For the first time, researchers can quantitatively predict blood circulation conditions that may cause pathological behavior of human blood von Willebrand factor (vWF) protein. Predictions from this new simulation method, developed at Lehigh University, can be used to optimize the design of mechanical pumps known as left ventricular assist devices used in patients with heart failure. The method also has the potential to improve the diagnosis and treatment of von Willebrand disease, the most common inherited bleeding disorder in the United States, according to the Centers for Disease Control and Prevention.
“This method consists of studying the kinetics of rare events”, explains the co-author Edmund Webb III, associate professor of mechanical engineering and mechanics at PC Rossin College of Engineering and Applied Science at Lehigh. “It usually means some type of transition. With protein, it often comes down to folding.
The protein known as vWF promotes blood clotting by helping platelets in the blood adhere to collagen in damaged blood vessel walls and form a plug that stops bleeding from a wound.
Typically, vWF circulates in the blood as a compact ball or blood cell. As it approaches an injury site, the increased blood flow caused by the laceration causes the blood cell to unravel. As the protein transforms into a chain form, the sites which are typically protected when vWf is globally shaped become exposed. These sites are “sticky” and they bind to platelets and collagen to initiate blood clots.
There are a number of ways the clotting process can go wrong, causing bleeding disorders. One of these is called von Willebrand disease (vWD), and it affects about 1% of Americans (or 1 in 100 people), according to the CDC. Its main symptoms include frequent nosebleeds, easy bruising, and heavy and / or longer bleeding after injury, childbirth, surgery or dental care, or during menstrual periods.
There are several types of vWD, and their severity varies depending on the degree of depletion of vWF in a patient’s blood. Some people don’t even know they have the disease because the level of vWF in their blood, although depleted, is still high enough to initiate clotting. Some people need to avoid certain activities to avoid injury. Others need regular infusions of vWF because they are sorely lacking in protein.
The main author of the study is Sagar Kania, a Rossin College doctoral student in mechanical engineering and mechanics. Kania and Webb carried out the work with their co-authors Lehigh, Alp Oztekin, professor of mechanical engineering and mechanics, Xuanhong Cheng, professor of bioengineering and materials science and engineering, and X. Frank Zhang, associate professor of bioengineering.
The team initially focused on understanding the blood flow conditions in which otherwise healthy vWF would exhibit unwanted disentangling. This is a question whose answer has a direct impact on the design of left ventricular assist devices (LVADs), which have been associated with unexpected vWF depletion and associated coagulation disorders, related to the vWD. Since the symptoms are essentially the same, from a medical point of view, in addition to being hereditary, von Willebrand disease can be acquired either through the action of a medical device or as a result of a medical condition. distinct.
The unwanted resolution of vWF is considered a necessary first step in pathological depletion of vWF and associated coagulation disorders. Under normal conditions, vWF is made in the walls of blood vessels and then secreted into the blood.
“And when it’s secreted, it’s way too big,” says Webb.
Thus, this secretion simultaneously activates an enzyme (called ADAMTS13) which cuts very long proteins into shorter lengths that are appropriately sized for their blood clotting functions. These shorter proteins contract into a globule shape, then circulate in the bloodstream until they meet an injury site, at which time they break down, stick to platelets and collagen, and initiate the process of plugging the blood. hole in damaged blood vessels.
The specific problem the team investigated for this article arises when vWF comes undone when it shouldn’t. In other words, not in response to injury. When this happens, the cutting enzyme can be activated again.
“So when secreted into the blood, von Willebrand factor proteins circulate under normal blood circulation conditions, and yet they unravel because they are very long,” explains Webb. “Because they fray, they are reduced to the normal size distribution. But under pathological conditions, they keep unraveling and they are cut to the point where they are too small to be functional. They become short segments which are no longer hemostatically active; so if you have a cut you cannot clot because you don’t have enough properly sized von Willebrand factor circulating.
So what are the blood circulation conditions that cause vWF to collapse when it shouldn’t? To answer this question, Kania and her co-authors combined the improved sampling technique (Weighted Ensemble) with molecular-scale simulations (Brownian Dynamics). This required running parallel simulations – calculations performed on many computers at the same time – supported by Lehigh’s Sol and Hawk compute clusters, as well as resources from Xtreme Science and Engineering Discovery Environment (XSEDE), a national supercomputing resource made possible by the National Science Foundation.
“The big problem,” explains Webb, “is that bleeding disorders can be associated with the clearance of von Willebrand factor on time scales ranging from a few minutes to a few hours. Molecular-scale simulations have to travel time sequentially, using a very, very small time step. For us, getting a one-second simulation is indeed an advanced calculation.
Webb further points out that developing a solid understanding of the statistical nature of rare disentangling events requires many such simulations, which makes such an approach intractable.
“This paper used a new simulation method combined with our pre-existing simulation method to answer questions on longer timescales. It’s commonly called timescale bridging, because we take a model designed to answer mic-to-millisecond questions and combine it with a new theoretical technique that allows us to answer questions about things that would happen on time scales of seconds, minutes, hours, even days.
It’s really a new approach to predicting this type of event, he says.
“This weighted ensemble method and its marriage to this type of problem has never been done before,” explains Webb. “Sagar made predictions about pathological flow conditions that appear to be quantitatively more accurate than what previously existed in the literature. So now we can say, “If some exposure to blood flow occurs, you’re going to have problems.” ”
This breakthrough is potentially very good news for patients with heart failure. This can help LVAD manufacturers to design blood pumps so that the flow they generate does not create pathological conditions for vWF.
Beyond benefiting those in need of medical implants, the team’s method may potentially help healthcare professionals better understand and potentially manipulate the complex flow conditions affecting the size distribution of vWF in their patients. patients. This could lead to better treatment of acquired and inherited VWD.
The ultimate goal, says Webb, is to take this kind of ability and knowledge beyond vWF to develop targeted drug therapy using flow-sensitive molecules that mimic the disentangling of vWF. So, if a patient is at risk for a heart attack or stroke due to plaque buildup (stenosis), the molecule could deliver a drug to that specific area.
“You’re designing a molecule that unfolds in specific flow fields associated with certain degrees of stenosis,” explains Webb. “The hope is that you get the medicine where you want it, and not anywhere else in the body. We’re working on it right now.