Recently, there has been considerable interest in the role von Willebrand Factor (VWF) may play in the complications of COVID-19, the infection caused by SARS-CoV-2, including in lay online media.
The SARS-CoV-2 virus attaches to the cells that line blood vessels and in some people causes a severe inflammatory response of those cells, a so-called endothelialitis. This story actually begins with the first cases described in Wuhan, China in late 2019 and early 2020. Preliminary reports initially from Wuhan and Shenzhen, China indicate that the patient’s blood type may play a role in the susceptibility and severity of symptoms in patients with COVID-19; individuals with blood type O appear to more resistant while those with type A may be more susceptible and experience more severe symptoms. Normally, the levels of VWF in plasma vary considerably between individuals and within the same individual at different times, as VWF is influenced by several variables, such as age, pregnancy, smoking, hormones, and blood group. It is thought that blood group contributes to about 30% of the variability in VWF levels in plasma: Among people not considered to have von Willebrand disease (i.e., normal population) VWF levels are 25-35% lower in individuals with blood group O than in individuals with non-O blood group and those with blood type AB have the highest levels.
VWF has two functions in the body. First is carrying factor VIII, the protein that is deficient or absent in hemophilia A. Its second role is to facilitate binding of platelets to arteries and veins. It is a very sticky protein that therefore plays a significant role in preventing and controlling bleeding by facilitating platelet binding to sites of injury to the blood vessels. As such, low levels of VWF are associated with bleeding (von Willebrand disease) while high levels may be associated with blood clots in the arteries and possibly in the veins of the body. In fact, when there is a pathologically high level of the stickiest VWF molecules, a severe and often fatal blood clotting disorder results known as thrombotic thrombocytopenic purpura (TTP). TTP is due to the deficiency of an enzyme, ADAMTS-13, that cuts these stickiest VWF molecules into smaller sizes making them less adhesive and therefore less dangerous. Therefore, we have known for years that VWF plays a role in blood clotting (and in preventing bleeding).
While the blood group may play a role and be associated with higher levels of VWF, a more important effect is the inflammatory response in the blood vessel cells causing them to release proteins made in the cells including VWF. Very high levels of VWF in the blood of patients with severe COVID-19 disease have been observed since those early cases and additional research has confirmed this to be true. It is not surprising that someone, in this case Dr Aksenova at St Petersburg University in Russia, put forward a hypothesis that a more severe case of COVID-19 disease may be associated with the elevated levels of VWF. Of course, this is thought-provoking as any hypothesis should be and is designed to stimulate further investigation. However, it is neither unique nor is it novel. Scientists in Switzerland, Italy, The Netherlands, India and the United States have already tested this hypothesis by examining the blood of patients with COVID-19 to look at the role VWF might play in the symptoms and death of some patients. It is thought that VWF plays a major role in the blood clots that develop in the lungs and other organs of patients with COVID-19 disease. Elevated levels of VWF due to the severe inflammation that occurs in the blood vessels is further worsened by a secondary deficiency of the ADAMTS-13 enzyme which is overwhelmed by the amount of VWF in the blood. This further contributes to very high VWF levels in the blood and a vicious cycle is created. Indeed, in the Italian study, these researchers showed that 5 out of 6 patients with dangerously low levels of ADAMTS-13 died.
How will the story end? We don’t know quite yet. There is much to be learned about this new virus, SARS-CoV-2 and how to mitigate its effects once someone is infected but know that scientists are actively researching these important questions day and night. In regard to those in the bleeding disorders community, there may be a silver lining— might von Willebrand disease have protective influence against serious symptoms? This chapter remains to be written but I am certain the story will continue to unfold.
Leonard Valentino, MD
President and CEO
National Hemophilia Foundation