Anticoagulant

Antithrombotic agents
Drug class
Class identifiers
ATC code B01
External links
MeSH D00534-class

Anticoagulants are a class of drugs that work to prevent blood coagulation (clotting). Such substances occur naturally in leeches and blood-sucking insects. A group of pharmaceuticals called anticoagulants can be used as an injection as a medication for thrombotic disorders. Oral anticoagulants are also available. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis equipment.

Anticoagulants are closely related to antiplatelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation. Specifically, anticoagulants manipulate the coagulation cascade that builds upon the initial platelet thrombus.

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:

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,[1] ATRIA,[2] and CHA2DS2-VASc.[3]

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.[4] Depletion of vitamin K by coumarin therapy increases risk of arterial calcification and heart valve calcification, especially if too much vitamin D is present.[5]

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.[6] 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.[7] Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.[7]

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 inhibitors of factor IIa (dabigatran) and factor Xa (rivaroxaban, apixaban and edoxaban) and they have been shown to be as good or possibly better than the coumarins with less serious side effects.[8] 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.[9]

Novel Oral Anticoagulants (NOACs)

Novel Oral Anticoagulants (NOACs) are a new class of anticoagulant drugs, which like warfarin, can help inhibit clot formation.[10] Most commonly prescribed NOACs are dabigatran, rivaroxaban, and apixaban.

Compared to warfarin, NOACs has a rapid onset action & relatively short half-lives and hence they carry out their function more rapidly and effectively, also allow for drugs to quickly reduce their anticoagulation effects as a result of the short half-life.[11]

Routine monitoring and dose adjustments of NOACs is less important than warfarin as they have better predictable anticoagulation activity. Both NOACs & warfarin are equivalently effect, but NOACs are less influenced by diet and medications compared to warfarin.[10] However, there is presently no countermeasure for NOACs unlike in warfarin; nonetheless, the short half-lives of NOACs will result in its effects to swiftly recede. Antidotes to NOACs are currently still in development.[11]

NOACs are a lot costlier compared to 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.[12]

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)

Further information: Vitamin K antagonist

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 (it has more predictable plasma levels) and has fewer side effects.

Synthetic pentasaccharide inhibitors of factor Xa

Direct factor Xa inhibitors

Main article: Direct Xa inhibitor

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 (LY517717) from Portola Pharmaceuticals, darexaban (YM150) from Astellas and more recent TAK-442 letaxaban (Takeda) and eribaxaban (PD0348292) (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%.[13] The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following negative results from a Phase II study.[14]

Direct thrombin inhibitors

Another type of anticoagulant is the direct thrombin inhibitor.[15] 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[16] or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats.[17][18])

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.[16][18]

Other types of anticoagulants

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

Society and culture

Warfarin (Coumadin) is the main agent used in the US and UK.[19] Acenocoumarol and phenprocoumon are used more commonly outside the US and the UK.

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.

See also

References

  1. ↑ "HAS-BLED Score for Major Bleeding risk". MDCalc. Retrieved 2014-08-15.
  2. ↑ "ATRIA Bleeding Risk". MDCalc. Retrieved 2014-08-15.
  3. ↑ "CHA2DS2-VASc". MDCalc. Retrieved 2014-08-15.
  4. ↑ Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S (2007). "Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation". Circulation 115 (21): 2689–96. doi:10.1161/CIRCULATIONAHA.106.653048. PMID 17515465.
  5. ↑ Adams J, Pepping J (1 Aug 2005). "Vitamin K in the treatment and prevention of osteoporosis and arterial calcification" (PDF). American Journal of Health-System Pharmacy 62 (15): 1574–81. doi:10.2146/ajhp040357. PMID 16030366. Retrieved 2012-10-03.
  6. ↑ Wittkowsky AK (September 2001). "Drug interactions update: drugs, herbs, and oral anticoagulation". J. Thromb. Thrombolysis 12 (1): 67–71. doi:10.1023/A:1012742628628. PMID 11711691.
  7. 1 2 American Physical Therapy Association (15 September 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (American Physical Therapy Association), retrieved 15 September 2014, which cites
    • Aissaoui, Nadia; Martins, Edith; Mouly, Stéphane; Weber, Simon; Meune, Christophe (2009). "A meta-analysis of bed rest versus early ambulation in the management of pulmonary embolism, deep vein thrombosis, or both". International Journal of Cardiology 137 (1): 37–41. doi:10.1016/j.ijcard.2008.06.020. ISSN 0167-5273.
    • Anderson, Cathy M.; Overend, Tom J.; Godwin, Julie; Sealy, Christina; Sunderji, Aisha (2009). "Ambulation after Deep Vein Thrombosis: A Systematic Review". Physiotherapy Canada 61 (3): 133–140. doi:10.3138/physio.61.3.133. ISSN 0300-0508.
  8. ↑ Werdan, Karl; Braun-Dullaeus, Rüdiger; Presek, Peter (Aug 2013). "Anticoagulation in Atrial Fibrillation: NOAC’s the Word". Deutsches Ärzteblatt International 110 (31-32): 523–524. doi:10.3238/arztebl.2013.0523. PMC 3782018. PMID 24069072. Things have changed dramatically with the introduction of the new oral anticoagulants (NOACs) — dabigatran, a factor IIa (thrombin) inhibitor, and the factor Xa inhibitors rivaroxaban and apixaban. Clinical trials have shown them therapeutically superior, or at least non-inferior, to VKAs, with less serious side effects.
  9. ↑ http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm467396.htm
  10. 1 2 "Novel anticoagulants".
  11. 1 2 "SDCEP Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs" (PDF).
  12. ↑ Costantinides, Fulvia; Rizzo, Roberto; Pascazio, Lorenzo; Maglione, Michele (2016-01-28). "Managing patients taking novel oral anticoagulants (NOAs) in dentistry: a discussion paper on clinical implications". BMC Oral Health 16. doi:10.1186/s12903-016-0170-7. ISSN 1472-6831. PMC 4731944. PMID 26822674.
  13. ↑ Steg, PG; Mehta, SR; Jukema, JW; Lip, GY; Gibson, CM; Kovar, F; Kala, P; Garcia-Hernandez, A; Renfurm, RW; Granger, CB; Ruby-1, Investigators (2011). "RUBY-1: A randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome". European Heart Journal 32 (20): 2541–54. doi:10.1093/eurheartj/ehr334. PMC 3295208. PMID 21878434.
  14. ↑ First Time European Approval for Xarelto in ACS http://decisionresources.com/The-Decision-Resources-Blog/May-2013/European-Approval-for-Xarelto-in-ACS-052913
  15. ↑ Di Nisio M, Middeldorp S, Büller HR (2005). "Direct thrombin inhibitors". N. Engl. J. Med. 353 (10): 1028–40. doi:10.1056/NEJMra044440. PMID 16148288.
  16. 1 2 Thrombate III label
  17. ↑ FDA website for ATryn (BL 125284)
  18. 1 2 Antithrombin (Recombinant) US Package Insert ATryn for Injection February 3, 2009
  19. ↑ Ron Winslow; Avery Johnson (2007-12-10). "Race Is on for the Next Blood Thinner". Wall Street Journal. p. A12. Retrieved 2008-01-06. ...in a market now dominated by one of the oldest mainstay pills in medicine: the blood thinner warfarin. At least five next-generation blood thinners are in advanced testing to treat or prevent potentially debilitating or life-threatening blood clots in surgery and heart patients. First candidates could reach the market in 2009.

External links

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