In recent years, many aspects of the molecular machinery that regulate these processes have been identified and this figure provides a schematic overview of the essential elements.
Step 4 Secretion of the WPB content is preceded by sequential steps of tethering, docking, and priming before fusion with the cellular membrane. Specific protein complexes are involved in each of these steps see boxes.
B On rare occasions, exposure to the extracellular environment causes a rapid deacidification of the organelle provoking the pH-dependent tubular VWF structure to collapse. This process is referred to as a lingering kiss. C Upon agonist-induced endothelial stimulation, multiple WPBs aggregate and might eventually fuse into a large secretory vesicle, referred to as secretory pods.
This results in the release of massive amounts of VWF multimers. These bundles are highly thrombogenic as they efficiently recruit platelets. This figure has been inspired by figures presented elsewhere. Recent work from the Springer group has shown that under acidic conditions the dimeric A1-CK region folds into an intertwined bouquet-like structure, with the domains being aligned in a side-by-side manner.
Insight into the packaging organization of VWF in the WPBs is not only of relevance to explain the typical morphology of these organelles, but may also be helpful in future studies to explain how WPB coresidents are incorporated.
Indeed, many other proteins, mostly involved in inflammation or hemostasis, have been identified in the WPBs besides VWF and its propeptide, such as P-selectin, interleukin-8, osteoprotegerin, angiopoietin-2, and in a selected subset of endothelial cells also FVIII. A number of studies have tried to elucidate the mechanism by which VWF is released from endothelial cells and how the balance between basal and regulated release of VWF is determined; only a brief summary will be provided here for review, see Nightingale and Cutler 38 and Rondaij et al There have been opposite views as to whether the majority of VWF released from endothelial cells originates from constitutive or regulated secretory pathways.
Circulating VWF mostly originates from this random fusion mechanism. However, in some instances, fusion of WPBs with the plasma membrane results in the selective release of WPB coresidents interleukin-8, eotaxin-3 , whereas VWF and its propeptide are retained within the cell Figure 4. Basal release of single WPBs is probably insufficient to produce the long endothelial cell-anchored VWF bundles that recruit platelets, as such strings are only observed upon endothelial stimulation in vitro and in vivo.
From a macroscopic point of view, 3 steps can be distinguished: 1 WPBs center to the perinuclear area, an event that is more or less pronounced, depending on the stimulation trigger 60 ; 2 The formation of VWF-enriched patches is observed, probably representing fusion of multiple WPBs and forming a secretory pod 60 , 64 ; 3 Bundles of assembled VWF multimers are released.
These bundles are highly prothrombotic in that they efficiently promote platelet adhesion. At the molecular level, the exocytosis process appears as a complex multistep process and only part of the essential players involved in the sequential steps tethering, docking, priming, and fusion have been identified.
Recently, an unexpected and novel type of regulation of VWF release has been reported by Torisu and colleagues. This new set of information thus suggests that VWF release is a combined process involving WPBs and autophagosomes, and follow-up studies aiming to understand how both types of organelles collaborate in this exocytosis process are required.
Following its release in the circulation, VWF is ready to function as molecular carrier ie, for FVIII, osteoprotegerin, galectins, and several other proteins and recruiter of platelets upon vascular injury. However, VWF is similar to other plasma proteins in that its circulatory lifespan is limited. These mechanisms may be unique to each protein, dependent on the need for protein renewal in the circulation. Indeed, when analyzing the half-life of endogenous VWF following desmopressin treatment, a large variation is observed between individuals, ranging from 4.
In particular, the presence of blood group ABO H structures appears to explain a large portion of this variation. This interindividual variation may also explain the large variation in the half-life of FVIII in hemophilia A patients. Our knowledge on the mechanism by which VWF is eliminated from the circulation is predominantly based on cellular and murine models. The use of Vwf -deficient mice first allowed the identification of tissues that are responsible for the clearance of VWF. The indication that the majority of VWF is targeted to the liver indicated that VWF is cleared via an active regulatory mechanism rather than via passive elimination.
Potential clearance pathways for VWF. VWF circulates as a globular protein, with the majority of its glycan structures being well sialylated. RQ and p. VM provoke exposure of LRP1-interactive sites in the absence of shear stress, which could perhaps explain the accelerated clearance of these mutants. It is unknown whether binding of mutant VWF is limited to macrophage LRP1 as seems to be the case for wt-VWF or whether interactions also include LRP1 on other cell types, like hepatocytes or even other as-yet-unidentified receptors.
Of note, the clearance receptors responsible for the discordant clearance of blood group O and non-O VWF have not been identified yet. ASGPR, asialoglycoprotein receptor. Reprinted from Casari et al 87 with permission. Macrophages may internalize proteins randomly via receptor-independent macropinocytosis, but it is unclear whether this is also true for VWF. In contrast, a number of receptors have been identified that interact with VWF, indicating that receptor-mediated endocytosis of VWF plays an important role in this regard Figure 5.
The first VWF receptor that was identified is the asialoglycoprotein receptor, also known as the Ashwell receptor. Rather, its relevance could become apparent when VWF molecules are hyposialylated, for instance upon pathogen infection or upon reduced activity of sialyltransferase enzymes. A third potential receptor is Siglec-5, a receptor present on macrophages that specifically interacts with sialic acid residues. It should further be noted that CLEC4M is selectively expressed on sinusoidal endothelial cells, suggesting a potential role for these cells in VWF removal from the circulation.
Because LRP1 deficiency prolongs VWF half-life not more than twofold, it seems conceivable that other, so-far-unidentified receptors contribute to VWF clearance as well. It is not surprising therefore that mutations in the VWF molecule may affect 1 or more of these steps. In this last part of the review, we would like to illustrate how these steps are modulated in the context of VWD-related mutations, thereby focusing on cysteine mutations, given that cysteines play an important role in the proper folding and maturation of the protein.
Cysteines contribute to the intrinsic folding of individual domains, tail-to-tail dimerization, and head-to-head multimerization.
Mutations provoking the dis appearance of cysteines may affect each of these processes. But how do such mutations affect WPB formation? Intuitively, one would predict that impaired dimerization or multimerization would prevent the formation of WPBs.
However, no general rule can be applied to such situations as exemplified by 3 Cys mutations located in the CK domain p. CysTyr, p. CysTrp, and p. These mutations impair C-terminal dimerization and consequently only N-terminal dimerization occurs, preventing the formation of long multimers. CysTyr, whereas round organelles are produced with mutation p. CysSer, demonstrating that WPBs may form even in the absence of multimerization.
Distortion of this bouquet structure may compromise the alignment of the tubules that make up the interior of WPBs. Again, these effects seem mutation specific, with some mutants being secreted normally eg, mutant p.
CysGly , whereas others are retained within the cells eg, p. CysArg , despite normal WPB formation. In a large study concerning VWD-type 1 patients, 5 of 15 mutations involving the dis appearance of a cysteine were associated with the absence of or partial response to desmopressin, further illustrating the heterogeneous effect of cysteine mutations on VWF secretion.
They may be associated with an abnormal recruitment of components of the secretory machinery. Alternatively, misfolding of the proteins due to the cysteine mutations may alert quality control mechanisms that maneuver the mutated proteins to the intracellular degradation pathway. Despite intracellular quality control systems, small or large amounts of mutated proteins may escape the cell, including those with cysteine mutations. Are such mutants then cleared similarly to normal VWF? In the last several years, 35 different mutations have been associated with increased clearance of the protein.
Three examples thereof have previously been described in detail by our group: p. CysPhe, p. CysArg, and p. In addition, recombinant variants display reduced survival in a murine model. Mutations may induce enhanced binding to the regular clearance receptors, such as LRP1. Studies in this direction are currently ongoing, and will provide more insight into how VWD-related mutations are associated with increased clearance of VWF.
Many interesting and relevant reports and reviews have been published concerning the topics discussed in this review. We apologize to those authors whose papers could not be referenced due to size restrictions. Correspondence: Peter J. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract. The factor is made of several identical subunits. To facilitate binding to various cells and proteins, these subunits are cut into smaller pieces by an enzyme called ADAMTS Von Willebrand factor helps platelets stick together and adhere to the walls of blood vessels at the site of a wound.
These groups of platelets form temporary clots, plugging holes in blood vessel walls to help stop bleeding. Von Willebrand factor also carries another blood clotting protein, coagulation factor VIII, to the area of clot formation.
More than mutations in the VWF gene have been found to cause von Willebrand disease. Mutations in the VWF gene that reduce the amount of von Willebrand factor cause type 1 von Willebrand disease.
People with type 1 von Willebrand disease have von Willebrand factor in their bloodstream, but at reduced amounts. Mutations that disrupt the function of the von Willebrand factor cause the four subtypes of type 2 von Willebrand disease. These mutations usually change one of the protein building blocks amino acids used to make von Willebrand factor, which can disrupt the factor's ability to bind to various cells and proteins needed to form a blood clot.
Mutations that result in an abnormally short, nonfunctional von Willebrand factor generally cause the more severe type 3 von Willebrand disease.
Although VWD occurs among men and women equally, women are more likely to notice the symptoms because of heavy or abnormal bleeding during their menstrual periods and after childbirth. This is the rarest type of VWD. Most people who have VWD are born with it. It almost always is inherited, or passed down, from a parent to a child. VWD can be passed down from either the mother or the father, or both, to the child.
While rare, it is possible for a person to get VWD without a family history of the disease. This can happen if a spontaneous mutation occurs. Whether a child receives the affected gene from a parent or as a result of a mutation, once the child has it, the child can later pass it along to his or her children. If VWD is acquired in this way, it cannot be passed along to any children.
Women with VWD might have heavy menstrual periods during which they experience. People with VWD might have longer than normal bleeding after injury, surgery, or childbirth. This bleeding may be characterized in the following ways:. The amount of bleeding depends on the type and severity of VWD. Other common bleeding events include:.
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