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.
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, ATRIA, and CHA2DS2-VASc.
Patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years. Depletion of vitamin K by coumadin therapy increases risk of arterial calcification and heart valve calcification, especially if too much vitamin D is present. 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. 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.
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. 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. Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.
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), non-vitamin K antagonist oral anticoagulants, or directly acting oral anticoagulants (DOACs). These agents include direct thrombin inhibitor (dabigatran) and factor Xa inhibitor (rivaroxaban, apixaban, betrixaban and edoxaban) and they have been shown to be as good or possibly better than the coumarins with less serious side effects. The newer anticoagulants (NOACs/DOACs), are more expensive than the traditional ones and should be used with care in patients with kidney problems. There is an antidote for the factor Xa inhibitors - Andexxa. Also, Idarucizumab was FDA approved for the reversal of dabigatran in 2015.
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. 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.
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.
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. 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.
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. 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.
Both NOACs and warfarin are equivalently effective, but NOACs are less influenced by diet and medications compared to warfarin. Additionally, rates of bleeding events for patients using NOACs are comparable to those of patients taking warfarin. 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.
NOACs are a lot more expensive than warfarin, after having taken into consideration the cost of frequent blood testing associated with warfarin.
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%. The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following negative results from a Phase II study.
Another type of anticoagulant is the direct thrombin inhibitor. 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.
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.
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.
The antithrombin protein itself is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats.)
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. 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.
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.
...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.
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.
4-Hydroxycoumarins belong to a class of vitamin K antagonist (VKA) anticoagulant drug molecules derived from coumarin by adding a hydroxy group at the 4 position to obtain 4-hydroxycoumarin, then adding a large aromatic substituent at the 3-position (the ring-carbon between the hydroxyl and the carbonyl). The large 3-position substituent is required for anticoagulant activity.
The primary mechanism of the 4-hydroxycoumarin drugs is the inhibition of vitamin K epoxide reductase. These compounds are not direct antagonists (in the pharmaceutical sense) of vitamin K, but rather act to deplete reduced vitamin K in tissues. For this reason vitamin K antagonizes their effect, and this has led to the loose terminology of vitamin K antagonism.Acenocoumarol
Acenocoumarol is an anticoagulant that functions as a vitamin K antagonist (like warfarin). It is a derivative of coumarin and is generic, so is marketed under many brand names worldwide.Antiphospholipid syndrome
Antiphospholipid syndrome or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots (thrombosis) in both arteries and veins as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia.
The diagnostic criteria require one clinical event (i.e. thrombosis or pregnancy complication) and two antibody blood tests spaced at least three months apart that confirm the presence of either lupus anticoagulant or anti-β2-glycoprotein-I (since β2-glycoprotein-I antibodies are a subset of anti-cardiolipin antibodies, an anti-cardiolipin assay can be performed as a less specific proxy).Antiphospholipid syndrome can be primary or secondary. Primary antiphospholipid syndrome occurs in the absence of any other related disease. Secondary antiphospholipid syndrome occurs with other autoimmune diseases, such as systemic lupus erythematosus (SLE). In rare cases, APS leads to rapid organ failure due to generalised thrombosis; this is termed "catastrophic antiphospholipid syndrome" (CAPS or Asherson syndrome) and is associated with a high risk of death.
Antiphospholipid syndrome often requires treatment with anticoagulant medication such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin/Coumadin is not used during pregnancy because it can cross the placenta, unlike heparin, and is teratogenic.Chlorophacinone
Chlorophacinone is an anticoagulant used as a rodenticide. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.Coumarin
Coumarin (; 2H-chromen-2-one) is an aromatic organic chemical compound in the benzopyrone chemical class, although it may also be seen as a subclass of lactones. It is a natural substance found in many plants, and a colorless crystalline substance in its standard state.
The name comes from a French term for the tonka bean, coumarou, one of the sources from which coumarin was first isolated as a natural product in 1820. It has a sweet odor, readily recognised as the scent of newly-mown hay, and has been used in perfumes since 1882. Sweet woodruff, meadowsweet, sweet grass and sweet-clover in particular are named for their sweet (i.e., pleasant) smell, which in turn is related to their high coumarin content. When it occurs in high concentrations in forage plants, coumarin is a somewhat bitter-tasting appetite suppressant, and is presumed to be produced by plants as a defense chemical to discourage predation.
Coumarin is used in certain perfumes and fabric conditioners. Coumarin has been used as an aroma enhancer in pipe tobaccos and certain alcoholic drinks, although in general it is banned as a flavorant food additive, due to concerns regarding its hepatotoxicity in animal models.
Coumarin was first synthesized in 1868. It is used in the pharmaceutical industry as a precursor reagent in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to dicoumarol, the notable ones being warfarin (brand name Coumadin) and some even more potent substances (see rat poison/rodenticide) that work by the same anticoagulant mechanism. 4-hydroxycoumarins are a type of vitamin K antagonist. Pharmaceutical (modified) coumarins were all developed from the study of sweet clover disease; see warfarin for this history. However, unmodified coumarin itself, as it occurs in plants, has no effect on the vitamin K coagulation system, or on the action of warfarin-type drugs.
Coumarin has clinical medical value by itself, as an edema modifier. Coumarin and other benzopyrones, such as 5,6-benzopyrone, 1,2-benzopyrone, diosmin, and others, are known to stimulate macrophages to degrade extracellular albumin, allowing faster resorption of edematous fluids. Other biological activities that may lead to other medical uses have been suggested, with varying degrees of evidence.
Coumarin is also used as a gain medium in some dye lasers, and as a sensitizer in older photovoltaic technologies.Coumatetralyl
Coumatetralyl is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type used as a rodenticide.Dicoumarol
Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant that functions as a functional vitamin K depleter (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases.
Dicoumarol is a natural chemical substance of combined plant and fungal origin. It is a derivative of coumarin, a bitter-tasting but sweet-smelling substance made by plants that does not itself affect coagulation, but which is (classically) transformed in mouldy feeds or silages by a number of species of fungi, into active dicoumarol. Dicoumarol does affect coagulation, and was discovered in mouldy wet sweet-clover hay, as the cause of a naturally occurring bleeding disease in cattle. See warfarin for a more detailed discovery history.
Identified in 1940, dicoumarol became the prototype of the 4-hydroxycoumarin anticoagulant drug class. Dicoumarol itself, for a short time, was employed as a medicinal anticoagulant drug, but since the mid-1950s has been replaced by its simpler derivative warfarin, and other 4-hydroxycoumarin drugs.
It is given orally, and it acts within two days.Direct Xa inhibitor
Direct factor Xa inhibitors ('xabans') are a class of anticoagulant drugs which act directly upon Factor X in the coagulation cascade, without using antithrombin as a mediator.Hematoma
A hematoma (US spelling) or haematoma (UK spelling) is a localized bleeding outside of blood vessels, due to either disease or trauma including injury or surgery and may involve blood continuing to seep from broken capillaries. A hematoma is benign and is initially in liquid form spread among the tissues including in sacs between tissues where it may coagulate and solidify before blood is reabsorbed into blood vessels. An ecchymosis is a hematoma of the skin larger than 10mm.They may occur among/within many areas such as skin and other organs, connective tissues, bone, joints and muscle.
A collection of blood (or even a hemorrhage) may be aggravated by anticoagulant medication (blood thinner). Blood seepage and collection of blood may occur if heparin is given via an intramuscular route; to avoid this, heparin must be given intravenously or subcutaneously.
It is not to be confused with hemangioma, which is an abnormal buildup/growth of blood vessels in the skin or internal organs.Hexolame
Hexolame, also known as 17β-((6-hydroxyhexyl)amino)estradiol, is a synthetic, steroidal estrogen and a 17β-aminoestrogen with anticoagulant effects that was first described in 1990 and was never marketed.Hirudin
Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches (such as Hirudo medicinalis) that has a blood anticoagulant property. This is fundamental for the leeches’ alimentary habit of hematophagy, since it keeps the blood flowing after the initial phlebotomy performed by the worm on the host’s skin.Lepirudin
Lepirudin is an anticoagulant that functions as a direct thrombin inhibitor.
Brand name: Refludan, Generic: Lepirudin rDNA for injection.
Lepirudin is a recombinant hirudin derived from yeast cells. It is almost identical to
hirudin extracted from Hirudo medicinalis. It differs by the substitution of leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate group on the tyrosine at position 63.
Lepirudin may be used as an anticoagulant when heparins (unfractionated or low-molecular-weight) are contraindicated because of heparin-induced thrombocytopenia.Lupus anticoagulant
Lupus anticoagulant is an immunoglobulin that binds to phospholipids and proteins associated with the cell membrane. Lupus anticoagulant is a misnomer, as it is actually a prothrombotic agent. Lupus anticoagulant antibodies in living systems cause an increase in inappropriate blood clotting. The name derives from their properties in vitro, as these antibodies increase laboratory coagulation tests such as the aPTT. Investigators speculate that the antibodies interfere with phospholipids used to induce in vitro coagulation. In vivo, the antibodies are thought to interact with platelet membrane phospholipids, increasing adhesion and aggregation of platelets, which accounts for the in vivo prothrombotic characteristics.
The condition was first described by hematologist C. Lockard Conley.Prolame
Prolame, also known as 17β-((3-hydroxypropyl)amino)estradiol, is a synthetic, steroidal estrogen and a 17β-aminoestrogen with anticoagulant effects that was first described in 1985 but was never marketed.Prothrombin time
The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – are assays evaluating the extrinsic pathway and common pathway of coagulation. This blood test is also called protime INR and PT/INR. They are used to determine the clotting tendency of blood, in the measure of warfarin dosage, liver damage, and vitamin K status. PT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X (Stuart–Prower factor).
PT is often used in conjunction with the activated partial thromboplastin time (aPTT) which measures the intrinsic pathway and common pathway of coagulation.Rodenticide
Rodenticides, colloquially rat poison, are typically non-specific pest control chemicals made and sold for the purpose of killing rodents.
Some rodenticides are lethal after one exposure while others require more than one. Rodents are disinclined to gorge on an unknown food (perhaps reflecting an adaptation to their inability to vomit), preferring to sample, wait and observe whether it makes them or other rats sick. This phenomenon of bait shyness or poison shyness is the rationale for poisons that kill only after multiple doses.
Besides being directly toxic to the mammals that ingest them, including dogs, cats, and humans, many rodenticides present a secondary poisoning risk to animals that hunt or scavenge the dead corpses of rats.Vitamin K epoxide reductase
Vitamin K epoxide reductase (VKOR) is an enzyme (EC 18.104.22.168) that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKORC is a member of a large family of predicted enzymes that are present in vertebrates, Drosophila, plants, bacteria and archaea. Its C1 subunit (VKORC1) is the target of anticoagulant warfarin. Four cysteine residues and one residue, which is either serine or threonine, are identified as likely active-site residues. In some plant and bacterial homologues, the VKORC1 homologous domain is fused with domains of the thioredoxin family of oxidoreductases.Warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to treat blood clots such as deep vein thrombosis and pulmonary embolism and to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Less commonly it is used following ST-segment elevation myocardial infarction (STEMI) and orthopedic surgery. It is generally taken by mouth but may also be used by injection into a vein.The common side effect is bleeding. Less common side effects may include areas of tissue damage and purple toes syndrome. Use is not recommended during pregnancy. It is recommended that the effects of warfarin typically be monitored by checking prothrombin time (INR) every one to four weeks. Many other medications and dietary factors can interact with warfarin, either increasing or decreasing its effectiveness. The effects of warfarin may be reversed with phytomenadione (vitamin K1), fresh frozen plasma, or prothrombin complex concentrate.Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K1. Without sufficient active vitamin K1, clotting factors II, VII, IX, and X have decreased clotting ability. The anticlotting protein C and protein S are also inhibited but to a lesser degree. A few days are required for full effect to occur and these effects can last for up to five days.Warfarin first came into commercial use in 1948 as a rat poison. In 1954 it was approved for medical use in the United States. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Warfarin is available as a generic medication. The wholesale cost in the developing world is about US$1.12 to 7.20 for a typical month of treatment. In the United States it usually costs less than $25 a month. In 2016 it was the 41st most prescribed medication in the United States with more than 18 million prescriptions.Warfarin necrosis
Warfarin-induced skin necrosis (or, more generally, Anticoagulant-induced skin necrosis) is a condition in which skin and subcutaneous tissue necrosis (tissue death) occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants (4-hydroxycoumarins, such as warfarin).Warfarin necrosis is a rare but severe complication of treatment with warfarin or related anticoagulants. The typical patient appears to be an obese, middle aged woman (median age 54 years, male to female ratio 1:3). This drug eruption usually occurs between the third and tenth days of therapy with warfarin derivatives. The first symptoms are pain and redness in the affected area. As they progress, lesions develop a sharp border and become petechial, then hard and purpuric. They may then resolve or progress to form large, irregular, bloody bullae with eventual necrosis and slow-healing eschar formation. Favored sites are breasts, thighs, buttocks and penis, all areas with subcutaneous fat. In rare cases, the fascia and muscle are involved.Development of the syndrome is associated with the use of large loading doses at the start of treatment.