Plasmin Cleaves Von Willebrand Factor at K1491-R1492 in the A1–A2 Linker Region in a Shear- and Glycan-Dependent Manner In Vitro

Brophy, Teresa M.; Ward, Soracha E.; McGimsey, Thomas R.; Schneppenheim, Sonja; Drakeford, Clive; O’Sullivan, Jamie M.; Chion, Alain; Budde, Ulrich; O’Donnell, James S.

doi:10.1161/atvbaha.116.308524

Cited by 32 publications

(35 citation statements)

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“…Finally, VWF plays a critical role in primary hemostasis and acts as a carrier for procoagulant FVIII. While the protein is known to be cleaved by the fibrinolytic enzyme plasmin, it is less clear whether the protein has a role in modulating the fibrinolytic process. In one study, there was no correlation between the plasma clot lysis time and VWF levels .…”

Section: Discussionmentioning

confidence: 99%

Influence of cryoprecipitate, Factor XIII, and fibrinogen concentrate on hyperfibrinolysis

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Influence of cryoprecipitate, Factor XIII, and fibrinogen concentrate on hyperfibrinolysis

et al. 2017

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“…In normal plasma, VWF multimeric composition is regulated by the metalloprotease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type‐1 repeats) which cleaves a specific scissile bond (Tyr 1605‐Met 1606) within the VWF A2 domain (Sadler, ). In addition to ADAMTS13, recent studies have suggested that other plasma proteases, including plasmin, can also cleave VWF multimers (Brophy et al , ).…”

Section: Vwf Biosynthesis Structure and Functionmentioning

confidence: 99%

“…The majority of the N‐ and O‐glycan chains of VWF are capped by terminal sialic acid residues (Canis et al , , ) (Fig B). This sialylation modulates the susceptibility of VWF to proteolysis (McGrath et al , ; Brophy et al , ), and also plays a major role in regulating VWF clearance (Fig B). Enzymatic removal of sialic acid residues from VWF markedly reduces plasma half‐life (Sodetz et al , ; Stoddart et al , ; O'Sullivan et al , ; Ward et al , ).…”

Section: Vwf Glycans and Enhanced Clearancementioning

confidence: 99%

von Willebrand factor clearance – biological mechanisms and clinical significance

et al. 2018

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The mechanisms involved in regulating von Willebrand factor (VWF) clearance remain poorly understood. However recent studies have shown that macrophages play a critical role in regulating the half-life of VWF, and have identified specific lectin (including asialoglycoprotein, macrophage galactose-type lectin, Sigec-5 and C-type lectin domain family 4 member M) and scavenger receptors (including low-density lipoprotein receptor-related protein-1, scavenger receptor A1 and stabilin-2) that are involved in VWF clearance. Further studies will be required to determine the relative importance of these individual receptors with respect to physiological and pathological VWF clearance. Nevertheless, recent clinical data have highlighted the importance of enhanced VWF clearance in the pathogenesis of type 1 von Willebrand disease (VWD). Moreover, increased clearance also contributes to reduced VWF levels in many patients with type 2 and type 3 VWD. Improved understanding regarding VWF clearance is not only of direct biological relevance, but may also have important implications for the development of novel therapeutic agents with extended plasma half-lives for the treatment of both VWD and haemophilia A.

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“…Different enzymes (including thrombin, plasmin, cathepsin G, neutrophil elastase, proteinase 3, matrix metalloproteinase 9, and granzyme M and B) have been associated with the regulation of VWF and platelet interaction. 44 Recent studies have also shown that plasmin can degrade VWF in microthrombi and break platelet-VWF complexes in vitro, 66,67 as well as stimulate ADAMTS13 activity in plasma. 68 In addition, recent work has demonstrated the interaction ULVWF multimers and the activation of the alternative pathway of complement, as well as the interactions of the complement system and the cleavage of ULVWF multimers.…”

Section: Future Directionsmentioning

confidence: 99%

Novel therapies in thrombotic thrombocytopenic purpura

Masias

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2018

Research and Practice in Thrombosis and Haemostasis

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Essentials The standard of care for patients with TTP remains daily plasma exchange in addition to immune suppressive therapy.Despite the improved treatment options for TTP, the acute mortality of TTP remains between 15‐20%.Caplacizumab reduces the time to platelet recovery and the exacerbation rate in acute TTP.A better understanding of the cause and treatments of long‐term complications of TTP are needed. Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and a consumptive thrombocytopenia, as a result of severe deficiency of ADAMTS13. The standard of care of the acute episode is treatment with plasma exchange and immunosuppression. After the acute episode is resolved, patients face a significant risk of relapse and long‐term complications associated with significant morbidity and even mortality. Novel treatments have been under development and will be discussed in this review. Caplacizumab, a nanobody that blocks the interaction between VWF and platelets, has shown promising results in decreasing the time to recover from the acute events that will hopefully translate into long‐term clinical benefit for patients. In addition, identifying biomarkers to allow us to better predict the risk for relapse and the development of these long‐term complications in patients with TTP are a few of the challenges that require our attention moving forward.

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Plasmin Cleaves Von Willebrand Factor at K1491-R1492 in the A1–A2 Linker Region in a Shear- and Glycan-Dependent Manner In Vitro

Abstract: Improved understanding of the plasmin-VWF interaction offers exciting opportunities to develop novel adjunctive therapies for the treatment of refractory thrombotic thrombocytopenic purpura.

Cited by 32 publications

References 74 publications

Influence of cryoprecipitate, Factor XIII, and fibrinogen concentrate on hyperfibrinolysis

Influence of cryoprecipitate, Factor XIII, and fibrinogen concentrate on hyperfibrinolysis

von Willebrand factor clearance – biological mechanisms and clinical significance

Novel therapies in thrombotic thrombocytopenic purpura

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