Haemostasis and Thrombosis
Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple in Basic Urological Sciences, 2021
Haemostasis is the mechanism that arrests bleeding. Coagulation is the generation of thrombin and the fibrin clot. Haemostasis comprises three steps: vascular spasm, platelet plug formation, coagulation . In response to vascular injury or inflammation, the endothelium becomes prothrombotic. It downregulates the expression of anti-thrombotic molecules. It expresses procoagulant tissue factor (TF). It expresses adhesion molecules which mediate platelet and leucocyte capture. It releases the von Willebrand factor (VWF) which mediates platelet capture and aggregation. A monolayer of endothelial cells (EC) lining all blood vessels – forms the intima with the basement membrane. Platelets change configuration to mediate clot retraction which strengthens the clot. Most procoagulants and anticoagulants are produced by the liver — except factors VWF and Factor VIII which are produced by the endothelium.
Case Study: Microfabrication: Spatializing Cell Signaling and Sensing Mechanisms
Jenny E. Sabin, Peter Lloyd Jones in LabStudio, 2017
Microfabrication methods provide a bridge between the physiological and complex in vivo environment and the controlled, but oversimplified cell culture methods. Soft lithography is a method in which microfabricated features on a wafer are molded into an elastomeric polymer. One of the primary features of microfabrication methods is control over the presentation of external signals at physiologically relevant spatial scales. This chapter presents one example where microfabrication methods have been useful in elucidating mechanisms and diagnosis: the formation of blood clots. The formation of a blood clot is a complex process that involves all three of the external signals: soluble molecules, surface-bound molecules, and mechanical forces. The subendothelial matrix is composed of a number of surface-bound proteins that platelets adhere to, in particular, collagens and von Willebrand factor. The mechanism by which platelets adhere to the subendothelial matrix is shear stress-dependent. Microfluidics channels were used to recreate the shear stresses and geometry of the microvasculature.
Bleeding tendency
Prasanna Sooriakumaran, Channa Jayasena, Professor Crispian Scully in Key Topics in Human Diseases for Dental Students, 2005
Various prothrombotic (e.g. von Willebrand factor, platelet activating factor) and antithrombotic (e.g. nitric oxide, tissue plasminogen activator) factors are involved in the above response. The clotting cascade involves a variety of coagulation factors and two distinct pathways (extrinsic and intrinsic) that come together as the final common pathway and result in the formation of cross-linked fibrin that stabilizes the platelet plug to form a clot. Heparin exerts its antithrombotic effect by inhibiting the intrinsic pathway, and warfarin works by inhibiting the extrinsic pathway. The activated partial thromboplastin time (APTT) is a measure of intrinsic function and is therefore increased by heparin therapy. The prothrombin time (PT) and the international normalized ratio (INR) are measures of extrinsic function and are increased by warfarin.
Von Willebrand factor (Vonvendi®): the first recombinant product licensed for the treatment of von Willebrand disease
Published in Expert Review of Hematology, 2016
Massimo Franchini, Pier Mannuccio Mannucci
Introduction: Von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder, characterized by a quantitative or qualitative defect of the multimeric adhesive glycoprotein von Willebrand factor (VWF). The mainstay of treatment of bleeding in VWD involves the use of desmopressin and plasma-derived factor VIII (FVIII)-VWF concentrates. In addition, a new recombinant VWF has been recently manufactured and licensed in the USA. Areas covered: This narrative review, after a brief presentation of the current therapeutic strategies in VWD, will focus on recombinant VWF, analyzing its characteristics and the results of the completed phase I and III trials. Finally, the potential role of this recombinant drug in the therapeutic scenario of VWD is discussed. Expert commentary: Based on the evidence from literature analysis, we can conclude that recombinant VWF is a novel, interesting therapeutic option for VWD, which could help to further personalize the management of this complex inherited bleeding disorder.
Cadmium regulates von Willebrand factor and occludin expression in glomerular endothelial cells of mice in a TNF-α-dependent manner
Published in Renal Failure, 2019
Zongguo Sun, Qi Xie, Jie Pan, Na Niu
Background: Cadmium (Cd) is an environmental pollutant that leads to nephrotoxicity. However, the mechanisms of Cd-induced glomerular injury have not been fully clarified. Von Willebrand factor (vWF) and occludin are important endothelial cell markers in renal vasculature. In this study, the effects of Cd on the vWF and occludin expression in mouse glomeruli was investigated. Objectives: The goal of this study was to analyze the expression of von Willebrand factor and occludin in glomerular endothelial cells of tumor necrosis factor-α−/− (TNF-α−/−) mice after treatment with Cd. Material and methods: C57BL6/J wild-type (WT) mice and TNF-α−/− mice (n = 6) were treated with Cd, and the kidney tissues were collected. The expression of von Willebrand factor and occludin was detected by using quantitative real-time PCR, immunofluorescence, and immunohistochemistry. In vitro, Human umbilical vascular endothelial cells (HUVECs) were used to examine the regulatory role of TNF-α on expression of von Willebrand factor and occludin. Results: We found that Cd significantly increases mRNA and protein expressions of von Willebrand factor and occludin in TNF-α−/− mice, but not in WT mice. In vitro, Cd significantly increased mRNA and protein expression of von Willebrand factor and occludin in HUVECs with TNF-α small interfering RNA (siRNA) transfection. Conclusions: These results suggest that TNF-α acts to balance homeostasis of glomerular endothelium after Cd treatments.
An update on type 2B von Willebrand disease
Published in Expert Review of Hematology, 2014
Sameh Mikhail, Ehab Saad Aldin, Michael Streiff, Amer Zeidan
Type 2B von Willebrand disease (VWD) accounts for fewer than 5% of all VWD patients. In this disease, mutations in the A1 domain result in increased von Willebrand factor (VWF) binding to platelet GPIbα receptors, causing increased platelet clearance and preferential loss of high molecular weight VWF multimers. Diagnosis is complicated because of significant clinical variations even among patients with identical mutations. Platelet transfusion often provides suboptimal results since transfused platelets may be aggregated by the patients’ abnormal VWF. Desmopressin may cause a transient decrease in platelet count that could lead to an increased risk of bleeding. Replacement therapy with factor VIII/VWF concentrates is the most effective approach to prevention and treatment of bleeding in type 2B VWD.
Related Knowledge Centers
- Hemostasis
- Thrombotic Thrombocytopenic Purpura
- Blood
- Viii
- Blood Coagulation Factors
- Von Willebrand Diseases
- Von Willebrand Disease