Blood clotting, medically called haemostasis or coagulation, is a very complicated process by which blood turns from a liquid into a solid, called a clot. The process is crucial for maintaining blood circulation in all higher animals; clots form, plugging broken blood vessels and preventing blood loss from ruptured veins or arteries. If blood could not clot, even the slightest cut could be fatal, as has been the case for haemophiliacs, until quite recently. Clot formation is a final effect of a sequence of reactions among about 30 proteins called coagulation factors. A product of one reaction is usually used in another reaction, and the complete set of these reactions is usually called a coagulation cascade. The cascade-like nature of blood coagulation explains why blood may not coagulate properly if even a single coagulation factor is absent, defective, or present in blood in an abnormal concentration. Thus, weak blood clotting may lead to haemorrhages, while excessive coagulation may cause the formation of clots within blood vessels. Both situations may be life-threatening, causing heart infarcts, brain strokes or serious diseases like deep vein thrombosis or pulmonary embolism.
Even normal blood coagulation may be dangerous, for example, in coronary heart disease, in which the coronary heart arteries are pathologically narrowed and may become plugged even by small clots traveling in the blood stream, which are otherwise harmless, or during medical procedures requiring blood to flow out of the patient’s body, such as cardiac surgeries. In any of these cases, blood coagulation may be limited by the use of drugs called anticoagulants, or blood thinners (although the latter term is a misnomer since these drugs do not influence the viscosity, or thickness, of blood). Probably the best known anticoagulant is heparin, which is also one of the oldest and fastest-acting.
As useful as anticoagulants are medically, they can be a double-edged sword. The action of anticoagulants may be complicated by many factors (such as eating foods rich in Vitamin K) and may have possible negative effects. Therefore, although patients taking anticoagulants undergo frequent coagulation tests, the risk of a haemorrhage remains very high in this group. If a massive haemorrhage occurs, the action of the anticoagulant should be immediately halted, or inhibited. Thus, a safe anticoagulant should have an efficient and fast-acting antidote, which would return normal blood clotting and stop haemorrhage.
Currently, only the type of heparin called unfractionated heparin (UFH) can be fully and immediately inhibited. This can take place when protamine, a basic protein obtained from semen of salmon-like fish, is administered intravenously. However, even in this case inhibition can be problematic since protamine can cause severe allergic reactions and potentially fatal side effects like anaphylactic shock or blood pressure drop. Of patients who are given protamine after heart surgery, nearly 2000 die a year in the U.S. alone. In order to reverse such outcomes, the quests for better anticoagulants, on one hand, and for safer and more efficient antidotes, on the other, continue.
A team of scientists working in the Department of Chemistry, Jagiellonian University, Kraków, Poland, headed by Dr. Krzysztof Szczubiałka, have synthesized and tested polymers that may be safer than protamine in neutralizing heparin. They are mostly based on polysaccharides—widespread, nontoxic, nonallergenic, and inexpensive biopolymers (i.e. polymers produced by living organisms). By properly chemically modifying these polymers, the scientists obtained substances that may act as alternatives to protamine. Chemical laboratory tests have shown that the molecules of modified polysaccharides halt heparin by attaching to its molecules. Particularly promising are derivatives of dextran, a polysaccharide that is already used in medicine to create blood replacement fluids. Recent tests, performed by the collaborating group headed by Professor Włodzimierz Buczko from Medical University of Białystok, Poland, have shown that modified dextran may be as efficient as protamine in neutralizing heparin in vivo in rats and mice, while not showing the dire side effects of protamine. These studies, if successful, may significantly improve the safety of heparin reversal. Given that millions of heart surgeries use protamine worldwide each year, and thousands of patients experience potentially fatal side effects, a safer alternative to protamine may save many human lives.
Jagiellonian University in Krakow