Clinical Studies on von Willebrand Disease

Whenever a disease is identified, one of the major questions asked is how can it be treated to be kept under control. Type 1 VWD is no exception to this rule, but complication lies with the actual diagnosis of the disease. Type 1 VWD is typically diagnosed with a person’s bleeding history since childhood, a family history of having the same bleeding condition, lower VWF concentrations, and mutations found in the VWF gene. Though not every case of the disease were found to have those exact characteristics.

When candidates are being evaluated to determine if they have type 1 VWD, studies show there have been some inconsistencies of how this is being conducted. Out of close to 4300 people that were being evaluated for VWD in one study, it was determined that 2.8% of those people who were diagnosed with type 1 VWD were done with the strictest parameters while about 8.3% were diagnosed with a much more relaxed criteria (Neff 2015). Part of this discrepancy directly involves whether diagnoses include a personal and familial bleeding history. One of the criteria of type 1 VWD is supposed to be the presence of unusual bleeding since childhood as well as other cases of bleeding conditions in the family (Ng, Motto, and Di Paola 2015). This is typically assessed via questionnaires. It has been found that these questionnaires, often referred to as bleeding assessment tools, are not reliable in generating the same results universally because not all administered questionnaires have the same selective specificity as well as having a different cut off score which would be the indicator if the candidates falls under the type 1 VWD criteria (Ng, Motto, and Di Paola 2015). This variable diagnosis model reflects how well researchers feel type 1 VWD is understood: no concrete structure.

With many mutations known to be correlated with the VWF gene, there are many instances where the low symptomatic VWF levels are present but there are no found mutations (Neff 2015). In addition to this, not all low levels of VWF are believed should be taken at face value. There are arguments that low VWF levels should be taken as a risk factor of abnormal bleeding rather than labeled as a disease (Neff 2015). In cases where the VWF plasma levels are the only factor which diagnoses someone with type 1 VWD, sometimes that “low” level is only a couple of standard deviation units from the mean of VWF levels present in the blood rather than below the 0.45 IU mL-1 (D. Lillicrap 2009). These slightly lower VWF levels are why the effects of type 1 VWD tend to be more mild bruising as well as minor bleeding from procedures such as tooth extraction compared to sustained heavy bleeding (J. Evan Sadler 2003). Due to these reasons, some feel rather than be labeled as a disease, type 1 VWD should be viewed more as a risk factor for more bleeding than usual. Just as red hair is seen as a risk factor for skin carcinoma, low VWF levels should be considered a risk factor of increased bleeding (J. Evan Sadler 2003).

Also, due to the inconsistencies of what levels of VWF are considered to low enough to merit diagnosis, most type 1 case may in fact be false positives for the disease. With having such variable cutoff levels for VWF in the blood, a large population could be mistakenly diagnosed with type 1 VWD if they have a lower VWF concentration and had one or two prolonged bleeding episodes in their lives (J. Evan Sadler 2003). For those actually with type 1 VWD, the intensity of the disorder is hardly consistent. Depending on the severity of the bleeding, type 1 patients may be able to recent treatment for their condition.

One of the main treatments for VWD as a whole is desmopressin. Desmopressin has been found to enhance the secretion of VWF and factor VIII from the Weibel-Palade bodies in the endothelial cells (Neff 2015). Though this treatment is known, it is not used often on type 1 patients. Out of the three types of VWD, type 1 is seen to be the least deadly and does not require immediate treatment the majority of the time. Though when it is needed, it is usually administered in a four-hour therapy session (Neff 2015).

Figure 4A. Desmopressin injections are treatments often administered to those with bleeding conditions by stimulating VWF release.

Desmopressin started to be used on VWD back in 2006 in efforts to curb the more extreme cases of VWD. As more joint hemorrhages and gastrointestinal bleeding occurred, the VWD Prophylaxis Network began to respond (Berntorp and Abshire 2006). This drug’s use was mainly used for type 3 patients but still useful in the other types of VWD. Desmopressin is seen to be effective in the majority of type 1 patients, though it does produce abnormal results in the subset of type 1 patients who experience enhanced clearance of the mature VWF protein (David Lillicrap 2013a). This development is most likely due to the fact that in this subset of the disease, VWF is regularly secreted from the cell, and therefore there is not much for the desmopressin to stimulate to enter the blood.

Though advancements are not made in the realm of VWD because current treatments are so effective and certain types have a much lower morbidity, the use of recombinant VWF has been developed and gone through clinical trials (David Lillicrap 2013a). This method produces non-mutant VWF as well as factor VIII in another organism. In this specific experiment, it was made in a Chinese hamster ovary cell line. Both products were isolated and purified and then injected into subjects. The treatment was found to boost VWF plasma concentrations as well at its activity. This treatment was found to even alleviate the enhanced clearance of VWF (David Lillicrap 2013a). Though functional on type 1 patients, this treatment just like desmopressin is reserved for the severe cases, usually for patients diagnosed with type 3 VWD.

 

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One thought on “Clinical Studies on von Willebrand Disease

  1. Greg Sacks

    May 8, 2017 at 6:29pm

    Hey there Nick,

    So I looked through a couple of your pages and I noticed something that I found curious. In one of the previous pages, you mentioned that there were two possible scenarios that needed to be explored in order to determined the source of low VWF. One possibility was diminished transcription of the VWF gene, while the other was diminished secretion of the protein. You then went on to cite studies which revealed that the problem was in the expression of the gene, not secretion of the protein. However, on this page you discuss Desmopressin as a treatment that functions by enhancing secretion of the protein. So, my question is that if the problem is low production of the protein, how would enhancing secretion alleviate the symptoms? In other words, would there be anything left to be secreted?

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      Barry Allen

      May 8, 2017 at 11:10pm

      So for Type 1, researchers have narrowed that low levels of functional VWF are due to either the protein not making it into the bloodstream or an accelerated clearance of the protein. In terms of insufficient protein being deposited into the plasma, they found that in one case transcription of VWF is diminished and therefore a lowered amount is available, but another instance of this disorder involves plenty of VWF made, but the problem lays in it being able to be secreted outside of the cells. Desmopressin would only be effective in the cases where VWF is stuck inside of the cells. With this treatment, a surge of VWF is now available in the bloodstream and it can go on conducting its normal activity to clotting blood at vascular injury sites.
      I hope this answers your question.

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