What is von Willebrand Disease Type 1?

Figure 1A. Image of Dr. Erik von Willebrand.

This bleeding disorder would not have been known if it was not for the preliminary work of a dedicated Finnish man. Erik Adolf von Willebrand lived from 1870-1949 and attended the University of Helsinki to earn his medical degree (Owens 2007).  Here is where he conducted his dissertational work revolving around blood under the eminent hematologist Professor Ossian Schauman (Lassila and Lindberg 2013).  During his time of practice, von Willebrand studied a vast amounts of topics, from administering insulin for diabetic coma treatment to determining ketone levels in urine (Owens 2007). It was not until the end of his medical career when he first encountered the bleeding disorder that would be named after him. His first run-in with this condition was when a five-year-old girl was brought to the hospital for excessive bleeding (Lassila and Lindberg 2013). Von Willebrand found it was a hereditary disease and traced its lineage to find 23 of the 66 family members had this bleeding condition that was different from hemophilia. The condition’s name was first hereditary pseudohemophilia (Owens 2007). Though the specifics of the disorder were not known at the time, von Willebrand laid the foundation for current researchers to build upon.

Von Willebrand Disease, VWD for short, involves a mutation of a protein called von Willebrand factor, or VWF. VWF is found in everyone, but specific mutations cause problems that lead to unusual bleeding. VWF is a glycoprotein, comprised of multiple identical subunits, that is eventually secreted in the blood stream (Mancuso et al. 1989). After the protein is initially made inside the cell, part of it has to be cut off and the larger remainder has to go through various modification before it is able to function as it is supposed to (David Lillicrap 2013b). One of these modifications includes having the protein folded in a certain conformation so it can properly bind with connective tissue, such as collagen, as well as a blood clotting protein called factor VIII (J. E. Sadler et al. 2006). These interactions help facilitate the repair of vascular damage by adhering blood platelets to the wound so the bleeding stops.  The malfunctioning of VWF is present in other diseases as well. Studies have found that oversized VWF multimers are responsible for both sickle shaped blood cells sticking to blood vessel walls in sickle cell anemia patients as well as binding calcium-rich normal shaped blood cells to the vessels walls as well. Both have the potential for reducing blood flow and causing tissue damage (Smeets et al. 2017).

The body has various mechanisms to inhibit the activity of VWF. Researchers have found there to be many different sized VWF multimers that conduct different behaviors; very large VWF multimers assemble and have been linked to healing vascular wounds. If there is not a high activity of the protein, reductases such as thrombospondin-1 have been found to bind with the multimers of VWF. This causes the multimers to disassociate with the overall protein and therefore reduce the size of VWF and stop its repair abilities (Xie, Chesterman, and Hogg 2001).   Metalloproteases have also been found to stop VWF functioning by cleaving certain areas of the protein and create an array of different size multimers, all of which were smaller than the original secreted factor (Smeets et al. 2017). The VWF proteins do not float around the blood indefinitely. These proteins typically have a half-life of 12-20 hours and then are cleared from the blood (Smeets et al. 2017).

VWD is broken into three types: type 1, type 2, and type 3. Type 1 is the most abundant and categorized as a reduction of functionally normal VWF in the blood whereas type 2 involves issues in creating normal VWF. Type 3 of the disease is due to a lack of the VWF all together (David Lillicrap 2013b). To be put in better terms, a patient with type 1 VWD is found to have a lower concentration of VWF circulating in the blood, but the ratio between the presence of the protein and the protein’s activity remains constant (J. E. Sadler et al. 2006). The presence of VWF can be assessed by introducing an antigen to bind to the protein, and then detecting the antigen. Current literature states that type 1 VWD can be due to mutations that led to less VWF being produced in the first place or an abnormal accelerated clearance rate of the protein (David Lillicrap 2013b).

Out of all VWD cases, about 65-75% of patients are afflicted with type 1. Though it has a rather high prevalence, there does not seem to a fair distribution of who develops the disease. While women are seen as having a greater risk than men of having VWD in general by a margin of almost 2:1, there is also a higher proportion of those with the “O” blood group to have type 1 VWD. It was found that those in this specific blood group have about 25% lower quantities of VWF in their blood, thus a greater chance of having type 1 VWD (David Lillicrap 2013b). Another study which focused on a Canadian population also found a similar linkage between lowered VWF levels and “O” blood types (J. E. Sadler et al. 2006). Type 1 VWD is highly examined in pregnant women as well. VWF levels fluctuate during pregnancy and rise overall by the time birth occurs. If the VWF concentration is low but above a certain threshold, the VWF and factor VIII proteins will increase as normal and will not cause any issues (Castaman 2013). There appears to be a variety of accepted thresholds in the literature. If pregnant women have type 1 VWD and causes the VWF levels to be too low, then their bodies cannot significantly increase their VWF levels and require treatments such as VWF replacement therapy (Castaman 2013). With the wide range of effects caused by type 1 VWD, researchers look towards any potential genetic defects that may cause this specific type of the disease.

 

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One thought on “What is von Willebrand Disease Type 1?

  1. Emily Robinson

    April 29, 2017 at 9:33pm

    You mention that there are three types of VWD and what happens with VWF levels within each of the three types. How does the disease manifest itself differently amongst the three types? For example, how do symptoms vary in people experiencing type 1 differ from those experiencing type 2 or 3? Additionally, can a person experience multiple types over time–can type 1 become type 3 or vice versa?

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    • Author

      Barry Allen

      May 2, 2017 at 8:21pm

      Hey Emily

      Great question. So Type 1 involves a decreased amount of VWF in the bloodstream which results in a diminished response to stop the bleeding. Type 2 patients make dysfunctional VWF which has a greater impact on the ability to coagulate platelets and stop the bleeding. There are four subtypes of Type 2. Type 3 is the most rare of the three. Patients suffer from this have an absence of VWF and a diminished presence of other factors that usually work along with VWF. The literature cites that all three have similar symptoms but varying intensity. Type 2 has the most severe symptoms of all.

      As for your next questioning, after reviewing my sources and doing a quick Google search, there is no evidence of developing multiple types of VWD. I imagine in the extreme case of accelerated clearance of VWF in Type 1 resulting in a undetectable level of VWF is still just considered Type 1 rather than changing classification. There is evidence of people developing VWD later in life (referred to as Acquired VWD) but nothing on having multiple types.

      Does that accurately answer your question?

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      • Emily Robinson

        May 2, 2017 at 8:34pm

        Yes that answers my question, thank you!

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  2. Melissa Reph

    May 2, 2017 at 8:23pm

    You say that VWD occurring in pregnant women is often prevented naturally by the body raising VWF levels prior to giving birth. Does this mean that VWD can come and go naturally in patients depending on the VWF levels their bodies create? The same way an iron deficiency may develop into anemia if iron levels continue to drop?

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  3. Author

    Barry Allen

    May 7, 2017 at 2:03pm

    That’s a very great question Melissa. Studies have shown that as people get older, their VWF concentration tend to increase. Pregnant women experience the same effect. The deciding factor of whether this case happening in those with Type 1 VWD was their initial VWF levels. Castaman states that if a pregnant woman’s VWF plasma concentration are above 30 U/dL, she stands a very fair chance of developing enough VWF that no complications will occur. However, if the levels are below 20 U/dL she might not be able to generate enough VWF and medical intervention will be necessary. The same general trend is seen with normal Type 1 patients, but with different thresholds. There have not been any cases that cite once healthy VWF levels are achieved that it then plummets again. Anemia seems to be different because there can be more of a dramatic fluctuating dynamic with the iron levels as compared to VWF levels in Type 1 patients.

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