Anticoagulant drugs: list and side effects

By Cristiano Antonino On Jul 27, 2022

Let’s talk about anticoagulant drugs: an anticoagulant is a compound capable of slowing down or interrupting the blood clotting process, used both in laboratory medicine, e.g. in blood counts, and in the form of drugs to regulate blood fluidity, and are used both for preventive purposes when a patient is at high risk of thrombosis, e.g. after a bone fracture (e.g. femur fracture in the elderly), after surgery or during atrial fibrillation, or for therapeutic purposes, when thrombosis has already occurred and it is necessary to prevent the detachment or extension of the thrombus

Thrombolytics, anticoagulants or antiaggregants?

Thrombolytics (streptokinase, urokinase…) are used in all those conditions in which the thrombus has already formed, while antiplatelet agents (Aspirin, Plavix…) and anticoagulants (heparin, dicumarol…) are administered to prevent the formation of new thrombi.

Anticoagulants and antiaggregants together

Taking anticoagulants and anti-platelets at the same time is not impossible, but must be done in selected cases and ONLY UNDER STRICT MEDICAL CONTROL, since they increase their potential effect synergistically.

It is ALWAYS important to inform your doctor of any antiplatelet drug therapy you are undergoing.

Anticoagulants and optimal INR

The effect of anticoagulants is highly variable between individuals and can vary over time even for the same individual.

The amount of the drug needed per person can be very different, with doses as much as ten times higher between individuals, as well as varying within the same individual.

Changing the order of magnitude, the subjective component is such a relevant element that, in order to assess the efficacy of the drug, it is necessary to refer not to the quantity taken, as is commonly the case, but to a laboratory test that measures the time it takes the blood to clot (prothrombin activity time).

The prothrombin time (TP) is measured with the percentage index INR (Index Normalized Ratio) which is the safest and most correct index we have: INR = patient TP / normal subject TP.

Values below 2 indicate blood that is too thick, while values above 3.5 indicate blood that is too fluid, above 4 the risk of even fatal bleeding.

In atrial fibrillation, on the other hand, a prothrombin activity of 40 per cent on average, or an INR of 2-2.5, is usually sufficient.

Patients administered anticoagulants are required to have a periodic blood test to measure their prothrombin time.

Anticoagulants: Heparin

Heparin is a glycosaminoglycan physiologically present in the secretory granules of mast cells.

The molecules interact with circulating antithrombin to provide a natural antithrombotic defence.

In therapy it is administered parenterally because it is not absorbed by the intestinal mucosa.

With intravenous administration (in continuous infusion or intermittent boluses) the antithrombotic action begins immediately; with subcutaneous administration (possible in the case of calcine heparin or low molecular weight heparins) the onset of action is delayed by one to two hours.

The use of heparin is also possible when oral anticoagulants are contraindicated, e.g. in pregnancy, as the molecule does not cross the placenta.

Of the complications, the most frequent are haemorrhagic manifestations, which are dose-dependent and may affect either the injection site (bruising or haematomas) or distant sites (epistaxis, haematuria, etc.).

The most dreaded complication is Heparin-induced thrombocytopenia (HIT syndrome): this is, paradoxically, a potentially fatal prothrombotic complication observed in 3% of patients treated with unfractionated heparin (ENF) and 0.5% of those treated with Low Molecular Weight Heparin (EBPM).

Its occurrence is much more frequent in surgical patients than in internal medicine patients.

Oral anticoagulants

Anticoagulant therapy constitutes the treatment of choice in the primary and secondary prevention of stroke in patients with atrial fibrillation (valvular and non-valvular), and of pulmonary embolism in patients with venous thrombosis: in particular with indirect oral anticoagulants if there is a moderate or high risk of venous thrombosis.

Dabigatran and factor X inhibitors from were a few years ago authorised in Europe for the primary prevention of the risk of venous thromboembolism in adults undergoing elective knee or hip replacement surgery, instead of the more familiar subcutaneous injections of heparin into the abdomen.

Warfarin, acenocoumarol, fenprocumone

Warfarin, acenocoumarol, fenprocumone are derived from dicumarol, a coumarin variant.

They are called indirect anticoagulants as they do not block the coagulation cascade but inhibit the formation of vitamin K-dependent coagulation factors (factor II, VII, IX and X) upstream.

Their full action is reached a few days after the start of administration, but the quantity to be administered must be monitored by periodically checking the INR, given the great variability in the absorption of the molecule (from subject to subject, and with daily doses that can vary greatly within the same week) and the interference with a very large number of substances (drugs and foodstuffs).

Even if the INR in the blood is checked two to three times a month, only 60% of patients treated with warfarin are maintained at an ideal INR between 2 and 3.

This type of antiplatelet (dicumarol) and vitamin K are competitive antagonists: vitamin K can be used in the event of an overdose of these drugs (before a haemorrhage starts) to reduce their effect.

Conversely, caution must be exercised when eating foods rich in vitamin K, due to drug interactions (micrograms = 1/1000 mg, per 100 g/uncooked edible portion:

very high (>1 milligram): basil if dried, thyme, sage (1 700 μg), parsley, dried coriander leaves
for bio-availability, although the phylloquinone content is much lower: spinach (498 µg), cabbage, broccoli, cauliflower.

Cooking does not remove significant amounts of vitamin K from food, and therefore does not change the risk of drug interaction.

On the other hand, already at 40 °C vitamin C, which is present in many of these foods, is destroyed to counterbalance the possible coagulating effect of vitamin K.

Vitamin C has a daction against clots (formed by lipids, cholesterol, calcium, macrophages and sometimes dead cells or mortar removed from them), because it is generally able to bind calcium well: it promotes the absorption of calcium from food during digestion – while it remains to be proven whether it also promotes absorption from the blood into bones and tissues, and frees clogged capillaries when the infection is in progress.

Like the other fat-soluble vitamins, vitamin K accumulates in the body, so in addition to the dose/day probably not exceeded, the amount of food ingested in the reference of a week is also important.

In the case of tomatoes and fennel, cooking has a partial inactivating effect on vitamin K.

A more important food-anticoagulant interaction is with garlic and onion, which are inhibitors of thromboxane – which with ADP is necessary for platelets to accumulate in the clot last to form the haemostatic plug.

Garlic contains ajoene and adenosine, onion adenosine (whose receptors regulate blood flow in the coronary arteries).

In addition, they contain bioavailable sulphur: the correct balance of sulphur amino acids (Sulphur amino acids -SAAs) such as cysteine, homocysteine, methionine and taurine, is considered a cardiovascular risk factor, however, with regard to the blood circulation thinning properties it must be considered that blood vessel dilation depends mainly on arginine and ornithine, which do not contain sulphur in their molecule, nor do they appear to be directly affected by interaction with sulphur amino acids.

Acetylsalicylic acid does not belong to the anticoagulant class of drugs, but nevertheless has an antiplatelet and blood-thinning effect and is often used with an enhancing effect in combination with anticoagulant drugs (e.g. clopidogrel).

In addition to the interaction between anticoagulants and vitamin K-rich foods (which reduce the efficacy of some drugs), the potentiating effect of foods rich in salicylic acid is not negligible.

Among the vegetables with the highest salicylic levels we have:

very high (> 1 mg): blackberries, blueberries, pears from the Indies, sultanas; peppers, tomatoes, radicchio, chicory; almonds, peanuts; Canella, cumin, curry powder, dried dill, garam masalla, oregano, hot chilli peppers, rosemary, thyme, turmeric, mustard;
high (between 0.5 and 1 mg): alfalfa, broccoli, cucumber, broad beans, spinach, sweet potatoes, granny smith apples, fresh avocado, cherries, red grapes, fresh tangerine, fresh tangelo, pine nuts, macadamia nuts, pistachio nuts, vegemite.

The doses of ASA in drugs are much higher, in the order of 0.6-0.9 g/day in children and 1-3 g/day in adults, so they are unlikely to be significantly altered by the amount of salicylates consumed through food (even if we eat a few ounces of the highest salicylate-containing foods, we get a few mg), and the interaction between foods with salicylates and drugs containing ASA is therefore negligible.

On the other hand, the interaction between foods with salicylates (mg/ 100 g edible portion) and coumarin anticoagulant drugs is not, since they are taken in doses of the same order of magnitude (2.5-5 mg/day), besides the fact that it is under investigation and not entirely clear how ASA potentiates the effect of certain anticoagulants, and the related side effect of internal haemorrhage, in particular cerebral haemorrhage and/or on elderly subjects, who are then also those most exposed to the opposite thrombotic risk.

Dabigatran

Recently introduced, dabigatran is a direct thrombin inhibitor.

It is administered orally and does not require monitoring by periodic INR checks or dosage adjustments.

Its efficacy and safety were equal to or better than those of adjusted doses of warfarin in patients with non-valvular atrial fibrillation followed for at least two years in a clinical trial.

Interactions with supplements and herbal medicines

Drug interactions are possible between dietary supplements, herbal medicines and oral anticoagulants:

enhance anticoagulant effect: ganoderma japonicum, salvia miltiorrhiza, ginkgo, cinchona, garlic, St. John’s Wort, white willow, spirea, tamarind;
diminish the anticoagulant effect: passion flower, juniper, verbena officinale and ginseng.

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