemorrhagic disorder, which is similar to congenital VWD with regard to the clinical and laboratory parameters; however, it is found in individuals with no positive family history and has no genetic basis. The etiology is varied, the commonest being hematoproliferative disorders and cardiovascular disorders. Other disorders associated with AVWD are autoimmune disorders such as systematic lupus erythematosus, hypothyroidism, and neoplasia, or it may also be drug induced. In quite a few cases, the etiology is unknown. The pathogenic mechanisms are different in different underlying disorders or they may be overlapping among these disorders. Some of the proposed mechanisms include the development of autoantibodies, selective absorption of high molecular weight von Willebrand factor (VWF) multimers, non‐selective absorption of VWF, mechanical destruction of VWF under high shear stress, and increased proteolysis. This report presents a concise review of the pathophysiological mechanisms of AVWD in these various underlying conditions.

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Multimeric composition of plasma von Willebrand factor in chronic myeloproliferative disorders

Cited by 21 publications

References 27 publications

Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

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

Pathophysiology of acquired von Willebrand disease: a concise review

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