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wrote the manuscript and contributed to all experiments; K.F., N.D.-V. 2017;37:845–855von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends.Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importance.Sequence and structure relationships within von Willebrand factor.Post-translational modifications required for coagulation factor secretion and function.Initial glycosylation and acidic pH in the Golgi apparatus are required for multimerization of von Willebrand factor.Biology and physics of von Willebrand factor concatamers.Shear-induced unfolding triggers adhesion of von Willebrand factor fibers.Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers.Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura.ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura.Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura.Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.Thrombotic thrombocytopenic purpura in humans and mice.Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease.Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome).Shigatoxin triggers thrombotic thrombocytopenic purpura in genetically susceptible ADAMTS13-deficient mice.Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura.Keeping von Willebrand Factor under Control: Alternatives for ADAMTS13.Plasmin cleavage of von Willebrand factor as an emergency bypass for ADAMTS13 deficiency in thrombotic microangiopathy.Proteolytic inactivation of ADAMTS13 by thrombin and plasmin.Modulation of the von Willebrand factor-dependent platelet adhesion through alternative proteolytic pathways.Pathological von Willebrand factor fibers resist tissue plasminogen activator and ADAMTS13 while promoting the contact pathway and shear-induced platelet activation.A shear-based assay for assessing plasma ADAMTS13 activity and inhibitors in patients with thrombotic thrombocytopenic purpura.The cooperative activity between the carboxyl-terminal TSP1 repeats and the CUB domains of ADAMTS13 is crucial for recognition of von Willebrand factor under flow.Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis.Carbohydrate moiety of von Willebrand factor is not necessary for maintaining multimeric structure and ristocetin cofactor activity but protects from proteolytic degradation.A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13.Simultaneous exposure of sites in von Willebrand factor for glycoprotein Ib binding and ADAMTS13 cleavage: studies with ristocetin.Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor.Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13.Binding of platelet glycoprotein Ibalpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13.An influence of ABO blood group on the rate of proteolysis of von Willebrand factor by ADAMTS13.Determination of a factor VIII-interactive region within plasmin responsible for plasmin-catalysed activation and inactivation of factor VIII(a).Proteolysis of platelet glycoprotein Ib by plasmin is facilitated by plasmin lysine-binding regions.Two clusters of charged residues located in the electropositive face of the von Willebrand factor A1 domain are essential for heparin binding.Platelet von Willebrand factor–structure, function and biological importance.Altered glycosylation of platelet-derived von Willebrand factor confers resistance to ADAMTS13 proteolysis.N-linked glycan stabilization of the VWF A2 domain.Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis.Human umbilical vein endothelial cells differ from other endothelial cells in failing to express ABO blood group antigens.Dissociation of ABH antigen expression from von Willebrand factor synthesis in endothelial cell lines.Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies.Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-1.An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome.Letter by Hugenholtz and Lisman regarding article, “plasmin cleavage of von Willebrand factor as an emergency bypass for ADAMTS13 deficiency in thrombotic microangiopathy”.Emerging roles for hemostatic dysfunction in malaria pathogenesis.Severe dengue is associated with consumption of von Willebrand factor and its cleaving enzyme ADAMTS-13.Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure.Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.The rate of hemolysis in sickle cell disease correlates with the quantity of active von Willebrand factor in the plasma.Shear-dependent changes in the three-dimensional structure of human von Willebrand factor.Shear-induced unfolding activates von Willebrand factor A2 domain for 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O’Donnell has served on the speaker’s bureau for Baxter, Bayer, Novo Nordisk, Boehringer Ingelheim, Leo Pharma, and Octapharma. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Acquired von Willebrand disease in multiple myeloma secondary to absorption of von Willebrand factor by plasma cells. Von Willebrand Disease Type III, Type III vWD (VWF Exon 7) Von Willebrand Disease Type I (VWF) Von Willebrand Disease Type II, Type II vWD (VWF) Canine Leukocyte Adhesion Deficiency Type I, CLADI ... XL-PRA1 (RPGR) Progressive Retinal Atrophy, PRA3 (FAM161A) Collie Eye Anomaly, Choroidal Hypoplasia, CEA (NHEJ1) J … Search for other works by this author on: For example, markedly decreased VWF function, as occurs in von Willebrand disease, is characterized by skin bruising, oral and nasal bleeding, menorrhagia, and sometimes by gastrointestinal bleeding.

Heparin inhibits plasmin cleavage of von Willebrand factor (VWF). Because VEGF is a potent activator of human ECs,To analyze whether recombinant ADAMTS13 in the peripheral blood could rescue the localized inhibition of ADAMTS13 activity, we applied a second mouse model, based on intradermal inoculation of melanoma cells (Comparable to previous results, 44.4% of the tumor microvessels of vehicle-treated control mice exhibited ULVWF fibers (Moreover, we found a strong reduction of the proteolytic activity of ADAMTS13 in tumor tissue compared with healthy skin using a new in situ activity assay (To resolve the molecular mechanisms of EC activation mediated by mouse melanoma cells, we incubated ECs with the supernatant of the melanoma cell line Ret established from skin tumors developing in We next asked whether inhibition of VEGF-A by tinzaparin and therefore VWF fiber formation affected metastasis formation in Because VEGF-A is a strong promoter of angiogenesis,Since the pioneering work by Moake et al in 1982, it is postulated that ULVWF fibers exist in patients suffering from TTP.Here, we show ULVWF network formation in the microvasculature of malignant melanoma of mice and humans (An important finding of this study is that EC-released VWF fibers markedly bind platelets (Obviously, an increasing body of evidence indicates that treatment with LMWHs such as tinzaparin is not only suitable to prevent cancer-associated thrombosis, but is also a potential antiagent for therapeutic use.Due to its complex composition, a plethora of potential mechanisms for heparin effects on metastasis are discussed. ), the German Cancer Aid (J.U. The pentasaccharide fondaparinux was used as control. Search for other works by this author on:

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The reaction mixtures were incubated at room temperature for 20 minutes and measured in a fluorescence spectrometer (excitation, 290 nm; emission, 320-450 nm; Tecan infinite M200, Tecan Group Ltd.).

Informed written consent was obtained from all participants in accordance with the Declaration of Helsinki and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines.

A detailed description is provided in the supplemental Methods.To investigate the role of tumor-mediated EC activation in vivo, we analyzed the distribution of VWF in vessels of primary skin tumors of Because VWF is an effective binding partner for circulating platelets, we assumed that melanoma cell-mediated EC activation may result in platelet aggregation.