How blood thinners work

Blood Thinners: a general overview on anticoagulants and antiplatelet medications

Blood-thinners are a class of drugs used to prevent the formation of blood clots in the blood vessels, which in turn helps reducing the occurrence of serious life-threatening conditions such as deep vein thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism. Blood-thinners are also widely used worldwide to prevent or reduce the risk for other serious conditions such as myocardial infarction, atrial fibrillation and ischemic stroke and to treat genetic and/or acquired conditions such as hypercoagulability.

Blood-thinners are divided in two broad categories: anticoagulants that prevent or lengthen the time it takes to form a blood clot (warfarin, heparins and inhibitors of factor Xa are some examples), and antiplatelet drugs, that prevent platelets from clumping together and form a clot (the most common example is aspirin).

Antiplatelet drugs are mostly used on the long-term prevention of thrombotic cerebrovascular or cardiovascular disease in patients who underwent heart prosthetics surgery, for example valve replacement surgery and after angioplasty and stent placement. All antiplatelet drugs share a common general mechanism of action, although some differences are still present. Overall they prevent the aggregation of platelets, a blood cell population that “groups together” wherever an injury or foreign body is present within the organism, forming a blood clot. Although the risk of bleeding is still present even with antiplatelet drugs, the chance of a life-threatening massive hemorrhage is very low. Nonetheless, if severe bleeding occurs, transfusion of platelets can be used to restore platelet function within the body.

Probably the most known antiplatelet agent is the acetylsalicylic acid (ASA), also known as aspirin. Originally developed as a nonsteroidal anti-inflammatory drugs (NSAID), it was later discovered that a low-dose daily aspirin intake may help prevent heart attacks and strokes. Aspirin mechanism of action consists of an irreversible inhibition of both the two variants of the enzyme cyclooxygenase (COX-1 and COX-2). As the COX-1 enzyme is responsible for the formation of thromboxane (TX)A2, a low dose of aspirin may reduce the formation of blood clots.

Several other types of antiplatelet drugs are available on the market, all with different mechanisms of actions: Reversible P2Y12 Antagonists (ticagrelor, cangrelor, elinogrel), Phosphodiesterase inhibitors (cilostazol), Glycoprotein IIB/IIIA inhibitors (abciximab, eptifibatide, tirofiban), and many others. Arguably, the most relevant of these categories however, are the Thienopyridines (clopidogrel, prasugrel, ticlopidine), that inhibit adenosine diphosphate (ADP)-dependent platelet function by irreversible modification of the platelet P2Y12 receptor. Clopidogrel was in fact was the second most sold drug in the world: before its patent expired in 2010, it grossed over USD $9 billion in sales, and it should be noted how 2010 was the same year when Xarelto was actually approved in the US market.

Anticoagulant drugs are quite a few, and they’re both used as short- and long-term treatments.

Heparins are injectable anticoagulants mostly used for short to medium-term treatment, and act by binding to the enzyme antithrombin III (AT), which then inhibits thrombin and factor Xa, effectively preventing blood clots from forming. As heparin is a biological substance, there are several types of heparins, the most useful of which is the Low molecular weight one, as it does not require coagulation parameters monitoring. All the other heparins instead require a continuous monitoring of the activated partial thromboplastin time (APTT).

The oldest and most known anticoagulant is the Vitamin-K inhibitor dicumarol. After its discovery in 1930, dicumarol was originally marketed in 1948 as a rat poison with the commercial name of “warfarin”. A few years later, a soldier tried to kill himself not to be enlisted into the Korean War by eating several doses of this drug, later to be saved by the doctors through the administration of a strong quantity of vitamin K. After this accident, a pharmaceutical warfarin-based drug called Coumadin was later approved by the FDA in 1954, to treat several blood-clotting conditions that were related to strokes. A Vitamin-K antagonist, Warfarin inhibits the synthesis of active forms of the calcium-dependent clotting factors II, VII, IX and X, and the regulatory factors protein C, protein S, and protein Z. Warfarin dosage needs to be constantly titrated by continuous monitoring of his actual degree of anticoagulation through prothrombin ratio (PR) and international normalized ratio (INR) measurements. Warfarin may in fact negatively interacts with several foods containing high Vitamin-K amounts such as spinach, kale, cabbage or broccoli, forcing the patient to follow a strict alimentary restriction. Warfarin can be also deadly if not correctly dosed (thus the need for continuous monitoring), as it poses a serious potential risk for internal bleeding and hemorrhages, although the quick administration of intravenous vitamin K may still reverse its effect. As in the case of all other anticoagulants, clinically and/or major relevant bleeding event rates during warfarin therapy may significantly increase up to double if the patients takes most common over-the-counter painkillers such as non-steroidal anti-inflammatory drugs (NSAIDs).

The last group of anticoagulants are the Novel Oral Anticoagulants (NOACs). Some of them act by interrupting the intrinsic and extrinsic pathways of the blood coagulation cascade through a direct inhibition of the Factor Xa. Among these are included rivaroxaban (Xarelto), apixaban (Eliquis) and edoxaban (Lixiana). Direct thrombin inhibitors (DTI) instead directly inhibit the enzyme thrombin (factor II), and the most common of them are Dabigatran (Pradaxa) and Argatroban, although this last one is only used as substitutes of the heparins, when those drugs cannot be used because of heparin-induced thrombocytopenia. A third DTI’s production, Ximelagatran, was stopped as it was associated with several cases of liver failure.

One of the major selling points of NOACs is the fact that they do not require continuous monitoring from the patient, nor dietary restrictions. However, in the case of a serious bleeding accident there’s no antidote available, and for this reason Xarelto and other NOACs are considered by many international agencies as high-alert medications with an “heightened risk of causing significant patient harm”. Due to the impossibility to reverse their effects, the overall lack of an antidote, and the inability of doctors to actually save a patient if a severe bleeding occurs, FDA reported that their risk is even higher than those that usually accompany treatment with antiblastic chemotherapy drugs such as carboplatin.

Article written by Dr. Claudio Butticè, Pharm.D.

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