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Copyright of Journal of Taibah University Medical Sciences is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Von Willebrand factor antigen (VWF) is a non-invasive marker for clinically significant portal hypertension (HVPG≥10 mmHg) and confers HVPG-independent prognostic information. While quantification of increased VWF-levels is not relevant in the context of von Willebrand disease, highly elevated VWF may be of clinical significance in ACLD. Thus, we have modified our analytical approach to quantify very high VWF-levels (i.e.,>420%) and investigated their prognostic value. Patients undergoing HVPG-measurement at the Vienna Hepatic Hemodynamic Lab with evidence of ACLD and information on VWF were considered. Clinical stages (CS) were defined as follows: Probable compensated ACLD (cACLD): LSM≥10kPa&HVPG<6 mmHg; 0: cACLD&6–9 mmHg; 1: cACLD&HVPG≥10 mmHg; 2: bleeding; 3: non-bleeding decompensation; 4: ≥2 decompensations. 124 (16%) of 793 patients had VWF>420%. The proportion of VWF>420% increased with disease severity (probable cACLD-0: 5(4%) vs. 1: 22(10%) vs. 2–4: 97(23%), p ≤ 0.001) as well as across HVPG (<6mmHg: 1(2%) vs. 6–9: 6(6%) vs. 10–15: 17(9%) vs. ≥16: 100(22%), p ≤ 0.001) and MELD (<10: 17(6%) vs. 10–14: 27(10%) vs. ≥15: 79(32%), p ≤ 0.001) strata. In patients with VWF>420%, median VWF was 533 (IQR:466–611)% and VWF was unrelated to HVPG (Spearman's ρ=0.139, p = 0.123), but showed direct correlations of weak/moderate strength with MELD (ρ=0.336, p < 0.001) and CRP (ρ=0.286, p = 0.001). In the subgroup with VWF>420%, VWF was predictive of decompensation/liver-related mortality (VWF per 10%; hazard ratio (HR): 1.02(95% confidence interval (95%CI): 1.01–1.04), p = 0.008, even after adjusting for other factors (VWF per 10%; adjusted HR: 1.02(95%CI: 1.00–1.05), p = 0.031). The proportion of patients with substantially elevated VWF values steadily increases with disease progression. While VWF is not reflective of HVPG in these patients, it is correlated with hepatic dysfunction and systemic inflammation. Importantly, quantification of high values provides prognostic information. [ABSTRACT FROM AUTHOR]

To investigate the effects of combined medication of nifedipine and magnesium sulfate on the blood pressure, pregnancy-associated plasma protein A (PAPP-A), vascular endothelial growth factor (VEGF), nitric oxide (NO), homocysteine (Hcy) and von Willebrand factor (vWF) in gestational hypertension patients. A total of 220 gestational hypertension patients were enrolled as the subjects, and divided into two groups randomly, i.e. the observation group and the control group. In observation group, patients took combined medication of nifedipine and magnesium sulfate, while those in the control group only took magnesium sulfate for treatment. Clinical efficacy, and the changes in blood pressure, PAPP-A, VEGF, NO, Hcy and vWF before and after treatment were compared between two groups. In the observation group and the control group, total effectiveness rates were 92.7% and 70.9%, respectively (p < 0.05). After treatment, we found significant decreases in PAPP-A, VEGF, NO, Hcy and vWF in patients of two groups, with more significant decreases in the observation group (p < 0.05). Incidence rates of the adverse reactions in two groups were 5.5% and 6.4%, respectively, without any statistically significant differences (p > 0.05). In the observation group, patients had fewer complications (p < 0.05). Combined medication of magnesium sulfate and nifedipine can decrease the levels of PAPP-A, VEGF, NO, Hcy and vWF in serum as well as the blood pressure of patients with gestational hypertension, with a reduction in incidence rate of complications and improvement in efficacy. [ABSTRACT FROM AUTHOR]

Background: Angiodysplasia is a vascular malformation associated with gastrointestinal bleeding, generally observed in the elderly. This condition is unexpectedly more frequent in patients with von Willebrand disease (VWD)-type 2A having low levels of VWF high-molecular-weight-multimers (HMWMs) and increased VWF-degradation fragments (1). Aim: To develop an innovative murine model of VWD-type 2A and study the role of degraded-VWF in vascular processes. Methods: Mice expressing human (h) VWF, carrying the type 2A (p.R1597W) variant or wild-type (as control) and human GPIba, have been generated (hVWF(p.R1597W) + / +/hGP1BA + / + and hVWF + / +/hGP1BA + / +). Haemoglobin (Hb), VWF:Ag, propeptide, multimer pattern and factor VIII activity were analyzed. Tail-clip and tail-vein-transection (TVT) bleeding assays were assessed. Results: Control hVWF + / +/hGP1BA + / + -mice expressed 15 ± 4% VWF:Ag, 44 ± 8% FVIII activity and normal VWF multimers. hVWF(p. R1597W) + / +/hGP1BA + / + -mice are viable and do not display spontaneous bleeding manifestations. These mice expressed 3 ± 1% VWF:Ag and 7 ± 1% FVIII activity combined with an abnormal multimer pattern, with only low multimers and few degradation bands visible. Despite the relatively low VWF:Ag levels, hVWF + / +/hGP1BA + / + -mice displayed normal haemostatic responses in both the severe- (tail-clip) and milder- (TVT) bleeding assays. In contrast, hVWF(p.R1597W) + / + / hGP1BA + / + -mice had a severe bleeding phenotype. Interestingly, in the TVT model, although the amount of blood shed was consistent with severe bleeding, 57% of type 2A mice were capable of forming an occlusive, although unstable clot within 15 min of the injury, differing from the bleeding profile of VWF-deficient mice. Conclusion: We developed a unique humanized mouse models for VWD-type 2A. Experiments are ongoing to study the vasculature of these mice. [ABSTRACT FROM AUTHOR]

Canine hemangiosarcoma (HSA) is one of the most common mesenchymal tumors in dogs. Its high metastatic and growth rates are usually associated with poor prognosis. Neoplastic cells of HSA can show various levels of cellular atypia in the same mass and may consist of various populations at different differentiated stages. Up to present, however, there is no report analyzing their differentiation states by comparing cellular atypia with differentiation-related protein expressions. To evaluate whether cellular atypia can be used as a differentiation marker in HSA, we analyzed correlation between cellular atypia and intensities of CD31 and von Willebrand Factor (vWF) staining in HSA cases. We also compared cellular atypia and expression levels of CD31 and vWF in each growth patterns. Our results show that cellular atypia was negatively correlated to CD31 and vWF expression levels but no significant correlation was found between growth patterns and cellular atypia or CD31 and vWF expression levels. Our study suggests that cellular atypia is useful for identifying differentiation levels in HSA cases. This study also provides useful information to determine differentiation levels of cell populations within HSA based only on morphological analysis, which will aid further HSA research such as identifying undifferentiation markers of endothelial cells or finding undifferentiated cell population in tissue sections. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Ischemic stroke risk rises with the increasing cardiovascular risk factors in patients with and without AF. How atrial fibrillation (AF) incrementally contributes to the risk for ischemic stroke with increasing age and multiple cardiovascular risk factors is unclear. Von Willebrand factor (vWF) is a biomarker of endothelial dysfunction. PATIENTS AND METHODS: We suggested that in older patients with high CHA2DS2-VASc Score, the vWF and ADAMTS13 would be comparable between patients with and without AF. Consecutive 196 old patients (≥ 60 years, 45.9% with concomitant AF) with and without nonvalve atrial fibrillation were recruited from April 2014 to April 2016. Data on baseline clinical characteristics were recorded at study entry. Plasma ADAMTS13 levels and plasma vWF levels were determined. Statistical analyses were performed using SPSS19.0 statistical software package. RESULTS: There were significant correlations between plasma vWf levels, ADMATS13 and CHA2DS2- VASc Score in older patients with and without AF (with AF: Spearman, r = 0.215, p < 0 .05; w ithout A F: S pearman, r = 0 .197, p < 0.05). Results of research indices in our older patients were as follows: vWf 180. 79 ± 28.27 IU/dL in AF and 153.5 ± 35.54 in non AF with p < 0.001, ADAMTS13 431.5 ± 160.33 IU/dL in AF and 536.7 ± 169.96 in non AF with p < 0.05. Results of research indices in our older patients (≥ 75 year) were as follows: vWf 181.4 ± 22.04 in AF and 174.1 ± 29.45 in non AF, and ADMATS-13 412.9 ± 130.76 IU/dL in AF and 451.7 ± 153.18 in non AF. There were no differences (p > 0.05). CHA2DS2-VASc Score can predict stroke risk in old patients without atrial fibrillation. At high CHA2DS2-VASc Score, the levels of vWF and ADAMTS13 have difference in old patients (60-74) with and without AF, but in such older patients, age (≥ 75 year), there were no differences. In elderly patients, atrial fibrillation has a limited effect on VWF, and the age is an important factor affecting the endothelial function. CONCLUSIONS: For elderly patients with a high incidence rate of stroke and thrombosis, we should pay more attention to the thrombotic events, and atrial fibrillation can be used as one of the risk factors involved and improving the risk scoring system of stroke. [ABSTRACT FROM AUTHOR]

During clot formation, platelets are subjected to various different signals and cues as they dynamically interact with extracellular matrix proteins such as von Willebrand factor (vWF), fibrin(ogen) and collagen. While the downstream signaling of platelet–ligand interactions is well-characterized, biophysical cues, such as hydrodynamic forces and mechanical stiffness of the underlying substrate, also mediate these interactions and affect the binding kinetics of platelets to these proteins. Recent studies have observed that, similar to nucleated cells, platelets mechanosense their microenvironment and exhibit dynamic physiologic responses to biophysical cues. This review discusses how platelet mechanosensing is affected by the hydrodynamic forces that dictate vWF–platelet interactions and fibrin polymerization and network formation. The similarities and differences in mechanosensing between platelets and nucleated cells and integrin-mediated platelet mechanosensing on both fibrin(ogen) and collagen are then reviewed. Further studies investigating how platelets interact with the mechanical microenvironment will improve our overall understanding of the hemostatic process. [ABSTRACT FROM AUTHOR]

Abstract: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease characterized by acute episodes of widespread microvascular thrombosis. The discovery that the plasmatic activity of the von Willebrand factor cleaving protease, ADAMTS13, is severely deficient in patients with TTP partially clarified the pathophysiology of the disease. However, the finding of severe deficiency of ADAMTS13 alone is unable to fully explain the clinical heterogeneity of the disease. The recent development of methods that measure ADAMTS13 activity with great analytical precision offers the opportunity to define the relationships between levels of ADAMTS13 activity below 10% (herein defined as “residual ADAMTS13 activity”) and the clinical manifestations of the disease. Recent studies suggest that the amount of residual activity of ADAMTS13 may be a major determinant of the clinical heterogeneity of TTP. Herein, we review the recent findings on residual ADAMTS13 activity and their implications for research and clinical practice in the field. [Copyright &y& Elsevier]

Summary: Thrombotic microangiopathy represents the clinical picture of thrombocytopenia and hemolytic anemia in the setting of small blood vessel thrombosis, accompanied by varying degrees of organ dysfunction. Well known to both nephrologists and hematologists alike, among the most common and best-studied thrombotic microangiopathy are hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. Despite sharing a strong clinical and historical relationship, these disorders represent distinct clinical and pathophysiological entities. This article reviews recent progress into the pathogenesis of thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, focusing on events taking place at the endothelial surface. [ABSTRACT FROM AUTHOR]

Background & Aims: Although they have normal liver histology and function, patients with chronic noncirrhotic nontumoral portal vein thrombosis (NC-PVT) frequently have abnormal results from coagulation tests. We investigated the significance of these results. Methods: We analyzed blood samples collected from 50 stable patients with NC-PVT secondary to a thrombophilic disorder (32%) or local factor (32%), or that was idiopathic (36%). We measured endogenous thrombin potential (ETP) with and without thrombomodulin, prothrombin time, activated partial thromboplastin time, coagulation factors (I, II, V, VII, VIII, IX, X, XI, and XII), antithrombin, proteins C and S, von Willebrand factor (vWF) antigen, vWF ristocetin cofactor, a disintegrin and metalloprotease with thrombospondin type 1 motifs 13 antigen, D-dimer, plasmin-antiplasmin complex, prothrombin fragment F1+2, activated factor VII, and clot lysis time. Samples from 50 age- and sex-matched healthy individuals were evaluated as controls. Results: Compared with controls, patients with NC-PVT had significant increases in prothrombin time and activated partial thromboplastin time; they had significant reductions in levels of procoagulant factors II, V, VII, IX, X, XI, and XII, and the anticoagulants antithrombin, protein C, and protein S. The patients had increased levels of factor VIII and vWF antigen. Irrespective of etiology, patients with NC-PVT had a significant increase in ETP with thrombomodulin and higher levels of factor VIIa, prothrombin fragment F1+2, D-dimer, and plasmin-antiplasmin complex than controls, indicating in vivo activation of coagulation and fibrinolysis. Conclusions: Patients with NC-PVT have hypercoagulability that is independent of the underlying etiology, based on in vitro analyses of thrombin-generation capacity and increased levels of biomarkers in blood samples. Further studies are required to determine if activation of hemostasis increases the risk for thrombotic events. [Copyright &y& Elsevier]

Summary: Auricular composite grafts represent a well-established technique in facial reconstruction surgery, with several advantages including high survival rate as well as less contraction and good colour match. Although the revascularisation of composite grafts reportedly occurs by inosculation and angiogenesis through both the dermal-dermal connections and the wound bed, we hypothesised that the auricular dermis might have a distinct vascular profile as compared with other regions, that might contribute to the high survival rate of auricular composite grafts. To elucidate this hypothesis, we investigated the dermal vascular profiles of several regions in fresh cadavers using a von-Willebrand factor antibody-binding technique. We assessed the vascular profiles by calculating the blood vessel density and the endothelial surface. Furthermore, we present herein some clinical cases using novel composite grafts in which graft revascularisation was likely based on the dermal-dermal connections. There was a positive correlation between the blood vessel density and the endothelial surface. We found that the postauricular dermis had a significantly richer vascularity than other skin graft donor sites such as the peri-clavicle, groin, back, buttocks and thigh, whereas the scalp and sole demonstrated an abundant vascularity as the postauricle. Unexpectedly, the cheek dermis, which is just adjacent to the auricular region, had a poor vascular profile. Because of its rapid and reliable revascularisation through dermal-dermal connections, the auricular composite graft should be more widely used in reconstructive surgery. It offers an especially good alternative in treating intractable ulcers and in tracheal reconstruction. [Copyright &y& Elsevier]

Abstract: In recent years it has been established that non-coding variants may be in linkage disequilibrium (LD) with coding variants up to several thousand base pairs away forming haplotype blocks. These non-coding markers may be haplotype specific and, therefore, informative regarding the surrounding coding sequence. In this study, we chose to study the VWA short tandem repeat (STR) as it is targeted in all major commercial kits utilized in routine forensic DNA profiling and is located in the von Willebrand Factor (vWF) gene; a gene associated with von Willebrand''s Disease (vWD). We examined the VWA STR together with single nucleotide polymorphisms (SNPs) located throughout the vWF gene to identify haplotype structures and the extent of LD between markers in the region. Several areas exhibiting LD were identified by population data analysis in the 178kilobase (178kb) vWF gene, which was supported by family studies. However, there appeared to be no evidence of LD blocks surrounding the VWA STR and evidence for recombination within 3kb of VWA, hence, it is unlikely that VWA STR alleles could be used to predict haplotypes within the vWF gene that are associated with different forms of vWD. [Copyright &y& Elsevier]

Background and Objectives: Von Willebrand factor (VWF) is a plasma glycoprotein involved in primary hemostasis but recent data suggest additional roles beyond hemostasis in angiogenesis and potentially in vascular smooth muscle cell (VSMC) proliferation. Our aim was to investigate how VWF can modulate VSMC proliferation and identified the underlying mechanisms and the in vivo pathophysiological relevance. Methods and Results: Cultured aortic VSMCs proliferation and migration were increased in the presence of VWF. VSMCs treatment with a siRNA targeting αv integrin or the RGT-peptide blocking αvβ3 signaling completely inhibited proliferation. VWF did not bind directly to αvβ3 on VSMCs. We identified that VWF A2 domain was able to bind VSMCs. Since the lowdensity lipoprotein-related receptor protein (LRP) family are known to act as co-receptors we hypothesized the involvement of a member in the signaling pathway. Using the universal LRP-inhibitor (RAP), we confirmed LRP-mediated VSMC proliferation. siRNA experiments and proximity ligation assay staining identified LRP4 as the VWF-counterreceptor on VSMCs and showed co-localization between αvβ3 and LRP4. Carotid ligations were applied to VWF +/+ and −/− mice and intimal hyperplasia (IH) was measured. Less VWF−/− mice developed IH compared to VWF +/+ mice. Finally the proliferative effect of VWF was confirmed in human atherosclerotic lesions from different vessels (aortas, carotids) showing a proximity between VWF and a-SM actin positive cells. Conclusions: VWF mediates VSMC proliferation through its A2 domain binding to the LRP4 receptor and integrin αvβ3signaling. The decreased IH following vascular injury suggests that targeting VWF-LRP4 interactions may contribute to limit remodeling. [ABSTRACT FROM AUTHOR]

• Immunohistochemistry results directly show VWF is increased during tumor progression. • VWF is expressed as low molecular weight multimer in OS cell line SAOS2. • VWF promotes platelet-induced metastasis of OS through VWF-GPIb pathway. von Willebrand factor (VWF) is exclusively expressed in endothelial cells (ECs) and megakaryocytes, which plays a crucial role in the initiation of arterial thrombosis. Recent studies have shown that VWF is also expressed in osteosarcoma (OS) cells and participates in adhesion of cancer cells to platelets, thus promoting metastasis of OS cells. However, it is unclear how OS cell-derived VWF-platelet interaction contributes to the metastasis of OS. We hypothesized that the interaction is mediated by the binding between VWF A1 and GPIbα of platelets, a molecular mechanism similar to that of thrombosis. The increased expression of VWF in SAOS2 cells may contribute to the enhancement of platelet adhesion through the VWF-GPIb pathway, which could promote the migration and invasion capacities of SAOS2 cells in vitro. Antibodies that block the pathway could significantly inhibit the platelet-induced metastasis of OS cells. Our results suggest a theoretical basis for the development of new anti-OS metastasis drugs, and further enrich the mechanism of OS metastasis. [ABSTRACT FROM AUTHOR]