scholarly journals COVID-19 Clot: What Is It? Why in the Lungs? Extracellular Histone, “Auto-Activation” of Prothrombin, Emperipolesis, Megakaryocytes, “Self-Association” of Von Willebrand Factor and Beyond

2020 ◽  
Author(s):  
Nadarajah Varatharajah
Keyword(s):  
Von Willebrand Factor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Extracellular Dna ◽  
Fibrous Network ◽  
Self Association ◽  
Vascular Occlusions ◽  
Von Willebrand ◽  
Willebrand Factor

COVID-19 thromboembolic disease has brought all of us back to the drawing board. In COVID-19, pre-existing activated endothelium with increased Von Willebrand factor (VWF), low density lipoprotein (LDL) promoting “self-association” and “sticking” of long VWF strings to the vascular endothelial wall, suppressed ADAMTS13 cleavage of VWF, hypoxia induced upregulation and activation of VWF, fibrous network from neutrophil extracellular traps (NETs) with free DNA and histone, all appear to be initiating the thrombogenesis. Worsening complement activation, cytokine storm and resulting endothelial destruction, unregulated thrombogenesis leads to vascular occlusions and hypoxia. At this stage, the presence of abundant extracellular DNA, histone and -defensins appears worse than the SARS-CoV-2 itself. Previously observed in vitro mechanisms like histone “auto-activating” prothrombin, histone activated platelets generating thrombin without FXII, thrombin and plasmin cleaving complement C5 appears highly likely in COVID-19. Megakaryocytes are actively producing platelets in the lungs and appear to play a major role in thrombogenesis of COVID-19 raising suspicion of emperipolesis. This focused review is a compilation of my observations in relation to the pathophysiology of the intravascular environment, mainly in COVID-19 lungs. Pathophysiology based clinical trials are paramount in reducing morbidity and mortality in COVID-19.

scholarly journals 418 Ultrasound molecular imaging of the role of von willebrand factor-mediated platelet adhesion in atherogenesis

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
K Ozawa ◽  
M Muller ◽  
O Varlamov ◽  
W Packwood ◽  
A Xie ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Distensibility ◽  
Research Fellowship ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Funding Acknowledgements JSPS Overseas Research Fellowship Background Platelets are known to be both pro-inflammatory and pro-mitogenic. However, the role of platelet-endothelial interactions in the initiation and growth of atherosclerotic lesions is not well understood. Purpose We used contrast-enhanced ultrasound (CEU) molecular imaging of the arterial endothelium to test the hypothesis that platelet attachment to endothelial Von Willebrand Factor (VWF) promotes atherogenesis. Methods We studied wild-type mice (WT), low-density lipoprotein deficient mice fed western diet to produce atherosclerosis (LDLR-/-), and LDLR-/- mice also deficient for ADAMTS-13 (LDLR-/-ADAMTS13-/-) which is the enzyme responsible for proteolytic cleavage of endothelial-associated VWF. Mice were studied at 20 weeks and 30 weeks of age. A subset of LDLR-/- mice were treated with recombinant ADAMTS13 1 hr prior to study. Proximal aortic CEU molecular imaging of P-selectin, vascular cell adhesion molecule (VCAM)-1, von Willebrand factor (VWF), and platelet GPIbα was performed. Aortic distensibility was assessed using high-frequency (30 MHz) transthoracic echocardiography and tail cuff blood pressure systems. NF-κB of aorta was assessed by ELISA kit. Plaque size and composition were assessed by histology. Platelets and macrophage immunohistochemistry were also performed on confocal microscopy. Results Aortic molecular imaging signal for P-selectin, VCAM-1, VWF, and platelet adhesion was significantly higher in LDLR-/- than WT mice, and increased by 2-fold between 20 and 30 wks of age. Signal for VWF and platelet adhesion was abolished 1 h after administration of ADAMTS13, confirming that platelet adhesion was VWF-mediated. At 20 and 30 wks of age, molecular imaging signal for all targets was 2-fold higher (p < 0.01) in LDLR-/-ADAMTS13-/- versus LDLR-/- mice. The LDLR-/-ADAMTS13-/- mice also had lower aortic distensibility (p < 0.05), had a 2-fold higher NF-κB signal (p < 0.05), and had a 2-fold greater total plaque area (p < 0.01). Fluorescent immunohistochemistry confirmed that the LDLR-/-ADAMTS13-/- mice also had greater platelets (p < 0.05) and increased macrophage content (p < 0.05) than LDLR-/- mice in aortic plaque. Conclusion In early to mid-stage atherosclerosis, abnormal regulation of endothelial-associated VWF results in platelet adhesion and secondary up-regulation of endothelial inflammatory adhesion molecules, thereby promoting atherosclerotic plaque progression. These results indicate an important role of platelet-endothelial interactions in early atherogenesis. Abstract 418 Figure

scholarly journals High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion

Blood ◽  
2016 ◽  
Vol 127 (5) ◽  
pp. 637-645 ◽  
Author(s):  
Dominic W. Chung ◽  
Junmei Chen ◽  
Minhua Ling ◽  
Xiaoyun Fu ◽  
Teri Blevins ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Density Lipoprotein ◽  
High Density ◽  
New Approach ◽  
Key Points ◽  
Self Association ◽  
Von Willebrand ◽  
Willebrand Factor

Key Points High-density lipoprotein and its major apolipoprotein ApoA-I prevent von Willebrand factor self-association. Targeting von Willebrand factor self-association could be a new approach to treating thrombotic disorders.

Macrophage LRP1 contributes to the clearance of von Willebrand factor

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2126-2134 ◽  
Author(s):  
Ghasem Rastegarlari ◽  
Julie N. Pegon ◽  
Caterina Casari ◽  
Soline Odouard ◽  
Ana-Maria Navarrete ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Receptor ◽  
Receptor Associated Protein ◽  
Density Lipoprotein Receptor ◽  
Stress Dependent ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Β2 Integrins

Abstract The relationship between low-density lipoprotein receptor–related protein-1 (LRP1) and von Willebrand factor (VWF) has remained elusive for years. Indeed, despite a reported absence of interaction between both proteins, liver-specific deletion of LRP1 results in increased VWF levels. To investigate this discrepancy, we used mice with a macrophage-specific deficiency of LRP1 (macLRP1−) because we previously found that macrophages dominate VWF clearance. Basal VWF levels were increased in macLRP1− mice compared with control mice (1.6 ± 0.4 vs 1.0 ± 0.4 U/mL). Clearance experiments revealed that half-life of human VWF was significantly increased in macLRP1− mice. Ubiquitous blocking of LRP1 or additional lipoprotein receptors by overexpressing receptor-associated protein in macLRP1− mice did not result in further rise of VWF levels (0.1 ± 0.2 U/mL), in contrast to macLRP1+ mice (rise in VWF, 0.8 ± 0.4 U/mL). This points to macLRP1 being the only lipoprotein receptor regulating VWF levels. When testing the mechanism(s) involved, we observed that VWF-coated beads adhered efficiently to LRP1 but only when exposed to shear forces exceeding 2.5 dyne/cm2, implying the existence of shear stress-dependent interactions. Furthermore, a mechanism involving β2-integrins that binds both VWF and LRP1 also is implicated because inhibition of β2-integrins led to increased VWF levels in control (rise, 0.19 ± 0.16 U/mL) but not in macLRP1− mice (0.08 ± 0.15 U/mL).

scholarly journals Vascular endothelial cell function and cardiovascular risk factors in patients with chronic renal failure.

1995 ◽  
Vol 5 (8) ◽  
pp. 1581-1584
Author(s):  
A B Haaber ◽  
I Eidemak ◽  
T Jensen ◽  
B Feldt-Rasmussen ◽  
S Strandgaard
Keyword(s):  
Von Willebrand Factor ◽  
Cell Function ◽  
Low Density Lipoprotein ◽  
Plasma Concentrations ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Endothelial Cell Function ◽  
Transcapillary Escape Rate ◽  
Von Willebrand ◽  
Willebrand Factor

Cardiovascular risk factors and markers of endothelial cell function were studied in nondiabetic patients with mild to moderate chronic renal failure. The transcapillary escape rate of albumin and the plasma concentrations of von Willebrand factor, fibrinogen, and plasma lipids were measured in 29 nondiabetic patients (GFR of 25 (11-44) mL/min x 1.73 m2 (median and range)) and 14 normal subjects. The proportion of smokers was similar between the groups. In the patients, the plasma concentration of von Willebrand factor was elevated by 61% (1.27 +/- 0.44 versus 0.79 +/- 0.28 U/mL; P < 0.01) (mean +/- SD) and that of fibrinogen was elevated by 72% (10.18 +/- 4.14 versus 5.92 +/- 2.01 mumol/L; P < 0.01). The plasma concentrations of lipoproteins showed an atherogenic pattern in the patients with increased levels of very low-density lipoprotein cholesterol (0.57 +/- 0.31 versus 0.33 +/- 0.13 mmol/L; P < 0.01) and triglycerides (1.26 +/- 0.25 versus 0.71 +/- 0.28 mmol/L; P < 0.01), but a decreased level of high-density lipoprotein cholesterol (1.23 +/- 0.33 versus 1.46 +/- 0.35 mmol/L; P < 0.05). Total cholesterol and low-density lipoprotein cholesterol were similar in the groups. The observed differences were further aggravated among smoking patients, particularly with respect to von Willebrand factor and triglycerides. The transcapillary escape rate of albumin was similar in the patients and the controls and was not correlated to the level of albuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Apolipoprotein B100/Low-Density Lipoprotein Regulates Proteolysis and Functions of von Willebrand Factor under Arterial Shear

2019 ◽  
Vol 119 (12) ◽  
pp. 1933-1946
Author(s):  
Wenjing Cao ◽  
Mohammad S. Abdelgawwad ◽  
Jingzhi Li ◽  
X. Long Zheng
Keyword(s):  
Von Willebrand Factor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Proteolytic Cleavage ◽  
Low Density ◽  
Dependent Manner ◽  
Binding Interaction ◽  
Apolipoprotein B100 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background Proteolytic cleavage of von Willebrand factor (VWF) by a plasma a disintegrin and metalloproteinase with a thrombospondin type 1 motifs, member 13 (ADAMTS13) is regulated by shear stress and binding of coagulation factor VIII, platelets or platelet glycoprotein 1b, and ristocetin to VWF. Objective Current study aims to identify novel VWF binding partners that may modulate VWF functions under physiological conditions. Methods A deoxyribonucleic acid aptamer-based affinity purification of VWF, followed by tandem mass spectrometry, functional, and binding assays was employed. Results Apolipoprotein B100/low-density lipoprotein (apoB100/LDL) was identified as a novel VWF-binding partner. Purified apoB100/LDL was able to accelerate the proteolytic cleavage of VWF by ADAMTS13 under shear in a concentration-dependent manner. This rate-enhancing activity was dramatically reduced when apoB100/LDL was oxidized. More interestingly, the oxidized apoB100/LDL appeared to compete with native apoB100/LDL for its enhancing activity on VWF proteolysis under shear. As a control, a purified apoA1/high-density lipoprotein (apoA1/HDL) or apoB48 exhibited a minimal or no activity enhancing VWF proteolysis by ADAMTS13 under the same conditions. Both VWF and ADAMTS13 were able to bind native or oxidized apoB100/LDL with high affinities. No binding interaction was detected between VWF (or ADAMTS13) and apoA1/HDL (or apoB48). Moreover, apoB100/LDL but not its oxidized products inhibited the adhesion of platelets to ultra large VWF released from endothelial cells under flow. Finally, significantly reduced ratios of high to low molecular weight of VWF multimers with increased levels of plasma VWF antigen were detected in LDLR−/− mice fed with high cholesterol diet. Conclusion These results indicate that apoB100/LDL may be a novel physiological regulator for ADAMTS13-VWF functions.

scholarly journals Rhesus brain microvascular endothelial cells are permissive for rhesus cytomegalovirus infection

2005 ◽  
Vol 86 (3) ◽  
pp. 545-549 ◽  
Author(s):  
James R. Carlson ◽  
W. L. William Chang ◽  
Shan Shan Zhou ◽  
Alice F. Tarantal ◽  
Peter A. Barry
Keyword(s):  
Endothelial Cells ◽  
Interleukin 1 ◽  
Low Density Lipoprotein ◽  
Fetal Brain ◽  
Density Lipoprotein ◽  
Rhesus Cytomegalovirus ◽  
Activation Conditions ◽  
Von Willebrand ◽  
Willebrand Factor

Endothelial cells (EC) are an important cell type for human cytomegalovirus (CMV) pathogenesis. To characterize better the role of EC in primate CMV natural history, rhesus macaque microvascular EC (MVEC) were purified from fetal brain and analysed for infectivity by rhesus cytomegalovirus (RhCMV). Rhesus brain MVEC (BrMVEC) in culture were positive for von Willebrand factor and CD105 expression, uptake of acetylated low-density lipoprotein, and formation of capillary-like tubules on Matrigel, all phenotypic hallmarks of EC. BrMVEC were fully permissive for infection by RhCMV strain 68-1, and detectable plaques formed within 5 days of infection. Infectivity of BrMVEC by RhCMV could be reduced, but not abolished, by treatment of cells either before or during infection with pro-inflammatory mediators tumour necrosis factor-α, interleukin-1β or phorbol 12-myristate 13-acetate. These results demonstrate that in vitro infection of rhesus BrMVEC is a dynamic process that is influenced by activation conditions.

Abnormal Structure of von Willebrand Factor in Myeloproliferative Syndrome Is Associated to Either Thrombotic or Bleeding Diathesis

1987 ◽  
Vol 58 (02) ◽  
pp. 753-757 ◽  
Author(s):  
M F López-Fernández ◽  
C López-Berges ◽  
R Martín ◽  
A Pardo ◽  
F J Ramos ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Proteinase Inhibitors ◽  
Relative Proportion ◽  
Variable Degree ◽  
Bleeding Diathesis ◽  
Myeloproliferative Syndrome ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe multimeric and subunit patterns of plasma von Willebrand factor (vWF) were analyzed in eight patients with myeloproliferative syndrome (MS) in order to investigate the possible existence of heterogeneity in the “in vivo” proteolytic cleavage of the protein, previously observed in this entity. Six patients lacked large vWF multimers, five of them having normal bleeding times (BT) and clinically documented episodes of thrombotic origin, whereas one patient had long BT and bleeding symptoms. Seven patients showed a relative increase in the 176 kDa subunit fragment while the 189 kDa polypeptide was increased in only one. In addition, another patient (and prior to any therapy) showed the presence of a new fragment of approximately 95 kDa which disappeared after Busulfan therapy. The collection of blood from these patients with proteinase inhibitors did not correct the abnormalities.The infusion of DDAVP to two patients with abnormal vWF was accompanied by: the appearance of larger vWF multimers which disappeared rapidly from plasma; an increase in the relative proportion of the satellite bands of each multimer and a further increase of the 176 kDa fragment. These data point to some heterogeneity in the vWF abnormality present in MS which may be related in part to a variable degree of proteolysis of vWF occurring “in vivo” rather than “in vitro”, and which may be associated to either a thrombotic or a bleeding diathesis. They also suggest that despite the presence of abnormal, already proteolyzed vWF, DDAVP-enhanced proteolysis occurs in MS to a similar extent to what is described in normal individuals.

Adverse Influence of Cigarette Smoking on the Endothelium

1993 ◽  
Vol 70 (04) ◽  
pp. 707-711 ◽  
Author(s):  
Andrew D Blann ◽  
Charles N McCollum
Keyword(s):  
Endothelial Cells ◽  
Von Willebrand Factor ◽  
Tobacco Smoke ◽  
Lipid Peroxides ◽  
Short Exposure ◽  
Acute Effects ◽  
Adverse Influence ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe effect of smoking on the blood vessel intima was examined by comparing indices of endothelial activity in serum from smokers with that from non-smokers. Serum from smokers contained higher levels of von Willebrand factor (p <0.01), the smoking markers cotinine (p <0.02) and thiocyanate (p <0.01), and was more cytotoxic to endothelial cells in vitro (p <0.02) than serum from non-smokers. The acute effects of smoking two unfiltered medium tar cigarettes was to briefly increase von Willebrand factor (p <0.001) and cytotoxicity of serum to endothelial cells in vitro (p <0.005), but lipid peroxides or thiocyanate were not increased by this short exposure to tobacco smoke. Although there were correlations between von Willebrand factor and smokers consumption of cigarettes (r = 0.28, p <0.02), number of years smoking (r = 0.41, p <0.001) and cotinine (r = 0.45, p <0.01), the tissue culture of endothelial cells with physiological levels of thiocyanate or nicotine suggested that these two smoking markers were not cytotoxic. They are therefore unlikely to be directly responsible for increased von Willebrand factor in the serum of smokers. We suggest that smoking exerts a deleterious influence on the endothelium and that the mechanism is complex.

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