Blood coagulation is the ability of blood to undergo transformation from a liquid form into a solid-like clot. Its primary goal is to prevent blood loss ensuing from the damage of a blood vessel. According to the Poisseuille law, the volume of liquid (in this case blood) leaking out from a tube (in this case disrupted blood vessel) is proportional to the fourth power of the tube radius. Therefore, a damage to even a small vessel could lead to fatal blood loss, provided the vessel can be quickly plugged by a clot before it is healed. Upon vessel repair the clot is dissolved as a result of a process called fibrinolysis.
Blood coagulation and fibrinolysis are kept in a delicate equilibrium called hemostasis. Any deviation from this equilibrium, is potentially life-threatening. Hemostatic pathologies, such as thromboembolism, underlying infacts and strokes, and, at the other extreme, haemorrhagic events are one of the leading causes of deaths worldwide.
Blood coagulation can be controlled using drugs called anticoagulants which reduce the tendency of blood to coagulate. The armamentarium of anticoagulants available is very wide. A well known example is heparin, a polymeric drug of natural origin. It is administered both in hospital settings (e.g. to prevent blood clotting during surgeries) and as subcutaneously injected self-administered drug. However, many anticoagulants share two major drawbacks. First, their anticoagulant action may be difficult to control and varies from patient to patient. Second, they either have no antidote (inhibitor), which could instantaneously stop their action in case of emergency such as a massive hemorrhage, the antidote shows severe adverse effects, or the antidote is only partially efficient. This is the case of protamine, the only available efficient inhibitor of intravenously administered heparin, which is, however, a weak inhibitor of subcutaneous heparin. Protamine itself may have very severe adverse effects including anaphylactic reactions, allergic reactions, and pulmonary hypotension. Thus, safer and efficient anticoagulants and anticoagulant inhibitors have been intensively searched for.
Goals of the research
Our research is focused on the synthesis, physicochemical characterization and in vitro and in vivo studies of both polymeric anticoagulants and polymeric inhibitors of heparin which could be safer than protamine. We also test the application of heparin inhibitors in bioanalytical assays.
Results
We have studied a wide range of cationic polymers which are able to inhibit heparin. Our studies evolved from modified natural polysaccharides such as dextran, hydroxypropylcellulose, cyclodextrins, to completely synthetic polymers, such as poly(allylamine hydrochloride) (PAH) modified with arginine and block copolymers composed of poly(ethylene glycol) block (PEG) and poly(3-methacryloylpropyltrimethylammonium chloride) block (PMAPTAC). The extensive optimization studies lead to the development of a Heparin Binding Copolymer (HBC) which in in vitro and in vivo (mice, rats) studies shows pharmacological parameters superior to those of protamine.
In the group of polymeric anticoagulants we have physicochemically and biologically characterized the di- and triblock copolymers containing neutral PEG block and anionic blocks of poly(sodium 4-styrenesulfonate) (PSSS) and poly(sodium 2-acrylamido-2-methyl-1-propylsulfonate) (PAMPS).
Collaboration
Poland
Prof. Andrzej Mogielnicki, Medical University of Białystok, Department of Pharmacodynamics
Prof. Em. Ryszard Korbut, Jagiellonian University, Collegium Medicum, Chair of Pharmacology
Japan
Prof. Shin-Ichi Yusa, University of Hyogo, Department of Applied Chemistry, Graduate School of Engineering, Kobe