The role of glycoprotein Ibalpha and von Willebrand factor interaction in stroke development

2010 ◽  
Vol 30 (03) ◽  
pp. 136-138 ◽  
Author(s):  
C. Kleinschnitz ◽  
B. Nieswandt ◽  
G. Stoll
Keyword(s):  
Ischemic Stroke ◽  
Von Willebrand Factor ◽  
Treatment Options ◽  
Serum Levels ◽  
Artery Occlusion ◽  
Downstream Signaling ◽  
Phospholipase D1 ◽  
Induced Changes ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryIschaemic stroke is a devastating disease with limited treatment options due to numerous uncertainties regarding the underlying pathophysiology. The contribution of glycoprotein (GP)Ibα and von Willebrand factor (VWF) in stroke development has only recently been established in mice. Complete blockade of GPIbα led to a significant reduction of infarct volumes in mice undergoing one hour of transient middle cerebral artery occlusion (tMCAO). High shear-induced changes in VWF confirmation are a prerequisite for VWF binding to collagen and GPIbα expressed on platelets. Importantly, transgenic VWF−/−mice were similarly protected against ischemic stroke after tMCAO, and hydrodynamic injection of a VWF-encoding plasmid restored VWF serum levels and the susceptibility towards stroke. Secreted VWF is rapidly cleaved by ADAMTS13. Accordingly, ADAMTS13 deficient mice developed larger infarction after tMCAO, while infusion of recombinant ADAMTS13 into wild-type mice was strokeprotective. In conclusion, there is compelling evidence that GPIbα/VWF interactions and downstream signaling via phospholipase D1 (PLD1) provide new therapeutic targets in ischemic stroke.

Deficiency of von Willebrand factor protects mice from ischemic stroke

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3600-3603 ◽  
Author(s):  
Christoph Kleinschnitz ◽  
Simon F. De Meyer ◽  
Tobias Schwarz ◽  
Madeleine Austinat ◽  
Karen Vanhoorelbeke ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Therapeutic Option ◽  
Artery Occlusion ◽  
Adhesion Receptor ◽  
Targeted Inhibition ◽  
Von Willebrand ◽  
Cerebral Artery Occlusion ◽  
Willebrand Factor

Abstract We recently demonstrated that blockade of the platelet adhesion receptor glycoprotein (GP) Ibα protects mice from ischemic stroke. Although von Willebrand factor (VWF) is the major ligand for GPIbα, GPIbα can engage other counterreceptors on endothelial cells, platelets, and leukocytes (eg, Mac-1 or P-selectin) potentially involved in stroke outcome. To further analyze whether VWF is of particular relevance for stroke development, VWF−/− mice underwent 60 minutes of middle cerebral artery occlusion. After 24 hours, VWF−/− mice had significantly smaller infarctions (P < .05) and less severe neurologic deficits (P < .01) compared with controls. This effect was sustained after 1 week, and intracranial bleeding was absent in VWF−/− mice as revealed by serial magnetic resonance imaging. Hydrodynamic injection of a VWF-encoding plasmid restored the susceptibility for stroke in VWF−/− mice. This study indicates that VWF is critically involved in cerebral ischemia. Hence, targeted inhibition of the GPIbα-VWF pathway might become a promising therapeutic option.

Abstract P769: Remodeling of the Leptomeningeal Collaterals Following Stroke Involves Selective Upregulation of Von Willebrand Factor (VWF)

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
TING WU ◽  
Jessica Stephenson ◽  
Gab Seok Kim ◽  
Monica Gireud ◽  
Sean P Marrelli
Keyword(s):  
Ischemic Stroke ◽  
Von Willebrand Factor ◽  
Cerebral Arteries ◽  
Artery Occlusion ◽  
Cortical Surface ◽  
Post Stroke ◽  
Inner Diameter ◽  
Von Willebrand ◽  
Cerebral Artery Occlusion ◽  
Willebrand Factor

Introduction: The leptomeningeal collaterals (LMCs) are arterial anastomoses that interconnect the distal branches of the major cerebral arteries. They distribute blood flow from adequately to poorly perfused vascular territories when needed. In normal conditions, the LMCs experience little net flow. However, during ischemic stroke, the LMCs are recruited to provide rescue flow to the ischemic territory. During prolonged or permanent stroke, the LMCs can rapidly remodel to provide increased perfusion capacity. Von Willebrand factor (VWF) is a secreted protein expressed in cerebral endothelium and has recently been implicated in angiogenesis. We sought to determine if VWF expression was increased in remodeling LMCs in the post-stroke brain. Methods: C57BL6 mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO). At 3 days after pdMCAO, mice were perfused with fluorescent tomato lectin to label vascular endothelium. The cortical surface was “planed off” by vibratome to provide largely contiguous cortical surface vessel preparations containing distalmost arterioles (DMAs) and the connected LMCs. VWF immunofluorescence intensity was measured in LMCs and the connecting DMAs of hemispheres ipsilateral and contralateral to the stroke. Inner diameter of the LMCs and DMAs were measured with Image J. Results: At 3 days post-stroke, LMCs of the stroke hemisphere demonstrated significant outward remodeling. Mean inner diameter of the ipsilateral versus contralateral LMCs were 44.5 ± 5.9 um versus 28.2 ± 1.2 um, respectively (p<0.02, 7-8 vessels from 3 mice). In contrast, the DMAs were unaltered in diameter, 35.2 ± 4.0 and 35.7 ± 3.1 um, respectively. VWF expression was significantly increased in the ipsilateral LMCs versus contralateral LMCs (2.8 fold, p<0.05) and versus ipsilateral DMAs (3.7 fold, p<0.02). The DMAs showed significantly lower VWF expression, which was unchanged between ipsilateral and contralateral hemispheres. Conclusions: We demonstrate that VWF is highly expressed in the remodeling LMCs (but not connecting DMAs) of the post-stroke brain. These findings suggest a novel and selective role for endothelial VWF in the LMC response to prolonged recruitment during ischemic stroke.

scholarly journals Detailed histological analysis of a thrombectomy-resistant ischemic stroke thrombus: a case report

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Senna Staessens ◽  
Olivier François ◽  
Linda Desender ◽  
Peter Vanacker ◽  
Tom Dewaele ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Von Willebrand Factor ◽  
Histological Analysis ◽  
Mechanical Thrombectomy ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Dna ◽  
Extracellular Traps ◽  
First Pass ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background Mechanical removal of a thrombus by thrombectomy can be quite challenging. For reasons that are not fully understood, some thrombi require multiple passes to achieve successful recanalization, whereas other thrombi are efficiently removed in a single pass. Since first pass success is associated with better clinical outcome, it is important to better understand the nature of thrombectomy resistant thrombi. The aim of this study was therefore to characterize the cellular and molecular composition of a thrombus that was very hard to retrieve via mechanical thrombectomy. Case presentation In a patient that was admitted with a right middle cerebral artery M1-occlusion, 11 attempts using various thrombectomy devices and techniques were required for removal of the thrombus. This peculiar case provided a rare opportunity to perform an in-depth histopathological study of a difficult to retrieve thrombus. Thrombus material was histologically analyzed using hematoxylin and eosin, Martius Scarlet Blue stain (red blood cells and fibrin), Feulgen stain (DNA), von Kossa stain (calcifications) and immunohistochemical analysis of von Willebrand factor, platelets, leukocytes and neutrophil extracellular traps. Histological analysis revealed abnormally high amounts of extracellular DNA, leukocytes, von Willebrand factor and calcifications. Extracellular DNA stained positive for markers of leukocytes and NETs, suggesting that a significant portion of DNA is derived from neutrophil extracellular traps. Conclusion In this unique case of a nearly thrombectomy-resistant stroke thrombus, our study showed an atypical composition compared to the common structural features found in ischemic stroke thrombi. The core of the retrieved thrombus consisted of extracellular DNA that colocalized with von Willebrand factor and microcalcifications. These results support the hypothesis that von Willebrand factor, neutrophil extracellular traps and microcalcifications contribute to mechanical thrombectomy resistance. Such information is important to identify novel targets in order to optimize technical treatment protocols and techniques to increase first pass success rates.

scholarly journals Relationship of Von Willebrand Factor with carotid artery and aortic arch calcification in ischemic stroke patients

2013 ◽  
Vol 230 (2) ◽  
pp. 210-215 ◽  
Author(s):  
Michelle A.H. Sonneveld ◽  
Anouk C. van Dijk ◽  
Evita G. van den Herik ◽  
Janine E. van Loon ◽  
Lonneke M.L. de Lau ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Carotid Artery ◽  
Aortic Arch ◽  
Von Willebrand Factor ◽  
Stroke Patients ◽  
Von Willebrand ◽  
Relationship Of ◽  
Willebrand Factor ◽  
Aortic Arch Calcification

scholarly journals The von Willebrand Factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice

Haematologica ◽  
2020 ◽  
pp. haematol.2019.241042 ◽  
Author(s):  
Frederik Denorme ◽  
Kimberly Martinod ◽  
Aline Vandenbulcke ◽  
Cécile V. Denis ◽  
Peter J. Lenting ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Von Willebrand Factor ◽  
Stroke Outcome ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals von Willebrand Factor Antigen, von Willebrand Factor Propeptide, and ADAMTS13 in Carotid Stenosis and Their Relationship with Cerebral Microemboli

2020 ◽  
Author(s):  
Stephen J. X. Murphy ◽  
Soon Tjin Lim ◽  
Fionnuala Hickey ◽  
Justin A. Kinsella ◽  
Deirdre R. Smith ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Carotid Stenosis ◽  
Blood Group ◽  
Von Willebrand Factor ◽  
Adamts13 Activity ◽  
Von Willebrand Factor Antigen ◽  
Asymptomatic Patients ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

Abstract Background The relationship between von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio, ADAMTS13 activity, and microembolic signal (MES) status in carotid stenosis is unknown. Methods This prospective, multicenter study simultaneously assessed plasma VWF:Ag levels, VWFpp levels and ADAMTS13 activity, and their relationship with MES in asymptomatic versus symptomatic moderate-to-severe (≥50–99%) carotid stenosis patients. One-hour transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES+ve or MES−ve. Results Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the “early phase” (≤4 weeks) and 37 patients in the “late phase” (≥3 months) after transient ischemic attack (TIA)/ischemic stroke. VWF:Ag levels were higher (p = 0.049) and VWFpp/VWF:Ag ratios lower (p = 0.006) in early symptomatic than in asymptomatic patients overall, and in early symptomatic versus asymptomatic MES−ve subgroups (p ≤0.02). There were no intergroup differences in VWFpp expression or ADAMTS13 activity (p ≥0.05). VWF:Ag levels and ADAMTS13 activity decreased (p ≤ 0.048) and VWFpp/VWF:Ag ratios increased (p = 0.03) in symptomatic patients followed up from the early to late phases after TIA/stroke. Although there were no differences in the proportions of symptomatic and asymptomatic patients with blood group O, a combined analysis of early symptomatic and asymptomatic patients revealed lower median VWF:Ag levels in patients with blood group O versus those without blood group O (9.59 vs. 12.32 µg/mL, p = 0.035). Discussion VWF:Ag expression, a marker of endothelial ± platelet activation, is enhanced in recently symptomatic versus asymptomatic carotid stenosis patients, including in MES−ve patients, and decreases with ADAMTS13 activity over time following atherosclerotic TIA/ischemic stroke.

Carotid enlargement and serum levels of von Willebrand factor in rheumatoid arthritis: a follow-up study

2012 ◽  
Vol 31 (12) ◽  
pp. 1727-1732 ◽  
Author(s):  
Mirjana Veselinovic ◽  
Vladimir Jakovljevic ◽  
Aleksandra Jurisic-Skevin ◽  
Slavco Toncev ◽  
Dragan M. Djuric
Keyword(s):  
Rheumatoid Arthritis ◽  
Von Willebrand Factor ◽  
Serum Levels ◽  
Follow Up Study ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Vascular Proteomics Reveals Critical Roles of ADAMTS18 in Stroke Associated with Imbalanced Level of Von Willebrand Factor Versus ADAMTS13

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3731-3731
Author(s):  
Rui Zhu ◽  
Yi-Hsuan Pan ◽  
Tiantian Lu ◽  
Suying Dang ◽  
Chen-Chung Liao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Carotid Artery ◽  
Von Willebrand Factor ◽  
Thrombus Formation ◽  
New Findings ◽  
Extracellular Matrix Components ◽  
Wet Weight ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adamts Gene

Abstract Background and Purpose -Stroke is the second leading cause of death worldwide. Acute ischemic stroke (AIS) is frequently induced by internal carotid artery thrombosis. Clinically, most arterial thrombus formation is initiated by platelets adhering to the damaged vessel wall. The adherent platelets become activated and bind with fibrinogen and von Willebrand factor (vWF), allowing formation of a platelet aggregate or mural thrombus. Identifying new mechanism involved in this pathogenesis is critical for understanding the molecular basis of thrombus formation and ultimately developing new therapeutic interventions for stroke. The ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family comprises 19 secreted metalloproteinases that cleave extracellular matrix components and have diverse functions in numerous disease and physiological contexts. Several ADAMTS genes (ADAMTS -7,-8, 12, and 13) have been shown to be involved in cardiovascular disease and pediatric stroke. ADAMTS18 remains "orphan" protease. We have previously shown that ADAMTS18 deficiency causes abnormal remodeling of the common carotid artery (CCA) and an increase in carotid thrombosis and size of cerebral infarct in mice. Thus, the stroke-prone Adamts18 KO mice could be valuable for identification of molecular signatures of accelerated carotid thrombosis related to stroke. One of the major steps yet to be taken by the field is the widespread use of proteomics to uncover the critical molecular events and signaling pathway involved in ADAMTS gene-related stroke. Methods and Results -Here, we carried out the first proteomics comparison of protein expression patterns in CCA and abdominal artery (AA) between Adamts18 knockout (KO) mice and their wild-type (WT) littermates. A total of 1654 proteins were identified in four separate CCA samples (0.4-1 mg/wet weight each), and 1810 proteins were detected in four separate AA samples (2.3-3.6 mg/wet weight each). The abundances of 154 proteins in CCA and 55 proteins in AA were significantly different between KO and WT mice. Ingenuity® Pathway Analysis revealed that ADAMTS18 deficiency predisposes mice to stroke by altering the abundance of many proteins related to cytoskeleton, prothrombotic activity, coagulation, angiogenesis, oxidative homeostasis, and energy metabolism. Western blotting and qRT-PCR analyses further revealed the imbalanced level of von Willebrand factor and ADAMTS13, the pivotal pathogenic factors of ischemic stroke, in CCA of KO mice. Conclusion and Significance -Results of this first vascular proteomic study of Adamts18 KO mice establish a substantial new resource for investigation of how ADAMTS gene affects cellular phenotypes of stroke. These new findings contribute to inform novel prevention strategies and direct therapeutic development for stroke. Disclosures No relevant conflicts of interest to declare.

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