Von Willebrand
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Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 826
Diana Schrick ◽  
Margit Tőkés-Füzesi ◽  
Barbara Réger ◽  
Tihamér Molnár

High rates of thrombosis are present in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Deeper insight into the prothrombotic state is essential to provide the best thromboprophylaxis care. Here, we aimed to explore associations among platelet indices, conventional hemostasis parameters, and viscoelastometry data. This pilot study included patients with severe COVID-19 (n = 21) and age-matched controls (n = 21). Each patient received 100 mg aspirin therapy at the time of blood sampling. Total platelet count, high immature platelet fraction (H-IPF), fibrinogen, D-dimer, Activated Partial Thromboplastin Time, von Willebrand factor antigen and von Willebrand factor ristocetin cofactor activity, plasminogen, and alpha2-antiplasmin were measured. To monitor the aspirin therapy, a platelet function test from hirudin anticoagulated whole blood was performed using the ASPI test by Multiplate analyser. High on-aspirin platelet reactivity (n = 8) was defined with an AUC > 40 cut-off value by ASPI tests. In addition, in vitro viscoelastometric tests were carried out using a ClotPro analyser in COVID-associated thromboembolic events (n = 8) (p = 0.071) nor the survival rate (p = 0.854) showed associations with high on-aspirin platelet reactivity status. The platelet count (p = 0.03), all subjects. COVID-19 patients presented with higher levels of inflammatory markers, compared with the controls, along with evidence of hypercoagulability by ClotPro. H-IPF (%) was significantly higher among non-survivors (n = 18) compared to survivors (p = 0.011), and a negative correlation (p = 0.002) was found between H-IPF and plasminogen level in the total population. The platelet count was significantly higher among patients with high on-aspirin platelet reactivity (p = 0.03). Neither the ECA-A10 (p = 0.008), and ECA-MCF (p = 0.016) were significantly higher, while the tPA-CFT (p < 0.001) was significantly lower among patients with high on-aspirin platelet reactivity. However, only fibrinogen proved to be an independent predictor of hypofibrinolysis in severe COVID-19 patients. In conclusion, a faster developing, more solid clot formation was observed in aspirin ‘non-responder’ COVID-19 patients. Therefore, an individually tailored thromboprophylaxis is needed to prevent thrombotic complications, particularly in the hypofibrinolytic cluster.

2021 ◽  
pp. 362-366
Mohammad Khaled Alsultan ◽  
Zeina Nizar Bdeir ◽  
Qussai Hassan ◽  
Tahani Ali

Nephropathic cystinosis (NC) is a rare autosomal recessive disease, which causes cysteine-crystals accumulation with progression to end-stage renal disease (ESRD). Von willebrand disease (VWD) type III is a rare subtype of von willebrand factor (VWF) abnormality, which is characterized by severe reduction of VWF and factor VIII activity. A 16-year-old patient with NC and VWD type III presented with uremic symptoms due to ESRD. Dialysis access was inserted and followed by hemodialysis (HD) for 4 months with a proper infusion of blood products. While renal transplant remains the treatment of choice of NC and superior to chronic HD, bleeding complications were a major concern in this case with coexisting VWD type III. However, with the meticulous implementation of the Hematology team’s daily recommendations, renal transplantation was successfully performed. This is the first case that mentions a new association between two inherited rare disorders, NC and VWD type III, and this entity has not been reported before. Moreover, successful kidney transplantation in our patient supports the possibility of these procedures in hereditary clotting disorders.

2021 ◽  
Sophia Gruber ◽  
Achim Loef ◽  
Adina Hausch ◽  
Res Joehr ◽  
Tobias Obser ◽  

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that is critically involved in hemostasis. Biosynthesis of long VWF concatemers in the endoplasmic reticulum and the (trans-)Golgi is still not fully understood. We use the single-molecule force spectroscopy technique magnetic tweezers to analyze a previously hypothesized conformational change in the D'D3 domain crucial for VWF multimerization. We find that the interface formed by submodules C8-3, TIL3, and E3 wrapping around VWD3 can open and expose two previously buried cysteines that are known to be vital for multimerization. By characterizing the conformational change at varying levels of force, we are able to quantify the kinetics of the transition and the stability of the interface. We find a pronounced destabilization of the interface upon lowering the pH from 7.4 to 6.2 and 5.5. This is consistent with initiation of the conformational change that enables VWF multimerization at the D'D3 domain by a decrease in pH in the trans-Golgi network and Weibel-Palade bodies. Furthermore, we find a stabilization of the interface in the presence of coagulation factor VIII (FVIII), providing evidence for a previously hypothesized binding site in submodule C8-3. Our findings highlight the critical role of the D'D3 domain in VWF biosynthesis and function and we anticipate our methodology to be applicable to study other, similar conformational changes in VWF and beyond.

2021 ◽  
Vol 19 (1) ◽  
Yuxin Zhang ◽  
Fengwu Chen ◽  
Aizhen Yang ◽  
Xiaoying Wang ◽  
Yue Han ◽  

Abstract Background Type 3 von Willebrand disease (VWD) exhibits severe hemorrhagic tendency with complicated pathogenesis. The C-terminal cystine knot (CTCK) domain plays an important role in the dimerization and secretion of von Willebrand factor (VWF). The CTCK domain has four intrachain disulfide bonds including Cys2724-Cys2774, Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806, and the single cysteine mutation in Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806 result in type 3 VWD, demonstrating the crucial role of these three disulfide bonds in VWF biosynthesis, however, the role of the remaining disulfide bond Cys2724-Cys2774 remains unclear. Method and results In this study, by the next-generation sequencing we found a missense mutation a c.8171G>A (C2724Y) in the CTCK domain of VWF allele in a patient family with type 3 VWD. In vitro, VWF C2724Y protein was expressed normally in HEK-293T cells but did not form a dimer or secrete into cell culture medium, suggesting that C2724 is critical for the VWF dimerization, and thus for VWF multimerization and secretion. Conclusions Our findings provide the first genetic evidence for the important role of Cys2724-Cys2774 in VWF biosynthesis and secretion. Therefore, all of the four intrachain disulfide bonds in CTCK monomer contribute to VWF dimerization and secretion.

2021 ◽  
Vol 8 ◽  
Yingqi Zhang ◽  
Savindi De Zoysa Ramasundara ◽  
Renee Ellen Preketes-tardiani ◽  
Vivian Cheng ◽  
Hongxu Lu ◽  

Understanding how platelets can sense and respond to hemodynamic forces in disturbed blood flow and complexed vasculature is crucial to the development of more effective and safer antithrombotic therapeutics. By incorporating diverse structural and functional designs, microfluidic technologies have emerged to mimic microvascular anatomies and hemodynamic microenvironments, which open the floodgates for fascinating platelet mechanobiology investigations. The latest endothelialized microfluidics can even recapitulate the crosstalk between platelets and the circulatory system, including the vessel walls and plasma proteins such as von Willebrand factor. Hereby, we highlight these exciting microfluidic applications to platelet mechanobiology and platelet–circulatory system interplay as implicated in thrombosis. Last but not least, we discuss the need for microfluidic standardization and summarize the commercially available microfluidic platforms for researchers to obtain reproducible and consistent results in the field.

Rashmi A. G. ◽  
Riya Kumar ◽  
Dayamayi A. S. ◽  
Spandana Nallapilli

Von Willebrand disease (VWD) is a hereditary bleeding disorder that can be severe and potentially life-threatening, particularly in pregnant women during labor and subsequently during early puerperium. There is no optimal treatment or management for this disorder. Hence, all efforts aim at early diagnosis and the focus is mainly on minimising and controlling blood loss. We described the case of a woman in the post-partum period with severe VWD, admitted in the obstetrics and gynaecology ward at Rajarajeswari Medical College and Hospital, Bangalore. Prompt diagnosis, initiation of pre-partum and intra-partum Von Willebrand factor (VWF)/clotting factor replacement therapy, vigilant post-partum monitoring of blood loss and systematic follow up will help expedite recovery and prevent adverse outcomes.

Haematologica ◽  
2021 ◽  
Katarina D. Kovacevic ◽  
Jürgen Grafeneder ◽  
Christian Schörgenhofer ◽  
Georg Gelbenegger ◽  
Gloria Gager ◽  

Von Willebrand Factor (VWF) and Factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary haemostasis and clotting respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomised, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favourable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: Single ascending dose of BT200 (0.18-48mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterised, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin induced aggregation, platelet function under high shear rates, and thrombin generation. Mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dosedependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagenadenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (p

Nikolett Wohner ◽  
Silvie Sebastian ◽  
Vincent Muczynski ◽  
Dana Huskens ◽  
Bas Laat ◽  

2021 ◽  
Shahan Mamoor

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding sushi, von Willebrand factor type A, EGF and pentraxin domain-containing 1, SVEP1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. SVEP1 was also differentially expressed in the brain metastases of patients with metastatic breast cancer. SVEP1 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of SVEP1 in primary tumors of the breast was correlated with distant metastasis-free survival in patients with normal-like subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. SVEP1 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

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