Anticoagulation: Past, Present, and Future Therapies

Abstract

Blood clots may cause as many as one-in-four deaths worldwide each year. Approximately, 100,000–300,000 patients die annually from clots in the United States alone, with potentially another 600,000 nonfatal cases. The economic toll is staggering; the United States may lose about $10 billion each year to such afflictions, though it could represent a nearly $55 billion market for drug developers. As more anticoagulants are brought to market, the list of potential indications approved by the Food and Drug Administration (FDA) and off-label use have expanded considerably. Anticoagulation therapy is now offered to those at risk for myocardial infarction, stroke, transient ischemic attack (TIA), and venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). In addition, anticoagulants are now commonly utilized in cases of atrial fibrillation, heart valve replacement, thrombophilia, prolonged immobility, and procoagulant diseases, such as cancer. This chapter discusses key attributes of anticoagulation agents, including their pharmacokinetics, pharmacodynamics, dosing considerations, significant drug interactions, monitoring parameters, and unique considerations for special patient populations. The chapter also provides an overview for converting between anticoagulants, currently available reversal agents, and future directions in anticoagulation therapy and research.

1. Introduction

Blood clots may cause as many as one-in-four deaths worldwide each year [1]. In the United States alone, approximately 100,000–300,000 patients die annually from clots, with potentially another 600,000 nonfatal cases [2]. The economic toll is staggering; the United States may lose about $10 billion each year to such afflictions, though it could represent a nearly $55 billion market for drug developers [1, 3]. Of note, public demand for anticoagulants has surged dramatically over the last decade. Pharmacoeconomic research shows that between 2011 and 2019, the number of medicare part D patients utilizing oral anticoagulants increased from 2.68 to 5.24 million while spending increased from $0.44 billion to $7.38 billion during that same period [4]. Similar research has found that between 2014 and 2019, total medicaid and medicare part D anticoagulation claims increased from 23.5 to 30.6 million, a nearly 30% increase in volume [5].

As more anticoagulants are brought to market, the list of potential indications—both FDA-approved and off-label—has expanded considerably. For example, anticoagulation therapy is now offered to those at risk for heart attack, stroke, transient ischemic attack (TIA), and venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) [5]. In addition, anticoagulants are now commonly utilized in cases of atrial fibrillation, heart valve replacement, thrombophilias, prolonged immobility, and procoagulant diseases, such as cancer [6, 7].

As indispensable as anticoagulant therapies are in modern healthcare, they represent a relatively recent scientific innovation. Table 1 illustrates a timeline of landmark anticoagulant developments, including the discovery of heparin in 1916 and the relatively recent approval of several direct oral anticoagulants (DOACs) and their reversal agents.

Year(s)	Development
1909	Hirudin extracted from medicinal leeches first used in clinics
1916	Jay McLean, a Johns Hopkins medical student, discovers unfractionated heparin (UFH)
1932	Scientists discover heparin requires a plasma factor (antithrombin or AT)
1935	Prothrombin time (Quick PT test) first developed
1939	University of Wisconsin researchers identify dicoumarol in sweet clover
1941	Dicumarol first administered to patients at Mayo Clinic; UFH first used in clinical practice
1943	Discovery of Vitamin K, leading to awarding of Nobel Prize to researchers
1948	Warfarin (dicoumarol derivative) marketed as rodenticide
1954	Warfarin approved by FDA for clinical use in the United States
1970s	Research starts on low molecular weight heparin (LMWH); Mechanism of action of Vitamin K discovered by scientists
1980s	First clinical studies of LMWH; Factor Xa identified as promising target for the development of new anticoagulants; International Normalized Ratio (INR) developed by World Health Organization
1993	Enoxaparin (LMWH) receives FDA approval
2000	Bivalirudin and argatroban receive FDA approval
2001	Fondaparinux receives FDA approval
2003	First DOAC, ximelagatran, approved but later withdrawn from market
2010	Dabigratran receives FDA approval
2011	Rivaroxaban receives FDA approval
2014	Apixaban receives FDA approval
2015	Edoxaban receives FDA approval; Idarucizumab (reversal agent for dabigatran) receives FDA approval
2018	Andexanet alfa (reversal agent for Factor Xa inhibitors) receives FDA approval
2020s	Cutting-edge research on contact pathway components (FXIa or FXIIa), antisense oligonucleotides, antibodies, and aptamers; Anti-Factor XIa antibody abelacimab tested in cancer-associated thrombosis

Table 1.

Landmarks developments in anticoagulation research and therapy [8, 9, 10, 11, 12, 13, 14, 15].

In the following sections, we will discuss key attributes—including pharmacokinetics, pharmacodynamics, dosing considerations, and significant drug interactions—for several current anticoagulants, crucial monitoring parameters, and unique considerations for special patient populations. Additionally, we provide an overview of converting between different anticoagulants, currently available reversal agents, and future directions in anticoagulation therapy and research.

2. Current anticoagulation therapies

2.1 Unfractionated heparin (UFH)

2.1.1 Definition/pharmacodynamics

Unfractionated heparin (UFH), derived from either porcine or bovine tissue, is an injectable anticoagulant that inactivates thrombin (IIa) and Factor Xa via antithrombin, thus inhibiting the coagulation cascade [16, 17]. It is preferred in patients with greater bleeding risk, critical illnesses, or those requiring surgical or invasive procedures [18].

2.1.2 Pharmacokinetics

Heparin is not absorbed through the gastrointestinal tract and is administered parenterally, achieving peak plasma concentration immediately after intravenous administration. Its volume of distribution is 0.07 L/kg, and it undergoes biphasic clearance with a rapid elimination phase (half-life of 10–90 minutes) and a slower elimination phase (half-life of 2–24 hours) primarily mediated by liver and reticuloendothelial cells [19]. Its short half-life (only 0.5–1.5 hours) allows for rapid onset and offset, usually within hours of discontinuation [20]. Additionally, it is an attractive option for those with impaired or unstable renal function (CrCL <30 mL/min) [21]. Moreover, it has minimal drug interactions courtesy of limited liver enzyme activity [22]. Intravenous (IV) drug delivery is recommended in cases of shock and/or hypotension due to inconsistent absorption from subcutaneous tissues caused by its plasma protein binding [23].

2.1.3 Dosing considerations

Dosing considerations for heparin depend on factors such as patient weight, age, and medical condition, with dose adjustments guided by activated partial thromboplastin time (aPTT) or anti-factor Xa levels [19].

2.1.4 Contraindications

UFH should be avoided in patients with a history of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis (HITT), those with a hypersensitivity to heparin or pork products, and those where testing (aPTT or anti-Xa) cannot be performed at regular intervals [19].

2.1.5 Drug interactions

Unfractionated heparin can interact with nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and indomethacin, potentially leading to increased bleeding risk and should be used cautiously in patients receiving heparin sodium [19]. Additionally, co-administration of UFH with glycoprotein IIb/IIIa antagonists may reduce platelet inhibition during treatment with these agents [19].

2.1.6 Adverse reactions

During post-marketing surveillance, the most common adverse reactions were hemorrhage, thrombocytopenia, HIT and HITT, hypersensitivity reactions, and elevations of aminotransferase levels [19].

2.2 Low molecular weight heparin (LMWH)

2.2.1 Definition/pharmacodynamics

As the name implies, this class consists of “fractionated” heparins with molecular weights less than half that of UFH. Members of this class include the injectables enoxaparin (Lovenox) and dalteparin (Fragmin) [24]. Commonly used for DVT/PE prevention and treatment, they are also used short term during elective percutaneous coronary intervention therapy or as “bridging therapy” in atrial fibrillation [25]. Mechanistically, this class strongly inhibits Factor Xa, with relatively small effects on activated partial thromboplastin time (aPTT) [24]. Agents have a higher binding affinity for Factor Xa, while UFH has a higher affinity for antithrombin. Peak therapeutic effect occurs 3–5 hours after administration [24].

2.2.2 Dosing considerations

Of note, the anticoagulant pharmacodynamic effects of LMWH are more consistent than UFH, with dosing based on body weight [23]. When prescribing LMWH, dosing may be affected by factors such as the patient’s weight, age, and medical condition, with dose adjustments guided by anti-factor Xa activity levels [26]. This class is preferred in pregnant patients and those with active malignancies [24, 25]. Table 2 provides greater detail on LMWH dosing considerations.

LMWH dosing considerations
Enoxaparin	Hip-replacement surgery: 30 mg SQ every 12 hours OR 40 mg SQ every 24 hours (started 12–24 hours after surgery) Knee-replacement surgery: 30 mg SQ every 12 hours (started 12–24 hours after surgery) Abdominal surgery: 40 mg SQ every 24 hours (started 2 hours before surgery) Acute mental illness: 40 mg SQ every 24 hours DVT treatment w/ or w/out PE; 1 mg/kg SQ every 12 hours OR 1.5 mg/kg SQ every 24 hours	Dosing considerations: Reduce dose if CrCl <30 mL/min VTE prophylaxis: 30 mg SQ every 24 hours VTE treatment: 1 mg/kg SQ every 24 hours (may convert conventional BID dosing into once-daily dosing)
Dalteparin	Hip-replacement surgery: 2500 units SQ given 2 hours before surgery, then 2500 units the evening after surgery (at least 6 hours after first dose), then 5000 units every 24 hours OR 5000 units every 24 hours, started evening before surgery Abdominal surgery: 2500 units SQ every 24 hours (started 1–2 hours before surgery) Acute mental illness: 5000 units SQ every 24 hours

Table 2.

Low molecular weight heparin—dosing considerations [27, 28].

Abbreviations: BID, twice a day; CrCL, creatinine clearance; SQ, subcutaneously; and VTE, venous thromboembolism.

2.2.3 Drug interactions/safety considerations

Like UFH, LMWH can potentially interact with NSAIDs, antiplatelet medications such as aspirin, clopidogrel, and ticagrelor, as well as with other anticoagulants such as warfarin, danaparoid, bivalirudin, rivaroxaban, apixaban, and dabigatran as they all impact the coagulation cascade and may elevate the risk of bleeding [27, 28]. Overall, LMWH has a lower incidence of heparin-induced thrombocytopenia (HIT) than UFH, though it may still trigger HIT antibody formation [29]. If major bleeding and thrombocytopenia are a concern, clinicians should obtain baseline platelet counts and closely monitor for HIT development [29].

2.2.4 Pharmacokinetics

Enoxaparin and dalteparin are eliminated by the kidneys and excreted in the urine [24, 30]. These agents have longer half-lives than UFH; the half-life of enoxaparin, for example, is around 4.5–7 hours, about 2–4 times longer than UFH. The route of administration strongly dictates the half-life of each agent [24, 27, 28, 30].

2.2.5 Contraindications

LMWHs should be avoided in patients with active bleeding, those with a hypersensitivity to pork heparin or pork products, and those displaying thrombocytopenia with a positive test for antiplatelet antibodies [27, 28].

2.2.6 Drug interactions

Due to increased risk of hemorrhage, LMWHs should be avoided or using cautiously with anticoagulants, antiplatelets, aspirin, and NSAIDs [27, 28].

2.2.7 Adverse reactions

During clinical trials, the most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea, and nausea ( Table 3 ) [27, 28].

Unfractionated heparin	Low molecular weight heparin
Less predictable anticoagulant response; May require frequent aPTT or anti-Xa monitoring; Shorter half-life (∼1 hour); More difficult administration (IV, subcutaneous); Typically do not require renal dose adjustment	More predictable anticoagulant response; Typically does not require anti-Xa monitoring; Longer half-life (3–4.5 hours); Easier administration (subcutaneous); Less risk of HIT; May require renal dose adjustment (if CrCl <30 mL/min); Recent studies suggest may have greater effectiveness and less bleeding than UFH

Table 3.

Advantages and disadvantages: Unfractionated heparin (UFH) vs. low molecular weight heparin (LMWH) [31, 32, 33, 34].

Abbreviations: aPTT, activated partial thromboplastin time; CrCL, creatinine clearance; HIT, heparin-induced thrombocytopenia; IV, intravenous; mL/min, milliliters per minute; and UFH, unfractionated heparin.

2.3 Vitamin K antagonists (VKAs)

2.3.1 Definition/pharmacodynamics

This medication class interferes with the cyclic interconversion of vitamin K, which is essential for synthesizing clotting factors and anticoagulant proteins. By inhibiting γ-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins—including coagulation factors II (prothrombin), VII, IX, and X, as well as of the anticoagulant proteins C and S—these agents interfere with the action of vitamin K in the body [35, 36, 37]. By inhibiting the production of such clotting factors, the body is less able to clot [35, 36, 37]. In general, VKAs pose challenges due to their narrow therapeutic index and unpredictable dose response, which can lead to bleeding complications and inadequate anticoagulation [35, 36, 37].

This class includes warfarin (Coumadin, Jantoven), phenprocoumon (Marcoumar, Marcumar), and acenocoumarol (Nicoumalone) [38]. Only warfarin and phenprocoumon are FDA-approved in the United States. VKAs, such as warfarin, usually exist in two different enantiomeric forms and are administered orally as a racemate [37]. They often have a delayed onset of action since it may take time for existing clotting factors to be removed from circulation [38, 39]. As a result, their full therapeutic effect may take several days to achieve and—due to the turnover time of clotting factors—their duration of action can persist well beyond the clearance of the actual drug [38, 39]. Therapeutically, VKAs are monitored using the international normalized ratio (INR), which was developed in the 1980s by the World Health Organization [40].

2.3.2 Pharmacokinetics

2.3.2.1 Absorption

Due to their 100% bioavailability, most VKAs are rapidly absorbed from the GI tract after oral administration; the sole exception is acenocoumarol, which undergoes extensive first-pass metabolism. Peak plasma concentrations are generally reached within a few hours. Gastrointestinal health, gut motility, and patient dietary choices, however, may impact the absorption of VKAs [38, 39].

2.3.2.2 Distribution

VKAs are often highly protein-bound (> 98%), especially to albumin, in the bloodstream. This protein binding can affect their later distribution to target tissues [38, 39].

2.3.2.3 Metabolism

Warfarin undergoes extensive metabolism, primarily via CYP2C9 liver enzymes. CYP2C9 is largely responsible for converting it from the “active” S-warfarin enantiomer to its “inactive” metabolites. By comparison, the R-warfarin enantiomer experiences limited metabolism and is eliminated largely unchanged. Genetic polymorphisms—or differences in gene expression—may lead to altered CYP2C9 activity, causing variable warfarin metabolism and clearance between individuals [37, 40]. Those with polymorphisms causing reduced enzyme activity may require smaller warfarin doses, while those with normal enzyme activity may require higher doses. Like warfarin, acenocoumarol and phenprocoumon are metabolized primarily by CYP2C9 and, to a far lesser extent, by CYP3A4 [38, 39]. Genetic variations can also influence the metabolism and clearance of these two drugs. Due to significant variability in patient responses to VKAs, individualized dosing regimens and close side effect monitoring are recommended [41, 42].

2.3.2.4 Elimination

Drug metabolites are largely eliminated via urine and feces, though specific mechanisms and pathways involved in excretion may vary. Warfarin is eliminated via first-order kinetics, with approximately 80% of metabolites found in urine and the remaining 20% in feces. The half-life of warfarin’s S-enantiomer ranges between 21 and 43 hours, while the R-enantiomer is 37–89 hours. Conversely, 65% of acenocoumarol is eliminated via urine, and approximately, 35% is eliminated in feces [38, 39]. With its biphasic kinetics, the half-life of S-acenocoumarol is 0.5 hours and 9 hours for R-acenocoumarol. On the other hand, phenprocoumon experiences first-order kinetics, though its elimination pathways are similar to acenocoumarol (65% urine, 35% feces). The half-life of both S- and R-phenprocoumon is 132 hours [38].

2.3.3 Dosing considerations

Per American Geriatrics Society 2023 Beers Criteria, warfarin should be avoided in older adults if possible. Generalized dosing nomograms for warfarin and phenprocoumon are presented below in Tables 4 and 5 [41, 42].

	Standard dosing for patients not expected to be sensitive to warfarin	Reduced dosing for patients expected to be sensitive to warfarin
Initial dose	5 mg daily × 3 days	2.5 mg daily × 3 days
Morning of day 4 = check INR
INR <1.5	7.5–10 mg daily × 2–3 days	5–7.5 mg daily × 2–3 days
1.5 to 1.9	5 mg daily × 2–3 days	2.5 mg daily × 2–3 days
2 to 3	2.5 mg daily × 2–3 days	1.25 mg daily × 2–3 days
3.1 to 4	1.25 mg daily × 2–3 days	0.5 mg daily × 2–3 days
INR > 4	Hold until INR < 3	Hold until INR < 3
*Maintenance dose: 2–10 mg once daily

Table 4.

Warfarin initiation—dosing nomogram [43, 44, 45].

Abbreviations: INR, international normalized ratio.

Day #1	15–20 mg orally
Day #2	9–12 mg orally
Day #3	0.75–9 mg orally while monitoring prothrombin time response
Maintenance dose	Goal: achieve prothrombin time of 1.5–2 times ranges from 0.75 to 4.5 mg/day

Table 5.

Phenprocoumon initiation—dosing nomogram [46].

2.3.4 Contraindications

Warfarin should be avoided in (a) pregnant patients or those with eclampsia or preeclampsia, (b) unsupervised patients with potential high levels of noncompliance, (c) those undergoing spinal punctures or procedures capable of severe uncontrolled bleeding, and (d) those with malignant hypertension [47].

2.3.5 Drug or food interactions

Other anticoagulants or antiplatelets, NSAIDs, and SSRIs may increase bleeding risk in those using VKAs, even if no INR increase is witnessed. In addition, some antibiotics, herbal products, cardiovascular medications, alcohol, and even grape juice may interact with VKAs [48]. More comprehensive drug interaction lists or even identification tools can be found online.

2.3.6 Adverse reactions

During clinical trials, the most common adverse reactions were fatal and nonfatal hemorrhage from any tissue or organ. Other documented reactions include vasculitis, hepatitis, elevated liver enzymes, nausea, vomiting, diarrhea, abdominal pain, flatulence, rash, and dermatitis [47].

3. Factor Xa inhibitors: injectable

3.1 Fondaparinux (Arixtra)

3.1.1 Definition

Fondaparinux (Arixtra) belongs to a class of anticoagulants known as Factor Xa inhibitors. Administered subcutaneously, this agent is used to prevent and treat blood clots in conditions such as DVT and PE, or in cases where patients are undergoing certain surgeries ( Table 6 ) [22, 49].

DVT prophylaxis following hip fracture, hip/knee replacement surgeries, or abdominal surgery	2.5 mg SQ once daily; After hemostasis, initial dose should be given 6–8 hours after surgery.
DVT and PE treatment	In cases of acute symptomatic DVT or PE, the recommended dose is 5 mg (ABW < 50 kg), 7.5 mg (ABW 50–100 kg), or 10 mg (BW > 100 kg) SQ once daily for at least 5 days.

Table 6.

Fondaparinux—dosing considerations [49].

Abbreviations: ABW, actual body weight; DVT, deep vein thrombosis; and PE, pulmonary embolism.

3.1.2 Pharmacodynamics

A synthetic anticoagulant, fondaparinux, specifically and reversibly binds to antithrombin III and inhibits Factor Xa, one of the most important enzymes in the coagulation cascade. Its binding enhances the inhibitory effect of antithrombin III on Factor Xa [22, 49, 50]. Ultimately, this process interferes with thrombin formation and prevents blood clot formation.

3.1.3 Pharmacokinetics

3.1.3.1 Absorption

With 100% bioavailability, fondaparinux experiences rapid and complete absorption into systemic circulation when injected subcutaneously [50].

3.1.3.2 Distribution

Due to its low volume of distribution (7–10 L), it distributes predominantly in the bloodstream and, to a lesser extent, in extravascular fluids and tissues [50].

3.1.3.3 Metabolism

With normal renal function, fondaparinux is minimally metabolized by the body and most doses are eliminated unchanged via the urine. A lack of hepatic metabolism leads to fewer drug interactions [49, 50].

3.1.3.4 Elimination

With normal renal function, it has an elimination half-life of 17–21 hours. The drug is primarily eliminated by renal clearance and the majority of each dose is excreted unchanged [49, 50].

3.1.4 Contraindications

Fondaparinux should be avoided in patients with severe renal impairment (CrCl <30 mL/min). Since this drug is eliminated primarily via the kidneys, there is significantly increased bleeding risk when used in such cases. It should also be avoided in patients with a body weight less than 50 kg undergoing hip fracture, hip replacement or knee replacement surgery, and abdominal surgery. Lastly, fondaparinux should be avoided in those with active major bleeds, bacterial endocarditis, or cases of thrombocytopenia associated with a positive test for antiplatelet antibodies [49].

3.1.5 Drug interactions

Concomitant use of anticoagulants, antiplatelets, NSAIDs, digoxin, and certain herbal products may lead to increased bleeding risk. Drug interactions by protein-binding displacement are minimal since fondaparinux does not bind significantly to plasma proteins other than antithrombin III [51].

3.1.6 Adverse reactions

During clinical trials, the most common adverse reactions were bleeding complications: major bleeding was seen in 1.2–3.4% of patients, while fatal bleeding was seen in 0.1% of patients. Mild local irritation (injection site bleeding, rash, and pruritus) has been documented after injecting fondaparinux. Other adverse reactions seen in ≥2% of patients included anemia, fever, nausea, edema, constipation, rash, vomiting, insomnia, hypokalemia, diarrhea, dyspepsia, and headache [49].

4. Factor Xa inhibitors: oral

4.1 Apixaban (Eliquis)

4.1.1 Pharmacokinetics

When taken orally, apixaban is rapidly absorbed and achieves maximum concentration 3–4 hours after administration, with a half-life of approximately 12 hours [52]. With a bioavailability of approximately 50%, about half of each dose reaches systemic circulation [52]. Food has minimal impact on bioavailability; the drug may be taken with or without food [52]. Since it is 87% protein-bound, with a volume of distribution of 21 L, it is largely distributed into the extracellular fluid [53]. Liver metabolism is limited; approximately, 25% of the drug is excreted by urine and more than 50% of the unchanged parent compound is excreted by feces [53]. Metabolism is primarily conducted by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2 [53]. Metabolic pathways include O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban [52]. Elimination occurs via biliary, renal, and intestinal excretion of unchanged drug. Renal impairment may affect drug clearance; dose adjustments are recommended with renal dysfunction ( Table 7 ) [55].

Reduction in risk of stroke/systemic embolism in NVAF	5 mg twice daily; Dose adjustments for NVAF patients: 2.5 mg twice daily in patients with at least two of the following: > 80 years old ABW < 60 kg Serum creatinine >1.5 mg/dL
Treatment of DVT/PE	10 mg twice daily for the first 7 days, then transition to 5 mg twice daily
Reduction in risk of recurrent DVT/PE following initial therapy	2.5 mg daily after at least 6 months of treatment for DVT or PE
Prophylaxis of DVT which may lead to PE, following hip or knee replacement surgery	2.5 mg twice daily for 35 days, starting 12–24 hours after hip/knee replacement surgery

Table 7.

Apixaban—dosing considerations [54].

Abbreviations: ABW, actual body weight; DVT, deep vein thrombosis; NVAF, nonvalvular atrial fibrillation; PE, pulmonary embolism.

4.1.2 Pharmacodynamics

An oral direct, reversible Factor Xa inhibitor, apixaban is commonly used for thromboprophylaxis in atrial fibrillation [55]. It selectively and reversibly inhibits free and clot-bound Factor Xa, reducing the conversion of prothrombin to thrombin; this prevents fibrin clot formation and indirectly inhibits platelet aggregation [55]. It exhibits dose-proportional increases in exposure after administration, with therapeutic effects observed 1–3 hours after dosing [55]. When major bleeding or urgent surgery occurs, the reversal agent andexanet alfa (Andexxa), a recombinant modified human factor Xa, may be utilized [55].

4.1.3 Contraindications

Apixaban should be avoided in those with active major bleeding or anaphylactic-level reactions to the drug [56].

4.1.4 Drug interactions

Concurrent use of strong CYP3A4 and P-glycoprotein (P-gp) inhibitors or inducers (e.g., ketoconazole, glucocorticoids, rifampin) may influence apixaban’s pharmacodynamics [50]. Other relevant interactions include the simultaneous use of other anticoagulants, antiarrhythmics, anti-rejection medications, epilepsy treatments, and NSAIDs. Major interactions with grapefruit juice or grapefruit products should be avoided due to risk of increased drug levels [57].

4.1.5 Adverse reactions

The most common adverse reactions (>1%) documented in clinical trials were related to bleeding [56].

4.2 Betrixaban (Bevyxxa)

4.2.1 Pharmacokinetics

Betrixaban is administered orally, absorbed rapidly, and achieves maximum concentration 3–4 hours afterward [58]. Amongst Factor Xa inhibitors, it has the longest half-life with a terminal half-life of 35–45 hours and an effective half-life of 19–27 hours, giving it a low peak-to-trough ratio [58]. Its bioavailability is approximately 35–45%; this can be lowered by approximately 50% if taken with fatty food, so patients should take it with low-fat foods [59]. It is 60% protein-bound—the lowest of all Factor Xa inhibitors—and has a volume of distribution of 32 L/kg [59]. It exhibits slightly nonlinear kinetics; disproportionate increases in plasma concentrations may be seen with dose increases [60]. It has minimal hepatic metabolism; it is not metabolized by CYP enzymes and it is minimally affected by cytochrome P450 activity, though betrixaban remains a P-gp substrate [58]. It is predominantly found as unchanged drug in human plasma, along with two CYP-independent inactive metabolites, which account for 15–18% of circulating drug-related material [58]. Elimination occurs primarily via the hepatobiliary system—as well as the P-gp efflux pump—with 85% elimination via feces and 11% elimination via urine [58].

4.2.2 Pharmacodynamics

Often used for VTE prophylaxis, it competitively and reversibly inhibits Factor Xa in a concentration-dependent manner without a cofactor such as antithrombin III needed for activity [58, 59, 60]. By directly binding to Factor Xa, decreased thrombin generation occurs, leading to decreased clot formation with no direct effect on platelet aggregation [58, 59].When major bleeding or urgent surgery occurs, the reversal agent andexanet alfa (Andexxa), a recombinant modified human factor Xa, may be utilized [58, 59].

4.2.3 Dosing considerations

The recommended initial single dose is 160 mg, followed by 80 mg once daily; all doses should be taken with food [61]. With severe renal impairment or concurrent use of P-gp inhibitors, a reduced initial dose of 80 mg, followed by 40 mg once daily, should be given. The recommended treatment duration is 35–42 days for all patients [61].

4.2.4 Contraindications

Betrixaban should be avoided in those with active major bleeding or anaphylactic-level reactions to the drug [61].

4.2.5 Drug interactions

There is a risk of severe bleeding when used with other anticoagulants. In addition, the concurrent use of strong P-gp inhibitors (e.g., ketoconazole, amiodarone, diltiazem) may increase drug concentration, leading to increased bleeding risk; as a result, prophylactic dosage reduction is recommended [58, 59, 60, 61, 62].

4.2.6 Adverse reactions

The most common adverse reaction (>5%) documented in clinical trials was bleeding [61].

4.3 Dabigatran (Pradaxa)

4.3.1 Definition

Dabigatran was approved by the European Medicines Agency in 2008 and the Food and Drug Administration (FDA) in October 2010 [62]. Mechanistically, it directly inhibits thrombin. It is primarily used to prevent stroke and systemic emboli in non-valvular atrial fibrillation (NVAF) cases. It is also used to treat and prevent DVT and PE, including after hip or knee replacement surgery ( Table 8 ).

Reduce stroke risk in NVAF	150 mg twice daily	If CrCl >30 mL/min
	75 mg twice daily	If CrCl 15–30 mL/min
Treat DVT/PE or prevent recurrence	150 mg twice daily	If CrCl >30 mL/min
Reduce DVT/PE risk after hip replacement surgery	110 mg post-surgery (1–4 hours later), then 220 mg once daily × 28–35 days	If CrCl >30 mL/min

Table 8.

Dabigatran—dosing considerations [63].

^*

Dosing recommendations unavailable for adult patients with (a) NVAF: CrCl <15 mL/min or on dialysis; (b) DVT/PE & HIP: CrCl ≤30 mL/min or on dialysis [60].

4.3.2 Pharmacokinetics

Dabigatran is administered orally as a prodrug dabigatran etexilate [62, 64]. It is rapidly absorbed from the GI tract with peak plasma concentrations 1–3 hours after ingestion. With a relatively high volume of distribution, it is extensively distributed into body tissues. Due to its 35–40% protein binding, it tends to bind reversibly to plasma proteins, such as albumin. It undergoes limited metabolism; its primary pathway involves ester hydrolysis, creating the inactive metabolite and dabigatran etexilate. This metabolite is further converted to inactive dabigatran glucuronides. In those with normal renal function, it has an elimination half-life of 12–17 hours. Nearly 80% of each dose is eliminated unchanged in the urine; reduced kidney function can significantly prolong its half-life [62, 65].

4.3.3 Pharmacodynamics

Dabigatran directly inhibits thrombin, which is responsible for converting fibrinogen into fibrin, initiating blood clot formation, and amplifying the coagulation process. By specifically targeting thrombin, it hinders fibrin generation and blood clot development. In in vitro and ex vivo studies, its binding affinity for thrombin was highly selective, nearly 700–10,000-fold greater than key factors in the coagulation cascade [66]. Dabigatran exhibits a predictable dose-response relationship. This allows for fixed dosing without the need for routine monitoring (e.g., INR), such as with vitamin K antagonists (warfarin) [62].

4.3.4 Contraindications

Dabigatran should be avoided in those with active major bleeding or anaphylactic-level reactions to the drug [63].

4.3.5 Drug interactions

Drugs, such as verapamil, amiodarone, quinidine, and dronedarone, may inhibit P-gp, which may elevate dabigatran levels and lead to increased bleeding risk [63]. Conversely, medications, such as rifampin and St. John’s Wort, may reduce drug levels and increase clot risk. Strong CYP3A4 inhibitors, such as ketoconazole, ritonavir, and clarithromycin, may also elevate dabigatran levels and bleeding risk [56, 58]. When used with antiplatelet drugs (aspirin or clopidogrel) or NSAIDs, such as naproxen or ibuprofen, increased bleeding risk may occur.

4.3.6 Adverse reactions

In clinical trials, the most common adverse reactions (>15%) were gastritis-like symptoms and bleeding [63].

4.4 Edoxaban (Savaysa)

4.4.1 Definition

Despite receiving FDA approval (2015) and being marketed later than other Factor Xa inhibitors, edoxaban is increasingly used for DVT and PE treatment and prevention, as well as stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation ( Table 9 ) [68].

Reduce stroke risk in NVAF	60 mg once daily	If CrCl 50–95 mL/min. Avoid if CrCl >95 mL/min due to increased risk of ischemic stroke compared to warfarin.
	30 mg once daily	If CrCl 15–50 mL/min
Treat DVT/PE	60 mg once daily	If CrCl >50 mL/min
	30 mg once daily	For patients with one or more of the following: CrCl 15–50 mL/min ABW < 60 kg Concomitant use of P-gp inhibitors

Table 9.

Edoxaban—dosing considerations [67].

Abbreviations: ABW, actual body weight; CrCL, creatinine clearance; DVT, deep vein thrombosis; and PE, pulmonary embolism.

4.4.2 Pharmacokinetics

With 62% bioavailability, it is rapidly absorbed in the GI tract and reaches peak concentration about 1–2 hours after ingestion [69, 70]. Its moderate volume of distribution allows for wide distribution throughout body tissues, and it binds extensively (about 55%) to plasma proteins, such as albumin. Edoxaban is poorly cleared in patients on hemodialysis treatment, which may lead to increased drug exposure [70, 71]. Its metabolism occurs primarily via CYP3A4 and, to a lesser extent, CYP2J2; this process creates major metabolites in the form of hydrolyzed products and minor oxidative metabolites. Edoxaban is eliminated via renal and fecal routes. Roughly 50% of each dose is excreted unchanged in the urine, which is facilitated by P-gp. The remaining 50% is eliminated through feces. Its elimination half-life of 10–14 hours allows for once-daily dosing in most patients [71].

4.4.3 Pharmacodynamics

It selectively inhibits Factor Xa, leading to decreased thrombin generation and blood clot formation. Furthermore, decreased thrombin levels indirectly inhibit platelet aggregation [70]. Like dabigatran, it demonstrates a predictable dose-response relationship. This attribute allows for fixed dosing without the need for regular monitoring like with vitamin K antagonists (warfarin) [70].

4.4.4 Contraindications

Edoxaban should be avoided in patients with active major bleeding [67].

4.4.5 Drug interactions

Combining edoxaban with other anticoagulants, antiplatelet drugs (aspirin or clopidogrel), NSAIDs, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) may increase bleeding risk [68]. Strong CYP3A4 inhibitors, such as ketoconazole, ritonavir, and clarithromycin, may elevate increase drug concentrations, while inducers, such as rifampin, may decrease concentrations [68, 71]. Dose adjustments and careful monitoring may be necessary. Since edoxaban is a P-gp substrate, medications that induce or inhibit P-gp—such as verapamil, amiodarone, quinidine, rifampin, and St. John’s Wort—may also influence drug levels [67].

4.4.6 Adverse reactions

In patients treated for non-valvular atrial fibrillation (NVAF), the most common adverse reactions (≥ 5%) were bleeding and anemia. In those treated for deep vein thrombosis (DVT) or pulmonary embolism (PE), the most common reactions (≥ 1%) were bleeding, rash, abnormal liver function tests, and anemia [67].

4.5 Rivaroxaban (Xarelto)

4.5.1 Definition

Receiving FDA approval in 2011, rivaroxaban was one of the first Factor Xa inhibitors on the market [72]. Since then, it has been used for postoperative thromboprophylaxis after knee or hip replacement surgeries, for primary and secondary stroke prevention in those with NVAF, and for secondary prevention after acute coronary syndrome (ACS) or peripheral arterial disease as an add-on to antiplatelet therapy [72, 73].

4.5.2 Pharmacokinetics

With 10,000-fold greater selectivity for Factor Xa, rivaroxaban competitively inhibits Xa without requiring cofactors, such as antithrombin [72]. Unlike other anticoagulants, it can inhibit both free and clot-bound Factor Xa. Though it is highly protein-bound, metabolism occurs primarily via CYP3A4/5 and CYP2J2, while excretion occurs mainly via urine (66%) and feces (28%). It has a half-life of 5–9 hours, though this interval may be prolonged up to 11–13 hours in older patients [74].

4.5.3 Pharmacodynamics

Dosing is generally fixed—ranging from 2.5 mg twice daily to 20 mg once daily—without monitoring [73]. The most common side effects for rivaroxaban include hemorrhage (5–28%), major hemorrhage (≤4%), abdominal pain (3%), wound secretion (3%), dizziness (2%), insomnia (2%), and pruritus (2%) [72]. Notably, it carries a boxed warning for increased risk of spinal or epidural hematomas, which may occur during epidural or spinal anesthesia procedures. This risk increases in those with indwelling epidural catheters or history of spinal surgery [73].

4.5.4 Dosing considerations

In patients on dialysis or with CrCl <30 mL/min, rivaroxaban use is not recommended [72, 73]. However, in cases where CrCl >50 mL/min, no dose adjustment is needed. In those with moderate renal impairment (30–50 mL/min), regimens aimed at preventing VTE recurrence should start at 15 mg twice daily (with food) for 21 days, followed by 20 mg once daily. If therapy continues beyond 6 months, doses can be reduced to 10 mg once daily. When used for VTE prophylaxis in surgical patients, therapy duration generally ranges from 12 to 35 days. When used in NVAF, dosing is either 20 mg (if CrCl >50 mL/min) or 15 mg once daily (if CrCl <50 mL/min) [72, 73].

Rivaroxaban should be avoided in patients with significant hepatic impairment (Child-Pugh Class B and C, with bleeding disorders) [70]. Its use has not been extensively studied in patients <18 years old, those with a BMI > 40 kg/m², or those weighing more than 120 kg; its use is not recommended in such populations. Lastly, rivaroxaban should be avoided in those with prosthetic heart valves, rheumatic heart disease, mechanical valves, or moderate-severe mitral stenosis [72, 73].

4.5.5 Contraindications

Rivaroxaban should be avoided in those with active major bleeding or anaphylactic-level reactions to the drug [73].

4.5.6 Drug interactions

Like other Factor Xa inhibitors, rivaroxaban may interact with strong CYP3A4 and P-gp inhibitors, leading to elevated drug levels and increased bleeding risk [72, 73]. Significant dosage adjustments and more frequent monitoring may be required in such cases. Due to increased bleeding risk, it should also be used cautiously with other antiplatelets such as aspirin, clopidogrel, or other P2Y12 inhibitors [72, 73].

4.5.7 Adverse reactions

In adult patients, the most common adverse reaction (>5%) was bleeding, while bleeding, cough, vomiting, and gastroenteritis was most common (>10%) in pediatric patients ( Table 10 ) [73].

Warfarin

Factor Xa inhibitors

More frequent lab monitoring required (INR); More forgiving of missed doses due to longer half-life; Far greater interpatient dosing variability; Slower onset and offset; Greater emphasis on “bridging” around procedures, based on risk profile; Greater food restrictions, including greens and food high in Vitamin K; Typically far more affordable at pharmacies

Less frequent lab monitoring; Less forgiving of missed doses due to shorter half-life; Fixed dosing for most patients; Faster onset and offset; Far fewer concerns with “bridging” around procedures; Far fewer food restrictions for users; Generally far more costly for patients; May require more dose adjustment with renal dysfunction (depending on Factor Xa agent); Recent trials have shown lower rates of major bleeds than warfarin while being noninferior

Table 10.

Advantages and disadvantages: Warfarin (coumadin, Jantoven) vs. factor Xa inhibitors [75, 76, 77, 78].

5. Monitoring parameters for anticoagulants

Anticoagulants are monitored, to varying degrees, to ensure therapy is safe and effective. Primary monitoring parameters include bleeding, clot formation, laboratory markers, therapeutic drug levels, and liver and kidney function [7].

With anticoagulant therapy, it is important to monitor for signs and symptoms of bleeding, which can take the form of nosebleeds (epistaxis), vomiting blood (hematemesis), mouth bleeding (oral hemorrhage), and blood in the urine (hematuria) or stool (hematochezia). A decline in certain laboratory markers—including hemoglobin, hematocrit, and platelet count—can also suggest active bleeding. These markers are often ordered as part of a complete blood count (CBC); significant declines may warrant therapeutic discontinuation [7].

Laboratory values can help to determine therapeutic levels for drugs, such as unfractionated heparin (UFH). UFH infusions can be monitored via anti-factor Xa (anti-Xa) or partial thromboplastin time (aPTT) levels. The aPTT indicates how quickly blood is clotting (measured in seconds) by assessing clotting factors in the intrinsic pathway [79]. A therapeutic aPTT is usually 1.5–2.5 times the patient’s baseline aPTT, though this test may be institution-specific. Hospitals may create protocols for heparin drip titration based on values of their specific assay. Conversely, anti-Xa assays measure overall heparin activity. The commonly desired anti-Xa level for UFH is 0.3–0.7, though this goal may be modified by the clinical team based on indication. Of note, subcutaneous heparin does not require aPTT or anti-Xa monitoring [80].

LMWH can be monitored using an anti-Xa assay calibrated specifically for enoxaparin; though this is not a required monitoring parameter, it has become more widely used in practice. Levels are often drawn for obese patients or those with low body weight, poor renal function, or active pregnancy. Anti-Xa levels should be drawn at their peak, which is usually 4–6 hours after administration. LMWH also requires that kidney function, or creatinine clearance, be closely monitored [80].

Monitoring for heparin-induced thrombocytopenia (HIT) is crucial with any heparin product. HIT is defined as a significant drop in platelet levels after heparin exposure, usually a 30–50% decrease in platelets or a platelet count below 150,000/mm³. Patients experiencing a newly formed VTE while on heparin should also be monitored for HIT [81].

Warfarin safety and efficacy are monitored via the international normalized ratio (INR), though most institutions measure prothrombin time (PT) with INR. The PT measures the time (in seconds) for blood to clot using clotting factors in the extrinsic and common pathways. INR remains the standardized way of reporting PT. The frequency of INR monitoring can depend on the setting. Hospitalized patients, for example, may have their INR measured daily, while those in outpatient settings may have their INR checked weekly and eventually up to once every 12 weeks [82].

In contrast to many anticoagulants, Factor Xa inhibitors do not require routine laboratory monitoring [83]. Currently, anti-Xa assays are not routinely used in the United States; anti-Xa assays must be specifically calibrated for individual agents [84]. Still, serum creatinine and liver function should be monitored at baseline and at least annually when using a Factor Xa inhibitor [82].

6. Special patient populations

6.1 Renal dysfunction

Patients with renal dysfunction are at a higher risk of bleeding and clotting; such patients often require anticoagulant therapy [85]. The choice of anticoagulant often depends on the renal function needed for drug removal. Some anticoagulants, for example, may require dose adjustments based on renal function, while others are contraindicated ( Table 11 ). Heparin, warfarin, and certain Factor Xa inhibitors are typically used in cases of renal dysfunction.

	Obese patients	Renal dysfunction	Liver dysfunction	Pregnant patients	Elderly patients
UFH	No adjustment necessary (may consider 5000 or 7500 units every 8 hours) for prophylaxis	No adjustment necessary	No adjustment necessary	Preferred (especially closer to delivery)	No adjustment necessary
LMWH	No adjustment necessary (may consider dose and frequent increase)	Renally adjusted for patients where CrCL <30 mL/min	No adjustment necessary	Preferred	No adjustment necessary
VKA	No adjustment necessary (may consider higher dose)	No adjustment necessary (may consider lower dose)	No adjustment necessary (may consider lower dose)	Typically avoid	Recommended to not be initial therapy; May require a lower dose
Factor Xa inhibitors – oral	Preferred: apixaban and rivaroxaban Avoid edoxaban if BMI > 40 kg/m^2 or weight > 120 kg Avoid dabigatran if BMI > 40 kg/m^2	Preferred: apixaban Avoid edoxaban if CrCL <15 or > 95 mL/min Avoid dabigatran, betrixaban, and rivaroxaban if CrCL <15 mL/min	Mild: no adjustments Moderate: avoid rivaroxaban, betrixaban, and edoxaban Severe: avoid apixaban, rivaroxaban, betrixaban, and edoxaban	Avoid	Preferred; Apixaban and edoxaban (may need to be dose-adjusted) Caution with dabigatran and rivaroxaban
Factor Xa inhibitors – injectable	No adjustment necessary	Contraindicated if CrCL <30 mL/min	No adjustment necessary	Potential option (especially if a history of HIT exists)	No adjustment necessary

Table 11.

Summary of different patient populations and dosing considerations [19, 27, 47, 49, 63, 67, 73].

Abbreviations: BMI, body mass index; CrCL, creatinine clearance, and HIT, heparin-induced thrombocytopenia.

Heparin is a preferred agent in renal dysfunction. UFH is principally eliminated by the liver; even in cases of renal failure, it does not need a dose adjustment [19]. For patients on hemodialysis, UFH is the agent of choice, though it does carry an increased risk of exposure with renal impairment. Prophylactic and treatment doses of enoxaparin should be renally adjusted with a CrCL<30 mL/min, though fondaparinux is contraindicated in such cases [27, 49].

Warfarin and apixaban are the recommended oral agents for renal dysfunction. Though warfarin lacks specific renal dosing recommendations [47], clinicians may consider starting such patients on lower doses and monitoring INRs more frequently for Factor Xa inhibitors; dosing depends largely on the indication. Generally speaking, dabigatran, edoxaban, betrixaban, and rivaroxaban should be avoided when CrCL <15 mL/min [61, 63, 67, 73]. Uniquely, edoxaban should be avoided when CrCL >95 mL/min [67]. In atrial fibrillation, apixaban doses should be adjusted if the serum creatinine is greater than 1.5 mg/dL (including hemodialysis) [56].

6.2 Hepatic impairment

Warfarin, fondaparinux, UFH, and LMWH do not require dose adjustments with liver impairment, though careful monitoring for bleeding is recommended ( Table 11 ) [19, 27, 47, 49]. With warfarin, impairment can impact clotting factor synthesis and lead to decreased metabolism [47]. As a result, such patients should be started on lower doses [82].

Recommendations tend to vary for Factor Xa inhibitors. No dose adjustment is required for apixaban in mild and moderate hepatic impairment; however, it should be avoided in severe impairment [56]. Rivaroxaban, betrixaban, and edoxaban should be avoided in moderate-severe impairment, though mild impairment requires no dose adjustment [61, 67, 73]. Dabigatran does not require dose adjustments with hepatic impairment [63]. Recent work has shown that patients with liver cirrhosis—especially older patients, those with a longer treatment duration, and those with a Child-Pugh Class C score—may display higher rates of bleeding, major bleeding, gastrointestinal bleeding, and intracranial hemorrhage [86]. However, when compared to conventional anticoagulants, Factor Xa inhibitors were associated with lower incidences of all bleeding and major bleeding in cirrhotic patients, though incidences of fatal bleeding, gastrointestinal bleeding, and intracranial hemorrhage remained higher [86].

6.3 Pregnancy

Choosing an anticoagulant during pregnancy requires balancing the need for anticoagulation with potential risks to the fetus and mother during labor ( Table 11 ). Heparin products are preferred during pregnancy since they do not cross the placenta or cause fetal anticoagulation. LMWH is recommended because it is easier to administer, has a more predictable response, and does not require continuous monitoring. However, UFH is preferred closer to delivery due to its shorter duration and easier reversal. Fondaparinux remains an option, especially for those with a history of HIT [87].

If pregnancy occurs with taking an oral anticoagulant, the patient should be switched to LMWH [87]. Since it can cross the placenta and cause fetal anticoagulation, warfarin is considered teratogenic and should be strictly avoided [47]. Factor Xa inhibitors have not been extensively studied in pregnancy, and therefore are not recommended [88].

6.4 Elderly

Due to the frequent exclusion of elderly patients from clinical trials, minimal data is available for such patients [89]. UFH, LMWH, and fondaparinux are generally regarded as safe in older adults ( Table 11 ) [19, 27, 85]. Since warfarin has been associated with a higher risk of (intracranial) bleeding, Factor Xa inhibitors are now preferred in such patients [90]. In atrial fibrillation, apixaban should be dose-adjusted for patients ≥80 years old (including those undergoing hemodialysis) [56]. Edoxaban dosing is similarly age-adjusted in atrial fibrillation [67]. Due to its elevated bleeding risk, rivaroxaban may be avoided in elderly populations [90]. In patients ≥75 years old, dabigatran should be used more cautiously than other Factor Xa inhibitors [63, 90, 91].

Warfarin is typically avoided as initial therapy in elderly patients, though switching anticoagulants may be unnecessary if patients have been stable on long-term warfarin therapy [89, 91]. If clinicians elect to start warfarin, lower starting doses are recommended because a greater INR response may be expected [47, 63, 82].

6.5 Obesity

In obese populations, no anticoagulant is preferred over others ( Table 11 ). However, neither fondaparinux nor warfarin requires dose adjustments in such patients, though clinicians should consider higher starting doses [49, 82]. Though UFH and LMWH do not have specific dosing adjustments, this may change in the future. Heparin is typically weight-based, but many institutions have a maximum rate when starting therapy. Prophylaxis UFH may be increased to 5000–7500 units every 8 hours, based on expert opinion. LMWH prophylactic dosing in obese patients is sometimes increased from enoxaparin 40 mg once daily to twice daily, and treatment dosing may be reduced (range: 0.7–1 mg/kg twice daily) [92].

Factor Xa inhibitors customarily do not require dose adjustments in obese populations. Data suggests apixaban and rivaroxaban can be used safely in obesity, though edoxaban is not recommended if BMI > 40 kg/m² or weight > 120 kg [67, 93]. Dabigatran should also be avoided where BMI > 40 kg/m² [63].

7. Converting between anticoagulants

See Tables 12 and 13 .

Anticoagulation conversion	Drug	Recommendations
Warfarin to direct oral anticoagulants (DOAC)	Apixaban	Discontinue warfarin and initiate apixaban when INR < 2
	Betrixaban	Discontinue warfarin and initiate betrixaban when INR < 2
	Dabigatran	Discontinue warfarin therapy and initiate dabigatran when an INR of <2 is achieved
	Edoxaban	Stop warfarin and initiate edoxaban when INR < 2.5
	Rivaroxaban	Discontinue warfarin therapy and initiate rivaroxaban when INR of <3 is achieved
Direct oral anticoagulants to warfarin	Apixaban	Discontinue apixaban and initiate warfarin therapy and parenteral anticoagulant (bridge) at the next scheduled apixaban dose; discontinue parenteral therapy upon attainment of therapeutic INR
	Betrixaban	There are currently no conversion recommendations since betrixaban is indicated only for VTE prophylaxis
	Dabigatran	CrCl >50 mL/min: initiate warfarin therapy 3 days prior to discontinuing dabigatran; CrCl between 30 and 50 mL/min: initiate warfarin therapy 2 days prior to discontinuing dabigatran; CrCl is between 15 and 30 mL/min: initiate warfarin 1 day prior to discontinuing dabigatran; CrCl <15 mL/min: no available recommendation
	Edoxaban	Oral edoxaban: A 50% edoxaban dose reduction is recommended upon initiation of warfarin therapy; obtain weekly INR levels; discontinue edoxaban upon attainment of INR > 2; Parenteral edoxaban: discontinue edoxaban and initiate warfarin therapy and parenteral anticoagulant (bridge) at the next scheduled edoxaban dose and discontinue upon attainment of INR > 2
	Rivaroxaban	Discontinue rivaroxaban and initiate warfarin therapy and parenteral anticoagulant (bridge) at the next scheduled rivaroxaban dose; discontinue parenteral therapy upon attainment of therapeutic INR

Table 12.

Converting between warfarin and direct oral anticoagulants (DOACs) [94, 95, 96].

Abbreviations: CrCL, creatinine clearance; INR, international normalized ratio; and VTE, venous thromboembolism.

Anticoagulation conversion	Drug (s)	Recommendations
Direct oral anticoagulants to parenteral anticoagulants	Apixaban	Discontinue apixaban and initiate parenteral agent at the next scheduled dose of apixaban
	Betrixaban	Betrixaban is indicated VTE prophylaxis, and thus the subsequent anticoagulant should be initiated as clinically needed irrespective of the time of the last dose of betrixaban
	Dabigatran	CrCl >30 mL/min: initiate dabigatran and start parenteral therapy 12 h post last dabigatran dose; CrCl <30 mL/min: discontinue dabigatran and initiate parenteral therapy 24 h post last dabigatran dose
	Edoxaban	Discontinue edoxaban and initiate parenteral therapy at the next scheduled dose of edoxaban
	Rivaroxaban	Discontinue rivaroxaban and initiate parenteral therapy at the next scheduled dose of rivaroxaban
Parenteral anticoagulants to direct oral anticoagulants	LMWH to Apixaban	LMWH: discontinue parenteral agent and initiate apixaban at the next scheduled dose of parenteral therapy
	UFH to Apixaban	UFH IV infusion: discontinue parenteral therapy and initiate apixaban 0–2 h after stopping UFH
	LMWH to Betrixaban	LMWH: discontinue parenteral agent and initiate betrixaban at the next scheduled dose of parenteral therapy
	UFH to Betrixaban	UFH IV infusion: discontinue parenteral agent and initiate betrixaban 0–2 h after stopping UFH
	LMWH to Dabigatran	LMWH: discontinue LMWH and initiate dabigatran 0–2 h before next scheduled dose of LMWH
	UFH to Dabigatran	UFH IV infusion: initiate dabigatran when discontinuing heparin infusion
	LMWH to Edoxaban	LMWH: discontinue LMWH and initiate edoxaban at the next scheduled dose of LMWH
	UFH to Edoxaban	UFH IV infusion: initiate edoxaban 4 h after stopping heparin infusion
	LMWH to Rivaroxaban	LMWH: discontinue LMWH and initiate rivaroxaban 0–2 h before next scheduled evening dose of LMWH
	Unfractionated Heparin to Rivaroxaban	UFH IV infusion: initiate rivaroxaban when discontinuing heparin infusion

Table 13.

Converting between DOACs and parenteral anticoagulants [94, 95, 96].

Abbreviations: CrCL, creatinine clearance; h, hours; IV, intravenous; LMWH, low molecular weight heparin; mL/min, milliliters per minute; UFH, unfractionated heparin; VTE, venous thromboembolism.

8. Bleeding risk and reversal agents

While anticoagulants are highly effective in managing thromboembolic events, they are often associated with hemorrhagic complications [35]. In fact, the risk of major bleeding events is 7.2 per 100 person-years, while fatal bleeding is 1.31 per 100 person-years, with an associated case-fatality rate of 13.4% in major bleeding in individuals anticoagulated for venous thromboembolism [97]. Though 5.1% of extracranial hemorrhages associated with warfarin therapy result in death at 30 days, warfarin-induced intracranial hemorrhage has a nearly 50% mortality rate [35, 98]. On the other hand, DOACs have been associated with lower rates of major hemorrhage and a significant reduction in the risk of intracranial hemorrhage and fatal bleeding. However, risk may vary by anticoagulant category. Additionally, elderly patients and individuals with impaired renal function on dabigatran may experience greater risk of extracranial hemorrhage [99, 100].

The primary reversal agent used for warfarin-associated bleeding is vitamin K. Via inhibition of vitamin K epoxide, warfarin blocks the synthesis of vitamin K-dependent clotting factors (Factors II, VII, IX, and X, protein C, and protein S); thus, vitamin K administration replenishes those factors, reversing warfarin’s effects. Vitamin K can be administered either orally or intravenously. Non-bleeding patients with an INR > 10 may receive 2.5–5 mg of vitamin K. Those with signs or symptoms of bleeding should be admitted to the hospital or emergency room, where they are usually managed with vitamin K 10 mg IV, infused over 30 minutes, plus Fresh Frozen Plasma 15–30 ml/kg or Prothrombin Complex Concentrates (PCC), 25–50 IU/Kg. PCC contains a mixture of clotting factors—II, VII, IX, and X, as well as protein C and protein S—providing a source of vitamin K-dependent clotting factors [101].

9. Unfractionated heparin and low molecular weight heparin reversal

The primary agent used for neutralizing UFH and LMWH is protamine sulfate, which is derived from fish sperm. The dose used for UFH reversal is 1 mg for every 100 units of UFH, with a maximum dose of 50 mg. Given protamine’s short half-life (∼7 minutes) and UFH’s half-life of 90 minutes, it is essential to time protamine administration based on UFH exposure. Thus, less protamine is required to reverse UFH over time. If reversal is indicated in patients less than 60 minutes post-bolus infusion, the full dose of protamine is recommended. The heparin dose given over the preceding 2 hour-period should be used to calculate the protamine dose in those on continuous UFH infusions given heparin’s half-life. After protamine administration, activated partial thromboplastin time (aPTT) monitoring is recommended. Elevated aPTT levels post-protamine administration may warrant additional protamine doses [102, 103, 104].

Given relatively short half-life of protamine (∼7 minutes) compared to LMWH (4–7 hours), proper timing of protamine administration is crucial; thus, careful monitoring is necessary with consideration for redosing [102]. Typically, 1 mg of protamine sulfate neutralizes 100 anti-Xa units of a LMWH. For enoxaparin, if it was last dosed ≤8 hours, then 1 mg protamine for every 1 mg enoxaparin is recommended; if it was dosed >8 hours prior, 0.5 mg protamine for every 1 mg enoxaparin is recommended. Depending on the enoxaparin dose and renal function, protamine sulfate may or may not be necessary for cases >12–24 hours post-enoxaparin administration. LMWH anti-Xa monitoring should be employed; patients with elevated levels should receive a second dose of 0.5 mg of protamine per 1 mg of enoxaparin. Protamine typically does not produce a complete reversal of anti-Xa activity; it may neutralize approximately 60–75% of enoxaparin anti-Xa activity [102, 103, 104]. It has been theorized that incomplete neutralization of anti-Xa activity likely reflects the inability of protamine to bind to LMWH fragments within the LMWH compounds with low sulfate charge density ( Table 14 ) [106, 107].

Drug	Reversal agent	Mechanism of action	Dosing information
Apixaban	Andexanet alfa	Andexanet alfa is a recombinant modified human Factor Xa protein that acts as a decoy, binding and sequestering Factor Xa inhibitors to restore normal hemostasis	Apixaban ≤5 mg, with the last dose taken <8 hours, or unknown: low dose andexanet alfa, 400 mg IV bolus administered at a rate of ∼30 mg/minute, followed by an IV infusion of 4 mg/minute for up to 120 minutes. These patients should receive low dose andexanet alfa if it had been ≥8 hours since the last dose.; Apixaban >5 mg or unknown, with the last dose taken <8 hours, or unknown: high dose andexanet alfa, 800 mg IV bolus administered at a rate of ∼30 mg/minute, followed by an IV infusion of 8 mg/minute for up to 120 minutes. These patients should receive low dose andexanet alfa if it has been ≥8 hours since the last dose.
Betrixaban	Andexanet alfa	Andexanet alfa is a recombinant modified human Factor Xa protein that acts as a decoy, binding and sequestering Factor Xa inhibitors to restore normal hemostasis	Off-label use; high dose andexanet alfa—800 mg bolus administered at 30 mg/min, followed by 8 mg/min, continuous infusion for up to 120 min or four-factor PCC 2000 units, is recommended for individuals with betrixaban-associated major bleeding, where a reversal agent is warranted.
Dabigatran	Idarucizumab	Monoclonal antibody fragment that specifically binds to and neutralizes the anticoagulant effects of dabigatran	The recommended dose is 5 g, available as two separate vials of idarucizumab containing 2.5 g/50 mL. There is limited data supporting the administration of an additional 5 g dose of the reversal agent.
Edoxaban	Andexanet alfa	Andexanet alfa is a recombinant modified human Factor Xa protein that acts as a decoy, binding and sequestering Factor Xa inhibitors to restore normal hemostasis	Off-label use; high dose andexanet alfa - 800 mg bolus administered at 30 mg/min, followed by 8 mg/min, continuous infusion for up to 120 min or four-factor PCC 2000 units, is recommended for individuals with edoxaban-associated major bleeding, where a reversal agent is warranted.
Rivaroxaban	Andexanet alfa	Andexanet alfa is a recombinant modified human Factor Xa protein that acts as a decoy, binding and sequestering Factor Xa inhibitors to restore normal hemostasis	Rivaroxaban ≤10 mg, with the last dose taken <8 hours, or unknown: low dose andexanet alfa, 400 mg IV bolus administered at a rate of ∼30 mg/minute, followed by an IV infusion of 4 mg/minute for up to 120 minutes. These patients should receive low dose andexanet alfa if it has been ≥8 hours since the last dose.; Rivaroxaban >10 mg or unknown, with the last dose taken <8 hours, or unknown: high dose andexanet alfa, 800 mg IV bolus administered at a rate of ∼30 mg/minute, followed by an IV infusion of 8 mg/minute for up to 120 minutes. These patients should receive low dose andexanet alfa if it had been ≥8 hours since the last dose.

Table 14.

Direct oral anticoagulants–reversal agents [102, 105].

Abbreviations: g/mL, grams per milliliter; IV, intravenous; mg, milligram; PCC, prothrombin complex concentrate.

10. Anticoagulation research and future directions

Anticoagulation treatments have evolved significantly over the last decade; this trend will likely continue for the foreseeable future. Pharmaceutical companies and researchers continue to explore targets and agents with improved efficacy, safety, and convenience of administration [108]. Newer agents are now directed at FXII and include products such as monoclonal antibodies (15H8, DO6, CSL312), the small molecule FXII304 (an antisense oligonucleotide), natural inhibitors such as infestin-4, and even Ixodes Iricinus contact phase inhibitor (Ir-CPI), an FXIa inhibitor [109]. Recent advances in precision medicine and pharmacogenomics—as well as a better understanding of individual variations in drug metabolism and response—may lead to more personalized anticoagulation therapy [110]. Further, research is warranted to evaluate the efficacy and safety of DOACs in special populations. By studying and better understanding their effects in these populations—including optimal dosing strategies—clinicians can ensure the most favorable outcomes. Specific DOAC reversal agents are now available, although they are used off-label in some instances and costs remain a major concern. Continued efforts are being made to expand the availability and employment of these reversal agents to manage bleeding complications. Developing more precise and convenient approaches for monitoring anticoagulation levels, with provider buy-in and routine assessment of individual patient response, can enhance the management of anticoagulant therapy. This may involve point-of-care testing devices, as seen in diabetes monitoring or innovative laboratory assays. Exploring anticoagulants combination therapies involving different mechanisms of action or targeting multiple coagulation pathways may also improve treatment outcomes. The concern, however, is bleeding risk; thus, benefit versus risk must be critically considered before employing such strategies. Patient adherence also remains a concern. Promoting patient education and adherence is crucial for optimal therapeutic outcomes. Utilizing artificial intelligence and digital health technologies, such as mobile applications, is a possibility that if appropriately employed and accepted by patients, could be a paradigm shift in anticoagulation management [111].

11. Conclusions

Blood clots are associated with significant morbidity and mortality, as well as significant economic burden in the United States and abroad. Fortunately, scientific innovation has led to the popularization of anticoagulants agents such as warfarin, UFH, and even DOACs. These medications are increasingly utilized for indications such as myocardial infarction, stroke, transient ischemic, venous thromboembolism (VTE), atrial fibrillation, and heart valve replacement. Before being utilized, several factors must be considered. These include pharmacokinetics, pharmacodynamics, indication-specific dosing, significant drug interactions, monitoring parameters, and therapeutic alterations for special patient populations, all of which have been addressed in this chapter. In addition, this chapter has offered insights into converting between different anticoagulants, use of available reversal agents, and future directions in anticoagulation therapy and research.