Anticoagulant

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

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, 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:

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] In a meta-analysis studying the effects of warfarin use in patients with end stage renal disease and atrial fibrillation, there was no increased risk of stroke incidence with warfarin use, but there was a significantly increased risk of all-cause bleeding, compared to alternate treatments (aspirin, dabigatran, rivaroxaban) or no warfarin use.[7] Although poor adherence to anticoagulation therapy is associated with a higher risk of stroke among high-risk patients (i.e. those with a CHA2DS2‐VASc score ≥2), the benefits of anticoagulation therapy may not outweigh the harms in patients with CHA2DS2‐VASc score 0 or 1.[8]

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.[9] 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.[10] Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.[10]

Types

A number of anticoagulants are available. The traditional ones (warfarin, other coumarins and heparins) are in widespread use, which are commonly known as vitamin K anticoagulants/vitamin K antagonist; since the 2000s a number of new agents have been introduced that are collectively referred to as the novel oral anticoagulants (NOACs), non-vitamin K antagonist oral anticoagulants, or directly acting oral anticoagulants (DOACs).[11] 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.[12] 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.[13]

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.[14] 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

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.[15] They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs). Between 2013/Q2 and 2014/Q4, DOAC use tripled, exhibiting how quickly these new drugs have been adopted by health care providers and patients.[16]

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.[17] Routine monitoring and dose adjustments of NOACs is less important than for warfarin, as they have better predictable anticoagulation activity. In certain circumstances, OCT angiography has the potential for evaluating the effects of intensified antithrombotic therapy.[11]

Both NOACs and warfarin are equivalently effective, but NOACs are less influenced by diet and medications compared to warfarin.[18] Additionally, rates of bleeding events for patients using NOACs are comparable to those of patients taking warfarin.[19] 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. Rates of adherence to NOACs are only modestly higher than adherence to warfarin among patients prescribed these drugs, and thus adherence to anticoagulation is universally poor, despite hopes that NOACs would lead to higher adherence rates.[20]

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

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 (DAPT), the drug did not demonstrate effectiveness and the risk of bleeding was increased by approximately 300%.[21] The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following negative results from a Phase II study.[22]

Direct thrombin inhibitors

Another type of anticoagulant is the direct thrombin inhibitor.[23] 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.

NOAC 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.[24]

Recommendations of modifications to usage/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 still be taken by the 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.

Antithrombin protein therapeutics

The antithrombin protein itself is used as a protein therapeutic that can be purified from human plasma[25] or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats.[26][27])

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.[25][27]

Other types of anticoagulants

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

Coagulation inhibitor measurement

A Bethesda unit (BU) is a measure of blood coagulation inhibitor activity. It is the amount of inhibitor that will inactivate half of a coagulant during the incubation period.[28] It is the standard measure used in the United States, and is so named because it was adopted as a standard at a conference in Bethesda, Maryland.[29]

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

References

  1. ↑ 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.
  2. ↑ "HAS-BLED Score for Major Bleeding risk". MDCalc. Retrieved 2014-08-15.
  3. ↑ "ATRIA Bleeding Risk". MDCalc. Retrieved 2014-08-15.
  4. ↑ "CHA2DS2-VASc". MDCalc. Retrieved 2014-08-15.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Tan, Jingwen; Liu, Shuiqing; Segal, Jodi B.; Alexander, G. Caleb; McAdams-DeMarco, Mara (2016-10-21). "Warfarin use and stroke, bleeding and mortality risk in patients with end stage renal disease and atrial fibrillation: a systematic review and meta-analysis". BMC Nephrology. 17: 157. doi:10.1186/s12882-016-0368-6. ISSN 1471-2369.
  8. ↑ Yao, Xiaoxi; Abraham, Neena S.; Alexander, G. Caleb; Crown, William; Montori, Victor M.; Sangaralingham, Lindsey R.; Gersh, Bernard J.; Shah, Nilay D.; Noseworthy, Peter A. (2016-02-01). "Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation". Journal of the American Heart Association. 5 (2): e003074. doi:10.1161/JAHA.115.003074. ISSN 2047-9980. PMC 4802483. PMID 26908412.
  9. ↑ 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.
  10. 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. PMC 2787576.
  11. 1 2 Aik Kah, Tan (June 2018). "The potential for evaluating the effects of intensified antithrombotic therapy using retinal optical coherence tomography angiography". Medical Hypotheses. 115: 54–57. doi:10.1016/j.mehy.2018.03.022. ISSN 0306-9877.
  12. ↑ 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.
  13. ↑ http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm467396.htm
  14. ↑ Efird LE, Chasler J, Alexander GC, McGuire M (Jun 21, 2016). "Prescribing Patterns of Novel Anticoagulants Within a Statewide Multispecialty Practice". American Journal of Pharmacy Benefits. 8 (3): 97–102.
  15. ↑ Douxfils, J.; Ageno, W.; Samama, C.-M.; Lessire, S.; ten Cate, H.; Verhamme, P.; Dogné, J.-M.; Mullier, F. (February 2018). "Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians". Journal of Thrombosis and Haemostasis. 16 (2): 209–219. doi:10.1111/jth.13912. PMID 29193737.
  16. ↑ Barnes, Geoffrey D.; Lucas, Eleanor; Alexander, G. Caleb; Goldberger, Zachary D. "National Trends in Ambulatory Oral Anticoagulant Use". The American Journal of Medicine. 128 (12): 1300–1305.e2. doi:10.1016/j.amjmed.2015.05.044. PMC 4658248.
  17. ↑ "Management of Dental Patients Taking Anticoagulants or Antiplatelet Drugs" (PDF). Scottish Dental Clinical Effectiveness Programme. August 2015.
  18. ↑ "Novel anticoagulants".
  19. ↑ Chang, Hsien-Yen; Zhou, Meijia; Tang, Wenze; Alexander, G. Caleb; Singh, Sonal (2015-04-24). "Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study". BMJ. 350: h1585. doi:10.1136/bmj.h1585. ISSN 1756-1833. PMID 25911526.
  20. ↑ Yao, Xiaoxi; Abraham, Neena S.; Alexander, G. Caleb; Crown, William; Montori, Victor M.; Sangaralingham, Lindsey R.; Gersh, Bernard J.; Shah, Nilay D.; Noseworthy, Peter A. (2016-02-01). "Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation". Journal of the American Heart Association. 5 (2): e003074. doi:10.1161/JAHA.115.003074. ISSN 2047-9980. PMC 4802483. PMID 26908412.
  21. ↑ 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.
  22. ↑ First Time European Approval for Xarelto in ACS http://decisionresources.com/The-Decision-Resources-Blog/May-2013/European-Approval-for-Xarelto-in-ACS-052913 Archived 2014-07-19 at the Wayback Machine.
  23. ↑ 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.
  24. ↑ 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.
  25. 1 2 "Thrombate III label" (PDF). Archived from the original (PDF) on 2012-11-15.
  26. ↑ Research, Center for Biologics Evaluation and. "Fractionated Plasma Products - ATryn". www.fda.gov.
  27. 1 2 "Antithrombin (Recombinant) US Package Insert ATryn for Injection February 3, 2009" (PDF).
  28. ↑ "Bethesda unit". Biology Online. Retrieved 2009-02-14.
  29. ↑ Schumacher, Harold Robert (2000). Handbook of Hematologic Pathology. Informa Health Care. p. 583. ISBN 978-0-8247-0170-3.
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