دورية أكاديمية
Microlyse: a thrombolytic agent that targets VWF for clearance of microvascular thrombosis.
| العنوان: | Microlyse: a thrombolytic agent that targets VWF for clearance of microvascular thrombosis. |
|---|---|
| المؤلفون: | de Maat S; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Clark CC; 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., Smits S; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., van Kleef ND; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., El Otmani H; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Waning M; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., van Moorsel M; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Szardenings M; Epitopic, Leipzig, Germany.; Ligand Development Unit, Fraunhofer IZI, Leipzig, Germany., Delaroque N; Ligand Development Unit, Fraunhofer IZI, Leipzig, Germany., Vercruysse K; TargED Biopharmaceuticals, Utrecht, The Netherlands., Urbanus RT; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Sebastian S; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Lenting PJ; Laboratory for Haemostasis, Inflammation and Thrombosis, INSERM Unité Mixte de Recherche 1176, Université Paris-Saclay, Le Kremlin-Bicêtre, France., Hagemeyer CE; Australian Centre for Blood Diseases, Monash University, Melbourne, Australia., Renné T; Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and., Vanhoorelbeke K; Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium., Tersteeg C; Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium., Maas C; Central Diagnostic Laboratory Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. |
| المصدر: | Blood [Blood] 2022 Jan 27; Vol. 139 (4), pp. 597-607. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| 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: | Fibrinolytic Agents/*therapeutic use , Thrombotic Microangiopathies/*drug therapy , von Willebrand Factor/*metabolism, Animals ; Female ; Humans ; Male ; Mice, Inbred C57BL ; Purpura, Thrombotic Thrombocytopenic/drug therapy ; Purpura, Thrombotic Thrombocytopenic/metabolism ; Recombinant Fusion Proteins/therapeutic use ; Thrombotic Microangiopathies/metabolism ; Mice |
| مستخلص: | 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 plasminogen activator [uPA]), plasminogen can directly bind to VWF. For optimal efficacy and safety, we aimed to focus and accelerate plasminogen activation at sites of microvascular occlusion. We here describe the development and characterization of Microlyse, a fusion protein consisting of a high-affinity VHH targeting the CT/CK domain of VWF and the protease domain of uPA, for localized plasminogen activation on microthrombi. Microlyse triggers targeted destruction of platelet-VWF complexes by plasmin on activated endothelial cells and in agglutination studies. At equal molar concentrations, Microlyse degrades microthrombi sevenfold more rapidly than blockade of platelet-VWF interactions with a bivalent humanized VHH (caplacizumab*). Finally, Microlyse attenuates thrombocytopenia and tissue damage (reflected by increased plasma lactate dehydrogenase activity, as well as PAI-1 and fibrinogen levels) more efficiently than caplacizumab* in an ADAMTS13-/- mouse model of TTP, without affecting hemostasis in a tail-clip bleeding model. These findings show that targeted thrombolysis of VWF by Microlyse is an effective strategy for the treatment of TTP and might hold value for other forms of VWF-driven thrombotic disease. (© 2022 by The American Society of Hematology.) |
| التعليقات: | Comment in: Blood. 2022 Jan 27;139(4):477-479. (PMID: 35084478) |
| المشرفين على المادة: | 0 (Fibrinolytic Agents) 0 (Recombinant Fusion Proteins) 0 (von Willebrand Factor) |
| تواريخ الأحداث: | Date Created: 20211109 Date Completed: 20220307 Latest Revision: 20240226 |
| رمز التحديث: | 20240226 |
| DOI: | 10.1182/blood.2021011776 |
| PMID: | 34752601 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
|---|---|
| DOI: | 10.1182/blood.2021011776 |