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

Meyer, Simon F. De; Budde, Ulrich; Deckmyn, Hans; Vanhoorelbeke, Karen

doi:10.1111/j.1538-7836.2011.04519.x

Cited by 9 publications

(9 citation statements)

References 13 publications

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“…The presence of proteolytic fragments of VWF in Adamts13 Ϫ/Ϫ mice further supports the notion that ADAMTS13-independent processes also regulate VWF size. 71 That said, the (patho)physiologic role of these proteases remains questionable because VWF fragments are still observed in neutropenic patients and after depletion of neutrophils in Adamts13 Ϫ/Ϫ mice. 71 Moreover, proteolysis of VWF strings by enzymes other than ADAMTS13 has only been reported for granzyme B, 70 and used concentrations were appreciably higher than those likely to be found in plasma.…”

Section: Do Other Proteases Digest Vwf Strings?mentioning

confidence: 99%

“…71 That said, the (patho)physiologic role of these proteases remains questionable because VWF fragments are still observed in neutropenic patients and after depletion of neutrophils in Adamts13 Ϫ/Ϫ mice. 71 Moreover, proteolysis of VWF strings by enzymes other than ADAMTS13 has only been reported for granzyme B, 70 and used concentrations were appreciably higher than those likely to be found in plasma. Whether proteases, such as proteinase 3, cathepsin G, elastase, and granzyme B, are relevant for VWF string proteolysis in vivo, perhaps after local accumulation at sites of inflammation remains to be studied.…”

Section: Do Other Proteases Digest Vwf Strings?mentioning

confidence: 99%

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Unwinding the von Willebrand factor strings puzzle

Ceunynck

Meyer

Vanhoorelbeke

2013

Blood

129

144

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Introductionvon Willebrand factor (VWF) strings correspond to ultra-large (UL) VWF multimers that, after secretion from the endothelium, remain anchored to the cell surface. As a result of this tethering and the rheologic forces of flow, these VWF multimers unravel, can bind platelets, and wave in the direction of the blood flow 1 (Figure 1). Since their discovery, platelet-decorated VWF strings have proved fascinating, and yet puzzling entities, with interesting and rather unique characteristics. VWF strings can be extraordinarily long, can be anchored to endothelial cells through a discrete number of attachment sites, contain active platelet binding sites, and are susceptible to specific proteolysis by its regulating protease, ADAMTS13 (a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13). VWF strings are considered prothrombotic and might therefore contribute to the pathophysiology of thrombotic disorders, such as thrombotic thrombocytopenic purpura (TTP) and arterial thrombosis. In addition, platelet-decorated VWF strings can also provide a reactive surface for leukocytes and parasite-infected red blood cells, which has suggested possible roles in both inflammation and malaria.In this review, we discuss the typical features of these intriguing VWF strings and highlight questions that remain to be resolved and that would provide a better understanding of VWF string biochemistry. VWF strings were first discovered and studied in the absence of ADAMTS13, a situation that does not mimic normal physiologic conditions. In the majority of pathophysiologic conditions, plasma ADAMTS13 activity levels are at most decreased, but very rarely absent. To this end, a discussion on the possible involvement of VWF strings in disease pathology might serve to put VWF string research into perspective. VWF, UL-VWF multimers, and ADAMTS13VWF is the largest biopolymer present in plasma, and consists of multimers ranging in size from 500 to 10 000 kDa, with the largest multimers being the most hemostatically active. 2,3 The building block of these multimers is a mature VWF subunit consisting of D, A, B, C, and CK domains, 4,5 although the domain organization of VWF has recently been reannotated. 6 In circulation, VWF multimers adopt a folded, globular conformation that shields the platelet glycoprotein Ib (GPIb) binding sites in the VWF A1 domain. 7,8 This folding serves to prevent spontaneous binding of platelets to VWF in circulation. However, immobilization of VWF at sites of vascular injury (via the VWF A3-collagen interaction) leads to VWF unfolding in response to the shear forces exerted by the flowing blood. This exposes VWF A1 domains that, in turn, reveal the binding sites for the platelet GPIb receptor. The VWF-GPIb interaction is characterized by a fast association/dissociation rate, which enables platelets to "roll" over the VWF surface and provide the opportunity to establish firm platelet adhesion through the collagen receptors. [9][10][11][12] This adhesion step, which is partic...

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Section: Do Other Proteases Digest Vwf Strings?mentioning

confidence: 99%

Section: Do Other Proteases Digest Vwf Strings?mentioning

confidence: 99%

Unwinding the von Willebrand factor strings puzzle

Ceunynck

Meyer

Vanhoorelbeke

2013

Blood

129

144

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“…As expected, murine rVWF expressed in HEK293T cells does not show any proteolytic fragments. De Meyer et al (38) could show that VWF in normal plasma from wild type mice shows the typical proteolytic pattern on multimer gels. But also in ADAMTS13 knock-out mice (ADAMTS13 -/-) VWF proteolytic bands were clearly visible by VWF multimer analysis.…”

Section: Vwf Multimers In Adamts13 Deficient Micementioning

confidence: 98%

Interactions of von Willebrand factor and ADAMTS13 in von Willebrand disease and thrombotic thrombocytopenic purpura

Budde¹,

Schneppenheim²

2014

Hamostaseologie

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The function of von Willebrand factor (VWF), a huge multimeric protein and a key factor in platelet dependent primary haemostasis, is regulated by its specific protease ADAMTS13. The ADAMTS13 dependent degradation of VWF to its proteolytic fragments can be visualized as a characteristic so-called triplet structure of individual VWF oligomers by multimer analysis. Lack of VWF high molecular weight multimers (VWF-HMWM) or their pathologically enhanced degradation underlies a particular type of von Willebrand disease, VWD type 2A with a significant bleeding tendency, and may also be observed in acquired von Willebrand syndrome due to cardiovascular disease. In these conditions multimer analysis is an obligatory and powerful tool for diagnosis of VWD. The opposite condition, the persistence of ultralarge VWF (UL-VWF) multimers may cause the microangiopathic life-threatening disorder thrombotic thrombocytopenic purpura (TTP). During the course of active TTP, UL-VWF is consumed in the hyaline thrombi formed in the microvasculature which will ultimately result in the loss of UL-VWF and VWF-HMWM. Therefore, VWF multimer analysis is not a valid tool to diagnose TTP in the active phase of disease but may be helpful for the diagnosis of TTP patients in remission.

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“…6,7,26 A number of candidate proteases capable of cleaving VWF have been identified, such as cytotoxic lymphocyte T celland natural killer cell-secreted granzyme B and M, 27,28 leukocytederived cathepsin G, elastase, matrix metalloproteinase 9, and plasmin. 22,29 Although elastase, matrix metalloproteinase, and cathepsin G have been shown to have either identical or proximal cleavage sites to ADAMTS13, plasmin and granzyme B and M appear to cleave VWF at more distant sites.…”

Section: Discussionmentioning

confidence: 99%