Featured Lendület Researcher: Zsuzsa Bagoly

Bagoly Zsuzsa

Most people think of strokes as being the same as the symptom cluster known in Hungarian as a cerebral haemorrhage and that it is actually bleeding that causes brain damage. In reality, a cerebral haemorrhage is only one type of stroke (which accounts for 15-20% of all strokes). A stroke is any event that causes a disturbance in the blood supply to the brain, and in the majority of cases – around 80% – it is not caused by bleeding, but by a blood clot blocking the cerebral artery.

Race against time

With a stroke, the surrounding area of the brain is deprived of oxygen and is damaged. It is a race against time: the sooner the blot clot can be dissolved, the more likely it is that the process can be reversed before it causes serious consequences.

“If this process can be reversed within a certain time window and circulation restored, then a stroke is by and large curable,”

says Bagoly, Associate Professor in the Division of Clinical Laboratory Science, Institute of Laboratory Medicine, University of Debrecen, and head of the newly formed Momentum research group. “We have two methods for removing or dissolving the blood clot. One is drug treatment, which we call thrombolysis, and this is the main focus of our Momentum grant.”

Thrombolysis is an infusion treatment that, if successful, virtually restores the original blood supply within an hour, so that the symptoms disappear. Another solution can be used if a large blood vessel becomes blocked. In this case, doctors use a catheter to get to the site of the blockage and pull the blood clot out of the artery in a corkscrew fashion. This procedure is only available in larger medical centres and can only be performed by a qualified specialist. The latter procedure has a slightly longer time window: it can usually be performed within six hours, but in some cases it can take up to 24 hours between the stroke and the treatment. Drug-based thrombolysis, on the other hand, can only be successfully used within 4.5 hours of the onset of symptoms.

Predicting the outcome of treatment

Although drug-based thrombolysis sounds simple in that a patient can be cured by being given an infusion, unfortunately this intervention is only successful in less than half of cases (around 30-40%). Unfortunately, in the majority of cases, the treatment is unsuccessful and, in rare cases, can cause bleeding complications. “When the balance of blood clotting tips to the other side of the scale (towards dissolution and bleeding), it can cause intracranial bleeding that can rarely be fatal. At present, there is no laboratory test that can clearly predict the possibility of this complication before treatment is started. Therefore, one strand of my project is to develop tests that can be used to predict the outcome of blood clot dissolution treatments,” continued the researcher.

Currently, when clinicians start a blood clot dissolution treatment, they have no way of knowing what the outcome will be. It is possible they can be effective, but it can also happen that they will be ineffective or that the patient will begin bleeding. The aim of the research team is to develop laboratory tests that can predict, in a very short time, what to expect from the treatment. Based on different clinical characteristics, such as age or stroke severity, the members of the Momentum research team will develop a scoring system that is easy to calculate and, together with laboratory tests, can predict the expected outcome of the therapy.

Help for clinicians

“This would be a great help for clinicians, as it would allow us to create the basis for personalised stroke treatment,” argues Bagoly.

Depending on the result of a test, clinicians could decide on the most appropriate way to open and recanalise the vessel, the combination of treatments, and when and how to start further treatments that affect blood clotting.

Although we might think that an infusion is safer than catheterisation, this is not necessarily the case with clot removal. The current practice is that if mechanical removal is available at the institution and the patient is suitable for it, it is usually tried, as it may be more successful. Many doctors are afraid of the bleeding caused by thrombolysis, and this fear limits its use in many smaller centres, according to Bagoly. If we had an easy-to-use, reliable test to predict the outcome of the treatment, it could improve the spread of the treatment in the future.

Another pillar of research is looking for the causes and blood clotting abnormalities behind the success or failure of treatment. They will investigate what causes patients to respond differently to treatment and their different risks of side effects. They will explore the biochemical mechanisms underlying this phenomenon, which alter certain properties of the clot, such as its structure and size – as one of the main limitations of infusion clot dissolution is the size of the clot. The third strand of the research team’s work is to investigate the genetic factors that influence the outcome of treatment. They will explore whether there are hereditary factors that determine how a patient responds to treatment.

They will also look at how genetic variants underlying a poor outcome or treatment failure affect the structure and properties of the clot. “The background for these studies is a large biobank that we have been building since 2011 in collaboration with the Debrecen Neurology Clinic. The biobank contains blood (plasma, serum) and DNA samples from more than 500 stroke patients,” says Bagoly. These samples will be used for experiments and sent to the group’s foreign collaboration partners.

The research team has collaboration partners in Australia, Sweden, Finland, the Netherlands, the UK, the US and Poland. The basis for collaborative experiments with foreign research groups is the supply of blood samples. “Over the course of our research we have already sent samples to Australia, which is of course a very expensive process. The plasma samples can only travel in dry ice, they cannot melt during transport, and after thawing they can only be used for one measurement.” The research team mainly conducts its experiments on blood samples from patients and control subjects, and on clots removed from patients. They will also launch a prospective study: they will start collecting blood samples from around 200 patients and follow their medical history to detect correlations between disease outcome and the molecular and genetic characteristics that can be detected in the patients’ blood.

The aim of the Momentum grant cannot, of course, be to develop a full range of new treatments to be introduced into clinical practice, as neither the time nor the resources are sufficient for this. However, Bagoly hopes that the correlations they have discovered will soon be able to help doctors choose the therapy they want to use for their patients. “If we can find a promising test that can be validated in the first year or two, that is, if the prospective study shows its usefulness, it can be introduced into clinical practice. As every minute counts in stroke treatment, only rapid tests can be used effectively at the bedside.

We believe that over the course of the Momentum grant, we will be able to develop a diagnostic procedure that will help doctors make quick, everyday decisions in the near future.

Our main goal is that the results of our experiments will contribute to more effective and safer stroke care in the long term.”