von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Abstract

To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra-and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. (Blood. 2015;125(13): 2019-2028 Introduction von Willebrand (VW) factor (VWF) is a multimeric glycoprotein present in blood plasma, the subendothelial matrix, as well as storage granules in endothelial cells (Weibel-Palade [WP] bodies [WPBs]) and platelets (a-granules).1 Although a series of novel functional properties of VWF has recently been proposed, 2 the protein is mostly known for its contribution to the hemostatic process: it mediates platelet adhesion and aggregation at sites of vascular injury and carries coagulation factor VIII (FVIII) in the circulation. 1 Patients lacking VWF manifest a severe hemorrhagic phenotype, originating from defective formation of platelet-rich thrombi and a secondary deficiency of FVIII impairing the generation of a fibrin network. Functional and/or quantitative deficiencies of VWF are known as von Willebrand disease (VWD), a disorder affecting 0.01% to 1% of the population. 3 Quantitative deficiencies of VWF result from changes in biosynthesis, secretion, and/or clearance of the protein. In this review, we will provide an overview of the current knowledge on each of these processes and we will discuss how they can be affected by the presence of protein defects. Part I: Basics of VWF biosynthesisPrimary structure VWF is produced in endothelial cells and megakaryocytes as a single prepropolypeptide of 2813 aa. The primary sequence of VWF was reported in 1986, and rapidly the presence of repeating domain structures within the protein was recognized. 4 The different domains are arranged in the order: D1-D2-D9-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK, with the D1-D2 domains representing the propeptide and the remainder corresponding to the mature VWF subunit (Figure 1). [4][5][6] Progress in structural and bioinformatical analysis of protein structures...

Emerging roles for hemostatic dysfunction in malaria pathogenesis

“…20,21 VWF circulates in normal plasma as a series of heterogeneous multimers and plays 2 essential roles in normal hemostasis. 21 First, VWF mediates the adhesion of platelets to exposed collagen at sites of vascular injury.…”

“…20,21 VWF circulates in normal plasma as a series of heterogeneous multimers and plays 2 essential roles in normal hemostasis. 21 First, VWF mediates the adhesion of platelets to exposed collagen at sites of vascular injury. 20 Second, VWF acts as a carrier molecule for procoagulant factor (F) VIII, thereby protecting it from premature proteolytic degradation and clearance.…”

Insuficiencia hepática crónica y hemostasia

“…Aún se continúa en la búsqueda del método que permita determinar con fiabilidad el estado hemostático real de los pacientes con falla hepática, algunos de los más prometedores hasta el más de unirse al factor VIII para evitar su pronta degradación (49). Durante la progresión del daño hepático existe una disminución de factores de coagulación, pero contrario a lo pensado también existe una elevación paralela del FvW y del factor VIII (50); el mecanismo subyacente parece ser la mayor actividad endotelial, el lugar de síntesis del FvW y el sitio donde se ubican las células involucradas en los procesos de fibrosis hepática que desembocarán en la reducción de los niveles de proteína C, S (factores anticoagulantes) y de la metaloproteasa ADAMTS 13 (a disintegrin and metalloproteinasa with thrombospondin type 1 motif n.° 13) (44).…”

Molecular diagnosis of von Willebrand disease

“…The propeptide, that is cleaved prior to protein secretion has a key role in the assembly of VWF multimers [13] and to traffic the VWF into the storage organelles (Weibel-Palade bodies of endothelial cells or platelet -granules) [14,15]. An update on the complex process of VWF biosynthesis, secretion and clearance has been reported recently by Lenting et al [16].…”