scholarly journals Elevated plasma von Willebrand factor levels are associated with subsequent ischemic stroke in persons with treated HIV infection

2021 ◽  
Author(s):  
Susan M Graham ◽  
Robin M Nance ◽  
Junmei Chen ◽  
Jennie Le ◽  
Dominic W Chung ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Viral Load ◽  
Hiv Infection ◽  
Von Willebrand Factor ◽  
Endothelial Activation ◽  
Apolipoprotein A1 ◽  
Soluble Cd14 ◽  
Amyloid A ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background We assessed whether key biomarkers of endothelial activation and hemostasis/thrombosis were elevated in individuals receiving effective antiretroviral therapy (ART) in the year before ischemic stroke. Methods We conducted a case-control study nested in the CNICS cohort, comparing 42 adjudicated cases with ischemic stroke to 83 controls matched for ART regimen. Angiopoietin-1, angiopoietin-2, C-reactive protein, interleukin-6, plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, ICAM-1, VCAM-1, apolipoprotein A1, ADAMTS13, and von Willebrand factor (VWF) were measured in stored plasma collected before the stroke event. We used conditional logistic regression to identify associations with ischemic stroke, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores. Results After adjustment for age and sex, higher plasma viral load and higher angiopoeitin-2, soluble CD14, and VWF were associated with increased odds of ischemic stroke; higher nadir CD4 count was associated with decreased odds of ischemic stroke. VWF remained associated with subsequent ischemic stroke after adjustment for ASCVD score (adjusted odds 1.74, 95%CI 1.01–2.98 per log2 increment). In a separate model adjusting for VACS score, only VWF (adjusted odds 1.80, 95% CI 1.04–3.12 per log2 increment) was associated with subsequent ischemic stroke. In a sensitivity analysis excluding participants with viral load ≥400 copies/mL, associations between VWF and ischemic stroke were attenuated, with risk estimates ranging from 1.59–1.64 per log2 increment. Conclusions Endothelial activation and related release and attachment of VWF may play an important role in ischemic stroke among persons living with treated HIV infection.

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 von Willebrand factor self-association is regulated by the shear-dependent unfolding of the A2 domain

2019 ◽  
Vol 3 (7) ◽  
pp. 957-968 ◽  
Author(s):  
Changjie Zhang ◽  
Anju Kelkar ◽  
Sriram Neelamegham
Keyword(s):  
Von Willebrand Factor ◽  
Ex Vivo ◽  
Association Studies ◽  
Apolipoprotein A1 ◽  
Platelet Glycoprotein ◽  
Functional Domain ◽  
Self Association ◽  
Von Willebrand ◽  
A2 Domain ◽  
Willebrand Factor

Abstract von Willebrand factor (VWF) self-association results in the homotypic binding of VWF upon exposure to fluid shear. The molecular mechanism of this process is not established. In this study, we demonstrate that the shear-dependent unfolding of the VWF A2 domain in the multimeric protein is a major regulator of protein self-association. This mechanism controls self-association on the platelet glycoprotein Ibα receptor, on collagen substrates, and during thrombus growth ex vivo. In support of this, A2-domain mutations that prevent domain unfolding due to disulfide bridging of N- and C-terminal residues (“Lock-VWF”) reduce self-association and platelet activation under various experimental conditions. In contrast, reducing assay calcium concentrations, and 2 mutations that destabilize VWF-A2 conformation by preventing coordination with calcium (D1498A and R1597W VWD type 2A mutation), enhance self-association. Studies using a panel of recombinant proteins that lack the A1 domain (“ΔA1 proteins”) suggest that besides pure homotypic A2 interactions, VWF-A2 may also engage other protein domains to control self-association. Addition of purified high-density lipoprotein and apolipoprotein-A1 partially blocked VWF self-association. Overall, similar conditions facilitate VWF self-association and ADAMTS13-mediated proteolysis, with low calcium and A2 disease mutations enhancing both processes, and locking-A2 blocking them simultaneously. Thus, VWF appears to have evolved 2 balancing molecular functions in a single A2 functional domain to dynamically regulate protein size in circulation: ADAMTS13-mediated proteolysis and VWF self-association. Modulating self-association rates by targeting VWF-A2 may provide novel methods to regulate the rates of thrombosis and hemostasis.

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 Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13

2020 ◽  
Vol 11 ◽  
Author(s):  
Junxian Yang ◽  
Zhiwei Wu ◽  
Quan Long ◽  
Jiaqi Huang ◽  
Tiantian Hong ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Therapeutic Strategy ◽  
Endothelial Activation ◽  
Endothelial Damage ◽  
Neutrophil Extracellular Trap ◽  
Activated Neutrophils ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

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.

Changes in ADAMTS 13 Activity and Von Willebrand Factor Parameters during Acute Dengue Infection.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1492-1492
Author(s):  
Darintr Sosothikul ◽  
Panya Seksarn ◽  
Sureeporn Pongsawaluk ◽  
Jeanne M. Lusher
Keyword(s):  
Von Willebrand Factor ◽  
Cell Activation ◽  
Dengue Infection ◽  
Plasma Concentrations ◽  
Endothelial Activation ◽  
Healthy Children ◽  
Endothelial Cell Activation ◽  
Convalescent Phase ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Dengue virus causes febrile illnesses: Dengue Fever (DF) and less frequently a life-threatening illness, Dengue Hemorrhagic Fever (DHF). The pathophysiology of hemostatic defect in dengue infection is thought to relate to the direct effect of virus or cytokines on endothelial activation. To study the state of endothelial activation during dengue infection, we measured plasma levels of von Willebrand factor antigen (vWF:Ag), vWF-collagen binding assay (vWF:CBA), and ADAMTS 13 activity in 42 children (20 with DF and 22 with DHF) during 3 phases of illness: febrile, toxic, and convalescent phase. 38 healthy children comprised as controls. Our data shows that both VWF:Ag and vWF:CBA levels were significantly higher in dengue patients (p ≤ 0.001 in both DF and DHF patients) versus controls. DHF patients had significantly higher of VWF: Ag (p = 0.01, versus DF). ADAMTS 13 activity levels were significantly decreased only in DHF patients during 3 phases of the illness (febrile; mean 78%; p = 0.016, toxic; mean 68%; p<0.001 and convalescent; mean 69%; p<0.001 compared to mean 104% of the controls). Compared to DF patients, DHF patients had significantly lower plasma concentrations of ADAMTS 13 activity during the febrile, toxic and convalescent phase (p = 0.039, p = 0.002 and p =0.003, respectively). Endothelial cell activation is a hallmark of dengue infection especially in DHF patients; indicated by a significant rise in VWF:Ag and vWF:CBA and a reciprocal decline in ADAMTS 13 activity.

Persistently Elevated Levels of von Willebrand Factor Antigen in HIV Infection

2000 ◽  
Vol 84 (08) ◽  
pp. 183-187 ◽  
Author(s):  
S. Bjørnsen ◽  
B. Lunden ◽  
K. Otterdal ◽  
E. C. Ng ◽  
W. Ameln ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Von Willebrand Factor ◽  
Cell Activation ◽  
High Viral Load ◽  
Endothelial Cell Activation ◽  
Cross Sectional ◽  
Hiv Rna ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryLevels of circulating von Willebrand factor (vWf) antigen are thought to reflect endothelial involvement in various disorders. In the present study we found markedly elevated plasma levels of vWf in HIV-infected patients demonstrated on both cross-sectional and longitudinal testing. Notably, we found that a persistent rise in vWf antigen was associated with progression of HIV-related disease. This elevation of vWf antigen represented functionally normal vWf as evaluated by plasma FVIII, ristocetin cofactor assay and vWf multimer analyses. While HIV-infected patients showed enhanced platelet activation, platelets did not contribute substantially to the increased vWf levels. The high vWf levels were significantly correlated with high viral load, and during HAART, the pronounced decline in HIV RNA levels was accompanied by a corresponding decrease in vWf. The persistent elevation of functionally normal vWf during HIV infection, most probably reflecting a persistent endothelial cell activation, may have an important role in the pathogenesis of HIV infection.

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