دورية أكاديمية
Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis.
| العنوان: | Plasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosis. |
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| المؤلفون: | El Otmani H; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Frunt R; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Smits S; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Barendrecht AD; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., de Maat S; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; TargED Biopharmaceuticals, Utrecht, The Netherlands., Fijnheer R; Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands., Lenting PJ; Laboratory for Haemostasis, Inflammation and Thrombosis, INSERM Unité Mixte de Recherche 1176, Université Paris-Saclay, Le Kremlin-Bicêtre, France., Tersteeg C; Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium. |
| المصدر: | Blood [Blood] 2024 May 16; Vol. 143 (20), pp. 2089-2098. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Biomarkers*/blood , Biomarkers*/metabolism , Fibrinolysin*/metabolism , Purpura, Thrombotic Thrombocytopenic*/metabolism , Purpura, Thrombotic Thrombocytopenic*/blood , Purpura, Thrombotic Thrombocytopenic*/diagnosis , von Willebrand Factor*/metabolism, Animals ; Female ; Humans ; Mice ; ADAMTS13 Protein/metabolism ; ADAMTS13 Protein/blood ; Thrombosis/metabolism ; Thrombosis/blood ; Thrombosis/pathology ; Thrombotic Microangiopathies/metabolism ; Thrombotic Microangiopathies/blood |
| مستخلص: | Abstract: von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. Here, we describe the development of a variable domain of heavy-chain-only antibody (VHH)-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in patients with TTP during acute attacks of thrombotic microangiopathy but not in those in remission. Finally, we show that therapeutic plasminogen activation in a mouse model of TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion. (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.) |
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| المشرفين على المادة: | EC 3.4.24.87 (ADAMTS13 Protein) EC 3.4.24.87 (ADAMTS13 protein, human) 0 (Biomarkers) EC 3.4.21.7 (Fibrinolysin) 0 (von Willebrand Factor) |
| تواريخ الأحداث: | Date Created: 20240125 Date Completed: 20240516 Latest Revision: 20240716 |
| رمز التحديث: | 20240716 |
| مُعرف محوري في PubMed: | PMC11143499 |
| DOI: | 10.1182/blood.2023021265 |
| PMID: | 38271661 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2023021265 |