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Anticoagulant
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Anticoagulant
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Anticoagulant
Drug class
Coagulation cascade and major classes of anticoagulants
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ATC codeB01
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MeSHD00534-class
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An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time.[1] Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.[2][3]

As a class of medications, anticoagulants are used in therapy for thrombotic disorders.[4] Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals.[5][6] Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart–lung machines, and dialysis equipment.[7][8] One of the first anticoagulants, warfarin, was initially approved as a rodenticide.[9]

Anticoagulants are closely related to antiplatelet drugs and thrombolytic drugs by manipulating the various pathways of blood coagulation.[10] Specifically, antiplatelet drugs inhibit platelet aggregation (clumping together), whereas anticoagulants inhibit specific pathways of the coagulation cascade, which happens after the initial platelet aggregation but before the formation of fibrin and stable aggregated platelet products.[11][12]

Common anticoagulants include warfarin and heparin.[13]

Medical uses

[edit]

The use of anticoagulants is a decision based on the risks and benefits of anticoagulation.[14] The biggest risk of anticoagulation therapy is the increased risk of bleeding.[15] 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 a risk of bleeding.[16][17] Generally, the benefit of anticoagulation is preventing or reducing the progression of a thromboembolic disease.[18] Some indications for anticoagulant therapy that are known to have benefit from therapy include:

In these cases, anticoagulation therapy prevents the formation or growth of dangerous clots.[30]

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 bleeding while on blood thinning agents.[15] Among these tools are HAS-BLED,[31] ATRIA,[32] HEMORR2HAGES,[33] and CHA2DS2-VASc.[34] The risk of bleeding using the risk assessment tools above must then be weighed against thrombotic risk to formally determine the patient's overall benefit in starting anticoagulation therapy.[35]

There is no evidence to indicate that adding anticoagulant therapy to standard treatment has a benefit for people with cerebral small vessel disease but not dementia, and there is an increased risk of a person with this disease experiencing a bleed with this approach.[36]

Adverse effects

[edit]

The most serious and common adverse side effects associated with anticoagulants are increased risk of bleeding, both nonmajor and major bleeding events.[37] The bleeding risk depends on the class of anticoagulant agent used, the patient's age, and pre-existing health conditions. Warfarin has an estimated incidence of bleeding of 15–20% per year and a life-threatening bleeding rate of 1–3% per year.[38] Newer non-vitamin K antagonist oral anticoagulants appear to have fewer life-threatening bleeding events than warfarin.[39][40] Additionally, patients aged 80 years or more may be especially susceptible to bleeding complications, with a rate of 13 bleeds per 100 person-years.[41] Bleeding risk is especially important to consider in patients with renal impairment and NOAC therapy because all NOACs, to some extent, are excreted by the kidneys.[42] Thus, patients with renal impairment may be at higher risk of increased bleeding.[43]

In people with cancer, a systematic review has found warfarin had no effect on death rate or the risk of blood clots.[44] However, it did increase the risk of major bleeding in 107 more people per 1000 population and minor bleeding in 167 more people per 1000 population.[44] Apixaban had no effect on mortality, recurrence of blood clots in blood vessels, or major or minor bleeding. However, this finding comes only from one study.[44]

Nonhemorrhagic adverse events are less common than hemorrhagic adverse events but should still be monitored closely.[39] Nonhemorrhagic adverse events of warfarin include skin necrosis, limb gangrene, and purple toe syndrome.[45] Skin necrosis and limb gangrene are most commonly observed on the third to eighth day of therapy.[46][47] The exact pathogenesis of skin necrosis and limb gangrene is not completely understood but it is believed to be associated with warfarin's effect on inhibiting the production of protein C and protein S.[48][49] Purple toe syndrome typically develops three to eight weeks after initiation of warfarin therapy.[50][51] Other adverse effects of warfarin are associated with depletion of vitamin K, which can lead to inhibition of G1a proteins and growth arrest-specific gene 6, which can lead to increased risk of arterial calcification and heart valve, especially if too much Vitamin D is present.[52][53] Warfarin's interference with G1a proteins has also been linked to abnormalities in fetal bone development in mothers who were treated with warfarin during pregnancy.[54][55] Long-term warfarin and heparin usage have also been linked to osteoporosis.[56][45]

Another potentially severe complication associated with heparin use is called heparin-induced thrombocytopenia (HIT).[57] There are two distinct types: HIT 1) immune-mediated and 2) non-immune-mediated.[57] Immune-mediated HIT most commonly arises five to ten days after exposure to heparin.[58] Pathogenesis of immune-mediated HIT is believed to be caused by heparin-dependent immunoglobulin antibodies binding to platelet factor 4/heparin complexes on platelets, leading to widespread platelet activation.[59]

Interactions

[edit]

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.[60][61][62] Many herbal supplements have blood-thinning properties, such as danshen and feverfew.[63] Multivitamins that do not interact with clotting are available for patients on anticoagulants.[64]

However, some foods and supplements encourage clotting.[65] These include alfalfa, avocado, cat's claw, coenzyme Q10, and dark leafy greens such as spinach.[66][67] Excessive intake of the food mentioned above should be avoided while 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.[68][69]

Grapefruit interferes with some anticoagulant drugs, increasing the time it takes for them to be metabolized out of the body, and should be eaten with caution when on anticoagulant drugs.[70]

Anticoagulants are often used to treat acute deep-vein thrombosis.[71][72] 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.[73] Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.[73]

Types

[edit]

Several anticoagulants are available. Warfarin, other coumarins, and heparins have long been used.[74] Since the 2000s, several agents have been introduced that are collectively referred to as direct oral anticoagulants (DOACs), previously named novel oral anticoagulants (NOACs) or non-vitamin K antagonist oral anticoagulants.[75][76][77][78] 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.[79] The newer anticoagulants (NOACs/DOACs) are more expensive than the traditional ones and should be used in caring for patients with kidney problems.[80]

Coumarins (vitamin K antagonists)

[edit]
Further information: Vitamin K antagonist

These oral anticoagulants are derived from coumarin found in many plants. A prominent member of this class, warfarin (Coumadin), was found to be the anticoagulant most prescribed in a large multispecialty practice.[81] The anticoagulant effect takes at least 48 to 72 hours to develop. Where an immediate effect is required, heparin is given concomitantly. These anticoagulants are used to treat patients with deep-vein thrombosis (DVT) and 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.[citation needed]

The coumarins brodifacoum and difenacoum are used as mammalicides (particularly as rodenticides) but are not used medically.[citation needed]

Heparin and derivative substances

[edit]

Heparin is the most widely used intravenous clinical anticoagulant worldwide.[82] Heparin is a naturally occurring glycosaminoglycan. There are three major categories of heparin: unfractionated heparin (UFH), low molecular weight heparin (LMWH), and ultra-low-molecular weight heparin (ULMWH).[83] Unfractionated heparin is usually derived from pig intestines and bovine lungs.[84] UFH binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation.[85] The activated AT then inactivates factor Xa, thrombin, and other coagulation factors.[86] 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.[87]

Low molecular weight heparin (LMWH)

[edit]

Low molecular weight heparin (LMWH) is produced through a controlled depolymerization of unfractionated heparin.[83] LMWH exhibits a higher anti-Xa/anti-IIa activity ratio and is useful as it does not require monitoring of the APTT coagulation parameter and has fewer side effects.[83]

Synthetic pentasaccharide inhibitors of factor Xa

[edit]
  • Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharides) in heparin that bind to antithrombin. It is a smaller molecule than low molecular-weight heparin.
  • Idraparinux
  • Idrabiotaparinux

Direct oral

[edit]

The direct oral anticoagulants (DOACs) were introduced in and after 2008.[88] There are five DOACs currently on the market: dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban.[89] They were also previously referred to as "new/novel" and "non-vitamin K antagonist" oral anticoagulants (NOACs).[90]

Compared to warfarin, DOACs have a rapid onset action and relatively short half-lives; hence, they carry out their function more rapidly and effectively, allowing drugs to reduce their anticoagulation effects quickly.[91] Routine monitoring and dose adjustments of DOACs are less important than for warfarin, as they have better predictable anticoagulation activity.[92] DOAC monitoring, including laboratory monitoring and a complete medication review, should generally be conducted before initiation of a DOAC, 1–3 months after initiation, and then every 6–12 months afterwards.[93]

Both DOACs and warfarin are equivalently effective, but compared to warfarin, DOACs have fewer drug interactions, no known dietary interactions, a wider therapeutic index, and have conventional dosing that does not require dose adjustments with constant monitoring.[94][92] However, there is no countermeasure for most DOACs, unlike for warfarin; nonetheless, the short half-lives of DOACs will allow their effects to recede swiftly. A reversal agent for dabigatran, idarucizumab, is currently available and approved for use by the FDA. Rates of adherence to DOACs are only modestly higher than adherence to warfarin among patients prescribed these drugs. Thus, adherence to anticoagulation is often poor despite hopes that DOACs would lead to higher adherence rates.[95]

DOACs are significantly more expensive than warfarin, but the patients on DOACs may experience reduced lab costs as they do not need to monitor their INR.[93]

Direct factor Xa inhibitors

[edit]
Main article: Direct Xa inhibitor

Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike heparins and fondaparinux, which work via antithrombin activation). Also included in this category are betrixaban from Portola Pharmaceuticals, the discontinued darexaban (YM150) from Astellas, and, more recently, the discontinued letaxaban (TAK-442) from Takeda and eribaxaban (PD0348292) from Pfizer. Betrixaban is significant as it was in 2018, the only oral factor Xa inhibitor approved by the FDA for use in acutely medically ill patients.[96] Darexaban development was discontinued in September 2011; in a trial for prevention of recurrences of myocardial infarction in addition to dual antiplatelet therapy (DAPT), the drug did not demonstrate effectiveness, and the risk of bleeding was increased by approximately 300%.[97] The development of letaxaban for acute coronary syndrome was discontinued in May 2011 following negative results from a Phase II study.[98]

Direct thrombin inhibitors

[edit]
Main article: Direct thrombin inhibitor

Another type of anticoagulant is the direct thrombin inhibitor.[99] 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[100] and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks.[101] In November 2010, dabigatran etexilate was approved by the FDA to prevent thrombosis in atrial fibrillation.

Relevance to dental treatments

[edit]

As in any invasive procedure, patients on anticoagulation therapy have an increased risk for bleeding, and caution should be used along with local hemostatic methods to minimize bleeding risk during the operation as well as postoperatively.[102] However, with regards to DOACs and invasive dental treatments, there has not been enough clinical evidence and experience to prove any reliable adverse effects, relevance or interaction between these two.[103] Further clinical prospective studies on DOACs are required to investigate the bleeding risk and hemostasis associated with surgical and dental procedures.[104]

Recommendations of modifications to the usage/dosage of DOACs before dental treatments are made based on the balance of the bleeding risk of each procedure and also the individual's own bleeding risks and renal functionality.[105] With low-bleeding-risk dental procedures, it is recommended that DOACs be continued by the patient to avoid any increase in the risk of a thromboembolic event.[106][107] For dental procedures with a higher risk of bleeding complications (i.e. complex extractions, adjacent extractions leading to a large wound, or more than three extractions), the recommended practice is for the patient to miss or delay a dose of their DOAC before such procedures to minimize the effect on bleeding risk.[108]

Antithrombin protein therapeutics

[edit]

The antithrombin protein is used as a protein therapeutic that can be purified from human plasma[109] or produced recombinantly (for example, Atryn, produced in the milk of genetically modified goats).[110][111]

The FDA approves Antithrombin as an anticoagulant for preventing clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.[109][111]

Other

[edit]

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

Reversal agents

[edit]

With the growing number of patients taking oral anticoagulation therapy, studies into reversal agents are gaining increasing interest due to major bleeding events and the need for urgent anticoagulant reversal therapy.[112] Reversal agents for warfarin are more widely studied, and established guidelines for reversal exist due to a longer history of use of warfarin and the ability to get a more accurate measurement of anticoagulation effect in a patient via measuring the INR (International Normalized Ratio).[113] In general, vitamin K is most commonly used to reverse the effect of warfarin in non-urgent settings.[114] However, in urgent settings or settings with extremely high INR (INR >20), hemostatic reversal agents such as fresh frozen plasma (FFP), recombinant factor VIIa, and prothrombin complex concentrate (PCC) have been utilized with proven efficacy.[115] Specifically with warfarin, four-factor PCC (4F-PCC) has been shown to have superior safety and mortality benefits compared to FPP in lowering INR levels.[112]

Although specific antidotes and reversal agents for DOACs are not as widely studied, idarucizumab (for dabigatran) and andexanet alfa (for factor Xa inhibitor) have been used in clinical settings with varying efficacy.[90] Idarucizumab is a monoclonal antibody, approved by the US FDA in 2015, that reverses the effect of dabigatran by binding to both free and thrombin-bound dabigatran.[116][117] Andexanet alfa is a recombinant modified human factor Xa decoy that reverses the effect of factor Xa inhibitors by binding at the active sites of factor Xa inhibitor and making it catalytically inactive.[118][119] Andexanet alfa was approved by the US FDA in 2018.[120] Another drug called ciraparantag, a potential reversal agent for direct factor Xa inhibitors, is still under investigation.[121] Additionally, hemostatic reversal agents have also been used with varying efficacy to reverse the effects of DOACs.[122][123]

Coagulation inhibitor measurement

[edit]

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.[124] 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.[125]

Laboratory use

[edit]

If blood is allowed to clot, laboratory instruments, blood transfusion bags, and medical and surgical equipment will get clogged up and non-operational. In addition, test tubes used for laboratory blood tests will have chemicals added to stop blood clotting. Besides heparin, most of these chemicals bind 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 and blood transfusion bags. It binds calcium but not as strongly as EDTA. The correct proportion of this anticoagulant to blood is crucial because of the dilution, which can be reversed with the addition of calcium. Formulations include plain sodium citrate, acid-citrate-dextrose, and more.
  • Oxalate has a mechanism similar to that of citrate. It is the anticoagulant used in fluoride/oxalate tubes to determine glucose and lactate levels. The fluoride inhibits glycolysis, which can throw off blood sugar measurements. Citrate/fluoride/EDTA tubes work better in this regard.[126]

Dental considerations for long-term users

[edit]

Dental practitioners play an important role in the early detection of anticoagulant overdose through oral manifestations, as the patient does not show any symptoms. Dental treatment of patients taking anticoagulant or antiplatelet medication raises safety concerns in terms of the potential risk of bleeding complications following invasive dental procedures. Therefore, certain guidelines for the dental care of patients taking these drugs are needed.

Detecting overdose

An overdose of anticoagulants usually occurs in people who have heart problems and need to take anticoagulants in the long term to reduce the risk of stroke from their high blood pressure.

An International Normalised Ratio (INR) test would be recommended to confirm the overdose so that the dosage can be adjusted to an acceptable standard. The INR test measures the time it takes for a clot to form in a blood sample relative to a standard.

An INR value of 1 indicates a level of coagulation equivalent to that of an average patient not taking warfarin, and values greater than 1 indicate a longer clotting time and, thus, a longer bleeding time.

Assessing bleeding risk

There are two main parts to the assessment of bleeding risk:

  • Assessment of the likely risk of bleeding associated with the required dental procedure
  • Assessment of the patient's individual-level bleeding risk

Managing bleeding risk

A patient who is on anticoagulants or antiplatelet medications may undergo dental treatments which are unlikely to cause bleeding, such as local anesthesia injection, basic gum charting, removal of plaque, calculus and stain above the gum level, direct or indirect fillings which are above the gingiva, root canal treatment, taking impression for denture or crown and fitting or adjustment of orthodontic appliances.  For all these procedures, it is recommended that the dentist treat the patient following the normal standard procedure and taking care to avoid any bleeding.

For a patient who needs to undergo dental treatments which are more likely to cause bleeding, such as simple tooth extractions (1-3 teeth with small wound size), drainage of swelling inside the mouth, periodontal charting, root planing,  direct or indirect filling which extends below the gingiva, complex filling, flap raising procedure, gingival recontouring and biopsies, the dentist needs to take extra precautions apart from the standard procedure. The recommendations[127] are as follows:

  • if the patient has another medical condition or is taking other medication that may increase bleeding risk, consult the patient's general medical practitioner or specialist
  • if the patient is on a short course of anticoagulant or antiplatelet therapy, delay the non-urgent, invasive procedure until the medication has been discontinued
  • plan treatment for early in the day and week, where possible, to allow time for the management of prolonged bleeding or re-bleeding if it occurs
  • perform the procedure as traumatically as possible, use appropriate local measures and only discharge the patient once hemostasis has been confirmed
  • if travel time to emergency care is a concern, place particular emphasis at the time of the initial treatment on the use of measures to avoid complications
  • advise the patient to take paracetamol, unless contraindicated, for pain relief rather than NSAIDs such as aspirin, ibuprofen, diclofenac or naproxen
  • provide the patient with written post-treatment advice and emergency contact details
  • follow the specific recommendations and advice given for the management of patients taking different anticoagulants or antiplatelet drugs

There is general agreement that in most cases, treatment regimens with older anticoagulants (e.g., warfarin) and antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, ticagrelor, and/or aspirin) should not be altered before dental procedures. The risks of stopping or reducing these medication regimens (i.e., thromboembolism, stroke, myocardial infarction) far outweigh the consequences of prolonged bleeding, which can be controlled with local measures. In patients with other existing medical conditions that can increase the risk of prolonged bleeding after dental treatment or receiving other therapy that can increase bleeding risk, dental practitioners may wish to consult the patient's physician to determine whether care can safely be delivered in a primary care office. Any suggested modification to the medication regimen before dental surgery should be done in consultation and on the advice of the patient's physician.

Based on limited evidence, the consensus appears to be that in most patients who are receiving the newer direct-acting oral anticoagulants (i.e., dabigatran, rivaroxaban, apixaban, or edoxaban) and undergoing dental treatment (in conjunction with usual local measures to control bleeding), no change to the anticoagulant regimen is required. In patients deemed to be at higher risk of bleeding (e.g., patients with other medical conditions or undergoing more extensive procedures associated with higher bleeding risk), consideration may be given, in consultation with and on advice of the patient's physician, to postponing the timing of the daily dose of the anticoagulant until after the procedure; timing the dental intervention as late as possible after last dose of anticoagulant; or temporarily interrupting drug therapy for 24 to 48 hours.

Research

[edit]

A substantial number of compounds are being investigated for use as anticoagulants. The most promising ones act on the contact activation system (factor XIIa and factor XIa); it is anticipated that this may provide agents that prevent thrombosis without conferring a risk of bleeding.[128]

As of November 2021, the direct factor XIa inhibitor milvexian is in Phase II clinical trials for the prevention of an embolism after surgery.[129]

Utilization

[edit]

Research has been conducted on changes in anticoagulant drug supply for hospitals in the US during the COVID-19 pandemic from 2018–2022. According to researchers, "there was a 43.4% decline in the total volume of anticoagulants and antiplatelets at US hospitals in March 2020, driven by a decrease in heparin volume."[130] Furthermore, it has been found that "Therapeutic AC [Anticoagulation] use declined from 32% in 2020 to 12% in 2022, especially after December 2021" and the introduction of the Omicron variant.[131]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Anticoagulant

View on Grokipedia
from Grokipedia
Anticoagulants are a class of medications that inhibit blood coagulation, preventing the formation or extension of blood clots in the vascular system. Unlike thrombolytics, which dissolve existing clots, anticoagulants primarily work to stop new clots from developing and to limit the growth of established ones, thereby reducing the risk of life-threatening conditions such as heart attacks, , and pulmonary embolisms. These drugs are essential in the prevention and treatment of venous thromboembolism (VTE), including deep vein thrombosis and , as well as in reducing risk among patients with or mechanical heart valves. Anticoagulants are also employed perioperatively to prevent clotting during surgeries and in the management of acute coronary syndromes. Their use has revolutionized cardiovascular and thrombotic care, but they carry a significant risk of complications, necessitating careful monitoring and individualized dosing. Anticoagulants are broadly classified into parenteral and oral agents, with distinct mechanisms targeting different components of the coagulation cascade. Parenteral anticoagulants include unfractionated (UFH) and low-molecular-weight heparins (LMWHs), which exert their effects by binding to III, thereby accelerating the inactivation of (factor IIa) and factor Xa. Oral anticoagulants encompass antagonists (VKAs) like , which competitively inhibit (VKORC1), depleting the active form of needed for the carboxylation and activation of clotting factors II, VII, IX, and X. In recent decades, direct oral anticoagulants (DOACs)—such as (a ) and rivaroxaban, apixaban, and (direct factor Xa inhibitors)—have gained prominence due to their predictable , lack of routine monitoring requirements, and lower risk of compared to VKAs. The selection of an anticoagulant depends on factors such as the clinical indication, patient renal function, bleeding risk, and drug interactions; for instance, DOACs are contraindicated in severe renal impairment, while warfarin requires frequent international normalized ratio (INR) testing. Ongoing research continues to refine reversal agents, such as for and for factor Xa inhibitors, and is developing new classes like inhibitors to further mitigate bleeding risks in emergencies.

Overview

Definition and Principles

Anticoagulants are pharmacological agents that inhibit the process of blood , thereby prolonging the of blood by interfering with various factors in the coagulation cascade. These substances act at different points along the cascade, either directly through inhibition or indirectly by enhancing natural anticoagulant pathways, to prevent the formation of , the protein mesh essential for stable clot development. Anticoagulants differ from antiplatelet agents in their primary mechanism of action; while antiplatelet drugs inhibit clot formation by blocking platelet activation and aggregation, anticoagulants specifically target the enzymatic steps of the coagulation cascade to disrupt formation. A core principle of anticoagulant therapy is that these agents do not actively dissolve pre-existing blood clots but instead stabilize them by preventing propagation and new clot formation. By impairing the coagulation process, anticoagulants inherently increase the risk of complications, as they compromise the body's normal hemostatic mechanisms that control blood loss. The therapeutic application of anticoagulants hinges on maintaining a delicate balance between preventing thrombotic events and minimizing hemorrhage risk, often requiring monitoring within a narrow to optimize and .

Coagulation Basics

is the physiological process that halts following vascular , preventing excessive loss while maintaining fluidity under normal conditions. It unfolds in three primary stages: vascular spasm, formation of a , and activation of the cascade to produce a stable clot. Vascular spasm, or , is the initial response, triggered by local reflexes, which narrows the injured vessel to reduce flow and limit hemorrhage. The second stage involves primary hemostasis through platelet plug formation. Circulating platelets adhere to exposed subendothelial collagen via von Willebrand factor, become activated, and release contents such as ADP and thromboxane A2 to recruit additional platelets, forming a temporary hemostatic plug that seals small breaches. This plug provides immediate but fragile control of bleeding until reinforced by the coagulation cascade. The coagulation cascade, or secondary hemostasis, amplifies the response to generate a durable fibrin meshwork that stabilizes the platelet plug. It comprises three interconnected pathways: the extrinsic, intrinsic, and common pathways, all converging to activate thrombin (factor IIa) and form fibrin. The extrinsic pathway initiates rapidly upon tissue injury, where exposed tissue factor binds and activates factor VII to form the tissue factor-VIIa complex, which then activates factor X. The intrinsic pathway, triggered by contact activation of factor XII on negatively charged surfaces, proceeds through sequential activation of factors XII, XI (with HMWK and prekallikrein), IX, and VIII (forming the tenase complex) to also generate factor Xa. Both pathways merge in the common pathway, where factor Xa assembles with factor Va, calcium, and phospholipids into the prothrombinase complex on platelet surfaces, converting prothrombin (factor II) to thrombin. Key factors include II (prothrombin), V (cofactor for prothrombinase), VII (tissue factor activator), and X (central to convergence). Thrombin plays a central amplifying role in the cascade, not only cleaving fibrinogen to form monomers that polymerize into a clot-stabilizing network but also providing by factors V, VIII, XI, and XIII (for cross-linking ), as well as stimulating further platelet aggregation. This enzymatic amplification ensures rapid and robust clot formation at injury sites while being tightly regulated to prevent systemic . To counterbalance procoagulant mechanisms and maintain vascular patency, the body employs physiological anticoagulants. Antithrombin inhibits thrombin (IIa) and factor Xa, enhanced by heparin-like glycosaminoglycans on endothelial cells. The protein C system, activated by thrombin-thrombomodulin complex, generates activated protein C (with protein S as cofactor) that proteolytically inactivates factors Va and VIIIa, downregulating the cascade. Tissue factor pathway inhibitor (TFPI) neutralizes the extrinsic pathway by inhibiting the tissue factor-VIIa complex after it activates factor X. Protein S also serves as a cofactor for TFPI, augmenting its inhibitory effects on early coagulation initiation. These regulators collectively prevent unwarranted clot propagation. Pathological arises when hemostatic mechanisms become dysregulated, leading to inappropriate clot formation within intact vessels. typically occurs in low-flow conditions, forming red thrombi rich in and red cells, often in deep veins. Arterial thrombosis, conversely, develops under high , producing platelet-rich white thrombi, commonly at sites of atherosclerotic plaque rupture. Both are precipitated by : (promoting factor accumulation), endothelial injury (exposing procoagulant surfaces), and hypercoagulability (from genetic, acquired, or inflammatory factors that tilt the balance toward clotting).

History

Early Discoveries

The discovery of heparin marked a pivotal moment in anticoagulation research. In 1916, Jay McLean, a second-year medical student at , accidentally identified an anticoagulant substance while investigating procoagulant properties of organ extracts. Working under William Henry Howell, McLean extracted a fraction from liver and tissues that inhibited clotting, contrasting with the procoagulant effects he observed in brain extracts. This finding, published in 1916, highlighted heparin's potential as a natural anticoagulant derived from mammalian tissues, though initial purification efforts focused on its cephalin component. Building on this, heparin transitioned from laboratory curiosity to clinical application in the 1930s. Canadian researchers Charles Best and advanced its therapeutic use, purifying heparin from bovine lung and demonstrating its efficacy in preventing in experimental models. By 1935, had conducted early human trials, administering heparin intravenously to patients with thrombotic conditions, which showed promising results in dissolving clots without excessive bleeding. Best's collaboration emphasized large-scale production methods, enabling broader testing for treatment, though early preparations were impure and costly. Parallel investigations into spontaneous hemorrhages in uncovered another anticoagulant pathway. In the , veterinarians in the American Midwest observed a fatal disorder in fed moldy sweet hay, characterized by prolonged clotting times and internal hemorrhages. By , biochemist Karl Paul Link at the University of Wisconsin isolated the causative agent, dicoumarol (also known as bishydroxycoumarin), from spoiled Melilotus species, identifying it as a potent that disrupted factors. This natural compound's structure inspired synthetic derivatives for medical use. From dicoumarol's framework, emerged as a refined anticoagulant. In 1948, Link's laboratory synthesized (initially Compound 42) as a more potent, water-soluble analog, initially marketed as a due to its ability to induce fatal hemorrhages in pests. Human therapeutic application began in the early 1950s, with initial trials in 1953 for postoperative , proving its oral efficacy and longer duration compared to , though it required careful dosing. Early anticoagulants faced significant hurdles that limited their adoption. Heparin's short plasma of about 1-2 hours necessitated continuous intravenous administration, complicating outpatient use and increasing infection risks from indwelling catheters. , while orally bioavailable, exhibited highly variable patient responses influenced by diet, , and drug interactions, often leading to inconsistent anticoagulation levels and the need for frequent monitoring via assays. These challenges spurred ongoing refinements in formulation and delivery by the mid-20th century.

Modern Advancements

The marked a pivotal era in anticoagulant standardization, with unfractionated heparin (UFH) undergoing rigorous purification and dosing protocols to enable safer intravenous administration in clinical settings, building on earlier discoveries to support its routine use in preventing and treating thromboembolic disorders. Concurrently, , initially approved by the FDA in 1954, gained widespread clinical adoption during this decade for managing (AF) and (DVT), following key studies that demonstrated its efficacy in reducing risk and recurrent venous when monitored via . These advancements shifted anticoagulants from experimental therapies to standardized staples in cardiovascular care, emphasizing the need for laboratory-guided dosing to balance efficacy and bleeding risks. The 1970s and 1980s saw the development of low-molecular-weight heparins (LMWHs) as a refinement of UFH, offering more predictable and to improve patient convenience and reduce monitoring requirements. Enoxaparin, a prominent LMWH derived from porcine intestinal mucosa, emerged from this period's research and received FDA approval in March 1993 for prophylaxis and treatment of DVT, as well as acute coronary syndromes, establishing it as a preferred alternative to UFH for outpatient use. This evolution addressed limitations of earlier agents, such as heparin's variable anticoagulant response, and paved the way for broader anticoagulation strategies. The 2000s heralded the rise of direct oral anticoagulants (DOACs), revolutionizing therapy with fixed-dose regimens that bypassed the need for frequent coagulation monitoring. received initial FDA approval in 2011 for venous prophylaxis after , followed by expanded indications, while was approved in 2010 as the first DOAC for prevention in nonvalvular , and followed in 2012 for the same purpose, offering superior convenience over antagonists like . These approvals were underpinned by large-scale trials demonstrating noninferiority or superiority in reducing and systemic with lower intracranial rates. In the 2020s, DOACs have seen further expansions in indications, including extended thromboprophylaxis in medically ill patients and pediatric use for certain venous thromboembolisms, alongside the introduction of LMWHs to enhance accessibility and reduce costs without compromising efficacy. Landmark evidence, such as the RE-LY trial, confirmed dabigatran's superiority over in preventing and systemic in AF patients, with a 150 mg twice-daily dose reducing events by 34% while maintaining comparable major bleeding risks, influencing global adoption. Regulatory milestones, including FDA approvals for these agents and their integration into guidelines like the 2019 ACC/AHA focused update, have prioritized DOACs as first-line options for nonvalvular AF, recommending them over for most eligible patients based on reduced and improved patient adherence.

Medical Uses

Primary Indications

Anticoagulants are primarily indicated for the prevention and treatment of venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and (PE), as well as prophylaxis in high-risk scenarios such as post-surgical settings. For patients with provoked VTE, guidelines recommend a finite duration of , typically 3 to 6 months, to cover the active treatment phase and reduce recurrence risk while balancing concerns. In unprovoked VTE, extended may be considered based on individual . Another key indication is stroke prevention in patients with (AFib) and other cardioembolic risks, where anticoagulants mitigate thromboembolic events by inhibiting clot formation in the left atrial appendage. The CHA2DS2-VASc score guides decision-making, recommending anticoagulation for men with a score of 2 or higher and women with a score of 3 or higher, as this identifies those at elevated annual risk exceeding 1%. This approach has been validated in large cohorts, showing significant reduction in ischemic incidence without disproportionate in appropriately selected patients. Anticoagulants are also essential in acute coronary syndromes (ACS), including ST-elevation myocardial infarction and non-ST-elevation ACS, where they are used peri-procedurally during percutaneous coronary intervention to prevent thrombotic complications. For mechanical heart valves, lifelong anticoagulation is mandated to prevent valve thrombosis and systemic embolization, particularly for mitral or older-generation aortic prostheses. In hypercoagulable states such as antiphospholipid syndrome (APS), long-term anticoagulation is recommended following initial thrombotic events, with intensity tailored to arterial versus venous involvement (e.g., INR target of 2-3 for venous thrombosis). Off-label uses include management of cancer-associated thrombosis, where anticoagulants address heightened VTE risk due to and treatments, often extending beyond standard durations based on ongoing cancer status. In sickle cell disease crises, such as , therapeutic anticoagulation may be employed to alleviate microvascular obstruction and improve outcomes, supported by evidence from randomized controlled trials such as the TASC trial, which showed reduced duration and opioid use without increased bleeding.

Administration Methods

Anticoagulants are administered through various routes depending on the clinical context, with intravenous (IV) delivery commonly used in acute settings for rapid onset, such as a heparin bolus to achieve immediate anticoagulation. Subcutaneous (SC) administration is preferred for maintenance therapy in non-acute scenarios, offering convenience while providing predictable absorption, as seen with low-molecular-weight heparin (LMWH) injections. Oral routes are standard for chronic management, enabling long-term use without invasive procedures, exemplified by direct oral anticoagulants (DOACs) and warfarin for outpatient therapy. Dosing principles vary by agent and patient factors; heparins typically require weight-based dosing to ensure efficacy and safety, such as initial SC unfractionated heparin at 333 units/kg followed by 250 units/kg. In contrast, most DOACs employ fixed doses adjusted for specific criteria like age, weight, or renal function, simplifying administration compared to individualized regimens. Bridging therapy involves overlapping parenteral anticoagulants, such as , with oral agents like for at least 5 days until the international normalized ratio (INR) reaches 2.0 or greater, preventing thrombotic gaps during initiation. The duration of anticoagulant therapy ranges from acute short-term use, often days to weeks in hospital settings, to lifelong administration in cases like mechanical heart valves to mitigate ongoing thromboembolic risk. Patient adherence is influenced by factors such as pill burden and dosing frequency, with once-daily oral regimens generally improving compliance over multiple daily doses or frequent monitoring requirements. Special formulations address unique populations; pediatric dosing is predominantly weight-based, with adjustments for age and body size to account for developmental , as in enoxaparin at 1 mg/kg twice daily for neonates and older children. Recent guidelines (as of 2025) recommend DOACs such as or over LMWH or VKAs in many pediatric patients with VTE. Renal adjustments are critical for agents cleared by the kidneys, such as reducing enoxaparin to 1 mg/kg once daily when creatinine clearance is below 30 mL/min to avoid accumulation and .

Types of Anticoagulants

Vitamin K Antagonists

Vitamin K antagonists (VKAs) represent a cornerstone class of oral anticoagulants primarily used for long-term prevention of thromboembolic events, exerting their effects by interfering with the vitamin K cycle essential for blood coagulation. These agents, including coumarin derivatives, target the hepatic synthesis of several procoagulant factors, distinguishing them from other anticoagulants that act more directly on the coagulation cascade. The primary mechanism of VKAs involves competitive inhibition of vitamin K epoxide reductase complex subunit 1 (VKORC1), an enzyme critical for recycling vitamin K to its reduced hydroquinone form (KH2). This inhibition disrupts the gamma-carboxylation of glutamate residues on vitamin K-dependent proteins, thereby reducing the activation of coagulation factors II (prothrombin), VII, IX, and X, as well as the anticoagulant proteins C and S. As a result, the functional levels of these factors decline over time, leading to an antithrombotic state; the process is indirect and time-dependent, with full anticoagulant effects typically manifesting after several days due to the existing half-lives of these factors in circulation. Warfarin, the prototypic and most widely prescribed VKA, exemplifies this class with its of R- and S-enantiomers, where the S-form is predominantly responsible for the anticoagulant potency. Standard maintenance dosing for ranges from 2 to 10 mg daily, adjusted based on individual response, with an onset of therapeutic effect occurring in 4 to 5 days as factor levels deplete. Unlike direct oral anticoagulants, VKAs like require careful to maintain efficacy while minimizing risks. Pharmacokinetically, warfarin is almost entirely absorbed from the and exhibits high , exceeding 99%, primarily to , which limits its distribution to the vascular compartment. It undergoes hepatic , with the more potent S-warfarin primarily hydroxylated by 2C9 () to inactive metabolites, while the R-enantiomer is handled by multiple CYP enzymes including and ; the elimination averages around 40 hours (ranging 20-60 hours), contributing to its prolonged duration of action. Renal clearance plays a minor role, as warfarin is excreted mainly via biliary and fecal routes as metabolites. A hallmark of VKAs is their narrow , necessitating individualized dosing to avoid under- or over-anticoagulation, compounded by significant interpatient variability influenced by genetic factors. Polymorphisms in the VKORC1 gene, such as the -1639G>A variant, can reduce enzyme activity and thus lower the required dose by up to 30-50% in affected individuals, while variants (e.g., *2 and *3 alleles) impair , further decreasing dose needs and elevating risk. These genetic influences account for approximately 30-40% of dose variability, underscoring the value of pharmacogenetic testing in optimization. Historically, warfarin originated from investigations into hemorrhagic disorders in caused by moldy sweet hay, leading to the isolation of dicoumarol in the ; this spurred the synthesis of in 1948 as a more potent , which was commercialized for before its repurposing for human anticoagulation in the . Today, remains first-line therapy for patients with mechanical heart valves, where its established efficacy in preventing valve outweighs alternatives in high-risk scenarios.

Heparins and Derivatives

Heparins are a class of parenteral anticoagulants derived from glycosaminoglycans, primarily acting by binding to III (ATIII) to enhance its inhibitory effects on the cascade. This binding induces a conformational change in ATIII, accelerating its inhibition of (factor IIa) and factor Xa by up to 1,000-fold, thereby preventing formation and propagation. Unfractionated heparin (UFH), the original form, features polysaccharide chains of varying lengths (average molecular weight 15,000 Da), allowing it to inhibit additional serine proteases such as factors IXa, XIa, and XIIa through ternary complex formation with ATIII. UFH is administered intravenously (IV) or subcutaneously (SC) due to its poor oral and rapid within minutes IV or 20-60 minutes SC. Its elimination is dose-dependent, ranging from 30 minutes at low doses (25 units/kg IV) to 90-150 minutes at higher doses (100 units/kg IV), primarily via a combination of rapid saturable cellular uptake and slower renal clearance. In clinical practice, UFH is favored in hospital settings for conditions requiring immediate anticoagulation, such as acute coronary syndromes or during procedures, where its short allows for close monitoring of anticoagulant effect via activated partial thromboplastin time (aPTT) and assessment of (HIT) risk, which occurs in 1-5% of patients exposed for 5-10 days. Low-molecular-weight heparins (LMWHs), produced by chemical or enzymatic of UFH (average molecular weight 4,000-6,000 Da), exhibit a higher anti-Xa to anti-IIa ratio (approximately 3:1 to 4:1) due to shorter chain lengths that preferentially potentiate ATIII-mediated Xa inhibition without forming the ternary complex for . Common examples include enoxaparin and dalteparin, administered SC once or twice daily with predictable , bioavailability of 90-100%, and half-lives of 4-5 hours for enoxaparin and 3-5 hours for dalteparin after SC dosing. LMWHs carry a lower HIT incidence (0.2-0.6%) compared to UFH, attributed to reduced release, making them suitable for outpatient prophylaxis and treatment of venous . LMWH pharmacokinetics are predominantly renal, with clearance inversely proportional to molecular weight, necessitating dose adjustments in renal impairment (creatinine clearance <30 mL/min) to avoid accumulation and prolonged effects; for instance, enoxaparin dosing is reduced to 1 mg/kg once daily in such cases. In obesity, fixed dosing based on total body weight may lead to under-anticoagulation, so weight-based adjustments (up to actual body weight) are recommended for enoxaparin and dalteparin to achieve therapeutic anti-Xa levels without routine monitoring.

Direct Oral Anticoagulants

Direct oral anticoagulants (DOACs) are a class of targeted antithrombotic agents that inhibit specific coagulation factors, providing an effective oral alternative to older anticoagulants for preventing and treating thromboembolic disorders. Unlike vitamin K antagonists such as , DOACs offer predictable pharmacokinetics due to their fixed dosing regimens and lack of significant protein binding variability, which eliminates the need for routine laboratory monitoring of anticoagulant effect. This class has demonstrated a reduced risk of intracranial hemorrhage compared to warfarin across multiple clinical trials, contributing to an improved safety profile in conditions like nonvalvular atrial fibrillation and venous thromboembolism. The DOACs are primarily divided into direct factor Xa inhibitors—rivaroxaban, apixaban, and edoxaban—and direct thrombin inhibitors, with dabigatran as the key representative. Direct factor Xa inhibitors competitively bind to the active site of factor Xa, a serine protease essential for the prothrombinase complex, thereby preventing the conversion of prothrombin to thrombin and halting downstream fibrin clot formation. These agents exhibit varying routes of clearance: rivaroxaban undergoes approximately one-third renal excretion with the remainder hepatic metabolism, apixaban is primarily hepatically cleared with about one-quarter renal elimination, and edoxaban relies on roughly half renal excretion. Their rapid onset of action and short half-lives allow for quick achievement of therapeutic levels without initial parenteral bridging in most cases. Dabigatran etexilate, the sole direct thrombin inhibitor in widespread use, is a prodrug rapidly converted to active dabigatran, which reversibly binds to the active site of thrombin (factor IIa), inhibiting its catalytic activity and preventing the cleavage of fibrinogen to fibrin as well as the activation of factors V, VIII, and XIII. Dabigatran is predominantly renally excreted, with about 80% of the dose eliminated unchanged by the kidneys, necessitating careful use in patients with impaired renal function. A specific reversal agent, idarucizumab, is available for dabigatran to rapidly neutralize its effects in cases of bleeding or urgent procedures. Dosing for DOACs is generally fixed and oral, tailored to the indication; for instance, apixaban is typically administered as 5 mg twice daily for stroke prevention in nonvalvular atrial fibrillation, with reductions to 2.5 mg twice daily recommended if at least two of the following criteria are met: age 80 years or older, serum creatinine ≥1.5 mg/dL, or body weight ≤60 kg. Similar adjustments apply to other DOACs based on renal function, such as creatinine clearance, to mitigate accumulation risks. The ARISTOTLE trial, a large randomized controlled study involving over 18,000 patients, established apixaban's superiority over warfarin, showing a 21% relative risk reduction in stroke or systemic embolism and a 31% reduction in major bleeding. Comparable efficacy and safety have been confirmed for rivaroxaban and edoxaban in trials like ROCKET-AF and ENGAGE AF-TIMI 48, respectively. Despite their advantages, DOACs have limitations, including the lack of a parenteral formulation for scenarios requiring immediate intravenous anticoagulation, such as acute coronary syndromes or bridging therapy. They are also contraindicated or require caution in valvular atrial fibrillation, particularly with mechanical heart valves, where warfarin remains the standard due to insufficient evidence of DOAC efficacy in this subgroup. Renal impairment further complicates their use, as dose adjustments or avoidance may be necessary when creatinine clearance falls below 30 mL/min, depending on the agent.

Other Agents

Fondaparinux is a synthetic pentasaccharide anticoagulant that acts as a selective indirect inhibitor of factor Xa by binding to antithrombin, enhancing its inhibitory activity without affecting thrombin directly. Administered subcutaneously, it is approved for the prevention and treatment of venous thromboembolism (VTE) following orthopedic surgery and for acute coronary syndromes. Off-label, fondaparinux serves as an alternative in patients with heparin-induced thrombocytopenia (HIT) due to its low risk of cross-reactivity with HIT antibodies. Antithrombin therapeutics, particularly recombinant human antithrombin (rhAT), are used to address congenital antithrombin deficiency, a condition that increases thrombotic risk. RhAT is administered intravenously to normalize antithrombin levels, primarily in perioperative settings to prevent thromboembolism during surgical or obstetrical procedures. It has also been employed off-label for heparin resistance in cardiac surgery, where antithrombin supplementation improves anticoagulation efficacy. Bivalirudin is a synthetic direct thrombin inhibitor that reversibly binds to the active site of thrombin, inhibiting both free and clot-bound thrombin without relying on antithrombin. Given intravenously, it is indicated for anticoagulation during percutaneous coronary intervention (PCI), particularly in patients with HIT where heparin is contraindicated. Clinical trials have demonstrated bivalirudin's efficacy in reducing ischemic events in HIT patients undergoing PCI, with a favorable bleeding profile compared to heparin. Drotrecogin alfa, a recombinant form of activated protein C, was developed as an anticoagulant with anti-inflammatory properties for severe sepsis and septic shock. It modulates coagulation by inactivating factors Va and VIIIa while providing cytoprotective effects on endothelial cells. However, due to increased bleeding risks observed in trials like PROWESS-SHOCK, which failed to show mortality benefits, drotrecogin alfa was withdrawn from the market in 2011. Among miscellaneous agents, argatroban is a direct thrombin inhibitor primarily metabolized by the liver, making it suitable for patients with renal impairment but requiring dose adjustments in hepatic dysfunction to avoid over-anticoagulation. It is used intravenously for prophylaxis and treatment of thrombosis in HIT patients. , a heparinoid composed mainly of low-molecular-weight heparan sulfate, inhibits factor Xa via antithrombin with minimal anti-thrombin II activity and low cross-reactivity in HIT. Administered subcutaneously or intravenously, it has been employed for VTE prevention and treatment in HIT cases, though its availability is limited following market withdrawal in some regions. These agents play a critical role in managing anticoagulation in special cases like HIT, where standard therapies are unsuitable.

Adverse Effects

Common Risks

The primary adverse effect associated with anticoagulant therapy is bleeding, resulting from the inhibition of coagulation factors that impairs normal hemostasis and prolongs bleeding time. This disruption in the clotting cascade increases susceptibility to hemorrhage at various sites, with severity ranging from minor events that resolve spontaneously to life-threatening major bleeds requiring intervention. Bleeding events are classified as major or minor based on clinical criteria such as the International Society on Thrombosis and Haemostasis (ISTH) definitions. Major bleeding includes fatal hemorrhage, symptomatic intracranial hemorrhage (ICH), or bleeds causing a hemoglobin drop of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells, or intervention at a critical site like the gastrointestinal (GI) tract. Examples of major bleeds encompass GI bleeding and ICH, which carry high morbidity. Minor bleeding, in contrast, involves non-severe events such as epistaxis, bruising, or hematuria that do not meet major criteria but can still impact quality of life. The annual incidence of major bleeding varies by anticoagulant class. In pivotal trials, direct oral anticoagulants (DOACs) demonstrated rates of 1-3% per year, such as 2.13% for in ARISTOTLE, 2.71-3.11% for in RE-LY, and 3.6% for in ROCKET-AF. Vitamin K antagonists like showed higher rates of 2-5% per year, including 3.09% in ARISTOTLE and 3.36% in RE-LY. In the ROCKET-AF trial, had a comparable major bleeding rate to (3.6% vs. 3.4%), but overall clinically relevant bleeding was similar at approximately 14-15% per year across groups. Site-specific risks differ between agents. Warfarin is associated with a higher ICH risk compared to DOACs, with relative risks of 0.31-0.67 for DOACs in meta-analyses of trials. For GI bleeding, meta-analyses indicate that standard-dose DOACs are associated with a higher risk compared to warfarin (HR 1.31, 95% CI 1.08-1.57), with rivaroxaban and higher-dose dabigatran showing increased risk, while apixaban may have a lower risk in some studies. Key risk factors for bleeding include advanced age (>75 years), history of prior bleeding, renal impairment, and , which amplify the anticoagulant effect or impair clearance. The score, validated for patients on anticoagulation, incorporates these factors (, abnormal renal/liver function, stroke history, bleeding predisposition, labile INR, elderly >65 years, drugs/alcohol) to predict one-year major bleeding risk, with scores ≥3 indicating high risk (approximately 5-10% annual incidence). Management of bleeding often involves reversal agents tailored to the anticoagulant, as detailed in specific guidelines.

Non-Bleeding Complications

(HIT) is an immune-mediated adverse effect primarily associated with unfractionated (UFH), occurring in 1-5% of patients receiving UFH for at least five days. It involves IgG antibodies binding to (PF4)- complexes, activating platelets and leading to and a paradoxical prothrombotic state that can cause venous or arterial . Diagnosis relies on the 4Ts score, a clinical pretest probability tool assessing , timing of onset, occurrence, and other causes of low platelets, with scores of 6-8 indicating high probability, 4-5 intermediate, and 0-3 low. Management involves immediate heparin discontinuation and initiation of non-heparin anticoagulants like or . Long-term use of UFH or (LMWH) is linked to and loss, particularly in patients requiring prolonged such as those on anticoagulation for more than three months. This effect stems from heparin's inhibition of function and promotion of activity, resulting in reduced and an increased , with studies showing decreases of 5-10% in after six months of UFH exposure. LMWH appears to pose a lower than UFH but still contributes to loss in extended use beyond 12 months. Monitoring via is recommended for at-risk patients, and alternative anticoagulants may be considered to mitigate this complication. Among direct oral anticoagulants (DOACs), is associated with dyspepsia in approximately 5-10% of users, often due to its core irritating the gastrointestinal mucosa, manifesting as epigastric discomfort, , or . (Xarelto) can cause mild elevations in liver enzymes in up to 4% of patients, typically transient and , though rare cases of clinically apparent have been reported, with a higher incidence compared to other DOACs. These gastrointestinal and hepatic effects are generally manageable with dose adjustments or supportive care, but liver function monitoring is advised during initiation. Warfarin-induced skin is a rare early complication, occurring within the first 3-10 days of therapy in 0.01-0.1% of patients, particularly those with underlying . It results from a transient hypercoagulable state as warfarin's inhibition of vitamin K-dependent factors causes a faster decline in (half-life ~8 hours) relative to procoagulant factors, leading to microvascular and full-thickness skin , often in fatty areas like breasts, thighs, or . Initial bridging with and low initial doses are preventive strategies, while treatment involves discontinuing and using alternative anticoagulants. Other rare non-bleeding complications include to heparins, which presents as immediate reactions such as urticaria, , or in less than 0.1% of cases, more commonly with LMWH in patients with prior exposure. Alopecia associated with is uncommon and reversible, affecting growth in a diffuse pattern due to possible , reported in fewer than 1% of long-term users.

Monitoring and Interactions

Laboratory Assessment

Laboratory assessment of anticoagulant therapy involves measuring coagulation parameters to guide dosing, ensure therapeutic efficacy, and prevent complications such as or . This is particularly crucial for traditional agents like antagonists and heparins, where variability in patient response necessitates regular monitoring, whereas direct oral anticoagulants (DOACs) typically require it only in select clinical scenarios. For , a , the international normalized ratio (INR), calculated from the (PT), serves as the standard measure of anticoagulant activity, with a target range of 2.0 to 3.0 for most indications such as or venous . In situations where PT/INR results may be unreliable—due to interferences like elevated or antiphospholipid antibodies—a chromogenic offers a more precise alternative by directly quantifying activity, independent of reagents, to better assess the intensity of anticoagulation. Unfractionated heparin (UFH) is monitored primarily using the activated partial thromboplastin time (aPTT), aiming for 1.5 to 2.5 times the laboratory's control value to correlate with adequate antithrombin activity and prevent under- or over-anticoagulation during intravenous administration. For low-molecular-weight heparins (LMWH) like enoxaparin, routine monitoring is not standard due to their predictable pharmacokinetics, but peak anti-factor Xa levels, drawn 3 to 5 hours post-dose, target 0.5 to 1.0 IU/mL for therapeutic twice-daily regimens in patients with renal impairment or obesity. DOACs, including factor Xa inhibitors (, , ) and (), do not require routine laboratory monitoring owing to their fixed dosing and rapid onset/offset. When assessment is warranted—such as for perioperative management or suspected overdose—calibrated chromogenic anti-Xa assays quantify levels of factor Xa inhibitors, while dilute (dTT) or ecarin (ECT) specifically detect activity, providing drug-specific plasma concentrations to inform clinical decisions. Point-of-care testing enhances rapid evaluation in dynamic settings like or critical care, where chromogenic assays can directly measure anticoagulant-specific effects, and viscoelastic tests such as (TEG) or rotational (ROTEM) provide whole-blood profiles of clot formation and lysis to detect residual anticoagulation and guide transfusion or reversal strategies. Genetic testing for warfarin therapy focuses on polymorphisms in (which metabolizes ) and VKORC1 (the drug's target enzyme), as variants in these genes explain up to 40% of dose variability and can predict time to therapeutic INR, with guidelines such as CPIC recommending the use of pharmacogenetic algorithms incorporating these genotypes to inform initial dosing when testing results are available, applicable to both adults and .

Drug and Dietary Interactions

Anticoagulants are susceptible to various and dietary interactions that can alter their therapeutic levels, , or profile, necessitating careful clinical to prevent thrombotic or complications. These interactions primarily involve metabolic pathways such as (CYP) enzymes and transporters like (P-gp), as well as dietary factors that antagonize anticoagulant mechanisms. Understanding these interactions is crucial for dose optimization and . For vitamin K antagonists like , drug interactions often occur through CYP modulation. CYP inducers such as rifampin accelerate , decreasing its anticoagulant effect and potentially lowering the international normalized ratio (INR). Conversely, CYP inhibitors like impair clearance, increasing INR and elevating bleeding risk. Dietary interactions with are prominent due to its , which inhibits -dependent clotting factors; consumption of -rich foods, such as , can antagonize 's effects by replenishing stores, leading to reduced anticoagulation. Direct oral anticoagulants (DOACs) exhibit interactions primarily via P-gp and pathways. For instance, the strong P-gp and inhibitor significantly boosts exposure by inhibiting its efflux and metabolism, increasing the risk of hemorrhage. Strong inducers like St. John's wort should be avoided with DOACs, as they enhance P-gp activity, reducing drug levels and compromising efficacy across agents like , , and . Heparins and their derivatives have fewer pharmacokinetic interactions due to their parenteral administration and renal clearance, but pharmacodynamic synergies with antiplatelet agents heighten risks. Concomitant use with aspirin, an antiplatelet, substantially increases the overall hemorrhage risk when combined with therapeutic anticoagulation, including unfractionated or . Management of these interactions emphasizes proactive strategies, including dose adjustments or avoidance of interacting agents. For example, doses of 15 mg or higher should be administered with food to enhance and ensure consistent absorption, as fasting conditions reduce exposure. Clinicians often recommend monitoring INR or other parameters following interaction onset to guide adjustments, though detailed quantification is addressed elsewhere. in the elderly exacerbates these risks; recent data indicate that multiple medications, including anticoagulants, contribute to higher rates of adverse drug events in older adults, with linked to increased drug-related problems and complications.

Reversal and Management

Reversal Agents

Reversal agents are specific antidotes used to neutralize the effects of anticoagulants in emergency situations, such as life-threatening , where rapid restoration of is critical. These agents are indicated primarily for major or , urgent surgery, or overdose, and their use should be guided by clinical guidelines to balance reversal efficacy against thrombotic risks. For vitamin K antagonists like , reversal involves a combination of for gradual correction and prothrombin complex concentrates (PCCs) for immediate . , administered intravenously at 5-10 mg, promotes hepatic synthesis of clotting factors II, VII, IX, and X, with typically within 6-24 hours and full effect by 24 hours; it is given concurrently with PCC to ensure sustained reversal. Four-factor PCC, containing factors II, VII, IX, and X along with proteins C and S and , provides rapid replacement of vitamin K-dependent factors, normalizing the international normalized ratio (INR) within minutes to hours at doses calculated based on body weight and INR (e.g., 25-50 units/kg). Heparin and its derivatives are reversed by , a basic protein that binds to form an inactive complex, thereby neutralizing its antithrombin-mediated anticoagulant activity. For unfractionated (UFH), protamine fully reverses effects at a dose of 1 mg per 100 units of (up to 50 mg per dose), administered slowly intravenously with monitoring of activated partial thromboplastin time (aPTT) 5-15 minutes post-dose. For low-molecular-weight heparins (LMWH) like enoxaparin, reversal is partial, targeting primarily the anti-factor IIa activity, with dosing at 1 mg protamine per 1 mg enoxaparin (or 1 mg per 100 anti-Xa units); a second dose of 0.5 mg per 1 mg may be needed if aPTT remains elevated after 2-4 hours. Direct oral anticoagulants (DOACs) have targeted reversal agents approved for emergency use. , a fragment specific to (a ), binds and neutralizes the drug with high affinity, achieving rapid reversal within minutes; the standard dose is 5 g intravenously as two 2.5 g boluses given no more than 15 minutes apart, suitable for life-threatening bleeds or urgent procedures. For factor Xa inhibitors such as , , and , acts as a protein that competitively binds the inhibitor, restoring factor Xa activity; dosing depends on the agent and timing but typically involves a low-dose regimen of 400 mg bolus at 30 mg/min followed by 4 mg/min infusion for up to 2 hours for recent low-dose intake, or high-dose (800 mg bolus + 8 mg/min infusion) for higher doses or longer intervals. Emerging universal reversal agents aim to address multiple anticoagulants in a single formulation. Ciraparantag, a synthetic small-molecule reversal agent, noncovalently binds to UFH, LMWH, and DOACs (including factor Xa inhibitors and ), rapidly reversing anticoagulation in phase 2 trials with effects lasting up to 24 hours; it is currently in phase 3 clinical trials for broader validation in emergency settings.

Peri-Procedural Strategies

Peri-procedural strategies for anticoagulant management aim to minimize both thromboembolic and bleeding risks during temporary interruptions for elective surgeries or invasive procedures. Risk stratification is essential, categorizing patients as high or low risk for based on factors such as the underlying condition (e.g., or venous thromboembolism), CHA2DS2-VASc score, and recent events like stent placement within the past month or mechanical heart valves for high risk, versus stable chronic conditions for low risk. The BRIDGE trial, a randomized controlled study of 1,884 patients with on (mean CHA2DS2-VASc score of 3.8), found that no bridging was noninferior to bridging with (LMWH) for preventing arterial thromboembolism (0.4% vs. 0.3%) and significantly reduced major bleeding (1.3% vs. 3.2%). Protocols for interruption vary by agent. For vitamin K antagonists (VKAs) like , therapy is typically discontinued 5 days before the procedure to allow the international normalized ratio (INR) to fall below 1.5, with bridging using therapeutic-dose LMWH started 3 days prior and stopped 24 hours before for high-risk patients; resumption occurs 12-24 hours postoperatively if is secured. For direct oral anticoagulants (DOACs), interruption is shorter: , , and are held for 1 day (last dose 24-48 hours prior) before low-bleeding-risk procedures and 2 days before high-bleeding-risk ones in patients with normal renal function, while requires 1-2 days for low risk and 2-4 days for high risk, extended by 1-2 additional days if creatinine clearance is 30-50 mL/min. Postoperatively, DOACs are resumed 24 hours after low-risk procedures or 48-72 hours after high-risk ones, without routine bridging. The PAUSE trial, involving 3,007 DOAC-treated patients with undergoing procedures, confirmed the safety of this renal-adjusted protocol, reporting major bleeding in 1.85% and arterial in 0.16%, with no venous events. The 2020 (ACC) Expert Consensus Decision Pathway for patients with or venous undergoing periprocedural management recommends interrupting anticoagulation without bridging for most low- to moderate-risk cases, prioritizing DOACs over VKAs when possible due to predictable and shorter half-lives. For venous specifically, the American Society of Hematology (ASH) 2018 guidelines on optimal anticoagulation therapy suggest against routine use of LMWH bridging during interruptions for invasive procedures in patients on VKAs or DOACs, as it increases without reducing . Clinical outcomes from these strategies show no significant increase in thromboembolic events with brief interruptions in low- to moderate-risk patients, as evidenced by the low event rates in the BRIDGE and PAUSE trials. For planned procedures, local hemostatic interventions (e.g., , topical agents) are favored over systemic reversal to avoid prolonging subtherapeutic anticoagulation periods.

Special Considerations

Dental Procedures

For patients on anticoagulant therapy undergoing minor dental procedures such as extractions or cleanings, guidelines recommend continuing therapy without interruption, as the bleeding risk remains low at approximately 4-5% for any postoperative , which can typically be managed with local hemostatic measures including absorbable sutures, gelatin sponges, and fibrin sealants. The (ADA) guidelines (last updated 2022, current as of 2025) endorse no alteration of direct oral anticoagulants (DOACs) or for these low-risk interventions, provided international normalized ratio (INR) is below 4; local application of (typically 4.8-5% solution rinsed for 2 minutes twice daily for 2-7 days post-procedure) is advised to enhance and reduce bleeding incidence by up to 50% in anticoagulated patients. For major dental procedures like implants or extensive oral , clinicians should assess bleeding risk using the score, which predicts major hemorrhage in anticoagulated patients (score ≥3 indicates high risk); a 1-day hold of DOACs may be considered in high-risk cases, balancing against thromboembolic potential, while may require INR monitoring and potential bridging if interruption is needed. Meta-analyses confirm no increased bleeding complications in anticoagulated versus non-anticoagulated patients during dental extractions when is continued, with relative risks of 0.68-0.79 for DOACs compared to antagonists, and severe events rare (less than 1%). Complications such as () are rare in dental settings, occurring in fewer than 0.1% of cases involving short-term exposure for . Recent 2024-2025 studies reinforce the safety of continuing anti-Xa inhibitors (e.g., , ) for simple tooth extractions, reporting no excess severe bleeding and advocating uninterrupted dosing to minimize thrombotic risks.

Use in Vulnerable Populations

In elderly patients, direct oral anticoagulants (DOACs) require dose adjustments to mitigate risks, which are heightened due to factors such as frailty, , and increased fall propensity. For , the standard 5 mg twice-daily dose is reduced to 2.5 mg twice daily in patients aged 80 years or older who meet at least one additional criterion, such as body weight ≤60 kg or serum ≥1.5 mg/dL, as per data and guidelines emphasizing reduced renal function and body size in this population. Similarly, dosing is lowered to 110 mg twice daily for patients over 80 years to balance efficacy against risk. These adjustments stem from pharmacokinetic studies showing slower drug clearance in older adults, leading to higher exposure and a 1.5- to 2-fold increased incidence compared to younger cohorts. Patients with renal impairment necessitate careful selection and dosing of anticoagulants, given the predominant renal excretion of many agents. , with approximately 80% renal clearance, is contraindicated when creatinine clearance (CrCl) is below 30 mL/min due to elevated plasma levels and associated or risks observed in pharmacokinetic modeling and observational data. In contrast, is preferred in moderate to severe renal impairment, including end-stage renal disease (CrCl <15 mL/min or dialysis), as it exhibits minimal renal elimination (about 27%) and demonstrated comparable efficacy to in reducing /systemic with lower major rates in randomized trials. Guidelines recommend monitoring CrCl at initiation and periodically, avoiding or in CrCl <30 mL/min unless benefits outweigh risks. During pregnancy, low-molecular-weight heparin (LMWH) is the cornerstone anticoagulant for venous thromboembolism (VTE) prevention and treatment, as DOACs are contraindicated due to their ability to cross the placenta and limited safety data from human studies. Warfarin is also avoided, particularly in the first trimester, owing to its teratogenic effects, including fetal warfarin syndrome with risks of nasal hypoplasia and stippled epiphyses documented in cohort studies. LMWH, administered subcutaneously at weight-based doses (e.g., enoxaparin 1 mg/kg twice daily), does not cross the placenta and has a well-established safety profile in prospective registries showing low rates of maternal hemorrhage (1-2%) and no fetal anticoagulation. In pediatric populations, anticoagulation strategies prioritize agents with established pediatric pharmacokinetics, as DOAC data remain limited. Enoxaparin is commonly used at weight-based dosing (e.g., 1.5 mg/kg subcutaneously every 12 hours for treatment) due to its predictable clearance and extensive trial evidence in children with VTE, supporting efficacy in 90-95% of cases without excessive bleeding. Rivaroxaban gained FDA approval in December 2021 for VTE treatment and prevention in children aged 2 years and older (with extensions to younger ages via suspension formulations), based on phase 3 trials like EINSTEIN Junior demonstrating non-inferiority to standard therapy with similar safety. For patients with cancer, particularly those with VTE, direct oral anticoagulants (DOACs) are suggested over (LMWH) for initial treatment according to the American Society of Hematology (ASH) 2021 guidelines, based on randomized trials showing reduced recurrence rates (e.g., 0.62 in meta-analyses) with comparable risks overall. However, LMWH remains preferred in cases such as gastrointestinal malignancies due to higher risks with DOACs (up to 3-fold in meta-analyses), arising from interactions with tumor-related factors.

Research Directions

Ongoing Clinical Trials

Several phase 2 and 3 clinical trials are actively investigating expansions of direct oral anticoagulants (DOACs) for extended venous thromboembolism (VTE) treatment, particularly in high-risk populations such as those with cancer. The API-CAT trial, a phase 3 study, evaluated reduced-dose apixaban (2.5 mg twice daily) versus full-dose (5 mg twice daily) for 12 months in patients with active cancer and acute VTE, demonstrating noninferiority in preventing recurrent VTE (HR 0.76; 95% CI 0.41-1.41) with lower clinically relevant bleeding (HR 0.75; 95% CI 0.58-0.97). Similarly, the HI-PRO trial assessed extended low-dose apixaban in patients with provoked deep vein thrombosis or pulmonary embolism, reporting a significant reduction in symptomatic VTE recurrence (1.3% vs. 10.0% with placebo; HR 0.13; 95% CI 0.04-0.36) alongside a major bleeding rate of 0.3%. Real-world utilization studies continue to highlight gaps in anticoagulant adherence and prescribing patterns. The GARFIELD-AF registry, an ongoing global , has documented persistent underuse of oral anticoagulants in eligible patients, with analyses from recent cohorts indicating that approximately 20-25% of high-risk individuals remain untreated due to concerns over or patient factors. A 2024 cross-sectional analysis of adherence metrics further revealed that persistence with DOACs drops to below 70% within the first year, influenced by socioeconomic barriers and , underscoring the need for targeted interventions. Factor XI inhibition remains a focus of late-stage trials for stroke prevention in atrial fibrillation. The OCEANIC-AF phase 3 trial, evaluating asundexian (50 mg daily) versus in over 7,000 patients, was terminated early in 2024 after an interim analysis showed higher rates of or systemic with asundexian (1.3% vs. 0.4%; hazard ratio 3.06; 95% CI 2.03-4.81), despite reduced events. Ongoing follow-up from this trial, extended into 2025, continues to assess long-term safety and potential dose adjustments for future FXIa inhibitors. Contemporary trials commonly employ composite endpoints balancing efficacy and safety, such as recurrent , systemic , major , and mortality. For instance, the RE-COVER trials for in acute VTE used a primary efficacy endpoint of symptomatic or fatal VTE recurrence (2.4% with vs. 2.1% with ; 1.10; 95% CI 0.65-1.84) and a safety endpoint of major (1.6% vs. 1.9%; 0.82; 95% CI 0.45-1.48), establishing a benchmark for net clinical benefit assessments in ongoing DOAC studies.

Emerging Therapies

Factor XI inhibitors represent a promising class of emerging anticoagulants that target the contact activation pathway of coagulation, potentially decoupling antithrombotic efficacy from bleeding risk by inhibiting thrombosis amplification while preserving hemostasis. Abelacimab, a monoclonal antibody targeting the zymogen form of factor XI to prevent its activation, demonstrated substantial reductions in bleeding events in the phase 3 AZALEA-TIMI 71 trial. In this study, the 150 mg monthly dose of abelacimab resulted in a 62% reduction in major or clinically relevant non-major bleeding compared to rivaroxaban (HR 0.38; 95% CI 0.24-0.60), with similar trends across subgroups including elderly patients and those on antiplatelet therapy. Milvexian, an oral small-molecule inhibitor of activated factor XIa, is advancing in the phase 3 LIBREXIA AF trial (recruiting as of 2025), evaluating its noninferiority to apixaban for stroke prevention in atrial fibrillation patients, with early modeling supporting doses that balance efficacy and safety. Asundexian, another oral factor XIa inhibitor, showed encouraging phase 2 results for secondary stroke prevention in the PACIFIC-Stroke trial, where it reduced recurrent ischemic events without increasing major bleeding when added to antiplatelet therapy, highlighting its potential in high-risk vascular patients. Complementing these direct anticoagulants, ciraparantag is under investigation as a universal reversal agent in phase 2 trials, designed to bind and neutralize multiple classes including direct oral anticoagulants and heparins through noncovalent interactions, offering rapid and sustained reversal without procoagulant effects in preclinical and early human studies. Atrial-selective approaches aim to address arrhythmia-associated more precisely. AP30663, a small-conductance calcium-activated (KCa2) channel blocker, achieved its primary endpoint in a phase 2 trial for recent-onset , cardioverting 55% of patients to within 90 minutes at the 5 mg/kg dose compared to 0% with , with a favorable safety profile limited to transient QT prolongation. Recent 2025 reviews anticipate inhibition as the next standard in anticoagulation, emphasizing its targeted disruption of pathological while minimizing hemostatic impairment, potentially transforming management in and beyond, though tempered by setbacks like the OCEANIC-AF termination.

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