Pathology of von Willebrand Disease

So much time and many resources are poured into studying VWD, but only a very limited amount is actually understood about the disease pathways. In addition to understanding cancer’s uncontrolled cell growth theme, there are many genes, both oncogenes as well as tumor suppressors, that have been identified as being involved and studied to determine how they contribute to cancer. The same understanding is not present in VWD, especially not for type 1.

Figure 3A. The general understanding for type 1 VWD is that the VWF do not adhere blood platelets to tears in blood vessels so to stop the bleeding. Figure from Rady Children’s Hospital San Diego VWD Page.

 

Researchers have labeled type 1 VWD as the most underdeveloped of all three types in terms of a disease pathway due to its high complexity (P.D. James and Lillicrap 2013). Though correlations have been made between mutations and the observed disease phenotypes, there are too many factors that influence VWF that muddles what type 1 VWD does to VWF directly. Researchers found that VWF levels were affected by thyroid hormones and therefore worry that these influences led to questionable results (P.D. James and Lillicrap 2013). Constant work, both in vitro and in vivo experiments, are done that still do not reveal any new details. Rather than large advancements made to uncover these mechanistic details, the literature reveals how more studies are conducted to understand how VWF interacts with the cellular environment and determine what can likely go wrong and lead to type 1 VWD pathogenic responses.

One of the main focuses worth studying is the biosynthesis of VWF and how it may be altered. Of the examined mutations within the VWF gene that have been linked to type 1 VWD, it appears that the majority of the mutations impact VWF biosynthesis in some unclarified manner (P.D. James and Lillicrap 2013).It was known that type 1 VWD had lower levels of VWF circulating the blood, but it had yet to be confirmed if the protein was not being made or just not being secreted into the bloodstream. Blood outgrowth endothelial cells, cells similar to the ones that line blood vessels, were closely studied to determine how this phenomenon was occurring. After introducing mutations that correlated with decreased VWF in the blood, researchers used real-time RT PCR to quantify how much of the VWF mRNA was present in the cells. The results indicated there was less of the RNA than normal, meaning that less of the VWF gene was being transcribed (Starke et al. 2013). Unsurprisingly, this decreased genomic activity correlated with the amount of VWF present in the cell as well as in the blood plasma. This supported the notion that there was a decrease in VWF biosynthesis as opposed to secretion. A separate study examined a popular type 1 VWD mutations using both human and mice samples. The Arg1205 mutation correlates with enhanced clearance of VWF from the blood. Subjects with this mutation had normal VWF synthesis, but the ratio of the propeptide to the mature peptide revealed there  was an increased removal of the mature peptide (Pruss et al. 2011). Results were similar for both the human and mice samples.

Investigations also targeted how does this bleeding disorder correlate with age. Those without the disease typically experience an increase in VWF concentration in plasma as well as its activity over time (Rydz et al. 2015). It was previously unexplored how the type 1 patients’ VWF concentrations differ over time. A small cohort of 31 subjects in Canada who were diagnosed with type 1 had their VWF levels taken twice over a span of five years to determine any notable change. Apart from the small sample size and the uncontrollable influences on VWF levels, researchers found both the concentration as well as the activity of VWF increased in relation to time (Rydz et al. 2015). This indicated that the disorder might alleviate over time if the VWF levels are not too low initially.

Where VWF is housed before secretion gives another target worth investigating. After VWF is made, it is stored in vessels called Weibel-Palade Bodies (WPBs) inside the endothelial cells (Starke et al. 2013) (Michaux et al. 2006). WPBs are rod-shaped storage vesicles that fold VWF into tubules and hold them until they have to be secreted into the bloodstream. Before being stored, VWF is dimerized and then forms multimers of dimers (Michaux et al. 2006). The propeptide is then cut but stays noncovalently associated with the mature multimers (Pruss et al. 2011). There are several components between packing and releasing the VWF from the WPBs that could go awry and trigger VWD pathogenesis. The authors indicate that the specific shape of the WPBs is crucial for the formation of the VWF tubules. In order for the WPBs to maintain that shape, an acidic environment is needed (Michaux et al. 2006). Upon exocytosis, the VWF enters a more basic environment and unwraps into long filaments to grab platelets to adhere them to the damaged site (Starke et al. 2013). If the VWF cannot unfurl and adhere to platelets, the VWD phenotype emerges and excessive bleeding commences (Michaux et al. 2006). This study lends itself to isolating a condition that could give rise to VWD. Though not a mechanistic detail, it provides another potential starting point to investigate, which may be useful for treatment if necessary.

Figure 3B. Mechanism for how functional VWF uncoils, binds to collagen and fixes vascular breaks by adhering platelets to the damaged site. Image from Michael D. Dacre.

 

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