Blood Von Willebrand Factor Research Articles

Carbon nanotube and nanofiber exposure and sputum and blood biomarkers of early effect among U.S. workers

BackgroundCarbon nanotubes and nanofibers (CNT/F) are increasingly used for diverse applications. Although animal studies suggest CNT/F exposure may cause deleterious health effects, human epidemiological studies have typically been small, confined to single workplaces, and limited in exposure assessment. ObjectivesWe conducted an industrywide cross-sectional epidemiological study of 108 workers from 12 U.S. sites to evaluate associations between occupational CNT/F exposure and sputum and blood biomarkers of early effect. MethodsWe assessed CNT/F exposure via personal breathing zone, filter-based air sampling to measure background-corrected elemental carbon (EC) (a CNT/F marker) mass and microscopy-based CNT/F structure count concentrations. We measured 36 sputum and 37 blood biomarkers. We used factor analyses with varimax rotation to derive factors among sputum and blood biomarkers separately. We used linear, Tobit, and unconditional logistic regression models to adjust for potential confounders and evaluate associations between CNT/F exposure and individual biomarkers and derived factors. ResultsWe derived three sputum and nine blood biomarker factors that explained 78% and 67%, respectively, of the variation. After adjusting for potential confounders, inhalable EC and total inhalable CNT/F structures were associated with the most sputum and blood biomarkers, respectively. Biomarkers associated with at least three CNT/F metrics were 72 kDa type IV collagenase/matrix metalloproteinase-2 (MMP-2), interleukin-18, glutathione peroxidase (GPx), myeloperoxidase, and superoxide dismutase (SOD) in sputum and MMP-2, matrix metalloproteinase-9, metalloproteinase inhibitor 1/tissue inhibitor of metalloproteinases 1, 8-hydroxy-2′-deoxyguanosine, GPx, SOD, endothelin-1, fibrinogen, intercellular adhesion molecule 1, vascular cell adhesion protein 1, and von Willebrand factor in blood, although directions of associations were not always as expected. ConclusionsInhalable rather than respirable CNT/F was more consistently associated with fibrosis, inflammation, oxidative stress, and cardiovascular biomarkers.

Endothelial dysfunction in rectal cancer patients chronically exposed to ionizing radiation.

We sought to identify the features of endothelial function in rectal cancer patients who were exposed to chronic ionizing radiation from a nuclear test site in Kazakhstan. We examined 146 individuals, 76 of whom were rectal cancer patients. The existence of a complex of disturbances of the endothelium and hemostasis systems in patients vs non-patients was revealed. Endothelial dysfunction was expressed as an increase of nitric oxide (NO) production along with decreases in vasodilatation function, and increased levels of von Willebrand factor in blood, along with an increase in the number of circulating endotheliocytes. Significant correlations between indicators of endothelial function and vascular-platelet hemostasis were observed. These changes and their interrelations were expressed more strongly in the patients who lived in the contaminated area around the nuclear test site. Such patients could have an increased risk of thrombosis and other complications after the treatment of a malignant neoplasm.

The Von Willebrand Factor A1–Collagen III Interaction Is Independent of Conformation and Type 2 Von Willebrand Disease Phenotype

The blood von Willebrand factor (VWF) mediates platelet adhesion to injured vessels by sequestering platelets from blood flow and depositing them to collagen and other exposed subendothelial matrix proteins. This process of capturing platelets to facilitate formation of platelet plugs occurs through transient interactions with platelet glycoprotein Ibα via the VWF A1 domain which also binds collagen. Using a conformationally diverse collection of natively folded and mutation-induced misfolded von Willebrand disease (VWD) variants, we test a recently proposed affinity up-regulation hypothesis which states that collagen binding changes the conformation of the A1 domain to a high-affinity GPIbα binding competent state. With surface plasmon resonance (SPR), we present this diversified collection to collagen and quantify the kinetics of association and dissociation to ascertain the conformational selectivity of collagen. With analytical rheology, we quantify real-time platelet pause times and translocation velocities across a Cu2+ HisTag-chelated and collagen-bound A1 single domain and A1A2A3 tridomain fragment of VWF under shear stress in an ex vivo shear flow microfluidic chamber. In contrast to expected hypothetical outcomes, collagen has limited conformational selectivity for binding A1. A1-collagen binding is independent of gain- or loss-of-function phenotype and under shear stress, platelet translocation pause times on collagen-bound A1A2A3 are either normal or shorter depending on whether A1 is concertedly bound with the A3 domain to collagen. With respect to A1, collagen has an inhibitory role that provides an explanation for the lack of thrombosis in patients with gain-of-function VWD.

A Novel Molecular Mechanism In The Interplay Of Platelet GPIb-VWF-Fibrin In Thrombus Formation

It is established that the interplay between von Willebrand factor (VWF) and fibrinogen is relevant for the platelet-platelet interaction in thrombus formation. Although the concentration of fibrinogen is much higher than that of VWF in blood, normally, they do not interact. In fact, VWF in plasma has a poor binding activity for fibrin(ogen)-coated surface, which exposes fibrin-specific sequences when it is immobilized. This observation suggests that 1) the site recognized by fibrin is inaccessible in plasma VWF, and 2) a conformational change in the VWF protein is a pre-requisite to bind fibrin. The latter may be supported by a previous study indicating that VWF has to bind to its platelet receptor glycoprotein (GP)Ib first in order to bind fibrin. Another line of evidence suggests that the binding of VWF to the polymerizing fibrin facilitates the interaction of platelet GPIb with the fibrin-bound VWF during the growth of the thrombus, a mechanism apparently defective in Bernard-Soulier syndrome (BSS) and von Willebrand disease (VWD). Consistent with this, fibrin monomer, like ristocetin, can induce the binding of VWF to GPIb. The C1C2 domains have been described as the fibrin-binding domain in VWF, and it is unknown whether the structures of these domains change to bind to fibrin. In contrast, conformational changes within the A1A2 domains of VWF induced by ristocetin result in the binding to GPIb and the protease ADAMTS-13. Therefore, we investigated a potential contact site for fibrin among the A1A2 domains of VWF. We characterized the interaction of each plasma (p)VWF, purified pVWF, recombinant A1A2A3 domains protein, single A1, and single A2 domains with fibrinogen, fibrin, or D-dimer. We also examined the effect of ristocetin in the VWF-fibrin binding. Both pVWF and purified pVWF bound to immobilized fibrin(ogen) in a ristocetin dependent manner. An A1A2A3 mutant expressing increased GPIb-binding activity bound to fibrin(ogen) in the absence of ristocetin. Both A1 and A2 domains, but not the A3 domain had binding activity for immobilized fibrin(ogen). Both soluble fibrin monomer and D-dimer, unlike fibrinogen in solution, had a significant binding activity for the immobilized A2 domain. Moreover, the A2 domain was capable of delaying fibrin polymerization in vitro. The use of conformation-specific monoclonal antibodies demonstrated that, like collagen, fibrin(ogen) induces a change in the structure of the A1 domain, and platelets interacted effectively with the fibrin(ogen)-bound A1 domain under high shear stress. Interestingly, in contrast to A3 or A1domain, flowing platelets did not adhere to the fibrin(ogen)-coated surface incubated with the A2 domain. In conclusion, we have demonstrated a previously unknown fibrin(ogen)-binding activity for the A1 and A2 domains in VWF. These observations reveal new mechanisms that may help to understand the pathophysiology of the bleeding in VWD, in which a number of natural occurring mutations that cause the disease are found within the A1 and A2 domains, and the poor fibrin polymerization observed in BSS. Furthermore, these outcomes may have implications for a better understanding of the high risk for thrombosis when the levels of both VWF and fibrinogen are increased. Disclosures:No relevant conflicts of interest to declare.

Stability of von willebrand factor in blood stored at 4°C

Von Willebrand factor activity (VIIIR:RCo) and factor VIII-related antigen (VIIIR:Ag) were studied in CPD blood stored at 4°C for 0, 1, 7, 14 and 21 days. VIIIR: RCo deteriorated in exponential fashion with a half-life of 4.2 days. This deterioration was accompanied by a change in the multimeric profile of VIIIR:Ag on crossed immunoelectrophoresis. There was only slight loss of VIIIR:Ag as measured by fluoroimmunoassay.