Dr Arvind Kohli
What are Anticoagulants Anticoagulants are life-saving drugs used to prevent both arterial and venous clots. Arterial clots are the most common cause of Heart attacks(myocardial infarction), Brain stroke, and limb gangrene. Venous clots, which typically arise in legs, as Deep Vein thrombosis may travel to the lungs to create a pulmonary embolism which shuts off circulation to part of the lung, and may cause death. Anticoagulants are used to prevent these events, and are commonly given to patients with atrial fibrillation (irregular heart beat), mechanical heart valves, after hip surgery for prosthetic grafts deep vein thrombosis etcThese medications can save lives, but also lead to catastrophes. They are singled out as high-risk medications by several patient safety organizations: . They carry a heightened risk of causing significant harm to patients when administered incorrectly or in error. Sixty percent of life-threatening or lethal errors involve intravenous drugs such as Heparin
Pathogenesis
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 hemophiliacs, 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 hemorrhages, 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 . Probably the best known anticoagulant is heparin, which is also one of the oldest and fastest-acting
Various Anticoagulants
A number of anticoagulants are available.
Coumarins (vitamin K antagonists). These oral anticoagulants are derived from coumarin, which is found in many plants. A prominent member of this class is warfarin (Coumadin) and was found to be the dominant anticoagulant prescribed in a large multispecialty practice It takes at least 48 to 72 hours for the anticoagulant effect to develop. Where an immediate effect is required, heparin must be given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves.and prophylaxis for venous thrombosis .
Heparin and derivative substances.Heparin is a biological substance, usually made from pig intestines. It works by activating antithrombin III, which blocks thrombin from clotting blood. .usually refered as Unfractionated Heparin and its use needs close monitoring with APTT test Dosage has to be every eight hourly
Low molecular weight heparin, like Enoxaparin and dalteparin are more highly processed product, are useful as they do not require monitoring of the APTT coagulation parameter and has fewer side effects. It has to administered twice a day.
Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharide) in heparin that bind to antithrombin. It is a smaller molecule than low molecular weight heparin. It has a longer duration of action than LMW heparins and can be prescribed once a day
Directly acting oral anticoagulants
The directly acting oral anticoagulants (DOACs) were introduced on and after 2008. There are five DOACs currently on the market: dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. They were also previously referred to as “new/novel” and “non-vitamin K antagonist” oral anticoagulants (NOACs). .
Compared to warfarin, NOACs have a rapid onset action and relatively short half-lives; hence, they carry out their function more rapidly and effectively, and allow for drugs to quickly reduce their anticoagulation effects. Routine monitoring and dose adjustments of NOACs is less important than for warfarin, as they have better predictable anticoagulation activity.
Both NOACs and warfarin are equivalently effective, but NOACs are less influenced by diet and medications compared to warfarin. Additionally, rates of bleeding events for patients using NOACs are comparable to those of patients taking warfarin. However, there is presently no countermeasure for most NOACs unlike in warfarin; nonetheless, the short half-lives of NOACs will result in its effects to swiftly recede.
NOACs are a lot more expensive than warfarin, after having taken into consideration the cost of frequent blood testing (INR) associated with warfarin and safety of NOACS in pregnancy and neonates is still not established
What makes anticoagulants so dangerous? First, there is a narrow therapeutic window of safety in the use of these medications. The primary action of anticoagulants, to increase bleeding time, can lead to hemorrhage at any site in the body. There are multiple food and drug interactions with anticoagulants, making the response to these drugs unpredictable. Frequent monitoring of clotting time is necessary, requiring painful and frequent blood tests. Even when this monitoring occurs, the level of anticoagulation is outside the therapeutic range almost half of the time. The risk of major bleeding with long-term treatment increases in the elderly – the population most in need of Coumadin for treatment of atrial fibrillation. These risks dissuade many prescribers from using Coumadin. Hence DOACS have replaced coumadins for this
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 such as dark green leafy vegetables spinach, broccoli, etc and fish like trout, tuna, salmon, etc) and may have possible negative effects. Therefore, although patients taking anticoagulants undergo frequent coagulation tests, the risk of a hemorrhage remains very high in this group. If a massive hemorrhage 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 hemorrhage.
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. A reversal agent for dabigatran, idarucizumab, is currently the only NOAC reversal agent
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.
(The author is Vascular Surgeon SSH GMC Jammu)
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