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Bursting Blood Clots: Medicine's Next Big Thing?

Bursting Blood Clots: Medicine's Next Big Thing?

CREATED Dec 9, 2013

CINCINNATI, Ohio (Ivanhoe Newswire) - If you're having a stroke, it's crucial that you get medical help as quickly as possible. The right treatment can mean the difference between life and death, and reduce future impairment. Now, doctors are testing a possible new, medical breakthrough for stroke victims.

Every second counts when you suffer a stroke.

"One side of the body doesn't work. They can't speak. They can't see," Arthur M. Pancioli, MD FACEP, Professor and Chairman in the Department of Emergency Medicine, University of Cincinnati, College of Medicine, told Ivanhoe.

Most strokes are caused by a blood clot that blocks the flow of blood to the brain. If you get help within three hours, you can get a drug called TPA, but Dr. Pancioli, an expert in emergency medicine, warns of the risks.

"With that drug, one in about 16 patients that you treat will have bleeding into the brain," Dr. Pancioli said.

Dr. George Shaw and researchers at the University of Cincinnati, College of Medicine are testing a breakthrough technique to dissolve human blood clots more quickly, without the risk of bleeding.

They're using a natural enzyme called plasmin.

"It's the most effective therapy we've ever looked at," George J. Shaw, MD, PhD, Emergency Medicine Associate Professor, University of Cincinnati, College of Medicine, told Ivanhoe.

The plasmin is loaded into a special bubble called a liposome. Through an IV, they send it directly to the blood clot.

"We pop that bubble with an ultrasound pulse and release the plasmin right where you want it," Dr. Shaw said. "I think it's going to be a major step forward for stroke therapy."

And it could be a major breakthrough for the millions of people who suffer a stroke.

As with TPA, doctors would still need to give the plasmin within three hours of the onset of stroke. Clinical trials with plasmin could start in five years.

RESEARCH SUMMARY

BACKGROUND: A stroke may also be considered a brain attack that happens when a blood clot blocks an artery. This prevents blood flow from the heart to the body causing dead brain cells and brain damage. When a stroke occurs, the abilities that are controlled by that part of the brain are lost due to the damaged brain cells. Motor functions such as memory, movement, and speech are all affected from a stroke and recovery is questionable. Recovery depends on the patient and the motivation to get better, as well as the location of the brain where the stroke occurred. (Source: http://www.stroke.org/site/PageServer?pagename=stroke)

PREVENTION: To prevent having a stroke, one might consider making a couple of lifestyle changes. Blood pressure, cigarette smoking, and alcohol are three main factors of how a stroke might occur. Cholesterol, diabetes, and weight can also be managed to be sure that you are not at risk. Transient Ischemic Attack (TIA), atrial fibrillation, and circulation are three conditions to be aware of when preventing a stroke. TIA is an incident that consists of stroke-like symptoms that last temporarily. 40 percent of individuals who experience TIA will have a stroke. (Source:http://www.stroke.org/site/PageServer?pagename=prevent)

SIGNS: The acronym F.A.S.T. was created to teach patients of potential stroke symptoms. "F" stands for face. If one side of the face is drooping while smiling, that could be a sign of stroke. "A" stands for arms; ask the person to raise their arms to see if one is also dropping. "S" is speech; ask the person to repeat a phrase and listen for slurring. "T" stands for time; use your time wisely if any of these signs occur and seek medical help. (Source:http://www.stroke.org/site/PageServer?pagename=prevent)

NEW TREATMENT: A new study from the University of Cincinnati College of Medicine has found that, when delivered via ultrasound, the natural enzyme plasmin is more effective at dissolving stroke-causing clots than the standard of care, recombinant tissue plasminogen activator (rt-PA). The delivery method involves trapping plasmin in bubble-like liposomes, delivering them to the clot intravenously and bursting it via ultrasound.  "That method is necessary," UC associate professor of emergency medicine George Shaw III, MD, PhD, was quoted as saying, "because plasmin cannot be delivered through traditional methods. Intravenous delivery of rt-PA is designed to solve that problem by catalyzing the conversion of existing plasminogen inside the body to plasmin, which in turn degrades blood clots."  In in-vitro study, Shaw and researchers enclosed plasmin and a gas bubble inside a liposome. Then, they delivered the liposome to a clot in an in-vitro lab clot model and dissolved it using ultrasound waves, thus delivering the plasmin enzyme to the clot. After 30 minutes, clots treated with plasmin showed significantly greater breakdown than clots treated with rt-PA. (Source: http://www.med.uc.edu/Home.aspx

INTERVIEW

George J. Shaw, MD, Emergency Medicine Associate Professor at the University of Cincinnati, College of Medicine, talks about what could be medicine's next big thing for treating stroke.

When a person suffers a stroke and goes to the ER, what is the standard of care now?  

Dr. Shaw: They would get appropriate labs drawn, an EKG, and a head CT.  CT stands for computed tomography.  It's a special x-ray of the head where we can see the 3D structure of the brain. If we are worried about a stroke, we are either looking for blood, or possible signs of what we call an ischemic stroke.  Ischemic stroke is the kind of stroke that is caused by a blood clot and that's about 80% of them.  In this area, we've got the ability to be able to call on the stroke team, which is a group of dedicated physicians.  They are based out of the University of Cincinnati and take care of stroke patients from about 13 hospitals in the area; so there is always somebody on call for that.  If you are going to have some kind of stroke, you want to be in this city. They can assist you in taking care of the patient and evaluating the patient.  Then, if the patient is actually having a stroke from a blood clot and it's early enough, then they can be treated with TPA, or tissue plasminogen activator, the clot busting drug that folks have heard about.  

How does TPA work?  

Dr. Shaw: TPA converts plasminogen, a chemical present in the blood stream and in the clot and turns it into plasmin.  The plasmin is an enzyme that breaks up the clot.  It breaks up what's called the fibrin mesh of the clot. 

Within how many hours of a stroke do you have to get TPA for it to be effective? 

Dr. Shaw: Within 3 hours of symptoms. This can be up to 4.5 hours in some limited circumstances.

What are the strengths of TPA and what are the weaknesses?  

Dr. Shaw: If you look at stroke survivors who got TPA 6 months after their stroke, they tend to do better neurologically than those who haven't gotten TPA.  The risks of it are that even if it's given properly, about 6 percent of people will have bleeding in the brain just from the TPA.  I've seen that a couple of times.  It's never good.  It's always bad.  In a couple of circumstances, it can be very devastating and could cause death. 

The bleeding from TPA is worrisome, correct?

Dr. Shaw: That is correct.

So, what about the time element? How frustrating is it for you as an emergency doctor that there is that time element to it? 

Dr. Shaw: That is a difficult target to hit. We actually have more time to treat a heart attack than we do to treat a stroke. For a heart attack, you have 6, 12, or whatever hours.  Obviously, the sooner the better, but you do have more time to try and treat that disease.  For stroke, you only have 3 hours and under certain circumstances, it can be as long as 4-1/2, but 3 hours is really what you should aim for.  After that, the benefit of TPA is not good. The risk for bleeding in the brain goes way up after about 3 hours. 

What are you doing here with the plasmin research?   

Dr. Shaw: TPA is a useful therapy.  It's what we've got, but it could be a lot better.  So, one we would like something that works better and two we would like something where hopefully you don't have as much bleeding as a complication.  I thought of plasmin because plasmin is the actual enzyme that breaks up the clot. 

Can you explain what you are doing with the plasmin? How would it work?

Dr. Shaw: Right now, plasmin cannot be given intravenously because the human body has a lot of chemicals that will soak it up and inhibit it.  This is a dangerous molecule to have running around in your bloodstream.  So, if I try and give it to a patient intravenously, like you can with TPA for stroke right now, it wouldn't do anything.  It will get soaked up.  It wouldn't get to the clot to be able to break it up.  You can give it intra-arterially, and right now the only way to do that is through a catheter placed in a major artery and then that catheter has to get all the way up to the brain.  I have two friends in Cincinnati who can do that who are on the stroke team, but most facilities don't have those kinds of people or that kind of equipment around.  So, intra-arterial is not going to help you in most circumstances.  So our idea is to take that plasmin and put it in what we call a liposome, a little bubble of lipid, and then put a gas bubble in there with it. So, the idea is to have that liposome with plasmin in it. targeted for the clot and we could give that IV and let it circulate, stick to the clot, and then pop that bubble with an ultrasound pulse to release the plasmin right where we want it.

So, you are really targeting the clot and you give it through an IV. Do you send the liposome bubble through an IV to the clot?

Dr. Shaw: Yes, that would be the idea.  Then you don't have to call somebody in with special equipment.  You don't have to give it intra-arterial.  You can give it like any other drug.

What is special about the bubble?  Why are you trying to encapsulate the plasmin in the bubble? 

Dr. Shaw: Well, encapsulating the plasmin shields it from all of the body's inhibitory enzymes.  So, you get rid of that problem. If you try and give it through an IV, it just gets destroyed and taken away.  The liposome helps shield it from those things.  The bubble needs to pop so the liposome can release the plasmin. If you expose that bubble to ultrasound, it will expand rapidly and it will just shatter that liposome and release the plasmin where you want it to be.

Once the liposome bubble gets to the area of the clot, what do you do next? 

Dr. Shaw: You would turn on the ultrasound for a brief period of time.  You just want to pop the bubble with it and then the plasmin is released, hopefully the clot gets lysed or broken up at that point.

How effective is the plasmin?  

Dr. Shaw: I think it is going to be very effective.  At least in some of the animal trials out there, it's quite effective.  In my lab, we are looking at it in human blood clots, but it's kind of a test tube model and it's the most effective therapy we have ever looked at.  We have been looking at these things and trying to improve TPA therapy for about 9 or 10 years now. 

How significant is this?  

Dr. Shaw: If everything works, and we got a lot of work to do, I think it's going to be a major step forward for stroke therapy.  It should be more effective, we have some data suggesting that it will be more effective in breaking up the clot, and it should be a lot safer. There is work by others in animal models using plasmin where they don't see any hemorrhage at all.  So, going from a 6 percent hemorrhage rate to something lower would be tremendous.

So, the lack of the bleeding in the aftermath is huge? 

Dr. Shaw: Yes, that would be huge.

Is there also a better time element to this as well?

Dr. Shaw: I suspect we are still only going to have 3 hours for this. The reason why you have that 3 hour window is because after the 3 hours part of the brain that's getting just enough oxygen to hang on by its fingernail, so to speak, those parts start dying. So, even if you get blood flow back after that, it's not really going to do that brain tissue any good.  It's already died.  So, I think the 3 hour window is still going to be with us, but it could be a more effective and a safer therapy.

How much more effective is plasmin in breaking down the clots than TPA?  

Dr. Shaw: From what we've seen in just breaking up the clot, it's about 5 or 6 times more effective; and by more effective, I mean, faster at breaking up the clot.  

Is there less bleeding or no bleeding?

Dr. Shaw: Right, that's what we are hoping for. 

So, what about human trials? How far away are we?

Dr. Shaw: We are a ways away from that.  Now we have managed to put the plasmin in the liposome with a bubble.  The next step would actually be to target it for clot and then look at an animal model for stroke. 

Who is funding this study? 

Dr. Shaw: Right now, we are funded by a pilot grant from the Cardiovascular Center of Excellence. That is part of the University of Cincinnati, Department of Internal Medicine.

FOR MORE INFORMATION, PLEASE CONTACT:

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University of Cincinnati Academic Health Center
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(513) 558-0207
kathryn.cosse@uc.edu
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