In 2003, NBC correspondent David Bloom boarded a plane and traveled to Iraq to cover the war. After spending days in the tight space of a tank, Bloom began experiencing pain behind his knees. The otherwise healthy 39-year-old dismissed the discomfort. Within days, however, his wife received a call that Bloom had died – not from an explosive device or gunshot, but from deep vein thrombosis (DVT), a condition in which blood clots formed in his lower legs and traveled to his lungs.
Although DVT is more likely to occur in individuals over 60, it can strike anyone. For some, an extended plane trip is enough to cause DVT. Sitting still for extended periods can cause blood to pool in the lower legs. For others, vein trauma from surgery, inflammation, or illness can cause blood clots. Only about one-half of the 2 million individuals who experience the condition each year have symptoms. Individuals may experience pain, swelling, tenderness, discoloration, and warmth at the affected site. Each year, up to 600,000 people are hospitalized, and approximately 300,000 Americans die from DVT-related pulmonary embolism in the United States.
To treat DVT, clinicians presently have two options. The first involves drug therapy to thin the blood and thus reduce the clot. The second choice is to invasively remove the clot using a plastic tube called a catheter. Both approaches carry a high risk of bleeding, and invasive procedures, such as catheter intervention, can also damage the blood vessel wall and cause infection.
However, there may soon be a third option. Investigators from the University of Michigan have developed a non-invasive technique that can break up the clots in deep veins, without the risks associated with drug therapy or invasive catheter therapy. The technique, known as histotripsy, was first developed for non-invasive, controlled erosion of tissue, but has recently been adapted for use in non-invasive breakdown of clots.
Investigators at the University of Michigan developed the histotripsy technique to achieve mechanical fractionation of tissues by using a number of short, high intensity ultrasound pulses. The histotripsy procedure is guided and monitored by ultrasound imaging in real time, and research is in progress for its use in non-invasive, highly controlled surgery in deep organs. The research team that developed this technique included Drs. Charles Cain, Brian Fowlkes, Timothy Hall, Will Roberts, and Zhen Xu.
More recently, the histotripsy approach was extended for use in the breakdown of clots (thrombolysis) by the team of Adam Maxwell, Charles Cain, Hitinder Gurm, and Zhen Xu at the University of Michigan. In 2008, the team led by Dr. Xu was awarded an NIBIB grant entitled “Image Guided Non-Invasive Ultrasonic Thrombolysis Using Histotripsy.” This project is investigating the thrombolytic aspects of histotripsy for the non-invasive treatment of deep-vein thrombosis (DVT).
Current treatments for DVT require a 2- to 3-day hospital stay, but Dr. Hitinder Gurm, an interventional cardiologist, and one of the collaborators with Zhen Xu and Adam Maxwell, states that histotripsy is 50 times faster than anything currently available. If this adaptation of the histotripsy technique passes all the necessary safety steps, Gurm anticipates that the procedure could be used as an outpatient treatment.
Similar in approach to lithotripsy, a noninvasive ultrasound method used to break up kidney stones, histotripsy relies on pulsed sound waves to fragment blood clots. Energy from an ultrasound probe or transducer located outside and above the clot causes microbubbles (made from tiny gas nuclei present in the blood) to form within the blood vessel. Through a process called cavitation, pulses of energy cause the microbubbles to expand, contract, and collapse. The repeated cycle of short, high-pressure pulses creates a millimeter-sized cloud of microbubbles that mechanically break the clot. “The cloud is like a Pac-Man chewing the clot,” says Xu, referring to the 1980s video game icon. It takes about 2 to 5 minutes to dissolve a 1-inch-long soft clot.
In the histotripsy system, an imaging transducer is closely aligned with the cloud-generating therapy transducer. This allows researchers to view microbubble cloud activity as it occurs. “We can see in real time when the cloud is generated, if it’s working, and if it has been effective in breaking up the clot,” says Xu. They also use color Doppler imaging to assess improvements in blood flow during the process.
A unique aspect of histotripsy is its influence on the cavitation process, which was previously considered uncontrollable. Xu and Maxwell achieve this precision using real-time cavitation monitoring and appropriate ultrasound pulse sequencing. The pulse sequence consists of a quick burst (less than 10 µs) of an ultrashort, high-pressure pulse. The pressures used to create cavitation are at least 10 times greater than pressures used in diagnostic ultrasound and comparable to pressure used in lithotripsy. “The idea is to generate the bubble cloud, fractionate a portion of the clot, and generate the seeds of the next cloud. All activity is finished before the next pulse arrives,” explains Xu.
Creating an Ultrasonic Safety Net
A potential concern with clot removal is that fragments may travel beyond the clot site and create a life-threatening situation by blocking a key artery such as the pulmonary artery in the lung. In conventional treatment, physicians sometimes insert a mechanical filter into the vessel to trap stray clot material. But as Xu and her colleagues developed the histotripsy technique, they discovered a new phenomenon that may eliminate the need for filters. “The cavitating bubble cloud induces a fluid flow in the vessel similar to a vortex,” she says. By creating a second microbubble cloud a short distance from the clot, they may trap and completely dissolve any stray clot fragments.
Although this noninvasive emboli trap (NET) technique has only been tested in vitro, Xu anticipates it could have a number of clinical applications. “If we can make the NET work in vivo, it will open the door to new applications such as trapping clots during cardiovascular operations,” she says.
Mature Clot Breakdown
Although Xu and Maxwell’s early studies have involved soft clots formed in plastic tubing and pig models, they are now investigating histotripsy’s ability to fragment harder, mature clots. The structure of older clots is similar to that of the vessel. “In these cases, it is difficult to differentiate between the clot and the vessel wall [because the clot has grown into the vessel wall],” says Xu. In this situation, the goal of the histotripsy is to create a channel through which the blood can flow rather than trying to fragment the entire clot. In preliminary animal studies, histotripsy did create a flow channel but required longer treatment times.
Toward Clinical Applications
Future work will focus on four components. The first involves investigating the basic science behind microbubble-cell interaction; understanding the physical mechanisms responsible for these interactions will help optimize the technology. The second component will determine the safety and efficacy of the histotripsy technique. A third area will explore what mechanisms are at work with the NET phenomenon, including fluid flow patterns. The final area involves engineering and software development to prepare the system for clinical use. Xu notes that the goal is to automate the histotripsy technique so that physicians can sit down at a console; locate the clot with ultrasound imaging; lock onto a clot using a beginning, middle, and end point; press a button; and let the system scan the blocked blood vessel. Work also will focus on integrating the therapy and imaging transducers and reducing their size. The researchers will also examine ways to transmit the ultrasound energy without submerging the therapy transducer in water.
“We combine the best of two worlds: the noninvasiveness of drug therapy and the localization of catheter procedures, but without the complications associated with those two approaches,” says Xu. “If we are successful in creating a clinical system, DVT treatment could become an office-based procedure. In the long term, we can open the door to treating other conditions caused by blood clots as well.”
This work is supported in part by the National Institute of Biomedical Imaging and Bioengineering.
"DVT at-a-glance." PreventDVT.org: The Coalition to Prevent Deep Vein Thrombosis. Available at http://www.preventdvt.org/docs/pdf/DVTAtAGlance.PDF.
NOTE: To open PDFs on this page, download and install the free Adobe Acrobat Reader.