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Heparin and the mysteries of coagulation

Heparin and the mysteries of coagulation

Prof. Krzysztof Szczubiałka talks about one of the basic anti-coagulants used in medicine – heparin – and some problems related to its removal from organism after treatment.

Łukasz Wspaniały: Heparin is a basic component of many anti-coagulants, including those that don't require a prescription. It's frequently used by specialists from different areas of medicine. What are its main advantages?

Dr hab. Krzysztof Szczubiałka, prof. UJ: Heparin is one of the oldest known medications, so it's effects are well known. Next year, we'll have the centenary of its discovery. It is naturally produced by the organisms of humans and animals, mostly in lungs, liver and muscles. Most of the heparin we use in medicine comes from pig intestines and cow lungs. Its particles are highly negatively charged – in fact, heparin is the most highly charged naturally occurring biopolymer. It's mostly used as an anti-coagulant, i.e. to prevent blood from clotting. It's widely known that blood forms clots when its leaves the circulatory system. This is the organism's defence mechanism, which protects it from bleeding out. But this same defence mechanism may cause diseases, leading to heart attacks and strokes. Blood coagulability may also pose a problem during heart surgery. To reduce coagulability, doctors administer large doses of heparin, which might lead to haemorrhages. It's very difficult to find the correct dosage, since the organism's reaction is non-linear – administering twice as much heparin does not automatically mean that coagulability will become twice as low for a certain period of time. Plus, the effects of heparin vary between patients.

Heparin - not as good as it seems?

As with every medication, there are some undesirable side effects of heparin. What are they?

There are two types of those. Some may occur immediately after administration, while others arise after prolonged use. In the first case, we've got haemorrhages which happen after a large dose of heparin is introduced into the patients organism during surgery. In the second, we may notice a decrease in the amount of platelets in about ten percent of patients which are treated with unfractionated heparin (one with the largest particles). Heparin may also lead to hyperkalaemia, i.e. an increase in the level of potassium in blood. Since it's difficult to predict the impact of heparin on a particular patient, it is necessary to constantly monitor their blood's coagulability. Additionally, prolonged use of heparin can cause thrombosis, the very disease it's supposed to help against.

It is often necessary to deactivate heparin in the patient's bloodstream. To that end, protamine are used. Is this method safe?

The levels of heparin always have to be reduced after heart surgery. The most common way to do that is to use protamine – a protein extracted from salmonid milt. In contrast to heparin, protamine particles are highly positively charged. These particles naturally react with each other and form a complex in which heparin is no longer anti-coagulative. However, we must remember that our organisms respond differently to an alien protein. I'm mainly talking here about people allergic to fish. In such cases, administering protamine may cause anaphylactic shock, hypotension or  bronchoconstriction. Paradoxically, overdosing protamine causes it to lose its anti-coagulative properties, so coagulability remains dangerously low. Studies show that in the United States alone, there are about a thousand life-threatening complications annually caused by administering protamine as an antidote to heparin. Our research is aimed at discovering a substance which could replace protamine. Another reason for searching for other methods is that the sources of protamine are dwindling. Main salmonid fisheries, located at the shores of Japan, have been contaminated after the Fukishima Daiichi nuclear disaster.

The road so far, the road ahead

Your research team has managed to synthesise a new, natural polymer substance useful for allowing a quick neutralisation and removal from the bloodstream. What's so innovative about this technology?

My research team – which is a part of a larger team led by Prof. Maria Nowakowska from the JU Faculty of Chemistry – focused on polysaccharides, which display anti-heparin properties after cationic modification (i.e. positively charging them). We've chosen them for a few reasons. They are biopolymers, substances well known to the organisms of humans and animals, particularly as building and supply material (e.g. cellulose and starch). They're non toxic and relatively cheap. We've researched a lot of different polysaccharides produced by various organisms. Our study began with chitosan, the second most commonly occurring biopolymer in nature, produced by crustaceans and fungi. Then we focused on dextran (produced by bacteria), pullulan (produced by fungi) and cyclodextrin (extracted from starch). We've subjected them all to cationic charging, so that they interact with heparin similarly to protamine. We recently started working with synthetic heparin inhibitors. Surprisingly, we found out that they can be as good as, or even better than, natural substances. For instance, we've proved that synthetic polymers we researched neutralise fine particle heparin, which was previously "antidoteless". Additionally, they're very well defined, as opposed to polysaccharides, which greatly vary depending on their source. Chitosan extracted from crustaceans is different than the one found in fungi. Differences in structure and mass may cause different physiological effects. With synthetic polymers, we can achieve the same properties every single time.

Further research on this subject is carried out at the JU Faculty of Chemistry. Should we expect more developments in this area?

As I said, we began nine years ago with cationically charged chitosan. Curiously, it turned out to be an exceptional polymer, with various beneficial properties. We discovered it has a strong antiviral quality. Prof. Ryszard Korbut's team (JU Chair in Pharmacology) found out that it prevents atherosclerosis. We then expanded our research to other polymers. Eventually, we were left with two. One is a natural cationic derivative of dextran, the other is a synthetic block polymer. Both are excellent at neutralising unfractionated heparin. Currently, our research is twofold. We're collaborating with Prof. Shin-Ichi Yusa's team form the University of Hyogo (Kobe, Japan) in the area of synthetic polymers. As for medical research, we also cooperate with Dr hab. Andrzej Mogielnicki's team from the Medical University of Białystok and the aforementioned team from JU Chair in Pharmacology. Next stages of the project will require a lot more funding, however. We could receive a substantial grant from the National Research and Development Centre, but we'd have to apply for it jointly with a pharmaceutical company. The problem is, those companies are not eager to engage themselves in projects in the early stages of development.

The future looks bright

The results of your study met with great interest of both Polish and foreign press. Which of your publications are the most prestigious?

In 2008, our work was published in Biomacromolecules, an important journal of the American Chemical Society. It reverberated in both the chemical and the medical academic environment. We've also been published in the Journal of Medicinal Chemistry and European Journal of Pharmacology. Our works are quoted by other researchers. Recently, we published an article in the PLoS One journal, in which we summarised our research to date. In it, we argued that cationically charged dextran and synthetic block polymer are just as safe as protamine when tested on cells and mice. Further reassurance of these substances' safety will come after large animal and human testing.

The method of heparin neutralisation you discovered is currently undergoing the process of patenting. It may very well soon be used by doctors. Will it be successful in medicine?

Yes, our method of heparin neutralisation is being patented. However, it's too early to be sure of any therapeutic uses of our polymers. The history of medicine holds many examples of promising substances which were later proven to be detrimental. In fact, nowadays most medications turn out this way because of the very rigorous regulations. Interestingly enough, protamine, introduced fifty years ago and widely used to this day, wouldn't be able to meet the requirements that are adhered to today. We hope that our research soon proves polymers may be used instead of protamine. It would be a tremendous success, and would allow us to save many patients' lives and improve the working conditions of doctors. Nevertheless, we need further research conducted by interdisciplinary teams of doctors, pharmacologists and chemists. I've managed to create such a consortium and I'm currently trying to secure funding for our project, which will be participating in a contest organised by the National Science Centre.

Pictures
Top – left to right: Dr hab. Krzysztof Szczubiałka, prof. UJ, Prof. Maria Nowakowska, Dr Kamil Kamiński
Bottom – Chitosan microspheres covered by erythrocytes

Original text: www.nauka.uj.edu.pl

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