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Exploring the "minimal" structure of a functional ADAMTS13 by mutagenesis and small-angle X-ray scattering KU Leuven

Karen Vanhoorelbeke
Human ADAMTS13 is a multidomain protein with metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains, followed by 7 additional T domains and 2 CUB (complement components C1r and C1s, sea urchin protein Uegf, and bone morphogenetic protein-1) domains. ADAMTS13 inhibits the growth of von Willebrand factor (VWF)-platelet aggregates by cleaving the cryptic Tyr1605-Met1606 bond in the VWF A2 domain. ...

Phylogenetic and functional analysis of ADAMTS13 identifies highly conserved domains essential for allosteric regulation KU Leuven

Karen Vanhoorelbeke
The metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats member 13) prevents microvascular thrombosis by cleaving von Willebrand factor (VWF) within platelet-rich thrombi, and cleavage depends on allosteric activation of ADAMTS13 by the substrate VWF. Human ADAMTS13 has a short propeptide, metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains (proximal ...

ADAMTS13 meets von Willebrand factor strings: a fluorescence microscopy approach KU Leuven

Karen De Ceunynck
ADAMTS13 and its substrate von Willebrand factor (VWF) circulate together in our blood where they exert crucial roles in hemostasis. The multimeric VWF protein captures platelets at sites of vascular injury thereby limiting blood loss. Upon endothelial perturbation, however, ultra-large (UL) VWF multimers are released that can spontaneously bind platelets and cause thrombus formation. ADAMTS13 regulates the size of these hyper-reactive VWF ...

Antibodies that conformationally activate ADAMTS13 allosterically enhance metalloprotease domain function KU Leuven

Elien Roose, Hans Deckmyn, Simon De Meyer, Karen Vanhoorelbeke
Plasma ADAMTS13 circulates in a folded conformation that is stabilized by an interaction between the central Spacer domain and the C-terminal CUB (complement components C1r and C1s, sea urchin protein Uegf, and bone morphogenetic protein-1) domains. Binding of ADAMTS13 to the VWF D4(-CK) domains or to certain activating murine monoclonal antibodies (mAbs) induces a structural change that extends ADAMTS13 into an open conformation that enhances ...

von Willebrand factor in experimental malaria-associated acute respiratory distress syndrome Institute of Tropical Medicine KU Leuven

Sirima Kraisin, Sebastien Verhenne, Thy, Kimberly Martinod, Claudia Tersteeg, Nele Vandeputte, Hans Deckmyn, Karen Vanhoorelbeke, Philippe E. Van den Steen, Simon F De Meyer, et al.

Background: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a lethal complication of severe malaria, characterized by marked pulmonary inflammation. Patient studies have suggested a link between von Willebrand factor (VWF) and malaria severity.

Objectives: To investigate the role of VWF in the pathogenesis of experimental MA-ARDS.

Methods: Plasmodium berghei NK65-E (PbNK65) parasites were injected in Vwf+/+ ...

Assessment of the dual role of clumping factor A in S. Aureus adhesion to endothelium in absence and presence of plasma Institute of Tropical Medicine KU Leuven

Jorien Claes, Bartosz Ditkowski, Laurens Liesenborghs, Tiago Rafael Veloso, Jose M Entenza, Philippe Moreillon, Thomas Vanassche, Peter Verhamme, Marc F Hoylaerts, Ruth Heying, et al.

Adhesion of Staphylococcus aureus to endothelial cells (ECs) is paramount in infective endocarditis. Bacterial proteins such as clumping factor A (ClfA) and fibronectin binding protein A (FnbpA) mediate adhesion to EC surface molecules and (sub)endothelial matrix proteins including fibrinogen (Fg), fibrin, fibronectin (Fn) and von Willebrand factor (vWF). We studied the influence of shear flow and plasma on the binding of ClfA and FnbpA ...

Oxygen removal during pathogen inactivation with riboflavin and UV light preserves protein function in plasma for transfusion Ghent University

Hendrik Feys, Britt Van Aelst, Katrien Devreese, Rosalie Devloo, J Coene, Philippe Vandekerckhove, Veerle Compernolle
Background and Objective : Photochemical pathogen inactivation technologies (PCT) for individual transfusion products act by inhibition of replication through irreversibly damaging nucleic acids. Concern on the collateral impact of PCT on the blood component's integrity has caused reluctance to introduce this technology in routine practice. This work aims to uncover the mechanism of damage to plasma constituents by riboflavin pathogen reduction ...

Towards a novel therapy to treat bleeding after left ventricular assist device implantation in patients with heart failure KU Leuven

Shannen Deconinck
Left ventricular assist devices (LVADs) are successfully used to treat patients waiting for a donor heart or as an alternative for heart transplantation. LVADs are mechanical circulatory support devices, which pump blood from the left ventricle to the aorta. Although LVAD implantation improves the quality of life of advanced stage heart failure patients, bleeding complications are a serious side effect. Indeed, gastrointestinal bleeding is one ...

Oxygen removal during pathogen inactivation with riboflavin and UV light preserves protein function in plasma for transfusion KU Leuven Ghent University

Philippe Vandekerckhove
Background and Objective: Photochemical pathogen inactivation technologies (PCT) for individual transfusion products act by inhibition of replication through irreversibly damaging nucleic acids. Concern on the collateral impact of PCT on the blood component's integrity has caused reluctance to introduce this technology in routine practice. This work aims to uncover the mechanism of damage to plasma constituents by riboflavin pathogen reduction ...

Microlyse: a thrombolytic agent that targets VWF for clearance of microvascular thrombosis KU Leuven

Karen Vanhoorelbeke, Claudia Tersteeg
Thrombotic microangiopathies are hallmarked by attacks of disseminated microvascular thrombosis. In thrombotic thrombocytopenic purpura (TTP), this is caused by a rise in thrombogenic ultra-large von Willebrand factor (VWF) multimers because of ADAMTS13 deficiency. We previously reported that systemic plasminogen activation is therapeutic in a TTP mouse model. In contrast to its natural activators (ie, tissue plasminogen activator and urokinase ...