Anticoagulant

Anticoagulants, commonly referred to as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as test tubes, serum-separating tubes, blood transfusion bags, and dialysis equipment.

Anticoagulants are closely related to antiplatelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation. Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit the coagulation cascade by clotting factors that happens after the initial platelet aggregation.

Common anticoagulants include warfarin and heparin.^[1]

Medical uses

The use of anticoagulants is a decision based upon the risks and benefits of anticoagulation. The biggest risk of anticoagulation therapy is the increased risk of bleeding. In otherwise healthy people, the increased risk of bleeding is minimal, but those who have had recent surgery, cerebral aneurysms, and other conditions may have too great of risk of bleeding. Generally, the benefit of anticoagulation is prevention of or reduction of progression of a disease. Some indications for anticoagulant therapy that are known to have benefit from therapy include:

• Atrial fibrillation — commonly forms an atrial appendage clot
• Coronary artery disease
• Deep vein thrombosis — can lead to pulmonary embolism
• Ischemic stroke
• Hypercoagulable states (e.g., Factor V Leiden) — can lead to deep vein thrombosis
• Myocardial infarction
• Pulmonary embolism
• Restenosis from stents

In these cases, anticoagulation therapy can prevent formation of dangerous clots or prevent growth of clots.

The decision to begin therapeutic anticoagulation often involves the use of multiple bleeding risk predictable outcome tools as non-invasive pre-test stratifications due to the potential for bleeds while on blood thinning agents. Among these tools are HAS-BLED,^[2] ATRIA,^[3] and CHA2DS2-VASc.^[4]

Adverse effects

Patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years.^[5] Depletion of vitamin K by coumadin therapy increases risk of arterial calcification and heart valve calcification, especially if too much vitamin D is present.^[6]

Interactions

Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John’s wort, turmeric, wheatgrass, and willow bark.^[7] Many herbal supplements have blood-thinning properties, such as danshen and feverfew. Multivitamins that do not interact with clotting are available for patients on anticoagulants.

However, some foods and supplements encourage clotting. These include alfalfa, avocado, cat's claw, coenzyme Q10, and dark leafy greens such as spinach. Their intake should be avoided whilst taking anticoagulants or, if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability.

Grapefruit interferes with some anticoagulant drugs, increasing the amount of time it takes for them to be metabolized out of the body, and so should be eaten only with caution when on anticoagulant drugs.

Anticoagulants are often used to treat acute deep vein thrombosis. People using anticoagulants to treat this condition should avoid using bed rest as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way.^[8] Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.^[8]

Types

A number of anticoagulants are available. The traditional ones (warfarin, other coumarins and heparins) are in widespread use. Since the 2000s a number of new agents have been introduced that are collectively referred to as the novel oral anticoagulants (NOACs) or directly acting oral anticoagulants (DOACs). These agents include direct thrombin inhibitor(dabigatran) and factor Xa inhibitor (rivaroxaban, apixaban and edoxaban) and they have been shown to be as good or possibly better than the coumarins with less serious side effects.^[9] The newer anticoagulants (NOACs/DOACs), are more expensive than the traditional ones and should be used with care in patients with kidney problems. Additionally, there is no antidote for the factor Xa inhibitors, so it is difficult to stop their effects in the body in cases of emergency (accidents, urgent surgery). Idarucizumab was FDA approved for the reversal of dabigatran in 2015.^[10]

Novel oral anticoagulants

Non Vitamin K antagonist oral anticoagulants (NOACs) inhibit clot formation and unlike warfarin are not Vitamin K antagonists.^[11]

The abbreviation has also been explained as novel oral anticoagulants.^[12] The most commonly prescribed NOACs are dabigatran, rivaroxaban, and apixaban.

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.^[13] 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.^[12] 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. A reversal agent for dabigatran, idarucizumab, is currently the only NOAC reversal agent approved for use by the FDA.

NOACs are a lot more expensive than warfarin, after having taken into consideration the cost of frequent blood testing associated with warfarin.

Relevance to dental treatments

With regards to NOAC medication and invasive dental treatments, there has not been enough clinical evidence and experience to prove any reliable side-effects, relevance or interaction between these two. Further clinical prospective studies on NOACs are required to investigate the bleeding risk and haemostasis associated to surgical dental procedures.^[14]

Recommendations of modifications to use/dosage of NOACs prior to dental treatments are made based on the balance of likely effects of each option of each procedure, and also the individual’s bleeding risks and renal functionality. With low bleeding risk of dental procedures, it is recommended that NOAC medicine is still taken by patient as per normal, so as to avoid increase in the risk of thromboembolic event. For dental procedures with a higher risk of bleeding complications, the recommended practice is for patient to miss or delay a dose of their NOAC before such procedures so as to minimize the effect on thromboembolic risk.

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). 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. Other examples are acenocoumarol, phenprocoumon, atromentin, and phenindione.

The coumarins brodifacoum and difenacoum are used as rodenticides, but are not used medically.

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. Heparin can be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in or on medical devices. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually have a green cap.

Low molecular weight heparin

Low molecular weight heparin, a more highly processed product, is useful as it does not require monitoring of the APTT coagulation parameter and has fewer side effects.

Synthetic pentasaccharide inhibitors of factor Xa

• 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.
• Idraparinux

Direct factor Xa inhibitors

Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike the heparins and fondaparinux, which work via antithrombin activation). Also betrixaban from Portola Pharmaceuticals, darexaban (YM150) from Astellas, and more recently letaxaban (TAK-442) from Takeda and eribaxaban (PD0348292) from Pfizer. The development of darexaban was discontinued in September 2011: in a trial for prevention of recurrences of myocardial infarction in top of dual antiplatelet therapy, the drug did not demonstrate effectiveness and the risk of bleeding was increased by approximately 300%.^[15] The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following negative results from a Phase II study.^[16]

Direct thrombin inhibitors

Another type of anticoagulant is the direct thrombin inhibitor.^[17] Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin; and the monovalent drugs argatroban and dabigatran. An oral direct thrombin inhibitor, ximelagatran (Exanta) was denied approval by the Food and Drug Administration (FDA) in September 2004 and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. In November 2010, dabigatran was approved by the FDA to treat atrial fibrillation.

Antithrombin protein therapeutics

The antithrombin protein itself is used as a protein therapeutic that can be purified from human plasma^[18] or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats.^[19][20])

Antithrombin is approved by the FDA as an anticoagulant for the prevention of clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.^[18][20]

Other types of anticoagulants

Many other anticoagulants exist, for use in research and development, diagnostics, or as drug candidates.

• Batroxobin, a toxin from a snake venom, clots platelet-rich plasma without affecting platelet functions (lyses fibrinogen).
• Hementin is an anticoagulant protease from the salivary glands of the giant Amazon leech, Haementeria ghilianii.
• Vitamin E

Laboratory use

Laboratory instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and become non-operational if blood is allowed to clot. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Apart from heparin, most of these chemicals work by binding calcium ions, preventing the coagulation proteins from using them.

• Ethylenediaminetetraacetic acid (EDTA) strongly and irreversibly chelates (binds) calcium ions, preventing blood from clotting.
• Citrate is in liquid form in the tube and is used for coagulation tests, as well as in blood transfusion bags. It binds the calcium, but not as strongly as EDTA. Correct proportion of this anticoagulant to blood is crucial because of the dilution, and it can be reversed with the addition of calcium. It can be in the form of sodium citrate or acid-citrate-dextrose.
• Oxalate has a mechanism similar to that of citrate. It is the anticoagulant used in fluoride oxalate tubes used to determine glucose and lactate levels.

See also

• Hypercoagulability in pregnancy
• Nitrophorin
• CHADS2 score

References

External links

• Staying Active and Healthy with Blood Thinners by the Agency for Healthcare Research and Quality
• New oral anticoagulants for stroke prevention in atrial fibrillation